Category Archive Autoimmune and Rare Diseases A – Z

Trifacial Neuralgia/Trigeminal neuralgia (TN), also called tic douloureux, is a chronic pain condition that affects the trigeminal or 5th cranial nerve, one of the most widely distributed nerves in the head. TN is a form of neuropathic pain (pain associated with nerve injury or nerve lesion.) The typical or “classic” form of the disorder (called “Type 1” or TN1) causes extreme, sporadic, sudden burning, or shock-like facial pain that lasts anywhere from a few seconds to as long as two minutes per episode.  These attacks can occur in quick succession, in volleys lasting as long as two hours.  The “atypical” form of the disorder (called “Type 2” or TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than Type 1.  Both forms of pain may occur in the same person, sometimes at the same time. The intensity of pain can be physically and mentally incapacitating.

TRIGEMINAL NEURALGIA is an extremely severe unilateral episodic facial pain that tends to come and go unpredictably in sudden shock-like attacks. The pain is normally triggered, for example by light touch, and is described as stabbing, shooting, excruciating or burning. It usually lasts for a few seconds but there can be many bursts of pain in quick succession.  There can be slight variations of trigeminal neuralgia which require different treatments.

Types of Trigeminal Neuralgia

The typical or “classic” form of the disorder (called TN1) causes extreme, sporadic, sudden burning or shock-like facial pain in the areas of the face where the branches of the nerve are distributed – lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw. Trigeminal neuralgia can progress and cause longer, more frequent bouts of searing pain. You may feel as though your pain came out of nowhere. Some people initially think their pain is a toothache or migraine headache.

The “atypical” form of the disorder (called TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than TN1. Both forms of pain may occur in the same person, sometimes at the same time

The subtypes of TN are defined by ICHD-3 as follows[rx]

• Classic TN: This is secondary to neuromuscular compression and fulfilling the criteria above. This requires demonstration of the compression on an MRI or during the surgery for neuromuscular compression, with associated morphological changes in the trigeminal nerve root.
• Secondary TN: This is defined as TN secondary to an underlying disease. Some of the reported causes are multiple sclerosis, arteriovenous malformation, and cerebellopontine angle tumor.
• Idiopathic TN: This is defined as TN with no abnormalities seen on MRI or electrophysiological tests.

The trigeminal nerve is one of 12 pairs of nerves that are attached to the brain. The nerve has three branches that conduct sensations from the upper, middle, and lower portions of the face, as well as the oral cavity, to the brain. The ophthalmic, or upper, branch supplies sensation to most of the scalp, forehead, and front of the head. The maxillary, or middle, branch stimulates the cheek, upper jaw, top lip, teeth, and gums, and to the side of the nose. The mandibular, or lower, branch supplies nerves to the lower jaw, teeth and gums, and bottom lip. More than one nerve branch can be affected by the disorder. Rarely, both sides of the face may be affected at different times in an individual, or even more rarely at the same time (called bilateral TN).

What causes trigeminal neuralgia?

TN is associated with a variety of conditions. TN can be caused by a blood vessel pressing on the trigeminal nerve as it exits the brain stem. This compression causes the wearing away or damage to the protective coating around the nerve (the myelin sheath). TN symptoms can also occur in people with multiple sclerosis, a disease that causes deterioration of the trigeminal nerve’s myelin sheath. Rarely, symptoms of TN may be caused by nerve compression from a tumor, or a tangle of arteries and veins called an arteriovenous malformation. Injury to the trigeminal nerve (perhaps the result of sinus surgery, oral surgery, stroke, or facial trauma) may also produce neuropathic facial pain.

The exact cause of trigeminal neuralgia remains unknown.[rx] The majority of cases are referred to as idiopathic, although many are associated with vascular compression of the trigeminal nerve close to its exit from the brainstem by an aberrant loop of an artery or vein. A minority of cases are due to conditions like multiple sclerosis or nerve compression by a tumor.[rx] Some rare causes of trigeminal neuralgia include focal arachnoid thickening, adhesion, traction, tethering or torsion, fibrous ring around the root, cerebellopontine angle tumors, brain stem infarction, aneurysm, and arteriovenous malformation.[rx][rx][rx][rx]

The trigeminal nerve starts at the pons. Most cases of trigeminal neuralgia are due to the compression of the trigeminal nerve root, within a few millimeters of its entry into the pons. Between 80% and 90% of the cases of TN are caused by compression by an adjacent artery or a vein.[rx] The blood vessel, which has been mostly implicated in about 75% to 80% of the cases, is the superior cerebellar artery. Other blood vessels that are known to cause TN include the anterior inferior cerebellar artery, the vertebral artery, and the petrosal vein.

Vascular Theory

Generally, it has been assumed that vascular contact at the root entry zone causes trigeminal neuralgia; however, TN also may be caused by contact at a transition zone between the central and peripheral myelin. Reportedly, the most common artery involved in this condition is the superior cerebellar artery, as seen in 75% to 80% of TN cases. Persistent primitive trigeminal artery variant, an anomaly that occurs between the carotid and basilar arteries or aneurysms of the persistent primitive trigeminal artery, vertebrobasilar dolichoectasia can cause TN. Sharper trigeminal-pontine angle cisterns and smaller cerebellopontine angle cisterns may facilitate neurovascular compression (NVC).[rx][rx][rx][rx][rx]

Extracranial Causes

The most common extracranial cause of trigeminal neuralgia is a perineural spread of head and neck malignancies, commonly squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, melanoma, and sarcoma.[rx][rx][rx][rx][rx]

What are the symptoms of trigeminal neuralgia?

Pain varies, depending on the type of TN, and may range from sudden, severe, and stabbing to a more constant, aching, burning sensation. The intense flashes of pain can be triggered by vibration or contact with the cheek (such as when shaving, washing the face, or applying makeup), brushing teeth, eating, drinking, talking, or being exposed to the wind. The pain may affect a small area of the face or may spread. Bouts of pain rarely occur at night, when the affected individual is sleeping.

TN is typified by attacks that stop for a period of time and then return, but the condition can be progressive. The attacks often worsen over time, with fewer and shorter pain-free periods before they recur. Eventually, the pain-free intervals disappear and medication to control the pain becomes less effective. The disorder is not fatal but can be debilitating. Due to the intensity of the pain, some individuals may avoid daily activities or social contacts because they fear an impending attack.

The trigeminal nerve is the fifth cranial nerve. It is responsible for the sensory supply of the face and the motor and sensory supply to the muscles of mastication. The trigeminal nerve starts at the pons and divides into three branches[rx]:

• Ophthalmic (V1): Supplies the eye, upper eyelid, and the forehead
• Maxillary (V2): Supplies lower eyelid, cheek, nostril, upper lip, and upper gum
• Mandibular (V3): Supplies the lower lip, lower gum, jaw and muscles of mastication

Trigeminal neuralgia symptoms may include one or more of these patterns:

• Episodes of severe, shooting or jabbing pain that may feel like an electric shock
• Spontaneous attacks of pain or attacks triggered by things such as touching the face, chewing, speaking or brushing teeth
• Bouts of pain lasting from a few seconds to several minutes
• Episodes of several attacks lasting days, weeks, months, or longer — some people have periods when they experience no pain
• Constant aching, burning feeling that may occur before it evolves into the spasm-like pain of trigeminal neuralgia
• Pain in areas supplied by the trigeminal nerve, including the cheek, jaw, teeth, gums, lips, or less often the eye and forehead
• Pain affecting one side of the face at a time though may rarely affect both sides of the face
• Pain focused in one spot or spread in a wider pattern
• Attacks that become more frequent and intense over time
• The attacks happen several times a day or a week, followed by periods during which you have none at all. These pain-free periods are known as remission.
• The pain usually affects only one side of the face.
• The attacks happen more often over time, and the pain can worsen.
• You feel the pain mostly in your cheek, jaw, teeth, gums, and lips. The eyes and forehead are affected less often.

Symptom triggers

Attacks of trigeminal neuralgia can be triggered by certain actions or movements, such as:

• talking
• smiling
• chewing
• brushing your teeth
• washing your face
• a light touch
• shaving or putting on make-up
• swallowing
• kissing
• a cool breeze or air conditioning
• head movements
• vibrations, such as walking or traveling in a car

However, pain can happen spontaneously with no trigger whatsoever.

The symptoms of several pain disorders are similar to those of trigeminal neuralgia. The most common mimicker of TN is trigeminal neuropathic pain (TNP). TNP results from an injury or damage to the trigeminal nerve. TNP pain is generally described as being constant, dull and burning. Attacks of sharp pain can also occur, commonly triggered by touch. Additional mimickers include:

• Temporal tendinitis
• Ernest syndrome (injury of the stylomandibular ligament
• Occipital neuralgia
• Cluster headaches/ migraines
• Giant cell arteritis
• Dental pain
• Post-herpetic neuralgia
• Glossopharyngeal neuralgia
• Sinus infection
• Ear infection
• Temporomandibular joint syndrome (TMJ)

Diagnosis of Child Trigeminal Neuralgia

TN diagnosis is based primarily on the person’s history and description of symptoms, along with results from physical and neurological examinations. Other disorders that cause facial pain should be ruled out before TN is diagnosed. Some disorders that cause facial pain include post-herpetic neuralgia (nerve pain following an outbreak of shingles), cluster headaches, and temporomandibular joint disorder (TMJ, which causes pain and dysfunction in the jaw joint and muscles that control jaw movement).  Because of overlapping symptoms and the large number of conditions that can cause facial pain, obtaining a correct diagnosis is difficult, but finding the cause of the pain is important as the treatments for different types of pain may differ.

Most people with TN eventually will undergo a magnetic resonance imaging (MRI) scan to rule out a tumor or multiple sclerosis as the cause of their pain. This scan may or may not clearly show a blood vessel compressing the nerve. Special MRI imaging procedures can reveal the presence and severity of compression of the nerve by a blood vessel.

A diagnosis of classic trigeminal neuralgia may be supported by an individual’s positive response to a short course of antiseizure medication. Diagnosis of TN2 is more complex and difficult but tends to be supported by a positive response to low doses of tricyclic antidepressant medications (such as amitriptyline and nortriptyline), similar to other neuropathic pain diagnoses.

Your doctor may conduct many tests to diagnose trigeminal neuralgia and determine underlying causes for your condition, including:

• A neurological examination. Touching and examining parts of your face can help your doctor determine exactly where the pain is occurring and — if you appear to have trigeminal neuralgia — which branches of the trigeminal nerve may be affected. Reflex tests also can help your doctor determine if your symptoms are caused by a compressed nerve or another condition.
• Magnetic resonance imaging (MRI). Your doctor may order an MRI scan of your head to determine if multiple sclerosis or a tumor is causing trigeminal neuralgia. In some cases, your doctor may inject a dye into a blood vessel to view the arteries and veins and highlight blood flow (magnetic resonance angiogram).

One published a set of guidelines for diagnosing TN is from the International Headache Society.

For classical TN

• Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
• Pain has at least one of the following characteristics:
  • Intense, sharp, superficial or stabbing
  • Precipitated from trigger zones or by trigger factors
• Attacks are stereotyped in the individuals patient
• There is no clinically evident neurologic deficit
• Not attributed to another disorder

For symptomatic TN

• Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, with or without persistence of aching between paroxysms, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
• Pain has at least one of the following characteristics
  • Intense, sharp, superficial or stabbing
  • Precipitated from trigger zones or by trigger factors.
• Attacks are stereotyped in the individual patient
• A causative lesion, other than vascular compression, has been demonstrated by special investigations and/or posterior fossa exploration.

Treatment of Child Trigeminal Neuralgia

Treatment options include medicines, surgery, and complementary approaches.

Pharmacologic Therapy

• The first-line treatment – for patients with classic TN and idiopathic TN is pharmacologic therapy. The most commonly used medication is the anticonvulsant drug, carbamazepine.[rx] It is usually started at a low dose, and the dose is gradually increased until it controls the pain. It controls pain for most people in the early stages of the disease. However, in some patients, the effectiveness of carbamazepine decreases over time. Possible side effects of carbamazepine include drowsiness, dizziness, double vision, and nausea. In patients with Asian ancestry, before starting carbamazepine, testing for the HLA-B allele is recommended, as its presence increases the risk of development of toxic epidermal necrolysis or Stevens-Johnson syndrome.[rx]

• Oxcarbazepine – is a newer drug and is being increasingly used as first-line therapy for TN in patients who do not respond to or who cannot tolerate carbamazepine (200 to 1200 mg/day) and oxcarbazepine (600 to 1800 mg/day). Possible side effects include double vision and dizziness. It can also cause hyponatremia. It should also be avoided in patients with the HLA-B 15:02 allele.

• Muscle relaxant – Baclofen is a muscle relaxant that can be used to treat TN. Baclofen, lamotrigine, clonazepam, topiramate, phenytoin, gabapentin, pregabalin, and sodium valproate can be used. Side effects include dizziness, sedation, and dyspepsia.

• Seizures, anticonvulsant medication – used to treat epilepsy and to delay or prevent the recurrence of depressive episodes in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome and medication lamotrigine, phenytoin, gabapentin, clonazepam, and valproic acid. Lamotrigine (200 to 400 mg/day), pregabalin (150 to 600 mg/day), gabapentin (1800 to 4200 mg/day), or topiramate (100 to 400 mg/day) may be considered. If the combination therapy fails, a switch to baclofen (40 to 80 mg/day) may be considered.[rx]

• Eslicarbazepine – an active metabolite of oxcarbazepine, and the new Nav1.7 blocker, vixotrigine, are being explored for pain relief in TN.[rx]

• Anticonvulsant medicines—used to block nerve firing—are generally effective in treating TN1 but often less effective in TN2. These drugs include carbamazepine, oxcarbazepine, topiramate, gabapentin, pregabalin, clonazepam, phenytoin, lamotrigine, and valproic acid.

• Tricyclic antidepressants – such as amitriptyline or nortriptyline can be used to treat pain. Common analgesics and opioids are not usually helpful in treating the sharp, recurring pain caused by TN1, although some individuals with TN2 do respond to opioids.  Eventually, if medication fails to relieve pain or produces intolerable side effects such as cognitive disturbances, memory loss, excess fatigue, bone marrow suppression, or allergy, then surgical treatment may be indicated. Since TN is a progressive disorder that often becomes resistant to medication over time, individuals often seek surgical treatment.

• Botulinum Toxin Injections – This can be beneficial for some patients, particularly the middle-aged and the elderly, who are refractory to medical therapy or who cannot tolerate medical therapy due to their side effects.[rx]

• Tetracaine nerve block – may be used as an additional treatment after carbamazepine, as can acupuncture and/or peripheral nerve stimulation.[rx] Patients with secondary TN also can respond well to pharmacotherapy. However, it is recommended to treat the underlying lesion or disease.

• There is controversy around opiate use such as morphine and oxycodone for treatment of TN, with varying evidence on its effectiveness for neuropathic pain. Generally, opioids are considered ineffective against TN and thus should not be prescribed.^[rx]

Surgical Therapy

• Microvascular decompression – This is one of the most common procedures used to treat trigeminal neuralgia. This is beneficial for patients with TN, where compression of the nerve root is the cause. [rx]This involves craniotomy and posterior fossa exploration for identifying and moving the blood vessel that is compressing the trigeminal nerve. A soft cushion is then inserted between the nerve and the vessel, to allow the nerve to recover, which eventually relieves the pain. In some patients, this procedure can result in sustained pain relief for greater than 10 years. Though this is the most effective procedure, it is also the most invasive one. Some of the complications associated with it are decreased hearing, cerebellar hematoma, CSF leaks, infarction, and facial weakness. It is believed to be the most effective long-term surgical treatment available currently for patients with TN.[rx]
• Ablative procedures include rhizotomy–  with thermocoagulation, chemical injection, or mechanical balloon compression. These procedures involve damaging the trigeminal nerve root, thereby interrupting the pain transmission signals to the brain. Rhizotomy with thermocoagulation uses an electrode to apply heat to damage the nerve fibers. Chemical rhizotomy involves injecting the chemical, glycerol to the trigeminal nerve, thereby damaging it. Balloon compression involves inserting a tiny balloon to the point of location of nerve fibers.[rx][rx] This balloon, on inflation, damages the nerve fibers. Some of the associated complications are postoperative dysesthesia, corneal numbness, sensory loss in trigeminal nerve distribution, and anesthesia Dolorosa.
• Radiosurgery – This procedure involves using radiosurgery instrumentation.[rx][rx][rx] This is a non-invasive procedure, wherein, a highly concentrated dose of ionizing radiation is delivered to a precise target at the trigeminal nerve root. The radiation creates a lesion near the nerve root, thereby interrupting the pain signals from transmission to the brain. The formation of the lesion can be slow, and hence the pain relief using this procedure is delayed by up to several weeks or months. As this is one of the least invasive procedures, it can be repeated in patients who have a recurrence of pain. Some of the associated complications can be facial sensory loss and paresthesias.
• Peripheral neurectomy and nerve block – The neurectomy can be performed on peripheral branches of the trigeminal nerve like the supraorbital, infraorbital, lingual, and alveolar nerves.[rx] This can be accomplished by alcohol injection, incision, cryotherapy, or radiofrequency lesioning. Peripheral neurectomy can be safe in elderly patients in remote and rural areas, where neurosurgical facilities are not readily available.[rx] However, the evidence regarding these peripheral techniques for trigeminal neuralgia is inconclusive.
• A rhizotomy (rhizolysis)–  is a procedure in which nerve fibers are damaged to block pain. A rhizotomy for TN always causes some degree of sensory loss and facial numbness. Several forms of rhizotomy are available to treat trigeminal neuralgia:
• Balloon compression – works by injuring the insulation on nerves that are involved with the sensation of light touch on the face. The procedure is performed in an operating room under general anesthesia. A tube called a cannula is inserted through the cheek and guided to where one branch of the trigeminal nerve passes through the base of the skull. A soft catheter with a balloon tip is threaded through the cannula and the balloon is inflated to squeeze part of the nerve against the hard edge of the brain covering (the dura) and the skull. After about a minute the balloon is deflated and removed, along with the catheter and cannula. Balloon compression is generally an outpatient procedure, although sometimes the patient may be kept in the hospital overnight. Pain relief usually lasts one to two years.
• Glycerol injection – is also generally an outpatient procedure in which the individual is sedated with intravenous medication. A thin needle is passed through the cheek, next to the mouth, and guided through the opening in the base of the skull where the third division of the trigeminal nerve (mandibular) exits. The needle is moved into the pocket of spinal fluid (cistern) that surrounds the trigeminal nerve center (or ganglion, the central part of the nerve from which the nerve impulses are transmitted to the brain). The procedure is performed with the person sitting up, since glycerol is heavier than spinal fluid and will then remain in the spinal fluid around the ganglion. The glycerol injection bathes the ganglion and damages the insulation of trigeminal nerve fibers. This form of rhizotomy is likely to result in the recurrence of pain within a year to two years. However, the procedure can be repeated multiple times.
• Radiofrequency thermal lesioning – (also known as “RF Ablation” or “RF Lesion”) is most often performed on an outpatient basis. The individual is anesthetized and a hollow needle is passed through the cheek through the same opening at the base of the skull where the balloon compression and glycerol injections are performed. The individual is briefly awakened and a small electrical current is passed through the needle, causing tingling in the area of the nerve where the needle tips rest. When the needle is positioned so that the tingling occurs in the area of TN pain, the person is then sedated and the nerve area is gradually heated with an electrode, injuring the nerve fibers.  The electrode and needle are then removed and the person is awakened. The procedure can be repeated until the desired amount of sensory loss is obtained; usually a blunting of sharp sensation, with preservation of touch. Approximately half of the people have symptoms that reoccur three to four years following RF lesioning. Production of more numbness can extend the pain relief even longer, but the risks of anesthesia dolorosa also increase.
• Stereotactic radiosurgery – (Gamma Knife, CyberKnife) uses computer imaging to direct highly focused beams of radiation at the site where the trigeminal nerve exits the brain stem. This causes the slow formation of a lesion on the nerve that disrupts the transmission of sensory signals to the brain. People usually leave the hospital the same day or the next day following treatment but won’t typically experience relief from pain for several weeks (or sometimes several months) following the procedure.  The International Radiosurgery Association reports that between 50 and 78 percent of people with TN who are treated with Gamma Knife radiosurgery experience “excellent” pain relief within a few weeks following the procedure. For individuals who were treated successfully, almost half have a recurrence of pain within three years.
• Decompression Surgery –  is the most invasive of all surgeries for TN, but also offers the lowest probability that pain will return. About half of individuals undergoing MVD for TN will experience recurrent pain within 12 to 15 years.  This inpatient procedure, which is performed under general anesthesia, requires that a small opening be made through the mastoid bone behind the ear. While viewing the trigeminal nerve through a microscope or endoscope, the surgeon moves away from the vessel (usually an artery) that is compressing the nerve and places a soft cushion between the nerve and the vessel. Unlike rhizotomies, the goal is not to produce numbness in the face after this surgery. Individuals generally recuperate for several days in the hospital following the procedure, and will generally need to recover for several weeks after the procedure.
• A neurectomy (also called partial nerve section) – which involves cutting part of the nerve, may be performed near the entrance point of the nerve at the brain stem during an attempted microvascular decompression if no vessel is found to be pressing on the trigeminal nerve. Neurectomies also may be performed by cutting superficial branches of the trigeminal nerve in the face. When done during microvascular decompression, a neurectomy will cause more long-lasting numbness in the area of the face that is supplied by the nerve or nerve branch that is cut. However, when the operation is performed in the face, the nerve may grow back and in time sensation may return.  With neurectomy, there is risk of creating anesthesia Dolorosa.

Surgical treatment for TN2 is usually more problematic than for TN1, particularly where vascular compression is not detected in brain imaging prior to a proposed procedure. Many neurosurgeons advise against the use of MVD or rhizotomy in individuals for whom TN2 symptoms predominate over TN1, unless vascular compression has been confirmed. MVD for TN2 is also less successful than for TN1.

Some individuals manage trigeminal neuralgia using complementary techniques, usually in combination with drug treatment. These therapies offer varying degrees of success. Some people find that low-impact exercise, yoga, creative visualization, aromatherapy, or meditation may be useful in promoting well-being. Other options include acupuncture, upper cervical chiropractic, biofeedback, vitamin therapy, and nutritional therapy. Some people report modest pain relief after injections of botulinum toxin to block the activity of sensory nerves.

Chronic pain from TN is frequently very isolating and depressing for the individual. Conversely, depression and sleep disturbance may render individuals more vulnerable to pain and suffering. Some individuals benefit from supportive counseling or therapy by a psychiatrist or psychologist. However, there is no evidence that TN is psychogenic in origin or caused by depression, and persons with TN require effective medical or surgical treatment for their pain.

References

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Tic Douloureux/Trigeminal neuralgia (TN), also called tic douloureux, is a chronic pain condition that affects the trigeminal or 5th cranial nerve, one of the most widely distributed nerves in the head. TN is a form of neuropathic pain (pain associated with nerve injury or nerve lesion.) The typical or “classic” form of the disorder (called “Type 1” or TN1) causes extreme, sporadic, sudden burning, or shock-like facial pain that lasts anywhere from a few seconds to as long as two minutes per episode.  These attacks can occur in quick succession, in volleys lasting as long as two hours.  The “atypical” form of the disorder (called “Type 2” or TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than Type 1.  Both forms of pain may occur in the same person, sometimes at the same time. The intensity of pain can be physically and mentally incapacitating.

TRIGEMINAL NEURALGIA is an extremely severe unilateral episodic facial pain that tends to come and go unpredictably in sudden shock-like attacks. The pain is normally triggered, for example by light touch, and is described as stabbing, shooting, excruciating or burning. It usually lasts for a few seconds but there can be many bursts of pain in quick succession.  There can be slight variations of trigeminal neuralgia which require different treatments.

Types of Trigeminal Neuralgia

The typical or “classic” form of the disorder (called TN1) causes extreme, sporadic, sudden burning or shock-like facial pain in the areas of the face where the branches of the nerve are distributed – lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw. Trigeminal neuralgia can progress and cause longer, more frequent bouts of searing pain. You may feel as though your pain came out of nowhere. Some people initially think their pain is a toothache or migraine headache.

The “atypical” form of the disorder (called TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than TN1. Both forms of pain may occur in the same person, sometimes at the same time

The subtypes of TN are defined by ICHD-3 as follows[rx]

• Classic TN: This is secondary to neuromuscular compression and fulfilling the criteria above. This requires demonstration of the compression on an MRI or during the surgery for neuromuscular compression, with associated morphological changes in the trigeminal nerve root.
• Secondary TN: This is defined as TN secondary to an underlying disease. Some of the reported causes are multiple sclerosis, arteriovenous malformation, and cerebellopontine angle tumor.
• Idiopathic TN: This is defined as TN with no abnormalities seen on MRI or electrophysiological tests.

The trigeminal nerve is one of 12 pairs of nerves that are attached to the brain. The nerve has three branches that conduct sensations from the upper, middle, and lower portions of the face, as well as the oral cavity, to the brain. The ophthalmic, or upper, branch supplies sensation to most of the scalp, forehead, and front of the head. The maxillary, or middle, branch stimulates the cheek, upper jaw, top lip, teeth, and gums, and to the side of the nose. The mandibular, or lower, branch supplies nerves to the lower jaw, teeth and gums, and bottom lip. More than one nerve branch can be affected by the disorder. Rarely, both sides of the face may be affected at different times in an individual, or even more rarely at the same time (called bilateral TN).

What causes trigeminal neuralgia?

TN is associated with a variety of conditions. TN can be caused by a blood vessel pressing on the trigeminal nerve as it exits the brain stem. This compression causes the wearing away or damage to the protective coating around the nerve (the myelin sheath). TN symptoms can also occur in people with multiple sclerosis, a disease that causes deterioration of the trigeminal nerve’s myelin sheath. Rarely, symptoms of TN may be caused by nerve compression from a tumor, or a tangle of arteries and veins called an arteriovenous malformation. Injury to the trigeminal nerve (perhaps the result of sinus surgery, oral surgery, stroke, or facial trauma) may also produce neuropathic facial pain.

The exact cause of trigeminal neuralgia remains unknown.[rx] The majority of cases are referred to as idiopathic, although many are associated with vascular compression of the trigeminal nerve close to its exit from the brainstem by an aberrant loop of an artery or vein. A minority of cases are due to conditions like multiple sclerosis or nerve compression by a tumor.[rx] Some rare causes of trigeminal neuralgia include focal arachnoid thickening, adhesion, traction, tethering or torsion, fibrous ring around the root, cerebellopontine angle tumors, brain stem infarction, aneurysm, and arteriovenous malformation.[rx][rx][rx][rx]

The trigeminal nerve starts at the pons. Most cases of trigeminal neuralgia are due to the compression of the trigeminal nerve root, within a few millimeters of its entry into the pons. Between 80% and 90% of the cases of TN are caused by compression by an adjacent artery or a vein.[rx] The blood vessel, which has been mostly implicated in about 75% to 80% of the cases, is the superior cerebellar artery. Other blood vessels that are known to cause TN include the anterior inferior cerebellar artery, the vertebral artery, and the petrosal vein.

Vascular Theory

Generally, it has been assumed that vascular contact at the root entry zone causes trigeminal neuralgia; however, TN also may be caused by contact at a transition zone between the central and peripheral myelin. Reportedly, the most common artery involved in this condition is the superior cerebellar artery, as seen in 75% to 80% of TN cases. Persistent primitive trigeminal artery variant, an anomaly that occurs between the carotid and basilar arteries or aneurysms of the persistent primitive trigeminal artery, vertebrobasilar dolichoectasia can cause TN. Sharper trigeminal-pontine angle cisterns and smaller cerebellopontine angle cisterns may facilitate neurovascular compression (NVC).[rx][rx][rx][rx][rx]

Extracranial Causes

The most common extracranial cause of trigeminal neuralgia is a perineural spread of head and neck malignancies, commonly squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, melanoma, and sarcoma.[rx][rx][rx][rx][rx]

What are the symptoms of trigeminal neuralgia?

Pain varies, depending on the type of TN, and may range from sudden, severe, and stabbing to a more constant, aching, burning sensation. The intense flashes of pain can be triggered by vibration or contact with the cheek (such as when shaving, washing the face, or applying makeup), brushing teeth, eating, drinking, talking, or being exposed to the wind. The pain may affect a small area of the face or may spread. Bouts of pain rarely occur at night, when the affected individual is sleeping.

TN is typified by attacks that stop for a period of time and then return, but the condition can be progressive. The attacks often worsen over time, with fewer and shorter pain-free periods before they recur. Eventually, the pain-free intervals disappear and medication to control the pain becomes less effective. The disorder is not fatal but can be debilitating. Due to the intensity of the pain, some individuals may avoid daily activities or social contacts because they fear an impending attack.

The trigeminal nerve is the fifth cranial nerve. It is responsible for the sensory supply of the face and the motor and sensory supply to the muscles of mastication. The trigeminal nerve starts at the pons and divides into three branches[rx]:

• Ophthalmic (V1): Supplies the eye, upper eyelid, and the forehead
• Maxillary (V2): Supplies lower eyelid, cheek, nostril, upper lip, and upper gum
• Mandibular (V3): Supplies the lower lip, lower gum, jaw and muscles of mastication

Trigeminal neuralgia symptoms may include one or more of these patterns:

• Episodes of severe, shooting or jabbing pain that may feel like an electric shock
• Spontaneous attacks of pain or attacks triggered by things such as touching the face, chewing, speaking or brushing teeth
• Bouts of pain lasting from a few seconds to several minutes
• Episodes of several attacks lasting days, weeks, months, or longer — some people have periods when they experience no pain
• Constant aching, burning feeling that may occur before it evolves into the spasm-like pain of trigeminal neuralgia
• Pain in areas supplied by the trigeminal nerve, including the cheek, jaw, teeth, gums, lips, or less often the eye and forehead
• Pain affecting one side of the face at a time though may rarely affect both sides of the face
• Pain focused in one spot or spread in a wider pattern
• Attacks that become more frequent and intense over time
• The attacks happen several times a day or a week, followed by periods during which you have none at all. These pain-free periods are known as remission.
• The pain usually affects only one side of the face.
• The attacks happen more often over time, and the pain can worsen.
• You feel the pain mostly in your cheek, jaw, teeth, gums, and lips. The eyes and forehead are affected less often.

Symptom triggers

Attacks of trigeminal neuralgia can be triggered by certain actions or movements, such as:

• talking
• smiling
• chewing
• brushing your teeth
• washing your face
• a light touch
• shaving or putting on make-up
• swallowing
• kissing
• a cool breeze or air conditioning
• head movements
• vibrations, such as walking or traveling in a car

However, pain can happen spontaneously with no trigger whatsoever.

The symptoms of several pain disorders are similar to those of trigeminal neuralgia. The most common mimicker of TN is trigeminal neuropathic pain (TNP). TNP results from an injury or damage to the trigeminal nerve. TNP pain is generally described as being constant, dull and burning. Attacks of sharp pain can also occur, commonly triggered by touch. Additional mimickers include:

• Temporal tendinitis
• Ernest syndrome (injury of the stylomandibular ligament
• Occipital neuralgia
• Cluster headaches/ migraines
• Giant cell arteritis
• Dental pain
• Post-herpetic neuralgia
• Glossopharyngeal neuralgia
• Sinus infection
• Ear infection
• Temporomandibular joint syndrome (TMJ)

Diagnosis of Child Trigeminal Neuralgia

TN diagnosis is based primarily on the person’s history and description of symptoms, along with results from physical and neurological examinations. Other disorders that cause facial pain should be ruled out before TN is diagnosed. Some disorders that cause facial pain include post-herpetic neuralgia (nerve pain following an outbreak of shingles), cluster headaches, and temporomandibular joint disorder (TMJ, which causes pain and dysfunction in the jaw joint and muscles that control jaw movement).  Because of overlapping symptoms and the large number of conditions that can cause facial pain, obtaining a correct diagnosis is difficult, but finding the cause of the pain is important as the treatments for different types of pain may differ.

Most people with TN eventually will undergo a magnetic resonance imaging (MRI) scan to rule out a tumor or multiple sclerosis as the cause of their pain. This scan may or may not clearly show a blood vessel compressing the nerve. Special MRI imaging procedures can reveal the presence and severity of compression of the nerve by a blood vessel.

A diagnosis of classic trigeminal neuralgia may be supported by an individual’s positive response to a short course of antiseizure medication. Diagnosis of TN2 is more complex and difficult but tends to be supported by a positive response to low doses of tricyclic antidepressant medications (such as amitriptyline and nortriptyline), similar to other neuropathic pain diagnoses.

Your doctor may conduct many tests to diagnose trigeminal neuralgia and determine underlying causes for your condition, including:

• A neurological examination. Touching and examining parts of your face can help your doctor determine exactly where the pain is occurring and — if you appear to have trigeminal neuralgia — which branches of the trigeminal nerve may be affected. Reflex tests also can help your doctor determine if your symptoms are caused by a compressed nerve or another condition.
• Magnetic resonance imaging (MRI). Your doctor may order an MRI scan of your head to determine if multiple sclerosis or a tumor is causing trigeminal neuralgia. In some cases, your doctor may inject a dye into a blood vessel to view the arteries and veins and highlight blood flow (magnetic resonance angiogram).

One published a set of guidelines for diagnosing TN is from the International Headache Society.

For classical TN

• Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
• Pain has at least one of the following characteristics:
  • Intense, sharp, superficial or stabbing
  • Precipitated from trigger zones or by trigger factors
• Attacks are stereotyped in the individuals patient
• There is no clinically evident neurologic deficit
• Not attributed to another disorder

For symptomatic TN

• Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, with or without persistence of aching between paroxysms, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
• Pain has at least one of the following characteristics
  • Intense, sharp, superficial or stabbing
  • Precipitated from trigger zones or by trigger factors.
• Attacks are stereotyped in the individual patient
• A causative lesion, other than vascular compression, has been demonstrated by special investigations and/or posterior fossa exploration.

Treatment of Child Trigeminal Neuralgia

Treatment options include medicines, surgery, and complementary approaches.

Pharmacologic Therapy

• The first-line treatment – for patients with classic TN and idiopathic TN is pharmacologic therapy. The most commonly used medication is the anticonvulsant drug, carbamazepine.[rx] It is usually started at a low dose, and the dose is gradually increased until it controls the pain. It controls pain for most people in the early stages of the disease. However, in some patients, the effectiveness of carbamazepine decreases over time. Possible side effects of carbamazepine include drowsiness, dizziness, double vision, and nausea. In patients with Asian ancestry, before starting carbamazepine, testing for the HLA-B allele is recommended, as its presence increases the risk of development of toxic epidermal necrolysis or Stevens-Johnson syndrome.[rx]

• Oxcarbazepine – is a newer drug and is being increasingly used as first-line therapy for TN in patients who do not respond to or who cannot tolerate carbamazepine (200 to 1200 mg/day) and oxcarbazepine (600 to 1800 mg/day). Possible side effects include double vision and dizziness. It can also cause hyponatremia. It should also be avoided in patients with the HLA-B 15:02 allele.

• Muscle relaxant – Baclofen is a muscle relaxant that can be used to treat TN. Baclofen, lamotrigine, clonazepam, topiramate, phenytoin, gabapentin, pregabalin, and sodium valproate can be used. Side effects include dizziness, sedation, and dyspepsia.

• Seizures, anticonvulsant medication – used to treat epilepsy and to delay or prevent the recurrence of depressive episodes in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome and medication lamotrigine, phenytoin, gabapentin, clonazepam, and valproic acid. Lamotrigine (200 to 400 mg/day), pregabalin (150 to 600 mg/day), gabapentin (1800 to 4200 mg/day), or topiramate (100 to 400 mg/day) may be considered. If the combination therapy fails, a switch to baclofen (40 to 80 mg/day) may be considered.[rx]

• Eslicarbazepine – an active metabolite of oxcarbazepine, and the new Nav1.7 blocker, vixotrigine, are being explored for pain relief in TN.[rx]

• Anticonvulsant medicines—used to block nerve firing—are generally effective in treating TN1 but often less effective in TN2. These drugs include carbamazepine, oxcarbazepine, topiramate, gabapentin, pregabalin, clonazepam, phenytoin, lamotrigine, and valproic acid.

• Tricyclic antidepressants – such as amitriptyline or nortriptyline can be used to treat pain. Common analgesics and opioids are not usually helpful in treating the sharp, recurring pain caused by TN1, although some individuals with TN2 do respond to opioids.  Eventually, if medication fails to relieve pain or produces intolerable side effects such as cognitive disturbances, memory loss, excess fatigue, bone marrow suppression, or allergy, then surgical treatment may be indicated. Since TN is a progressive disorder that often becomes resistant to medication over time, individuals often seek surgical treatment.

• Botulinum Toxin Injections – This can be beneficial for some patients, particularly the middle-aged and the elderly, who are refractory to medical therapy or who cannot tolerate medical therapy due to their side effects.[rx]

• Tetracaine nerve block – may be used as an additional treatment after carbamazepine, as can acupuncture and/or peripheral nerve stimulation.[rx] Patients with secondary TN also can respond well to pharmacotherapy. However, it is recommended to treat the underlying lesion or disease.

• There is controversy around opiate use such as morphine and oxycodone for treatment of TN, with varying evidence on its effectiveness for neuropathic pain. Generally, opioids are considered ineffective against TN and thus should not be prescribed.^[rx]

Surgical Therapy

• Microvascular decompression – This is one of the most common procedures used to treat trigeminal neuralgia. This is beneficial for patients with TN, where compression of the nerve root is the cause. [rx]This involves craniotomy and posterior fossa exploration for identifying and moving the blood vessel that is compressing the trigeminal nerve. A soft cushion is then inserted between the nerve and the vessel, to allow the nerve to recover, which eventually relieves the pain. In some patients, this procedure can result in sustained pain relief for greater than 10 years. Though this is the most effective procedure, it is also the most invasive one. Some of the complications associated with it are decreased hearing, cerebellar hematoma, CSF leaks, infarction, and facial weakness. It is believed to be the most effective long-term surgical treatment available currently for patients with TN.[rx]
• Ablative procedures include rhizotomy–  with thermocoagulation, chemical injection, or mechanical balloon compression. These procedures involve damaging the trigeminal nerve root, thereby interrupting the pain transmission signals to the brain. Rhizotomy with thermocoagulation uses an electrode to apply heat to damage the nerve fibers. Chemical rhizotomy involves injecting the chemical, glycerol to the trigeminal nerve, thereby damaging it. Balloon compression involves inserting a tiny balloon to the point of location of nerve fibers.[rx][rx] This balloon, on inflation, damages the nerve fibers. Some of the associated complications are postoperative dysesthesia, corneal numbness, sensory loss in trigeminal nerve distribution, and anesthesia Dolorosa.
• Radiosurgery – This procedure involves using radiosurgery instrumentation.[rx][rx][rx] This is a non-invasive procedure, wherein, a highly concentrated dose of ionizing radiation is delivered to a precise target at the trigeminal nerve root. The radiation creates a lesion near the nerve root, thereby interrupting the pain signals from transmission to the brain. The formation of the lesion can be slow, and hence the pain relief using this procedure is delayed by up to several weeks or months. As this is one of the least invasive procedures, it can be repeated in patients who have a recurrence of pain. Some of the associated complications can be facial sensory loss and paresthesias.
• Peripheral neurectomy and nerve block – The neurectomy can be performed on peripheral branches of the trigeminal nerve like the supraorbital, infraorbital, lingual, and alveolar nerves.[rx] This can be accomplished by alcohol injection, incision, cryotherapy, or radiofrequency lesioning. Peripheral neurectomy can be safe in elderly patients in remote and rural areas, where neurosurgical facilities are not readily available.[rx] However, the evidence regarding these peripheral techniques for trigeminal neuralgia is inconclusive.
• A rhizotomy (rhizolysis)–  is a procedure in which nerve fibers are damaged to block pain. A rhizotomy for TN always causes some degree of sensory loss and facial numbness. Several forms of rhizotomy are available to treat trigeminal neuralgia:
• Balloon compression – works by injuring the insulation on nerves that are involved with the sensation of light touch on the face. The procedure is performed in an operating room under general anesthesia. A tube called a cannula is inserted through the cheek and guided to where one branch of the trigeminal nerve passes through the base of the skull. A soft catheter with a balloon tip is threaded through the cannula and the balloon is inflated to squeeze part of the nerve against the hard edge of the brain covering (the dura) and the skull. After about a minute the balloon is deflated and removed, along with the catheter and cannula. Balloon compression is generally an outpatient procedure, although sometimes the patient may be kept in the hospital overnight. Pain relief usually lasts one to two years.
• Glycerol injection – is also generally an outpatient procedure in which the individual is sedated with intravenous medication. A thin needle is passed through the cheek, next to the mouth, and guided through the opening in the base of the skull where the third division of the trigeminal nerve (mandibular) exits. The needle is moved into the pocket of spinal fluid (cistern) that surrounds the trigeminal nerve center (or ganglion, the central part of the nerve from which the nerve impulses are transmitted to the brain). The procedure is performed with the person sitting up, since glycerol is heavier than spinal fluid and will then remain in the spinal fluid around the ganglion. The glycerol injection bathes the ganglion and damages the insulation of trigeminal nerve fibers. This form of rhizotomy is likely to result in the recurrence of pain within a year to two years. However, the procedure can be repeated multiple times.
• Radiofrequency thermal lesioning – (also known as “RF Ablation” or “RF Lesion”) is most often performed on an outpatient basis. The individual is anesthetized and a hollow needle is passed through the cheek through the same opening at the base of the skull where the balloon compression and glycerol injections are performed. The individual is briefly awakened and a small electrical current is passed through the needle, causing tingling in the area of the nerve where the needle tips rest. When the needle is positioned so that the tingling occurs in the area of TN pain, the person is then sedated and the nerve area is gradually heated with an electrode, injuring the nerve fibers.  The electrode and needle are then removed and the person is awakened. The procedure can be repeated until the desired amount of sensory loss is obtained; usually a blunting of sharp sensation, with preservation of touch. Approximately half of the people have symptoms that reoccur three to four years following RF lesioning. Production of more numbness can extend the pain relief even longer, but the risks of anesthesia dolorosa also increase.
• Stereotactic radiosurgery – (Gamma Knife, CyberKnife) uses computer imaging to direct highly focused beams of radiation at the site where the trigeminal nerve exits the brain stem. This causes the slow formation of a lesion on the nerve that disrupts the transmission of sensory signals to the brain. People usually leave the hospital the same day or the next day following treatment but won’t typically experience relief from pain for several weeks (or sometimes several months) following the procedure.  The International Radiosurgery Association reports that between 50 and 78 percent of people with TN who are treated with Gamma Knife radiosurgery experience “excellent” pain relief within a few weeks following the procedure. For individuals who were treated successfully, almost half have a recurrence of pain within three years.
• Decompression Surgery –  is the most invasive of all surgeries for TN, but also offers the lowest probability that pain will return. About half of individuals undergoing MVD for TN will experience recurrent pain within 12 to 15 years.  This inpatient procedure, which is performed under general anesthesia, requires that a small opening be made through the mastoid bone behind the ear. While viewing the trigeminal nerve through a microscope or endoscope, the surgeon moves away from the vessel (usually an artery) that is compressing the nerve and places a soft cushion between the nerve and the vessel. Unlike rhizotomies, the goal is not to produce numbness in the face after this surgery. Individuals generally recuperate for several days in the hospital following the procedure, and will generally need to recover for several weeks after the procedure.
• A neurectomy (also called partial nerve section) – which involves cutting part of the nerve, may be performed near the entrance point of the nerve at the brain stem during an attempted microvascular decompression if no vessel is found to be pressing on the trigeminal nerve. Neurectomies also may be performed by cutting superficial branches of the trigeminal nerve in the face. When done during microvascular decompression, a neurectomy will cause more long-lasting numbness in the area of the face that is supplied by the nerve or nerve branch that is cut. However, when the operation is performed in the face, the nerve may grow back and in time sensation may return.  With neurectomy, there is risk of creating anesthesia Dolorosa.

Surgical treatment for TN2 is usually more problematic than for TN1, particularly where vascular compression is not detected in brain imaging prior to a proposed procedure. Many neurosurgeons advise against the use of MVD or rhizotomy in individuals for whom TN2 symptoms predominate over TN1, unless vascular compression has been confirmed. MVD for TN2 is also less successful than for TN1.

Some individuals manage trigeminal neuralgia using complementary techniques, usually in combination with drug treatment. These therapies offer varying degrees of success. Some people find that low-impact exercise, yoga, creative visualization, aromatherapy, or meditation may be useful in promoting well-being. Other options include acupuncture, upper cervical chiropractic, biofeedback, vitamin therapy, and nutritional therapy. Some people report modest pain relief after injections of botulinum toxin to block the activity of sensory nerves.

Chronic pain from TN is frequently very isolating and depressing for the individual. Conversely, depression and sleep disturbance may render individuals more vulnerable to pain and suffering. Some individuals benefit from supportive counseling or therapy by a psychiatrist or psychologist. However, there is no evidence that TN is psychogenic in origin or caused by depression, and persons with TN require effective medical or surgical treatment for their pain.

References

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Fothergill Disease/Trigeminal neuralgia (TN), also called tic douloureux, is a chronic pain condition that affects the trigeminal or 5th cranial nerve, one of the most widely distributed nerves in the head. TN is a form of neuropathic pain (pain associated with nerve injury or nerve lesion.) The typical or “classic” form of the disorder (called “Type 1” or TN1) causes extreme, sporadic, sudden burning, or shock-like facial pain that lasts anywhere from a few seconds to as long as two minutes per episode.  These attacks can occur in quick succession, in volleys lasting as long as two hours.  The “atypical” form of the disorder (called “Type 2” or TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than Type 1.  Both forms of pain may occur in the same person, sometimes at the same time. The intensity of pain can be physically and mentally incapacitating.

TRIGEMINAL NEURALGIA is an extremely severe unilateral episodic facial pain that tends to come and go unpredictably in sudden shock-like attacks. The pain is normally triggered, for example by light touch, and is described as stabbing, shooting, excruciating or burning. It usually lasts for a few seconds but there can be many bursts of pain in quick succession.  There can be slight variations of trigeminal neuralgia which require different treatments.

Types of Trigeminal Neuralgia

The typical or “classic” form of the disorder (called TN1) causes extreme, sporadic, sudden burning or shock-like facial pain in the areas of the face where the branches of the nerve are distributed – lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw. Trigeminal neuralgia can progress and cause longer, more frequent bouts of searing pain. You may feel as though your pain came out of nowhere. Some people initially think their pain is a toothache or migraine headache.

The “atypical” form of the disorder (called TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than TN1. Both forms of pain may occur in the same person, sometimes at the same time

The subtypes of TN are defined by ICHD-3 as follows[rx]

• Classic TN: This is secondary to neuromuscular compression and fulfilling the criteria above. This requires demonstration of the compression on an MRI or during the surgery for neuromuscular compression, with associated morphological changes in the trigeminal nerve root.
• Secondary TN: This is defined as TN secondary to an underlying disease. Some of the reported causes are multiple sclerosis, arteriovenous malformation, and cerebellopontine angle tumor.
• Idiopathic TN: This is defined as TN with no abnormalities seen on MRI or electrophysiological tests.

The trigeminal nerve is one of 12 pairs of nerves that are attached to the brain. The nerve has three branches that conduct sensations from the upper, middle, and lower portions of the face, as well as the oral cavity, to the brain. The ophthalmic, or upper, branch supplies sensation to most of the scalp, forehead, and front of the head. The maxillary, or middle, branch stimulates the cheek, upper jaw, top lip, teeth, and gums, and to the side of the nose. The mandibular, or lower, branch supplies nerves to the lower jaw, teeth and gums, and bottom lip. More than one nerve branch can be affected by the disorder. Rarely, both sides of the face may be affected at different times in an individual, or even more rarely at the same time (called bilateral TN).

What causes trigeminal neuralgia?

TN is associated with a variety of conditions. TN can be caused by a blood vessel pressing on the trigeminal nerve as it exits the brain stem. This compression causes the wearing away or damage to the protective coating around the nerve (the myelin sheath). TN symptoms can also occur in people with multiple sclerosis, a disease that causes deterioration of the trigeminal nerve’s myelin sheath. Rarely, symptoms of TN may be caused by nerve compression from a tumor, or a tangle of arteries and veins called an arteriovenous malformation. Injury to the trigeminal nerve (perhaps the result of sinus surgery, oral surgery, stroke, or facial trauma) may also produce neuropathic facial pain.

The exact cause of trigeminal neuralgia remains unknown.[rx] The majority of cases are referred to as idiopathic, although many are associated with vascular compression of the trigeminal nerve close to its exit from the brainstem by an aberrant loop of an artery or vein. A minority of cases are due to conditions like multiple sclerosis or nerve compression by a tumor.[rx] Some rare causes of trigeminal neuralgia include focal arachnoid thickening, adhesion, traction, tethering or torsion, fibrous ring around the root, cerebellopontine angle tumors, brain stem infarction, aneurysm, and arteriovenous malformation.[rx][rx][rx][rx]

The trigeminal nerve starts at the pons. Most cases of trigeminal neuralgia are due to the compression of the trigeminal nerve root, within a few millimeters of its entry into the pons. Between 80% and 90% of the cases of TN are caused by compression by an adjacent artery or a vein.[rx] The blood vessel, which has been mostly implicated in about 75% to 80% of the cases, is the superior cerebellar artery. Other blood vessels that are known to cause TN include the anterior inferior cerebellar artery, the vertebral artery, and the petrosal vein.

Vascular Theory

Generally, it has been assumed that vascular contact at the root entry zone causes trigeminal neuralgia; however, TN also may be caused by contact at a transition zone between the central and peripheral myelin. Reportedly, the most common artery involved in this condition is the superior cerebellar artery, as seen in 75% to 80% of TN cases. Persistent primitive trigeminal artery variant, an anomaly that occurs between the carotid and basilar arteries or aneurysms of the persistent primitive trigeminal artery, vertebrobasilar dolichoectasia can cause TN. Sharper trigeminal-pontine angle cisterns and smaller cerebellopontine angle cisterns may facilitate neurovascular compression (NVC).[rx][rx][rx][rx][rx]

Extracranial Causes

The most common extracranial cause of trigeminal neuralgia is a perineural spread of head and neck malignancies, commonly squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, melanoma, and sarcoma.[rx][rx][rx][rx][rx]

What are the symptoms of trigeminal neuralgia?

Pain varies, depending on the type of TN, and may range from sudden, severe, and stabbing to a more constant, aching, burning sensation. The intense flashes of pain can be triggered by vibration or contact with the cheek (such as when shaving, washing the face, or applying makeup), brushing teeth, eating, drinking, talking, or being exposed to the wind. The pain may affect a small area of the face or may spread. Bouts of pain rarely occur at night, when the affected individual is sleeping.

TN is typified by attacks that stop for a period of time and then return, but the condition can be progressive. The attacks often worsen over time, with fewer and shorter pain-free periods before they recur. Eventually, the pain-free intervals disappear and medication to control the pain becomes less effective. The disorder is not fatal but can be debilitating. Due to the intensity of the pain, some individuals may avoid daily activities or social contacts because they fear an impending attack.

The trigeminal nerve is the fifth cranial nerve. It is responsible for the sensory supply of the face and the motor and sensory supply to the muscles of mastication. The trigeminal nerve starts at the pons and divides into three branches[rx]:

• Ophthalmic (V1): Supplies the eye, upper eyelid, and the forehead
• Maxillary (V2): Supplies lower eyelid, cheek, nostril, upper lip, and upper gum
• Mandibular (V3): Supplies the lower lip, lower gum, jaw and muscles of mastication

Trigeminal neuralgia symptoms may include one or more of these patterns:

• Episodes of severe, shooting or jabbing pain that may feel like an electric shock
• Spontaneous attacks of pain or attacks triggered by things such as touching the face, chewing, speaking or brushing teeth
• Bouts of pain lasting from a few seconds to several minutes
• Episodes of several attacks lasting days, weeks, months, or longer — some people have periods when they experience no pain
• Constant aching, burning feeling that may occur before it evolves into the spasm-like pain of trigeminal neuralgia
• Pain in areas supplied by the trigeminal nerve, including the cheek, jaw, teeth, gums, lips, or less often the eye and forehead
• Pain affecting one side of the face at a time though may rarely affect both sides of the face
• Pain focused in one spot or spread in a wider pattern
• Attacks that become more frequent and intense over time
• The attacks happen several times a day or a week, followed by periods during which you have none at all. These pain-free periods are known as remission.
• The pain usually affects only one side of the face.
• The attacks happen more often over time, and the pain can worsen.
• You feel the pain mostly in your cheek, jaw, teeth, gums, and lips. The eyes and forehead are affected less often.

Symptom triggers

Attacks of trigeminal neuralgia can be triggered by certain actions or movements, such as:

• talking
• smiling
• chewing
• brushing your teeth
• washing your face
• a light touch
• shaving or putting on make-up
• swallowing
• kissing
• a cool breeze or air conditioning
• head movements
• vibrations, such as walking or traveling in a car

However, pain can happen spontaneously with no trigger whatsoever.

The symptoms of several pain disorders are similar to those of trigeminal neuralgia. The most common mimicker of TN is trigeminal neuropathic pain (TNP). TNP results from an injury or damage to the trigeminal nerve. TNP pain is generally described as being constant, dull and burning. Attacks of sharp pain can also occur, commonly triggered by touch. Additional mimickers include:

• Temporal tendinitis
• Ernest syndrome (injury of the stylomandibular ligament
• Occipital neuralgia
• Cluster headaches/ migraines
• Giant cell arteritis
• Dental pain
• Post-herpetic neuralgia
• Glossopharyngeal neuralgia
• Sinus infection
• Ear infection
• Temporomandibular joint syndrome (TMJ)

Diagnosis of Child Trigeminal Neuralgia

TN diagnosis is based primarily on the person’s history and description of symptoms, along with results from physical and neurological examinations. Other disorders that cause facial pain should be ruled out before TN is diagnosed. Some disorders that cause facial pain include post-herpetic neuralgia (nerve pain following an outbreak of shingles), cluster headaches, and temporomandibular joint disorder (TMJ, which causes pain and dysfunction in the jaw joint and muscles that control jaw movement).  Because of overlapping symptoms and the large number of conditions that can cause facial pain, obtaining a correct diagnosis is difficult, but finding the cause of the pain is important as the treatments for different types of pain may differ.

Most people with TN eventually will undergo a magnetic resonance imaging (MRI) scan to rule out a tumor or multiple sclerosis as the cause of their pain. This scan may or may not clearly show a blood vessel compressing the nerve. Special MRI imaging procedures can reveal the presence and severity of compression of the nerve by a blood vessel.

A diagnosis of classic trigeminal neuralgia may be supported by an individual’s positive response to a short course of antiseizure medication. Diagnosis of TN2 is more complex and difficult but tends to be supported by a positive response to low doses of tricyclic antidepressant medications (such as amitriptyline and nortriptyline), similar to other neuropathic pain diagnoses.

Your doctor may conduct many tests to diagnose trigeminal neuralgia and determine underlying causes for your condition, including:

• A neurological examination. Touching and examining parts of your face can help your doctor determine exactly where the pain is occurring and — if you appear to have trigeminal neuralgia — which branches of the trigeminal nerve may be affected. Reflex tests also can help your doctor determine if your symptoms are caused by a compressed nerve or another condition.
• Magnetic resonance imaging (MRI). Your doctor may order an MRI scan of your head to determine if multiple sclerosis or a tumor is causing trigeminal neuralgia. In some cases, your doctor may inject a dye into a blood vessel to view the arteries and veins and highlight blood flow (magnetic resonance angiogram).

One published a set of guidelines for diagnosing TN is from the International Headache Society.

For classical TN

• Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
• Pain has at least one of the following characteristics:
  • Intense, sharp, superficial or stabbing
  • Precipitated from trigger zones or by trigger factors
• Attacks are stereotyped in the individuals patient
• There is no clinically evident neurologic deficit
• Not attributed to another disorder

For symptomatic TN

• Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, with or without persistence of aching between paroxysms, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
• Pain has at least one of the following characteristics
  • Intense, sharp, superficial or stabbing
  • Precipitated from trigger zones or by trigger factors.
• Attacks are stereotyped in the individual patient
• A causative lesion, other than vascular compression, has been demonstrated by special investigations and/or posterior fossa exploration.

Treatment of Child Trigeminal Neuralgia

Treatment options include medicines, surgery, and complementary approaches.

Pharmacologic Therapy

• The first-line treatment – for patients with classic TN and idiopathic TN is pharmacologic therapy. The most commonly used medication is the anticonvulsant drug, carbamazepine.[rx] It is usually started at a low dose, and the dose is gradually increased until it controls the pain. It controls pain for most people in the early stages of the disease. However, in some patients, the effectiveness of carbamazepine decreases over time. Possible side effects of carbamazepine include drowsiness, dizziness, double vision, and nausea. In patients with Asian ancestry, before starting carbamazepine, testing for the HLA-B allele is recommended, as its presence increases the risk of development of toxic epidermal necrolysis or Stevens-Johnson syndrome.[rx]

• Oxcarbazepine – is a newer drug and is being increasingly used as first-line therapy for TN in patients who do not respond to or who cannot tolerate carbamazepine (200 to 1200 mg/day) and oxcarbazepine (600 to 1800 mg/day). Possible side effects include double vision and dizziness. It can also cause hyponatremia. It should also be avoided in patients with the HLA-B 15:02 allele.

• Muscle relaxant – Baclofen is a muscle relaxant that can be used to treat TN. Baclofen, lamotrigine, clonazepam, topiramate, phenytoin, gabapentin, pregabalin, and sodium valproate can be used. Side effects include dizziness, sedation, and dyspepsia.

• Seizures, anticonvulsant medication – used to treat epilepsy and to delay or prevent the recurrence of depressive episodes in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome and medication lamotrigine, phenytoin, gabapentin, clonazepam, and valproic acid. Lamotrigine (200 to 400 mg/day), pregabalin (150 to 600 mg/day), gabapentin (1800 to 4200 mg/day), or topiramate (100 to 400 mg/day) may be considered. If the combination therapy fails, a switch to baclofen (40 to 80 mg/day) may be considered.[rx]

• Eslicarbazepine – an active metabolite of oxcarbazepine, and the new Nav1.7 blocker, vixotrigine, are being explored for pain relief in TN.[rx]

• Anticonvulsant medicines—used to block nerve firing—are generally effective in treating TN1 but often less effective in TN2. These drugs include carbamazepine, oxcarbazepine, topiramate, gabapentin, pregabalin, clonazepam, phenytoin, lamotrigine, and valproic acid.

• Tricyclic antidepressants – such as amitriptyline or nortriptyline can be used to treat pain. Common analgesics and opioids are not usually helpful in treating the sharp, recurring pain caused by TN1, although some individuals with TN2 do respond to opioids.  Eventually, if medication fails to relieve pain or produces intolerable side effects such as cognitive disturbances, memory loss, excess fatigue, bone marrow suppression, or allergy, then surgical treatment may be indicated. Since TN is a progressive disorder that often becomes resistant to medication over time, individuals often seek surgical treatment.

• Botulinum Toxin Injections – This can be beneficial for some patients, particularly the middle-aged and the elderly, who are refractory to medical therapy or who cannot tolerate medical therapy due to their side effects.[rx]

• Tetracaine nerve block – may be used as an additional treatment after carbamazepine, as can acupuncture and/or peripheral nerve stimulation.[rx] Patients with secondary TN also can respond well to pharmacotherapy. However, it is recommended to treat the underlying lesion or disease.

• There is controversy around opiate use such as morphine and oxycodone for treatment of TN, with varying evidence on its effectiveness for neuropathic pain. Generally, opioids are considered ineffective against TN and thus should not be prescribed.^[rx]

Surgical Therapy

• Microvascular decompression – This is one of the most common procedures used to treat trigeminal neuralgia. This is beneficial for patients with TN, where compression of the nerve root is the cause. [rx]This involves craniotomy and posterior fossa exploration for identifying and moving the blood vessel that is compressing the trigeminal nerve. A soft cushion is then inserted between the nerve and the vessel, to allow the nerve to recover, which eventually relieves the pain. In some patients, this procedure can result in sustained pain relief for greater than 10 years. Though this is the most effective procedure, it is also the most invasive one. Some of the complications associated with it are decreased hearing, cerebellar hematoma, CSF leaks, infarction, and facial weakness. It is believed to be the most effective long-term surgical treatment available currently for patients with TN.[rx]
• Ablative procedures include rhizotomy–  with thermocoagulation, chemical injection, or mechanical balloon compression. These procedures involve damaging the trigeminal nerve root, thereby interrupting the pain transmission signals to the brain. Rhizotomy with thermocoagulation uses an electrode to apply heat to damage the nerve fibers. Chemical rhizotomy involves injecting the chemical, glycerol to the trigeminal nerve, thereby damaging it. Balloon compression involves inserting a tiny balloon to the point of location of nerve fibers.[rx][rx] This balloon, on inflation, damages the nerve fibers. Some of the associated complications are postoperative dysesthesia, corneal numbness, sensory loss in trigeminal nerve distribution, and anesthesia Dolorosa.
• Radiosurgery – This procedure involves using radiosurgery instrumentation.[rx][rx][rx] This is a non-invasive procedure, wherein, a highly concentrated dose of ionizing radiation is delivered to a precise target at the trigeminal nerve root. The radiation creates a lesion near the nerve root, thereby interrupting the pain signals from transmission to the brain. The formation of the lesion can be slow, and hence the pain relief using this procedure is delayed by up to several weeks or months. As this is one of the least invasive procedures, it can be repeated in patients who have a recurrence of pain. Some of the associated complications can be facial sensory loss and paresthesias.
• Peripheral neurectomy and nerve block – The neurectomy can be performed on peripheral branches of the trigeminal nerve like the supraorbital, infraorbital, lingual, and alveolar nerves.[rx] This can be accomplished by alcohol injection, incision, cryotherapy, or radiofrequency lesioning. Peripheral neurectomy can be safe in elderly patients in remote and rural areas, where neurosurgical facilities are not readily available.[rx] However, the evidence regarding these peripheral techniques for trigeminal neuralgia is inconclusive.
• A rhizotomy (rhizolysis)–  is a procedure in which nerve fibers are damaged to block pain. A rhizotomy for TN always causes some degree of sensory loss and facial numbness. Several forms of rhizotomy are available to treat trigeminal neuralgia:
• Balloon compression – works by injuring the insulation on nerves that are involved with the sensation of light touch on the face. The procedure is performed in an operating room under general anesthesia. A tube called a cannula is inserted through the cheek and guided to where one branch of the trigeminal nerve passes through the base of the skull. A soft catheter with a balloon tip is threaded through the cannula and the balloon is inflated to squeeze part of the nerve against the hard edge of the brain covering (the dura) and the skull. After about a minute the balloon is deflated and removed, along with the catheter and cannula. Balloon compression is generally an outpatient procedure, although sometimes the patient may be kept in the hospital overnight. Pain relief usually lasts one to two years.
• Glycerol injection – is also generally an outpatient procedure in which the individual is sedated with intravenous medication. A thin needle is passed through the cheek, next to the mouth, and guided through the opening in the base of the skull where the third division of the trigeminal nerve (mandibular) exits. The needle is moved into the pocket of spinal fluid (cistern) that surrounds the trigeminal nerve center (or ganglion, the central part of the nerve from which the nerve impulses are transmitted to the brain). The procedure is performed with the person sitting up, since glycerol is heavier than spinal fluid and will then remain in the spinal fluid around the ganglion. The glycerol injection bathes the ganglion and damages the insulation of trigeminal nerve fibers. This form of rhizotomy is likely to result in the recurrence of pain within a year to two years. However, the procedure can be repeated multiple times.
• Radiofrequency thermal lesioning – (also known as “RF Ablation” or “RF Lesion”) is most often performed on an outpatient basis. The individual is anesthetized and a hollow needle is passed through the cheek through the same opening at the base of the skull where the balloon compression and glycerol injections are performed. The individual is briefly awakened and a small electrical current is passed through the needle, causing tingling in the area of the nerve where the needle tips rest. When the needle is positioned so that the tingling occurs in the area of TN pain, the person is then sedated and the nerve area is gradually heated with an electrode, injuring the nerve fibers.  The electrode and needle are then removed and the person is awakened. The procedure can be repeated until the desired amount of sensory loss is obtained; usually a blunting of sharp sensation, with preservation of touch. Approximately half of the people have symptoms that reoccur three to four years following RF lesioning. Production of more numbness can extend the pain relief even longer, but the risks of anesthesia dolorosa also increase.
• Stereotactic radiosurgery – (Gamma Knife, CyberKnife) uses computer imaging to direct highly focused beams of radiation at the site where the trigeminal nerve exits the brain stem. This causes the slow formation of a lesion on the nerve that disrupts the transmission of sensory signals to the brain. People usually leave the hospital the same day or the next day following treatment but won’t typically experience relief from pain for several weeks (or sometimes several months) following the procedure.  The International Radiosurgery Association reports that between 50 and 78 percent of people with TN who are treated with Gamma Knife radiosurgery experience “excellent” pain relief within a few weeks following the procedure. For individuals who were treated successfully, almost half have a recurrence of pain within three years.
• Decompression Surgery –  is the most invasive of all surgeries for TN, but also offers the lowest probability that pain will return. About half of individuals undergoing MVD for TN will experience recurrent pain within 12 to 15 years.  This inpatient procedure, which is performed under general anesthesia, requires that a small opening be made through the mastoid bone behind the ear. While viewing the trigeminal nerve through a microscope or endoscope, the surgeon moves away from the vessel (usually an artery) that is compressing the nerve and places a soft cushion between the nerve and the vessel. Unlike rhizotomies, the goal is not to produce numbness in the face after this surgery. Individuals generally recuperate for several days in the hospital following the procedure, and will generally need to recover for several weeks after the procedure.
• A neurectomy (also called partial nerve section) – which involves cutting part of the nerve, may be performed near the entrance point of the nerve at the brain stem during an attempted microvascular decompression if no vessel is found to be pressing on the trigeminal nerve. Neurectomies also may be performed by cutting superficial branches of the trigeminal nerve in the face. When done during microvascular decompression, a neurectomy will cause more long-lasting numbness in the area of the face that is supplied by the nerve or nerve branch that is cut. However, when the operation is performed in the face, the nerve may grow back and in time sensation may return.  With neurectomy, there is risk of creating anesthesia Dolorosa.

Surgical treatment for TN2 is usually more problematic than for TN1, particularly where vascular compression is not detected in brain imaging prior to a proposed procedure. Many neurosurgeons advise against the use of MVD or rhizotomy in individuals for whom TN2 symptoms predominate over TN1, unless vascular compression has been confirmed. MVD for TN2 is also less successful than for TN1.

Some individuals manage trigeminal neuralgia using complementary techniques, usually in combination with drug treatment. These therapies offer varying degrees of success. Some people find that low-impact exercise, yoga, creative visualization, aromatherapy, or meditation may be useful in promoting well-being. Other options include acupuncture, upper cervical chiropractic, biofeedback, vitamin therapy, and nutritional therapy. Some people report modest pain relief after injections of botulinum toxin to block the activity of sensory nerves.

Chronic pain from TN is frequently very isolating and depressing for the individual. Conversely, depression and sleep disturbance may render individuals more vulnerable to pain and suffering. Some individuals benefit from supportive counseling or therapy by a psychiatrist or psychologist. However, there is no evidence that TN is psychogenic in origin or caused by depression, and persons with TN require effective medical or surgical treatment for their pain.

References

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Trigeminal neuralgia (TN), also called tic douloureux, is a chronic pain condition that affects the trigeminal or 5th cranial nerve, one of the most widely distributed nerves in the head. TN is a form of neuropathic pain (pain associated with nerve injury or nerve lesion.) The typical or “classic” form of the disorder (called “Type 1” or TN1) causes extreme, sporadic, sudden burning, or shock-like facial pain that lasts anywhere from a few seconds to as long as two minutes per episode.  These attacks can occur in quick succession, in volleys lasting as long as two hours.  The “atypical” form of the disorder (called “Type 2” or TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than Type 1.  Both forms of pain may occur in the same person, sometimes at the same time. The intensity of pain can be physically and mentally incapacitating.

TRIGEMINAL NEURALGIA is an extremely severe unilateral episodic facial pain that tends to come and go unpredictably in sudden shock-like attacks. The pain is normally triggered, for example by light touch, and is described as stabbing, shooting, excruciating or burning. It usually lasts for a few seconds but there can be many bursts of pain in quick succession.  There can be slight variations of trigeminal neuralgia which require different treatments.

Types of Trigeminal Neuralgia

The typical or “classic” form of the disorder (called TN1) causes extreme, sporadic, sudden burning or shock-like facial pain in the areas of the face where the branches of the nerve are distributed – lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw. Trigeminal neuralgia can progress and cause longer, more frequent bouts of searing pain. You may feel as though your pain came out of nowhere. Some people initially think their pain is a toothache or migraine headache.

The “atypical” form of the disorder (called TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than TN1. Both forms of pain may occur in the same person, sometimes at the same time

The subtypes of TN are defined by ICHD-3 as follows[rx]

• Classic TN: This is secondary to neuromuscular compression and fulfilling the criteria above. This requires demonstration of the compression on an MRI or during the surgery for neuromuscular compression, with associated morphological changes in the trigeminal nerve root.
• Secondary TN: This is defined as TN secondary to an underlying disease. Some of the reported causes are multiple sclerosis, arteriovenous malformation, and cerebellopontine angle tumor.
• Idiopathic TN: This is defined as TN with no abnormalities seen on MRI or electrophysiological tests.

The trigeminal nerve is one of 12 pairs of nerves that are attached to the brain. The nerve has three branches that conduct sensations from the upper, middle, and lower portions of the face, as well as the oral cavity, to the brain. The ophthalmic, or upper, branch supplies sensation to most of the scalp, forehead, and front of the head. The maxillary, or middle, branch stimulates the cheek, upper jaw, top lip, teeth, and gums, and to the side of the nose. The mandibular, or lower, branch supplies nerves to the lower jaw, teeth and gums, and bottom lip. More than one nerve branch can be affected by the disorder. Rarely, both sides of the face may be affected at different times in an individual, or even more rarely at the same time (called bilateral TN).

What causes trigeminal neuralgia?

TN is associated with a variety of conditions. TN can be caused by a blood vessel pressing on the trigeminal nerve as it exits the brain stem. This compression causes the wearing away or damage to the protective coating around the nerve (the myelin sheath). TN symptoms can also occur in people with multiple sclerosis, a disease that causes deterioration of the trigeminal nerve’s myelin sheath. Rarely, symptoms of TN may be caused by nerve compression from a tumor, or a tangle of arteries and veins called an arteriovenous malformation. Injury to the trigeminal nerve (perhaps the result of sinus surgery, oral surgery, stroke, or facial trauma) may also produce neuropathic facial pain.

The exact cause of trigeminal neuralgia remains unknown.[rx] The majority of cases are referred to as idiopathic, although many are associated with vascular compression of the trigeminal nerve close to its exit from the brainstem by an aberrant loop of an artery or vein. A minority of cases are due to conditions like multiple sclerosis or nerve compression by a tumor.[rx] Some rare causes of trigeminal neuralgia include focal arachnoid thickening, adhesion, traction, tethering or torsion, fibrous ring around the root, cerebellopontine angle tumors, brain stem infarction, aneurysm, and arteriovenous malformation.[rx][rx][rx][rx]

The trigeminal nerve starts at the pons. Most cases of trigeminal neuralgia are due to the compression of the trigeminal nerve root, within a few millimeters of its entry into the pons. Between 80% and 90% of the cases of TN are caused by compression by an adjacent artery or a vein.[rx] The blood vessel, which has been mostly implicated in about 75% to 80% of the cases, is the superior cerebellar artery. Other blood vessels that are known to cause TN include the anterior inferior cerebellar artery, the vertebral artery, and the petrosal vein.

Vascular Theory

Generally, it has been assumed that vascular contact at the root entry zone causes trigeminal neuralgia; however, TN also may be caused by contact at a transition zone between the central and peripheral myelin. Reportedly, the most common artery involved in this condition is the superior cerebellar artery, as seen in 75% to 80% of TN cases. Persistent primitive trigeminal artery variant, an anomaly that occurs between the carotid and basilar arteries or aneurysms of the persistent primitive trigeminal artery, vertebrobasilar dolichoectasia can cause TN. Sharper trigeminal-pontine angle cisterns and smaller cerebellopontine angle cisterns may facilitate neurovascular compression (NVC).[rx][rx][rx][rx][rx]

Extracranial Causes

The most common extracranial cause of trigeminal neuralgia is a perineural spread of head and neck malignancies, commonly squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, melanoma, and sarcoma.[rx][rx][rx][rx][rx]

What are the symptoms of trigeminal neuralgia?

Pain varies, depending on the type of TN, and may range from sudden, severe, and stabbing to a more constant, aching, burning sensation. The intense flashes of pain can be triggered by vibration or contact with the cheek (such as when shaving, washing the face, or applying makeup), brushing teeth, eating, drinking, talking, or being exposed to the wind. The pain may affect a small area of the face or may spread. Bouts of pain rarely occur at night, when the affected individual is sleeping.

TN is typified by attacks that stop for a period of time and then return, but the condition can be progressive. The attacks often worsen over time, with fewer and shorter pain-free periods before they recur. Eventually, the pain-free intervals disappear and medication to control the pain becomes less effective. The disorder is not fatal but can be debilitating. Due to the intensity of the pain, some individuals may avoid daily activities or social contacts because they fear an impending attack.

The trigeminal nerve is the fifth cranial nerve. It is responsible for the sensory supply of the face and the motor and sensory supply to the muscles of mastication. The trigeminal nerve starts at the pons and divides into three branches[rx]:

• Ophthalmic (V1): Supplies the eye, upper eyelid, and the forehead
• Maxillary (V2): Supplies lower eyelid, cheek, nostril, upper lip, and upper gum
• Mandibular (V3): Supplies the lower lip, lower gum, jaw and muscles of mastication

Trigeminal neuralgia symptoms may include one or more of these patterns:

• Episodes of severe, shooting or jabbing pain that may feel like an electric shock
• Spontaneous attacks of pain or attacks triggered by things such as touching the face, chewing, speaking or brushing teeth
• Bouts of pain lasting from a few seconds to several minutes
• Episodes of several attacks lasting days, weeks, months, or longer — some people have periods when they experience no pain
• Constant aching, burning feeling that may occur before it evolves into the spasm-like pain of trigeminal neuralgia
• Pain in areas supplied by the trigeminal nerve, including the cheek, jaw, teeth, gums, lips, or less often the eye and forehead
• Pain affecting one side of the face at a time though may rarely affect both sides of the face
• Pain focused in one spot or spread in a wider pattern
• Attacks that become more frequent and intense over time
• The attacks happen several times a day or a week, followed by periods during which you have none at all. These pain-free periods are known as remission.
• The pain usually affects only one side of the face.
• The attacks happen more often over time, and the pain can worsen.
• You feel the pain mostly in your cheek, jaw, teeth, gums, and lips. The eyes and forehead are affected less often.

Symptom triggers

Attacks of trigeminal neuralgia can be triggered by certain actions or movements, such as:

• talking
• smiling
• chewing
• brushing your teeth
• washing your face
• a light touch
• shaving or putting on make-up
• swallowing
• kissing
• a cool breeze or air conditioning
• head movements
• vibrations, such as walking or traveling in a car

However, pain can happen spontaneously with no trigger whatsoever.

The symptoms of several pain disorders are similar to those of trigeminal neuralgia. The most common mimicker of TN is trigeminal neuropathic pain (TNP). TNP results from an injury or damage to the trigeminal nerve. TNP pain is generally described as being constant, dull and burning. Attacks of sharp pain can also occur, commonly triggered by touch. Additional mimickers include:

• Temporal tendinitis
• Ernest syndrome (injury of the stylomandibular ligament
• Occipital neuralgia
• Cluster headaches/ migraines
• Giant cell arteritis
• Dental pain
• Post-herpetic neuralgia
• Glossopharyngeal neuralgia
• Sinus infection
• Ear infection
• Temporomandibular joint syndrome (TMJ)

Diagnosis of Child Trigeminal Neuralgia

TN diagnosis is based primarily on the person’s history and description of symptoms, along with results from physical and neurological examinations. Other disorders that cause facial pain should be ruled out before TN is diagnosed. Some disorders that cause facial pain include post-herpetic neuralgia (nerve pain following an outbreak of shingles), cluster headaches, and temporomandibular joint disorder (TMJ, which causes pain and dysfunction in the jaw joint and muscles that control jaw movement).  Because of overlapping symptoms and the large number of conditions that can cause facial pain, obtaining a correct diagnosis is difficult, but finding the cause of the pain is important as the treatments for different types of pain may differ.

Most people with TN eventually will undergo a magnetic resonance imaging (MRI) scan to rule out a tumor or multiple sclerosis as the cause of their pain. This scan may or may not clearly show a blood vessel compressing the nerve. Special MRI imaging procedures can reveal the presence and severity of compression of the nerve by a blood vessel.

A diagnosis of classic trigeminal neuralgia may be supported by an individual’s positive response to a short course of antiseizure medication. Diagnosis of TN2 is more complex and difficult but tends to be supported by a positive response to low doses of tricyclic antidepressant medications (such as amitriptyline and nortriptyline), similar to other neuropathic pain diagnoses.

Your doctor may conduct many tests to diagnose trigeminal neuralgia and determine underlying causes for your condition, including:

• A neurological examination. Touching and examining parts of your face can help your doctor determine exactly where the pain is occurring and — if you appear to have trigeminal neuralgia — which branches of the trigeminal nerve may be affected. Reflex tests also can help your doctor determine if your symptoms are caused by a compressed nerve or another condition.
• Magnetic resonance imaging (MRI). Your doctor may order an MRI scan of your head to determine if multiple sclerosis or a tumor is causing trigeminal neuralgia. In some cases, your doctor may inject a dye into a blood vessel to view the arteries and veins and highlight blood flow (magnetic resonance angiogram).

One published a set of guidelines for diagnosing TN is from the International Headache Society.

For classical TN

• Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
• Pain has at least one of the following characteristics:
  • Intense, sharp, superficial or stabbing
  • Precipitated from trigger zones or by trigger factors
• Attacks are stereotyped in the individuals patient
• There is no clinically evident neurologic deficit
• Not attributed to another disorder

For symptomatic TN

• Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, with or without persistence of aching between paroxysms, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
• Pain has at least one of the following characteristics
  • Intense, sharp, superficial or stabbing
  • Precipitated from trigger zones or by trigger factors.
• Attacks are stereotyped in the individual patient
• A causative lesion, other than vascular compression, has been demonstrated by special investigations and/or posterior fossa exploration.

Treatment of Child Trigeminal Neuralgia

Treatment options include medicines, surgery, and complementary approaches.

Pharmacologic Therapy

• The first-line treatment – for patients with classic TN and idiopathic TN is pharmacologic therapy. The most commonly used medication is the anticonvulsant drug, carbamazepine.[rx] It is usually started at a low dose, and the dose is gradually increased until it controls the pain. It controls pain for most people in the early stages of the disease. However, in some patients, the effectiveness of carbamazepine decreases over time. Possible side effects of carbamazepine include drowsiness, dizziness, double vision, and nausea. In patients with Asian ancestry, before starting carbamazepine, testing for the HLA-B allele is recommended, as its presence increases the risk of development of toxic epidermal necrolysis or Stevens-Johnson syndrome.[rx]

• Oxcarbazepine – is a newer drug and is being increasingly used as first-line therapy for TN in patients who do not respond to or who cannot tolerate carbamazepine (200 to 1200 mg/day) and oxcarbazepine (600 to 1800 mg/day). Possible side effects include double vision and dizziness. It can also cause hyponatremia. It should also be avoided in patients with the HLA-B 15:02 allele.

• Muscle relaxant – Baclofen is a muscle relaxant that can be used to treat TN. Baclofen, lamotrigine, clonazepam, topiramate, phenytoin, gabapentin, pregabalin, and sodium valproate can be used. Side effects include dizziness, sedation, and dyspepsia.

• Seizures, anticonvulsant medication – used to treat epilepsy and to delay or prevent the recurrence of depressive episodes in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome and medication lamotrigine, phenytoin, gabapentin, clonazepam, and valproic acid. Lamotrigine (200 to 400 mg/day), pregabalin (150 to 600 mg/day), gabapentin (1800 to 4200 mg/day), or topiramate (100 to 400 mg/day) may be considered. If the combination therapy fails, a switch to baclofen (40 to 80 mg/day) may be considered.[rx]

• Eslicarbazepine – an active metabolite of oxcarbazepine, and the new Nav1.7 blocker, vixotrigine, are being explored for pain relief in TN.[rx]

• Anticonvulsant medicines—used to block nerve firing—are generally effective in treating TN1 but often less effective in TN2. These drugs include carbamazepine, oxcarbazepine, topiramate, gabapentin, pregabalin, clonazepam, phenytoin, lamotrigine, and valproic acid.

• Tricyclic antidepressants – such as amitriptyline or nortriptyline can be used to treat pain. Common analgesics and opioids are not usually helpful in treating the sharp, recurring pain caused by TN1, although some individuals with TN2 do respond to opioids.  Eventually, if medication fails to relieve pain or produces intolerable side effects such as cognitive disturbances, memory loss, excess fatigue, bone marrow suppression, or allergy, then surgical treatment may be indicated. Since TN is a progressive disorder that often becomes resistant to medication over time, individuals often seek surgical treatment.

• Botulinum Toxin Injections – This can be beneficial for some patients, particularly the middle-aged and the elderly, who are refractory to medical therapy or who cannot tolerate medical therapy due to their side effects.[rx]

• Tetracaine nerve block – may be used as an additional treatment after carbamazepine, as can acupuncture and/or peripheral nerve stimulation.[rx] Patients with secondary TN also can respond well to pharmacotherapy. However, it is recommended to treat the underlying lesion or disease.

• There is controversy around opiate use such as morphine and oxycodone for treatment of TN, with varying evidence on its effectiveness for neuropathic pain. Generally, opioids are considered ineffective against TN and thus should not be prescribed.^[rx]

Surgical Therapy

• Microvascular decompression – This is one of the most common procedures used to treat trigeminal neuralgia. This is beneficial for patients with TN, where compression of the nerve root is the cause. [rx]This involves craniotomy and posterior fossa exploration for identifying and moving the blood vessel that is compressing the trigeminal nerve. A soft cushion is then inserted between the nerve and the vessel, to allow the nerve to recover, which eventually relieves the pain. In some patients, this procedure can result in sustained pain relief for greater than 10 years. Though this is the most effective procedure, it is also the most invasive one. Some of the complications associated with it are decreased hearing, cerebellar hematoma, CSF leaks, infarction, and facial weakness. It is believed to be the most effective long-term surgical treatment available currently for patients with TN.[rx]
• Ablative procedures include rhizotomy–  with thermocoagulation, chemical injection, or mechanical balloon compression. These procedures involve damaging the trigeminal nerve root, thereby interrupting the pain transmission signals to the brain. Rhizotomy with thermocoagulation uses an electrode to apply heat to damage the nerve fibers. Chemical rhizotomy involves injecting the chemical, glycerol to the trigeminal nerve, thereby damaging it. Balloon compression involves inserting a tiny balloon to the point of location of nerve fibers.[rx][rx] This balloon, on inflation, damages the nerve fibers. Some of the associated complications are postoperative dysesthesia, corneal numbness, sensory loss in trigeminal nerve distribution, and anesthesia Dolorosa.
• Radiosurgery – This procedure involves using radiosurgery instrumentation.[rx][rx][rx] This is a non-invasive procedure, wherein, a highly concentrated dose of ionizing radiation is delivered to a precise target at the trigeminal nerve root. The radiation creates a lesion near the nerve root, thereby interrupting the pain signals from transmission to the brain. The formation of the lesion can be slow, and hence the pain relief using this procedure is delayed by up to several weeks or months. As this is one of the least invasive procedures, it can be repeated in patients who have a recurrence of pain. Some of the associated complications can be facial sensory loss and paresthesias.
• Peripheral neurectomy and nerve block – The neurectomy can be performed on peripheral branches of the trigeminal nerve like the supraorbital, infraorbital, lingual, and alveolar nerves.[rx] This can be accomplished by alcohol injection, incision, cryotherapy, or radiofrequency lesioning. Peripheral neurectomy can be safe in elderly patients in remote and rural areas, where neurosurgical facilities are not readily available.[rx] However, the evidence regarding these peripheral techniques for trigeminal neuralgia is inconclusive.
• A rhizotomy (rhizolysis)–  is a procedure in which nerve fibers are damaged to block pain. A rhizotomy for TN always causes some degree of sensory loss and facial numbness. Several forms of rhizotomy are available to treat trigeminal neuralgia:
• Balloon compression – works by injuring the insulation on nerves that are involved with the sensation of light touch on the face. The procedure is performed in an operating room under general anesthesia. A tube called a cannula is inserted through the cheek and guided to where one branch of the trigeminal nerve passes through the base of the skull. A soft catheter with a balloon tip is threaded through the cannula and the balloon is inflated to squeeze part of the nerve against the hard edge of the brain covering (the dura) and the skull. After about a minute the balloon is deflated and removed, along with the catheter and cannula. Balloon compression is generally an outpatient procedure, although sometimes the patient may be kept in the hospital overnight. Pain relief usually lasts one to two years.
• Glycerol injection – is also generally an outpatient procedure in which the individual is sedated with intravenous medication. A thin needle is passed through the cheek, next to the mouth, and guided through the opening in the base of the skull where the third division of the trigeminal nerve (mandibular) exits. The needle is moved into the pocket of spinal fluid (cistern) that surrounds the trigeminal nerve center (or ganglion, the central part of the nerve from which the nerve impulses are transmitted to the brain). The procedure is performed with the person sitting up, since glycerol is heavier than spinal fluid and will then remain in the spinal fluid around the ganglion. The glycerol injection bathes the ganglion and damages the insulation of trigeminal nerve fibers. This form of rhizotomy is likely to result in the recurrence of pain within a year to two years. However, the procedure can be repeated multiple times.
• Radiofrequency thermal lesioning – (also known as “RF Ablation” or “RF Lesion”) is most often performed on an outpatient basis. The individual is anesthetized and a hollow needle is passed through the cheek through the same opening at the base of the skull where the balloon compression and glycerol injections are performed. The individual is briefly awakened and a small electrical current is passed through the needle, causing tingling in the area of the nerve where the needle tips rest. When the needle is positioned so that the tingling occurs in the area of TN pain, the person is then sedated and the nerve area is gradually heated with an electrode, injuring the nerve fibers.  The electrode and needle are then removed and the person is awakened. The procedure can be repeated until the desired amount of sensory loss is obtained; usually a blunting of sharp sensation, with preservation of touch. Approximately half of the people have symptoms that reoccur three to four years following RF lesioning. Production of more numbness can extend the pain relief even longer, but the risks of anesthesia dolorosa also increase.
• Stereotactic radiosurgery – (Gamma Knife, CyberKnife) uses computer imaging to direct highly focused beams of radiation at the site where the trigeminal nerve exits the brain stem. This causes the slow formation of a lesion on the nerve that disrupts the transmission of sensory signals to the brain. People usually leave the hospital the same day or the next day following treatment but won’t typically experience relief from pain for several weeks (or sometimes several months) following the procedure.  The International Radiosurgery Association reports that between 50 and 78 percent of people with TN who are treated with Gamma Knife radiosurgery experience “excellent” pain relief within a few weeks following the procedure. For individuals who were treated successfully, almost half have a recurrence of pain within three years.
• Decompression Surgery –  is the most invasive of all surgeries for TN, but also offers the lowest probability that pain will return. About half of individuals undergoing MVD for TN will experience recurrent pain within 12 to 15 years.  This inpatient procedure, which is performed under general anesthesia, requires that a small opening be made through the mastoid bone behind the ear. While viewing the trigeminal nerve through a microscope or endoscope, the surgeon moves away from the vessel (usually an artery) that is compressing the nerve and places a soft cushion between the nerve and the vessel. Unlike rhizotomies, the goal is not to produce numbness in the face after this surgery. Individuals generally recuperate for several days in the hospital following the procedure, and will generally need to recover for several weeks after the procedure.
• A neurectomy (also called partial nerve section) – which involves cutting part of the nerve, may be performed near the entrance point of the nerve at the brain stem during an attempted microvascular decompression if no vessel is found to be pressing on the trigeminal nerve. Neurectomies also may be performed by cutting superficial branches of the trigeminal nerve in the face. When done during microvascular decompression, a neurectomy will cause more long-lasting numbness in the area of the face that is supplied by the nerve or nerve branch that is cut. However, when the operation is performed in the face, the nerve may grow back and in time sensation may return.  With neurectomy, there is risk of creating anesthesia Dolorosa.

Surgical treatment for TN2 is usually more problematic than for TN1, particularly where vascular compression is not detected in brain imaging prior to a proposed procedure. Many neurosurgeons advise against the use of MVD or rhizotomy in individuals for whom TN2 symptoms predominate over TN1, unless vascular compression has been confirmed. MVD for TN2 is also less successful than for TN1.

Some individuals manage trigeminal neuralgia using complementary techniques, usually in combination with drug treatment. These therapies offer varying degrees of success. Some people find that low-impact exercise, yoga, creative visualization, aromatherapy, or meditation may be useful in promoting well-being. Other options include acupuncture, upper cervical chiropractic, biofeedback, vitamin therapy, and nutritional therapy. Some people report modest pain relief after injections of botulinum toxin to block the activity of sensory nerves.

Chronic pain from TN is frequently very isolating and depressing for the individual. Conversely, depression and sleep disturbance may render individuals more vulnerable to pain and suffering. Some individuals benefit from supportive counseling or therapy by a psychiatrist or psychologist. However, there is no evidence that TN is psychogenic in origin or caused by depression, and persons with TN require effective medical or surgical treatment for their pain.

References

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Phakomatosis TS is also known as Cerebral sclerosis, Bourneville Phakomatosis, Bourneville disease, Tuberous sclerosis, tuberous sclerosis complex is a neurocutaneous disorder (phakomatosis) characterized by the development of multiple benign tumors of the embryonic ectoderm (e.g. skin, eyes, and nervous system).

Tuberous sclerosis complex is a multisystemic, autosomal dominant neurocutaneous genetic disorder with complete penetrance, hamartomatous growths in multiple organ systems that can evolve with hamartomas in multiple organs, by causing the growth of benign tumors, so-called hamartomas. As brain, skin, kidneys, heart, liver, lungs, and less frequently retina, gingiva, bones, and gastrointestinal tract can be affected, TSC patients require coordinated care of many specialties.

Hamartomas – plural of hamartoma; benign overgrowths of a mature cell type normal to the site or organ. They may be congenital or acquired

Tuberous sclerosis (also called tuberous sclerosis complex, or TSC) is a rare, multi-system genetic disease that causes non-cancerous (benign) tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and can result in a combination of symptoms including seizures, impaired intellectual development, autism, behavioral problems, skin abnormalities, and kidney disease.

The severity of symptoms varies widely. Symptoms range from mild—allowing people to live independent, productive lives—to more severe symptoms that can affect everyday life and even be life-threatening. Many people with TSC show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.

The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify with age and becomes hard or sclerotic. TSC occurs in all races and ethnic groups, and in both genders.

Causes of Tuberous Sclerosis Complex

TSC is caused by defects, or mutations, on two genes—TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene is on chromosome 9 and produces a protein called hamartin. The TSC2 gene is on chromosome 16 and produces the protein tuberin. Scientists believe these proteins act as growth suppressors by inhibiting the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.

Mutations in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins likely work together to help regulate cell growth and size. The proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way.

People with tuberous sclerosis complex are born with one mutated copy of the TSC1 or TSC2 gene in each cell. This mutation prevents the cell from making functional hamartin or tuberin from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For some types of tumors to develop, a second mutation involving the other copy of the TSC1 or TSC2 gene must occur in certain cells during a person’s lifetime.

When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin; cells with two altered copies of the TSC2 gene are unable to produce any functional tuberin. The loss of these proteins allows the cell to grow and divide in an uncontrolled way to form a tumor. In people with tuberous sclerosis complex, a second TSC1 or TSC2 mutation typically occurs in multiple cells over an affected person’s lifetime. The loss of hamartin or tuberin in different types of cells leads to the growth of tumors in many different organs and tissues.

Is TSC inherited?

Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2—meaning neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.

In cases where TSC is inherited, only one parent needs to have the faulty gene in order to pass it on to a child (called autosomal dominant inheritance). If a parent has TSC, each child has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and may have either a milder or a more severe form of the disorder.

In rare instances, people acquire TSC through a process called gonadal mosaicism. These individuals have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent’s reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved. In cases of gonadal mosaicism, genetic testing of a blood sample might not reveal the potential for passing the disease to offspring.

Symptoms of Tuberous Sclerosis Complex

TSC can affect many different systems of the body, causing a variety of signs and symptoms that range from very mild to quite severe. Common symptoms include:

Benign tumors are most common in the brain, kidneys, heart, lungs, and skin. Cancerous tumors are rare in TSC and those that do occur primarily affect the kidneys.

Three types of brain lesions are seen in TSC:

• Cortical tubers – for which the disease is named, generally form on the surface of the brain but may also appear in the deep areas of the brain
• Subependymal nodules (SEN) – which form in the walls of the ventricles—the fluid-filled cavities of the brain, and
• Subependymal giant-cell astrocytomas (SEGA) – which develop from SEN and grow such that they may block the flow of fluid within the brain—causing a buildup of fluid and pressure that can lead to headaches and blurred vision.

Tumors called cardiac rhabdomyomas are often found in the hearts of infants and young children with TSC, and they are often seen on prenatal fetus ultrasound exams. If the tumors are large or there are multiple tumors, they can block circulation and cause death. However, if they do not cause problems at birth—when in most cases they are at their largest size—they usually become smaller with time and do not affect the individual in later life.

Benign tumors called pakoras are sometimes found in the eyes of individuals with TSC, appearing as white patches on the retina. Generally, they do not cause vision loss or other vision problems, but they can be used to help diagnose the disease.

Additional tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas. Bone cysts, rectal polyps, gum fibromas, and dental pits may also occur.

Seizures affect most individuals with TSC at some point during their life. While some kinds of seizures caused by TSC result in obvious convulsive movements, others alter awareness, behavior, or postural tone without convulsions. Seizures also can be difficult to control by medication, and sometimes surgery or other measures are used.

Cognitive disabilities affect some people with TSC. Developmental delay occurs in about one-half to two-thirds of people with TSC. Delays range from mild learning disabilities to severe impairment.

Behavior problems, including aggression, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior occur in children with TSC and can be difficult to manage. About one-third of children with TSC meet the criteria for autism spectrum disorder.

Radiographic features

Tuberous sclerosis has a significant number of manifestations, involving many organ systems. The most common radiographic manifestations are:

• cortical or subependymal tubers and white matter abnormalities
• renal angiomyolipomas
• cardiac rhabdomyoma(s)

Neurological

• cortical/subcortical tubers: 50% are in the frontal lobe; high T2 and low T1 with only 10% of tubers showing enhancement; frequently calcify after two years of age
• subependymal hamartomas
  • 88% are associated with calcification, although calcification absent in early childhood
  • visible within the first six months of age ⁴
  • variable signal, frequently high T1 and iso to high T2
  • enhancement is variable and is not a useful feature in distinguishing them from subependymal giant cell astrocytomas (SGCA); only serial growth is reliable ^5,6
• subependymal giant cell astrocytomas (SGCA)
  • peak occurrence 8-18 years
  • tend to be large and demonstrate growth ^5,6
  • tend to have intense enhancement
• white matter abnormalities
  • variable appearance, with nodular, ill-defined, cystic and band-like lesions seen
  • radial bands are thought to be relatively specific for TS ⁷
• retinal phakomas
• rarer findings
  • cerebellar atrophy
  • infarcts (due to occlusive vascular disorders)
  • cerebral aneurysms
  • dysgenesis of the corpus callosum
  • Chiari malformations
  • microcephaly
  • arachnoid cysts
  • chordoma

Abdominal

• renal angiomyolipoma(s)
  • tuberous sclerosis accounts for 20% of all angiomyolipomas ³
  • angiomyolipomas are seen in 55-75% of patient with tuberous sclerosis
  • tend to be multiple, large and bilateral
  • tend to grow and require surgical treatment, as the probability of hemorrhage is proportional to the size
  • micro and macro aneurysms may be present ³
  • fat may not be visible in up to 4.5% ¹
• renal cysts: the TSC2 gene is located adjacent to the PCKD1 gene ³
  • 18-53% of patients with tuberous sclerosis ¹
• renal cell carcinoma and oncocytomas
  • although rates of renal cell carcinoma are the same as in the general population, in patients with tuberous sclerosis, renal cell carcinoma tends to occur at a younger age ¹
• retroperitoneal lymphangiomyomatosis (LAM)
  • histologically identical to pulmonary LAM
  • retroperitoneal cystic lesions
  • chylous ascites, enlarged lymph nodes, dilatation of the thoracic duct
• gastrointestinal polyps
• pancreatic neuroendocrine tumors ¹²
• hepatic angiomyolipoma(s)

Thoracic

• lymphangioleiomyomatosis (LAM)
  • rare (1%)
  • some studies have described a lymphangiomyomatosis-like change to be present in 25-40% of female patients with tuberous sclerosis
  • indistinguishable from sporadic LAM
  • pneumothorax and chylous pleural effusions common
  • ~80% 10-year survival
• multifocal micronodular pneumocyte hyperplasia (MMPH)
  • rare
  • characterized by multicentric well-demarcated nodular proliferation of type II pneumocytes
  • benign, non-progressive
  • differential diagnoses: miliary pulmonary opacities
• cardiac rhabdomyomas
  • benign striated muscle tumor characterized by the presence of spider cells
  • seen in 50-65% of patients with tuberous sclerosis
  • 40-80% of patients with cardiac rhabdomyomas have tuberous sclerosis
  • multiple or single
  • typically involve the ventricular septum
  • occur before the age of 1 year (75% of cases) ¹
  • typically regress before birth with spontaneous regression in 70% of children by age 4
• thoracic duct and aortic/pulmonary artery aneurysm
• myocardial fatty foci ¹⁴

Musculoskeletal

• sclerotic bone lesions: 40-66% ¹
• hyperostosis of the inner table of the calvaria
• periosteal new bone
• scoliosis
• bone cysts ⁸

Skin

Cutaneous lesions are present in ~95% of cases, but are rarely appreciated radiographically ⁸:

• hypopigmented macules (ash leaf spots): seen in 90% of patients ¹
• facial angiofibromas (Pringle nodules or adenoma sebaceum); seen in 75% of patients
• fibrous plaques of the forehead (15-20%)
• confetti lesions: variant of leukoderma spots
• shagreen patches: seen in 20-30% of patients
• periungual fibroma (Koenen tumors): 20% of patients

Skin abnormalities vary widely in individuals with TSC. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:

• Hypomanic macules – (“ash leaf spots”), which are white or lighter patches of skin that may appear anywhere on the body and are caused by a lack of skin pigment or melanin—the substance that gives skin its color.

• Facial angiofibromas (also called adenoma sebaceous) – are reddish spots or bumps which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.

• Forehead plaques – are raised, discolored areas on the forehead which are common and unique to TSC and may help doctors diagnose the disorder.

• Shagreen patches – are areas of thick leathery, pebbly skin, usually found on the lower back or nape of the neck.

• Ungual or subungual fibromas – are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These usually appear later in life, ages 20-50.

• Other skin features – that are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders; café au lait spots or flat brown marks; and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.

Kidney problems such as cysts and angiomyolipomas (benign growths of fatty tissue and muscle cells) occur in an estimated 70 to 80 percent of individuals with TSC. They usually occur between ages 15 and 30.

• Cysts are usually small, appear in limited numbers, and most often cause no serious problems. A very small percent of individuals with TSC develop large numbers of cysts during childhood, which may lead to bleeding, anemia, and kidney failure.
• Angiomyolipomas are the most common kidney lesions in TSC and can be found in people without TSC. Angiomyolipomas caused by TSC are usually found in both kidneys and in most cases do not produce symptoms. However, they can sometimes grow so large that they cause pain or kidney failure. Bleeding from angiomyolipomas may also occur, causing both pain and weakness. If severe bleeding does not stop naturally, there may be severe blood loss, resulting in profound anemia and a life-threatening drop in blood pressure, warranting urgent medical attention.
• Other rare kidney problems include renal cell carcinoma, developing from an angiomyolipoma, and oncocytomas, benign tumors unique to individuals with TSC.

Lung lesions are present in about one-third of adult women with TSC and are much less commonly seen in men.  Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH).  LAM is a tumor-like disorder in which cells proliferate in the lungs, and there is lung destruction with cyst formation. A range of symptoms can occur with LAM, with many TSC individuals having no symptoms, while others suffer from breathlessness, which can progress and be severe. MMPH is a more benign tumor that occurs in men and women equally.

As per the recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference, the diagnostic criteria for tuberous sclerosis include the following major and minor features[rx][rx]:

Major Features

• Hypomelanotic macules (more than 2, and at least 5-mm in diameter)
• Angiofibromas (more than 2) or fibrous cephalic plaque
• Ungual fibromas (more than 1)
• Shagreen patch
• Multiple retinal hamartomas
• Cortical dysplasias
• Subependymal nodules
• Subependymal giant cell astrocytoma
• Cardiac rhabdomyoma
• Lymphangioleiomyomatosis
• Angiomyolipomas (more than 1)
• More than 2 angiofibromas, which are skin-colored growths of blood vessels in the skin or a thick (fibrous) patch of skin on the forehead
• 2 or more periungual fibromas or hard growths, around or under the fingernails or toenails
• More than 3 light-colored areas on the skin, known as hypomelanotic macules or ash leaf spots
• Shagreen patch, meaning a rough growth of tissue on the surface of the skin
• Tubers, or thickened areas, found in the brain
• Nodules (round growths) found in the brain
• Subependymal giant cell astrocytoma (SEGA), a type of brain cancer
• Cardiac rhabdomyoma, which is a benign, noncancerous heart growth
• Angiomyolipoma of the kidney, which are benign growths that can cause serious medical problems; there is a low risk that these tumors could become cancerous
• Lymphangiomyomatosis, which are multiple cysts or fluid-filled growths along the lymphatic system under the skin
• Multiple hemangioblastomas, which are growths of newly formed blood vessels, of the brain, spinal cord, or eye
• One or more hemangioblastomas in addition to kidney cysts, pancreatic cysts, pheochromocytoma, which is a rare growth in the cells of one of the adrenal glands, or kidney cancer

Minor Features

• Confetti skin lesions
• Dental enamel Pitts (more than 3)
• Intraoral fibromas (more than 1)
• Retinal achromic patch
• Multiple renal cysts
• Nonrenal hamartomas
• Multiple pits or dents in the teeth
• Fibromas (growths) of the gums inside the mouth
• Multiple kidney cysts
• Pale discolorations in the skin, called “confetti.”
• Changes in the retina inside the eye
• Hamartomas, which are benign tissue growths

Definitive diagnosis is established in patients with two major features or one major feature with at least 2 minor features, while “possible diagnosis” is recognized in patients with one major feature or at least 2 minor features.[rx][rx]

Diagnosis of Tuberous Sclerosis Complex

Diagnosing TSC is based upon clinical criteria.  The first clue may be the presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules) or the identification of cardiac tumor rhabdomyoma.

Diagnosis of the disorder is based on a careful clinical exam in combination with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain—which may show tubers in the brain, and an ultrasound of the heart, liver, and kidneys, which may show tumors in those organs. Doctors should carefully examine the skin for a wide variety of skin features, the fingernails, and toenails for ungual fibromas; the teeth and gums for dental pits and/or gum fibromas; and the eyes for retinal lesions. A small hand-help lamp that uses black light, otherwise known as ultraviolet light, may show hypomelanotic macules which are sometimes hard to see on infants and individuals with pale or fair skin. A doctor experienced in the diagnosis of TSC should evaluate a potential patient.

In infants, TSC may be suspected if the child has cardiac rhabdomyomas at birth or seizures (especially the kind called infantile spasms) in the first six months of life. With a careful examination of the skin and brain, it may be possible to diagnose TSC in a very young infant. However, many children are not diagnosed until later in life when their seizures begin and other symptoms such as facial angiofibromas appear.

Treatment of Tuberous Sclerosis Complex

Treatment is

• mTOR inhibitor medicines – can be used to treat brain tumours, kidney tumours and epilepsy caused by TSC

• anti-epileptic medicines – to treat the associated seizures. Medication needs to be carefully monitored to make sure the child isn’t over-sedated

• brain surgery – if seizures cannot be controlled, it may be possible to remove lesions in the brain to reduce seizures

• skin treatments – dermatologists can provide advice on both surgical and medical treatment for the skin signs of TSC, including mTOR inhibitor creams.

• occupational therapy – can help children acquire skills and strategies

• speech therapy – can assist communication skills.

There is no cure for TSC, although treatment is available for a number of the symptoms. Antiepileptic drugs may be used to control seizures. Vigabatrin is a particularly useful medication in TSC and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of infantile spasms in TSC, although it has significant side effects. The FDA has approved the drug everolimus (Afinitor®) to treat subependymal giant cell astrocytomas (SEGA brain tumors) and angiomyolipoma kidney tumors, in addition to intractable seizures (seizures not controlled well by medicine). Specific medications may be prescribed for behavior problems. Intervention programs including special school programs and various therapies (such as physical, occupational, and speech therapies) may benefit individuals with special needs and developmental issues. Surgery may be needed in case of complications connected to tubers, subependymal nodules, or SEGA, as well as in risk of hemorrhage from kidney tumors. Respiratory insufficiency due to LAM can be treated with supplemental oxygen therapy or lung transplantation, if severe.

Skin lesions, particularly facial angiofibromas, may be psychologically distressing for some patients. Laser treatment or electrosurgery can be used to remove angiofibroma.

The topical mTOR inhibitor sirolimus 0.2% gel (also called rapamycin) has proved helpful in reducing angiofibromas in a clinical trial involving 36 adults and children. One study has also reported improvement in hypopigmented macules. A larger prospective, multicentre, randomized, double-blind, vehicle-controlled trial enrolled 179 patients with tuberous sclerosis-related facial angiofibromas and found improvement in more than 80% of patients treated with topical 1% rapamycin with most occurring in the first month.

Infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).

Treatment may require the coordinated efforts of a team of specialists. Pediatricians and general internists, neurologists, dermatologists, cardiologists, dental specialists, eye specialists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.

The treatment for tuberous sclerosis is supportive and symptomatic. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.

Anti-seizure drugs (anticonvulsants) may be prescribed to control seizures. The specific drug that is used will depend on several factors including the specific type of seizure, an affected individual’s age, other organ systems that are affected, and the severity of symptoms. Conventional anticonvulsants drugs that may be administered include phenobarbital, Dilantin (phenytoin), Klonopin (clonazepam), Depakene/Depakote (valproic acid/divalproex sodium), Tegretol (carbamazepine), Trileptal (oxcarbazepine), Topamax (topiramate), Lamictal (lamotrigine), Zonegran (zonisemide), Vimpat (lacosamide), Banzel (rufinamide), Onfi (clobazam), and others. All these anticonvulsants have potential side effects and require careful monitoring by a physician.

Two drugs have been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of seizures associated with tuberous sclerosis. FDA approved Afinitor (everolimus) for the treatment of seizures in adult and pediatric patients aged 2 years and older with tuberous sclerosis in 2018, and Epidiolex (cannabidiol) for patients one year and older in 2020.

Sabril (vigabatrin) was approved in 2009 by the FDA to treat infantile spasms in children ages 1 month to 2 years. Treatment of children with tuberous sclerosis and infantile spasms with vigabatrin has been found to be effective. Visual field loss is an important safety concern with the use of this medication. The FDA has also approved adreno-corticotrophic hormone or ACTH (Acthar gel) for the treatment of infantile spasms. This medication has also been used to treat infants with tuberous sclerosis. These medications are used cautiously because of their side effects.

No specific anti-seizure medication works for all affected individuals. Often, a combination of different drugs may be required to treat some individuals. Alternative treatments include the ketogenic diet or the glycemic diet. Sometimes, seizures can be difficult to treat and medications or diets that initially worked will no longer provide benefit (refractory seizures). In some instances, seizure surgery to remove areas of brain dysplasia may be necessary to help to control seizures that don’t respond or stop responding to medications. Less invasive surgical options to control seizures include the implanting of a vagal nerve stimulator (VNS device). This is a small electrical stimulator placed under the skin over the upper chest and connected to one vagal nerve in order to provide intermittent electrical stimulus, like a pacemaker to the brain.

Surgery of other organs may be necessary if the ability of a particular organ to function properly is impaired by the presence of a tumor. For example, the obstruction of cerebrospinal fluid (CSF) circulation inside the brain (intracranial hypertension) because of a benign tumor may require a shunting procedure to drain the liquid or the surgical removal of the tumor.

In 2012, the FDA approved the use of Afinitor (everolimus) for the treatment of children and adults with tuberous sclerosis who have a subependymal giant cell astrocytoma that cannot be removed or can be only partially removed by surgery. The FDA also approved everolimus for the treatment of adults with tuberous sclerosis who have an angiomyolipoma of the kidney that does not require surgery right away. In some instances, angiomyolipomas will require surgery or embolization therapy. Cutting off the blood supply (arterial embolization) to a kidney tumor may be used to shrink down the size of the tumor. Embolization is usually followed by treatment with corticosteroids and surgical removal (resection) of the tumor that spares the kidney or by destruction (ablation) of the tumor. Large cystic lesions of the kidneys may also require surgical decompression or removal.

In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.^[rx]

• Take a personal and family history covering three generations. Genetic counseling and tests determine if other individuals are at risk.

• A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).

• Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.

• Assess children for behavioral issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.

• Scan the abdomen for tumors in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.

• In adult women, test pulmonary function and perform a high-resolution computed tomography (HRCT) of the chest.

• Examine the skin under a Wood’s lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas).

• In infants under three, perform an echocardiogram to spot rhabdomyoma, and electrocardiogram (ECG) for any arrhythmia.

• Use a fundoscopy to spot retinal hamartomas or achromic patches.

A benign tumor inside the heart (rhabdomyoma) may not cause symptoms and generally does not require treatment as they often regress on their own within the first several years after birth. If symptomatic, however, surgical removal (resection) may be necessary. Reports in the medical literature have detailed the off-label use of mTOR inhibitors to treat these tumors with positive results. Some affected individuals may be prescribed certain medications to treat irregular heartbeats (arrhythmias).

Individuals taking mTOR inhibitors for internal tumors (e.g. SEGAs or angiomyolipomas) may see improvement in skin lesions. Topical formulations of mTOR inhibitors have shown promise in treating facial angiofibromas. Individuals with no immediate indication for mTOR inhibitor treatment may undergo certain procedures to improve the appearance of skin lesions including dermabrasion, laser therapy, or surgical removal (excision) of a lesion.

In 2015, the FDA approved the use of mTOR inhibitors for the treatment of lung complications such as LAM in individuals with tuberous sclerosis. Because LAM occurs most often in young women of childbearing age, researchers have speculated that female hormones such as estrogen play a role in the development of the disorder. A link between LAM and female hormones has not been proven. However, many physicians have explored the use of agents that lower the production or effects of estrogen in the body. The results have varied greatly among individuals. Such agents may include medroxyprogesterone acetate. Estrogen-containing medications and dietary supplements should be discontinued in patients with LAM.

Supplemental oxygen therapy may be necessary for some individuals with impaired lung function. In individuals with severe lung disease that is resistant to treatment, a lung transplant may ultimately become necessary.

Because TSC is a lifelong condition, individuals need to be regularly monitored by a doctor to make sure they are receiving the best possible treatments. Due to the many varied symptoms of TSC, care by a clinician experienced with the disorder is recommended.

Basic laboratory studies have revealed insight into the function of the TSC genes and have led to use of rapamycin (mTOR) inhibitors and related drugs for treating some of the manifestations of TSC.

Associate Treatment

• Surgery. If a growth affects the ability of a specific organ — such as the kidney or heart — to function, the growth may be surgically removed. Sometimes surgery helps control seizures caused by brain growths that don’t respond to medication. Surgical procedures such as dermabrasion or laser treatment may improve the appearance of skin growths.
• Various types of therapy. Early intervention services, such as occupational, physical or speech therapy, can help children with tuberous sclerosis who have special needs in these areas improve their ability to manage daily tasks and activities.
• Educational and vocational services. Early intervention and special needs services can help children with developmental delays and behavior issues adapt to the classroom so that they can meet their full potential. When needed, social, vocational and rehabilitation services may continue throughout life.
• Psychiatric and behavior management. Talking with a mental health provider may help children accept and adjust to living with this disorder. A mental health provider can also help address behavioral, social or emotional issues and recommend resources.

Ongoing monitoring

Tuberous sclerosis is a lifelong condition that requires careful monitoring and follow-up because many signs and symptoms may take years to develop. A schedule of regular follow-up monitoring throughout life may include tests similar to those done during diagnosis. Early identification of problems can help prevent complications.

What is the prognosis?

The prognosis for individuals with TSC is highly variable and depends on the severity of symptoms. Those individuals with mild symptoms usually do well and have a normal life expectancy, while paying attention to TSC-specific issues. Individuals who are severely affected can suffer from severe mental retardation and persistent epilepsy.

All individuals with TSC are at risk for life-threatening conditions related to brain tumors, kidney lesions, or LAM. Continued monitoring by a physician experienced with TSC is important. With appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.

QUESTIONS

1. Tuberous sclerosis complex is a genodermatosis:

   1. Autosomal dominant with hamartomas that affect multiple organs.

   2. Autosomal recessive with hamartomas that affect multiple organs.

   3. Autosomal dominant predominantly affecting females, and the most commonly affected organs are skin, central nervous system, heart, lungs and kidneys.

   4. Autosomal recessive with vascular malformations in many organs, being the most affected skin and central nervous system.

2. The classical tuberous sclerosis triad is characterized by:

   1. Shagreen patch, facial angiofibromas and mental retardation.

   2. Epilepsy, sebaceous adenoma and shagreen patch.

   3. Facial angiofibromas, fibrous cephalic plaque and epilepsy.

   4. Mental retardation, epilepsy and sebaceous adenoma (angiofibroma).

3. Choose the sentence with the correct sequence:

   • ( ) Skin lesions are found in more than 90% of cases, the majority appearing in the 3^rd decade of life.

   • ( ) “Ash-leaf” lesions tend to follow Blaschko lines when on the trunk, typical for type 3 mosaicism.

   • ( ) Hypopigmented macules in “confetti” or guttate leukoderma are hypopigmented macules that appear over the years.

   • ( ) Hypopigmented macules are many times found since birth, allowing for the early diagnosis of the disease when associated to other clinical findings.

     1. F T T F

     2. F F F T

     3. T T F T

     4. F T F T

4. About connective tissue nevi and ungual fibromas or Koenen tumors, it is correct to say that:

   1. Connective tissue nevi seen in TSC are normal-colored to brown plaques restricted to the lumbosacral region.

   2. Shagreen patch many times have the aspect of orange peel and are found on the upper back.

   3. Fibrous cephalic plaque is present in more than 80% of cases, being most commonly found on one side of the forehead.

   4. Koenen tumor usually appears during adolescence and has a predilection for females and the toes.

5. According to the systemic manifestations of TSC, we can affirm that the correct items are:

   1. Angiomyolipomas increase progressively from infancy and stop growing in the elderly.

   2. Renal lesions have an indolent, clinically asymptomatic course, with no potentially severe repercussions in the patient’s life.

   3. In cases of patients that evolve with hematuria in adulthood, the possibility of malignant transformation of the angiomyolipomas must be kept in mind, since they are usually asymptomatic.

   4. Lymphangioleiomyomatosis affects predominantly younger women with the first manifestations after early adolescence.

   5. Rhabdomyoma is the most common cardiac tumor and tends to grow progressively in the first year, when it stabilizes and continues until adulthood.

      1. 1 – 3

      2. 2 – 4

      3. 3 – 5

      4. 1 – 4

   6. Choose the INCORRECT option:

      1. The identification of the pathogenic TSC1 or TSC2 DNA mutation is not enough to establish the diagnosis of TSC.

      2. Molecular testing yields a positive result in 75% to 90% of TSC patients.

      3. In 10% to 25% of patients, conventional genetic testing does not identify the pathogenic TSC1 or TSC2 mutation.

      4. The identification of the pathogenic mutation for TSC in conventional genetic testing configures an independent diagnostic criterion.

6. About the diagnostic criteria for the tuberous sclerosis complex, reviewed in 2012, in the second International Tuberous Sclerosis Complex Consensus Conference, all are included as extracutaneous manifestations, EXCEPT:

   1. Subependymal giant cell astrocytoma.

   2. Cardiac rhabdomyoma.

   3. Lymphangioleiomyomatosis.

   4. Pigmented hamartomas of the iris.

7. It is a MAJOR clinical criterion for the diagnosis of TSC:

   1. ≥ 5 hypopigmented macules with at least 3mm diameter.

   2. ≥ 3 facial angiofibromas.

   3. ≥ 2 intraoral fibromas.

   4. > 3 dental enamel pits.

8. From the dermatological point of view, many destructive or surgical treatment options are used to reduce the development of and remove facial angiofibromas. It is correct to say that:

   1. The destructive procedures are usually comfortable for the patient and can be performed at any age.

   2. It usually is not necessary to repeat laser treatments periodically because the lesions tend not to recur.

   3. Are therapeutic options for facial angiofibromas dermabrasion, surgical excision, electrocautery, and laser.

   4. It is not necessary to combine therapeutic methods to optimize results since that regardless of the treatment chosen, all provide satisfactory results.

9. Diagnostic suspicion of TSC comes from the following findings, EXCEPT:

   1. Antenatal detection of cardiac rhabdomyomas.

   2. Post-natal identification of hypopigmented patches on the skin.

   3. Visualization of ephelis on the axillary or inguinal regions.

   4. Seizures in childhood, particularly with spasms.

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Bourneville Pringle Syndrome is also known as Cerebral sclerosis, Bourneville Phakomatosis, Bourneville disease, Tuberous sclerosis, tuberous sclerosis complex is a neurocutaneous disorder (phakomatosis) characterized by the development of multiple benign tumors of the embryonic ectoderm (e.g. skin, eyes, and nervous system).

Tuberous sclerosis complex is a multisystemic, autosomal dominant neurocutaneous genetic disorder with complete penetrance, hamartomatous growths in multiple organ systems that can evolve with hamartomas in multiple organs, by causing the growth of benign tumors, so-called hamartomas. As brain, skin, kidneys, heart, liver, lungs, and less frequently retina, gingiva, bones, and gastrointestinal tract can be affected, TSC patients require coordinated care of many specialties.

Hamartomas – plural of hamartoma; benign overgrowths of a mature cell type normal to the site or organ. They may be congenital or acquired

Tuberous sclerosis (also called tuberous sclerosis complex, or TSC) is a rare, multi-system genetic disease that causes non-cancerous (benign) tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and can result in a combination of symptoms including seizures, impaired intellectual development, autism, behavioral problems, skin abnormalities, and kidney disease.

The severity of symptoms varies widely. Symptoms range from mild—allowing people to live independent, productive lives—to more severe symptoms that can affect everyday life and even be life-threatening. Many people with TSC show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.

The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify with age and becomes hard or sclerotic. TSC occurs in all races and ethnic groups, and in both genders.

Causes of Tuberous Sclerosis Complex

TSC is caused by defects, or mutations, on two genes—TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene is on chromosome 9 and produces a protein called hamartin. The TSC2 gene is on chromosome 16 and produces the protein tuberin. Scientists believe these proteins act as growth suppressors by inhibiting the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.

Mutations in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins likely work together to help regulate cell growth and size. The proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way.

People with tuberous sclerosis complex are born with one mutated copy of the TSC1 or TSC2 gene in each cell. This mutation prevents the cell from making functional hamartin or tuberin from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For some types of tumors to develop, a second mutation involving the other copy of the TSC1 or TSC2 gene must occur in certain cells during a person’s lifetime.

When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin; cells with two altered copies of the TSC2 gene are unable to produce any functional tuberin. The loss of these proteins allows the cell to grow and divide in an uncontrolled way to form a tumor. In people with tuberous sclerosis complex, a second TSC1 or TSC2 mutation typically occurs in multiple cells over an affected person’s lifetime. The loss of hamartin or tuberin in different types of cells leads to the growth of tumors in many different organs and tissues.

Is TSC inherited?

Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2—meaning neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.

In cases where TSC is inherited, only one parent needs to have the faulty gene in order to pass it on to a child (called autosomal dominant inheritance). If a parent has TSC, each child has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and may have either a milder or a more severe form of the disorder.

In rare instances, people acquire TSC through a process called gonadal mosaicism. These individuals have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent’s reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved. In cases of gonadal mosaicism, genetic testing of a blood sample might not reveal the potential for passing the disease to offspring.

Symptoms of Tuberous Sclerosis Complex

TSC can affect many different systems of the body, causing a variety of signs and symptoms that range from very mild to quite severe. Common symptoms include:

Benign tumors are most common in the brain, kidneys, heart, lungs, and skin. Cancerous tumors are rare in TSC and those that do occur primarily affect the kidneys.

Three types of brain lesions are seen in TSC:

• Cortical tubers – for which the disease is named, generally form on the surface of the brain but may also appear in the deep areas of the brain
• Subependymal nodules (SEN) – which form in the walls of the ventricles—the fluid-filled cavities of the brain, and
• Subependymal giant-cell astrocytomas (SEGA) – which develop from SEN and grow such that they may block the flow of fluid within the brain—causing a buildup of fluid and pressure that can lead to headaches and blurred vision.

Tumors called cardiac rhabdomyomas are often found in the hearts of infants and young children with TSC, and they are often seen on prenatal fetus ultrasound exams. If the tumors are large or there are multiple tumors, they can block circulation and cause death. However, if they do not cause problems at birth—when in most cases they are at their largest size—they usually become smaller with time and do not affect the individual in later life.

Benign tumors called pakoras are sometimes found in the eyes of individuals with TSC, appearing as white patches on the retina. Generally, they do not cause vision loss or other vision problems, but they can be used to help diagnose the disease.

Additional tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas. Bone cysts, rectal polyps, gum fibromas, and dental pits may also occur.

Seizures affect most individuals with TSC at some point during their life. While some kinds of seizures caused by TSC result in obvious convulsive movements, others alter awareness, behavior, or postural tone without convulsions. Seizures also can be difficult to control by medication, and sometimes surgery or other measures are used.

Cognitive disabilities affect some people with TSC. Developmental delay occurs in about one-half to two-thirds of people with TSC. Delays range from mild learning disabilities to severe impairment.

Behavior problems, including aggression, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior occur in children with TSC and can be difficult to manage. About one-third of children with TSC meet the criteria for autism spectrum disorder.

Radiographic features

Tuberous sclerosis has a significant number of manifestations, involving many organ systems. The most common radiographic manifestations are:

• cortical or subependymal tubers and white matter abnormalities
• renal angiomyolipomas
• cardiac rhabdomyoma(s)

Neurological

• cortical/subcortical tubers: 50% are in the frontal lobe; high T2 and low T1 with only 10% of tubers showing enhancement; frequently calcify after two years of age
• subependymal hamartomas
  • 88% are associated with calcification, although calcification absent in early childhood
  • visible within the first six months of age ⁴
  • variable signal, frequently high T1 and iso to high T2
  • enhancement is variable and is not a useful feature in distinguishing them from subependymal giant cell astrocytomas (SGCA); only serial growth is reliable ^5,6
• subependymal giant cell astrocytomas (SGCA)
  • peak occurrence 8-18 years
  • tend to be large and demonstrate growth ^5,6
  • tend to have intense enhancement
• white matter abnormalities
  • variable appearance, with nodular, ill-defined, cystic and band-like lesions seen
  • radial bands are thought to be relatively specific for TS ⁷
• retinal phakomas
• rarer findings
  • cerebellar atrophy
  • infarcts (due to occlusive vascular disorders)
  • cerebral aneurysms
  • dysgenesis of the corpus callosum
  • Chiari malformations
  • microcephaly
  • arachnoid cysts
  • chordoma

Abdominal

• renal angiomyolipoma(s)
  • tuberous sclerosis accounts for 20% of all angiomyolipomas ³
  • angiomyolipomas are seen in 55-75% of patient with tuberous sclerosis
  • tend to be multiple, large and bilateral
  • tend to grow and require surgical treatment, as the probability of hemorrhage is proportional to the size
  • micro and macro aneurysms may be present ³
  • fat may not be visible in up to 4.5% ¹
• renal cysts: the TSC2 gene is located adjacent to the PCKD1 gene ³
  • 18-53% of patients with tuberous sclerosis ¹
• renal cell carcinoma and oncocytomas
  • although rates of renal cell carcinoma are the same as in the general population, in patients with tuberous sclerosis, renal cell carcinoma tends to occur at a younger age ¹
• retroperitoneal lymphangiomyomatosis (LAM)
  • histologically identical to pulmonary LAM
  • retroperitoneal cystic lesions
  • chylous ascites, enlarged lymph nodes, dilatation of the thoracic duct
• gastrointestinal polyps
• pancreatic neuroendocrine tumors ¹²
• hepatic angiomyolipoma(s)

Thoracic

• lymphangioleiomyomatosis (LAM)
  • rare (1%)
  • some studies have described a lymphangiomyomatosis-like change to be present in 25-40% of female patients with tuberous sclerosis
  • indistinguishable from sporadic LAM
  • pneumothorax and chylous pleural effusions common
  • ~80% 10-year survival
• multifocal micronodular pneumocyte hyperplasia (MMPH)
  • rare
  • characterized by multicentric well-demarcated nodular proliferation of type II pneumocytes
  • benign, non-progressive
  • differential diagnoses: miliary pulmonary opacities
• cardiac rhabdomyomas
  • benign striated muscle tumor characterized by the presence of spider cells
  • seen in 50-65% of patients with tuberous sclerosis
  • 40-80% of patients with cardiac rhabdomyomas have tuberous sclerosis
  • multiple or single
  • typically involve the ventricular septum
  • occur before the age of 1 year (75% of cases) ¹
  • typically regress before birth with spontaneous regression in 70% of children by age 4
• thoracic duct and aortic/pulmonary artery aneurysm
• myocardial fatty foci ¹⁴

Musculoskeletal

• sclerotic bone lesions: 40-66% ¹
• hyperostosis of the inner table of the calvaria
• periosteal new bone
• scoliosis
• bone cysts ⁸

Skin

Cutaneous lesions are present in ~95% of cases, but are rarely appreciated radiographically ⁸:

• hypopigmented macules (ash leaf spots): seen in 90% of patients ¹
• facial angiofibromas (Pringle nodules or adenoma sebaceum); seen in 75% of patients
• fibrous plaques of the forehead (15-20%)
• confetti lesions: variant of leukoderma spots
• shagreen patches: seen in 20-30% of patients
• periungual fibroma (Koenen tumors): 20% of patients

Skin abnormalities vary widely in individuals with TSC. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:

• Hypomanic macules – (“ash leaf spots”), which are white or lighter patches of skin that may appear anywhere on the body and are caused by a lack of skin pigment or melanin—the substance that gives skin its color.

• Facial angiofibromas (also called adenoma sebaceous) – are reddish spots or bumps which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.

• Forehead plaques – are raised, discolored areas on the forehead which are common and unique to TSC and may help doctors diagnose the disorder.

• Shagreen patches – are areas of thick leathery, pebbly skin, usually found on the lower back or nape of the neck.

• Ungual or subungual fibromas – are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These usually appear later in life, ages 20-50.

• Other skin features – that are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders; café au lait spots or flat brown marks; and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.

Kidney problems such as cysts and angiomyolipomas (benign growths of fatty tissue and muscle cells) occur in an estimated 70 to 80 percent of individuals with TSC. They usually occur between ages 15 and 30.

• Cysts are usually small, appear in limited numbers, and most often cause no serious problems. A very small percent of individuals with TSC develop large numbers of cysts during childhood, which may lead to bleeding, anemia, and kidney failure.
• Angiomyolipomas are the most common kidney lesions in TSC and can be found in people without TSC. Angiomyolipomas caused by TSC are usually found in both kidneys and in most cases do not produce symptoms. However, they can sometimes grow so large that they cause pain or kidney failure. Bleeding from angiomyolipomas may also occur, causing both pain and weakness. If severe bleeding does not stop naturally, there may be severe blood loss, resulting in profound anemia and a life-threatening drop in blood pressure, warranting urgent medical attention.
• Other rare kidney problems include renal cell carcinoma, developing from an angiomyolipoma, and oncocytomas, benign tumors unique to individuals with TSC.

Lung lesions are present in about one-third of adult women with TSC and are much less commonly seen in men.  Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH).  LAM is a tumor-like disorder in which cells proliferate in the lungs, and there is lung destruction with cyst formation. A range of symptoms can occur with LAM, with many TSC individuals having no symptoms, while others suffer with breathlessness, which can progress and be severe. MMPH is a more benign tumor that occurs in men and women equally.

As per the recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference, the diagnostic criteria for tuberous sclerosis include the following major and minor features[rx][rx]:

Major Features

• Hypomelanotic macules (more than 2, and at least 5-mm in diameter)
• Angiofibromas (more than 2) or fibrous cephalic plaque
• Ungual fibromas (more than 1)
• Shagreen patch
• Multiple retinal hamartomas
• Cortical dysplasias
• Subependymal nodules
• Subependymal giant cell astrocytoma
• Cardiac rhabdomyoma
• Lymphangioleiomyomatosis
• Angiomyolipomas (more than 1)
• More than 2 angiofibromas, which are skin-colored growths of blood vessels in the skin or a thick (fibrous) patch of skin on the forehead
• 2 or more periungual fibromas or hard growths, around or under the fingernails or toenails
• More than 3 light-colored areas on the skin, known as hypomelanotic macules or ash leaf spots
• Shagreen patch, meaning a rough growth of tissue on the surface of the skin
• Tubers, or thickened areas, found in the brain
• Nodules (round growths) found in the brain
• Subependymal giant cell astrocytoma (SEGA), a type of brain cancer
• Cardiac rhabdomyoma, which is a benign, noncancerous heart growth
• Angiomyolipoma of the kidney, which are benign growths that can cause serious medical problems; there is a low risk that these tumors could become cancerous
• Lymphangiomyomatosis, which are multiple cysts or fluid-filled growths along the lymphatic system under the skin
• Multiple hemangioblastomas, which are growths of newly formed blood vessels, of the brain, spinal cord, or eye
• One or more hemangioblastomas in addition to kidney cysts, pancreatic cysts, pheochromocytoma, which is a rare growth in the cells of one of the adrenal glands, or kidney cancer

Minor Features

• Confetti skin lesions
• Dental enamel Pitts (more than 3)
• Intraoral fibromas (more than 1)
• Retinal achromic patch
• Multiple renal cysts
• Nonrenal hamartomas
• Multiple pits or dents in the teeth
• Fibromas (growths) of the gums inside the mouth
• Multiple kidney cysts
• Pale discolorations in the skin, called “confetti.”
• Changes in the retina inside the eye
• Hamartomas, which are benign tissue growths

Definitive diagnosis is established in patients with two major features or one major feature with at least 2 minor features, while “possible diagnosis” is recognized in patients with one major feature or at least 2 minor features.[rx][rx]

Diagnosis of Tuberous Sclerosis Complex

Diagnosing TSC is based upon clinical criteria.  The first clue may be the presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules) or the identification of cardiac tumor rhabdomyoma.

Diagnosis of the disorder is based on a careful clinical exam in combination with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain—which may show tubers in the brain, and an ultrasound of the heart, liver, and kidneys, which may show tumors in those organs. Doctors should carefully examine the skin for a wide variety of skin features, the fingernails, and toenails for ungual fibromas; the teeth and gums for dental pits and/or gum fibromas; and the eyes for retinal lesions. A small hand-help lamp that uses black light, otherwise known as ultraviolet light, may show hypomelanotic macules which are sometimes hard to see on infants and individuals with pale or fair skin. A doctor experienced in the diagnosis of TSC should evaluate a potential patient.

In infants, TSC may be suspected if the child has cardiac rhabdomyomas at birth or seizures (especially the kind called infantile spasms) in the first six months of life. With a careful examination of the skin and brain, it may be possible to diagnose TSC in a very young infant. However, many children are not diagnosed until later in life when their seizures begin and other symptoms such as facial angiofibromas appear.

Treatment of Tuberous Sclerosis Complex

Treatment is

• mTOR inhibitor medicines – can be used to treat brain tumours, kidney tumours and epilepsy caused by TSC

• anti-epileptic medicines – to treat the associated seizures. Medication needs to be carefully monitored to make sure the child isn’t over-sedated

• brain surgery – if seizures cannot be controlled, it may be possible to remove lesions in the brain to reduce seizures

• skin treatments – dermatologists can provide advice on both surgical and medical treatment for the skin signs of TSC, including mTOR inhibitor creams.

• occupational therapy – can help children acquire skills and strategies

• speech therapy – can assist communication skills.

There is no cure for TSC, although treatment is available for a number of the symptoms. Antiepileptic drugs may be used to control seizures. Vigabatrin is a particularly useful medication in TSC and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of infantile spasms in TSC, although it has significant side effects. The FDA has approved the drug everolimus (Afinitor®) to treat subependymal giant cell astrocytomas (SEGA brain tumors) and angiomyolipoma kidney tumors, in addition to intractable seizures (seizures not controlled well by medicine). Specific medications may be prescribed for behavior problems. Intervention programs including special school programs and various therapies (such as physical, occupational, and speech therapies) may benefit individuals with special needs and developmental issues. Surgery may be needed in case of complications connected to tubers, subependymal nodules, or SEGA, as well as in risk of hemorrhage from kidney tumors. Respiratory insufficiency due to LAM can be treated with supplemental oxygen therapy or lung transplantation, if severe.

Skin lesions, particularly facial angiofibromas, may be psychologically distressing for some patients. Laser treatment or electrosurgery can be used to remove angiofibroma.

The topical mTOR inhibitor sirolimus 0.2% gel (also called rapamycin) has proved helpful in reducing angiofibromas in a clinical trial involving 36 adults and children. One study has also reported improvement in hypopigmented macules. A larger prospective, multicentre, randomized, double-blind, vehicle-controlled trial enrolled 179 patients with tuberous sclerosis-related facial angiofibromas and found improvement in more than 80% of patients treated with topical 1% rapamycin with most occurring in the first month.

Infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).

Treatment may require the coordinated efforts of a team of specialists. Pediatricians and general internists, neurologists, dermatologists, cardiologists, dental specialists, eye specialists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.

The treatment for tuberous sclerosis is supportive and symptomatic. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.

Anti-seizure drugs (anticonvulsants) may be prescribed to control seizures. The specific drug that is used will depend on several factors including the specific type of seizure, an affected individual’s age, other organ systems that are affected, and the severity of symptoms. Conventional anticonvulsants drugs that may be administered include phenobarbital, Dilantin (phenytoin), Klonopin (clonazepam), Depakene/Depakote (valproic acid/divalproex sodium), Tegretol (carbamazepine), Trileptal (oxcarbazepine), Topamax (topiramate), Lamictal (lamotrigine), Zonegran (zonisemide), Vimpat (lacosamide), Banzel (rufinamide), Onfi (clobazam), and others. All these anticonvulsants have potential side effects and require careful monitoring by a physician.

Two drugs have been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of seizures associated with tuberous sclerosis. FDA approved Afinitor (everolimus) for the treatment of seizures in adult and pediatric patients aged 2 years and older with tuberous sclerosis in 2018, and Epidiolex (cannabidiol) for patients one year and older in 2020.

Sabril (vigabatrin) was approved in 2009 by the FDA to treat infantile spasms in children ages 1 month to 2 years. Treatment of children with tuberous sclerosis and infantile spasms with vigabatrin has been found to be effective. Visual field loss is an important safety concern with the use of this medication. The FDA has also approved adreno-corticotrophic hormone or ACTH (Acthar gel) for the treatment of infantile spasms. This medication has also been used to treat infants with tuberous sclerosis. These medications are used cautiously because of their side effects.

No specific anti-seizure medication works for all affected individuals. Often, a combination of different drugs may be required to treat some individuals. Alternative treatments include the ketogenic diet or the glycemic diet. Sometimes, seizures can be difficult to treat and medications or diets that initially worked will no longer provide benefit (refractory seizures). In some instances, seizure surgery to remove areas of brain dysplasia may be necessary to help to control seizures that don’t respond or stop responding to medications. Less invasive surgical options to control seizures include the implanting of a vagal nerve stimulator (VNS device). This is a small electrical stimulator placed under the skin over the upper chest and connected to one vagal nerve in order to provide intermittent electrical stimulus, like a pacemaker to the brain.

Surgery of other organs may be necessary if the ability of a particular organ to function properly is impaired by the presence of a tumor. For example, the obstruction of cerebrospinal fluid (CSF) circulation inside the brain (intracranial hypertension) because of a benign tumor may require a shunting procedure to drain the liquid or the surgical removal of the tumor.

In 2012, the FDA approved the use of Afinitor (everolimus) for the treatment of children and adults with tuberous sclerosis who have a subependymal giant cell astrocytoma that cannot be removed or can be only partially removed by surgery. The FDA also approved everolimus for the treatment of adults with tuberous sclerosis who have an angiomyolipoma of the kidney that does not require surgery right away. In some instances, angiomyolipomas will require surgery or embolization therapy. Cutting off the blood supply (arterial embolization) to a kidney tumor may be used to shrink down the size of the tumor. Embolization is usually followed by treatment with corticosteroids and surgical removal (resection) of the tumor that spares the kidney or by destruction (ablation) of the tumor. Large cystic lesions of the kidneys may also require surgical decompression or removal.

In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.^[rx]

• Take a personal and family history covering three generations. Genetic counseling and tests determine if other individuals are at risk.

• A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).

• Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.

• Assess children for behavioral issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.

• Scan the abdomen for tumors in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.

• In adult women, test pulmonary function and perform a high-resolution computed tomography (HRCT) of the chest.

• Examine the skin under a Wood’s lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas).

• In infants under three, perform an echocardiogram to spot rhabdomyoma, and electrocardiogram (ECG) for any arrhythmia.

• Use a fundoscopy to spot retinal hamartomas or achromic patches.

A benign tumor inside the heart (rhabdomyoma) may not cause symptoms and generally does not require treatment as they often regress on their own within the first several years after birth. If symptomatic, however, surgical removal (resection) may be necessary. Reports in the medical literature have detailed the off-label use of mTOR inhibitors to treat these tumors with positive results. Some affected individuals may be prescribed certain medications to treat irregular heartbeats (arrhythmias).

Individuals taking mTOR inhibitors for internal tumors (e.g. SEGAs or angiomyolipomas) may see improvement in skin lesions. Topical formulations of mTOR inhibitors have shown promise in treating facial angiofibromas. Individuals with no immediate indication for mTOR inhibitor treatment may undergo certain procedures to improve the appearance of skin lesions including dermabrasion, laser therapy, or surgical removal (excision) of a lesion.

In 2015, the FDA approved the use of mTOR inhibitors for the treatment of lung complications such as LAM in individuals with tuberous sclerosis. Because LAM occurs most often in young women of childbearing age, researchers have speculated that female hormones such as estrogen play a role in the development of the disorder. A link between LAM and female hormones has not been proven. However, many physicians have explored the use of agents that lower the production or effects of estrogen in the body. The results have varied greatly among individuals. Such agents may include medroxyprogesterone acetate. Estrogen-containing medications and dietary supplements should be discontinued in patients with LAM.

Supplemental oxygen therapy may be necessary for some individuals with impaired lung function. In individuals with severe lung disease that is resistant to treatment, a lung transplant may ultimately become necessary.

Because TSC is a lifelong condition, individuals need to be regularly monitored by a doctor to make sure they are receiving the best possible treatments. Due to the many varied symptoms of TSC, care by a clinician experienced with the disorder is recommended.

Basic laboratory studies have revealed insight into the function of the TSC genes and have led to use of rapamycin (mTOR) inhibitors and related drugs for treating some of the manifestations of TSC.

Associate Treatment

• Surgery. If a growth affects the ability of a specific organ — such as the kidney or heart — to function, the growth may be surgically removed. Sometimes surgery helps control seizures caused by brain growths that don’t respond to medication. Surgical procedures such as dermabrasion or laser treatment may improve the appearance of skin growths.
• Various types of therapy. Early intervention services, such as occupational, physical or speech therapy, can help children with tuberous sclerosis who have special needs in these areas improve their ability to manage daily tasks and activities.
• Educational and vocational services. Early intervention and special needs services can help children with developmental delays and behavior issues adapt to the classroom so that they can meet their full potential. When needed, social, vocational and rehabilitation services may continue throughout life.
• Psychiatric and behavior management. Talking with a mental health provider may help children accept and adjust to living with this disorder. A mental health provider can also help address behavioral, social or emotional issues and recommend resources.

Ongoing monitoring

Tuberous sclerosis is a lifelong condition that requires careful monitoring and follow-up because many signs and symptoms may take years to develop. A schedule of regular follow-up monitoring throughout life may include tests similar to those done during diagnosis. Early identification of problems can help prevent complications.

What is the prognosis?

The prognosis for individuals with TSC is highly variable and depends on the severity of symptoms. Those individuals with mild symptoms usually do well and have a normal life expectancy, while paying attention to TSC-specific issues. Individuals who are severely affected can suffer from severe mental retardation and persistent epilepsy.

All individuals with TSC are at risk for life-threatening conditions related to brain tumors, kidney lesions, or LAM. Continued monitoring by a physician experienced with TSC is important. With appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.

QUESTIONS

1. Tuberous sclerosis complex is a genodermatosis:

   1. Autosomal dominant with hamartomas that affect multiple organs.

   2. Autosomal recessive with hamartomas that affect multiple organs.

   3. Autosomal dominant predominantly affecting females, and the most commonly affected organs are skin, central nervous system, heart, lungs and kidneys.

   4. Autosomal recessive with vascular malformations in many organs, being the most affected skin and central nervous system.

2. The classical tuberous sclerosis triad is characterized by:

   1. Shagreen patch, facial angiofibromas and mental retardation.

   2. Epilepsy, sebaceous adenoma and shagreen patch.

   3. Facial angiofibromas, fibrous cephalic plaque and epilepsy.

   4. Mental retardation, epilepsy and sebaceous adenoma (angiofibroma).

3. Choose the sentence with the correct sequence:

   • ( ) Skin lesions are found in more than 90% of cases, the majority appearing in the 3^rd decade of life.

   • ( ) “Ash-leaf” lesions tend to follow Blaschko lines when on the trunk, typical for type 3 mosaicism.

   • ( ) Hypopigmented macules in “confetti” or guttate leukoderma are hypopigmented macules that appear over the years.

   • ( ) Hypopigmented macules are many times found since birth, allowing for the early diagnosis of the disease when associated to other clinical findings.

     1. F T T F

     2. F F F T

     3. T T F T

     4. F T F T

4. About connective tissue nevi and ungual fibromas or Koenen tumors, it is correct to say that:

   1. Connective tissue nevi seen in TSC are normal-colored to brown plaques restricted to the lumbosacral region.

   2. Shagreen patch many times have the aspect of orange peel and are found on the upper back.

   3. Fibrous cephalic plaque is present in more than 80% of cases, being most commonly found on one side of the forehead.

   4. Koenen tumor usually appears during adolescence and has a predilection for females and the toes.

5. According to the systemic manifestations of TSC, we can affirm that the correct items are:

   1. Angiomyolipomas increase progressively from infancy and stop growing in the elderly.

   2. Renal lesions have an indolent, clinically asymptomatic course, with no potentially severe repercussions in the patient’s life.

   3. In cases of patients that evolve with hematuria in adulthood, the possibility of malignant transformation of the angiomyolipomas must be kept in mind, since they are usually asymptomatic.

   4. Lymphangioleiomyomatosis affects predominantly younger women with the first manifestations after early adolescence.

   5. Rhabdomyoma is the most common cardiac tumor and tends to grow progressively in the first year, when it stabilizes and continues until adulthood.

      1. 1 – 3

      2. 2 – 4

      3. 3 – 5

      4. 1 – 4

   6. Choose the INCORRECT option:

      1. The identification of the pathogenic TSC1 or TSC2 DNA mutation is not enough to establish the diagnosis of TSC.

      2. Molecular testing yields a positive result in 75% to 90% of TSC patients.

      3. In 10% to 25% of patients, conventional genetic testing does not identify the pathogenic TSC1 or TSC2 mutation.

      4. The identification of the pathogenic mutation for TSC in conventional genetic testing configures an independent diagnostic criterion.

6. About the diagnostic criteria for the tuberous sclerosis complex, reviewed in 2012, in the second International Tuberous Sclerosis Complex Consensus Conference, all are included as extracutaneous manifestations, EXCEPT:

   1. Subependymal giant cell astrocytoma.

   2. Cardiac rhabdomyoma.

   3. Lymphangioleiomyomatosis.

   4. Pigmented hamartomas of the iris.

7. It is a MAJOR clinical criterion for the diagnosis of TSC:

   1. ≥ 5 hypopigmented macules with at least 3mm diameter.

   2. ≥ 3 facial angiofibromas.

   3. ≥ 2 intraoral fibromas.

   4. > 3 dental enamel pits.

8. From the dermatological point of view, many destructive or surgical treatment options are used to reduce the development of and remove facial angiofibromas. It is correct to say that:

   1. The destructive procedures are usually comfortable for the patient and can be performed at any age.

   2. It usually is not necessary to repeat laser treatments periodically because the lesions tend not to recur.

   3. Are therapeutic options for facial angiofibromas dermabrasion, surgical excision, electrocautery, and laser.

   4. It is not necessary to combine therapeutic methods to optimize results since that regardless of the treatment chosen, all provide satisfactory results.

9. Diagnostic suspicion of TSC comes from the following findings, EXCEPT:

   1. Antenatal detection of cardiac rhabdomyomas.

   2. Post-natal identification of hypopigmented patches on the skin.

   3. Visualization of ephelis on the axillary or inguinal regions.

   4. Seizures in childhood, particularly with spasms.

References

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Sclerosis tuberose is also known as Cerebral sclerosis, Bourneville Phakomatosis, Bourneville disease, Tuberous sclerosis, tuberous sclerosis complex is a neurocutaneous disorder (phakomatosis) characterized by the development of multiple benign tumors of the embryonic ectoderm (e.g. skin, eyes, and nervous system).

Tuberous sclerosis complex is a multisystemic, autosomal dominant neurocutaneous genetic disorder with complete penetrance, hamartomatous growths in multiple organ systems that can evolve with hamartomas in multiple organs, by causing the growth of benign tumors, so-called hamartomas. As brain, skin, kidneys, heart, liver, lungs, and less frequently retina, gingiva, bones, and gastrointestinal tract can be affected, TSC patients require coordinated care of many specialties.

Hamartomas – plural of hamartoma; benign overgrowths of a mature cell type normal to the site or organ. They may be congenital or acquired

Tuberous sclerosis (also called tuberous sclerosis complex, or TSC) is a rare, multi-system genetic disease that causes non-cancerous (benign) tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and can result in a combination of symptoms including seizures, impaired intellectual development, autism, behavioral problems, skin abnormalities, and kidney disease.

The severity of symptoms varies widely. Symptoms range from mild—allowing people to live independent, productive lives—to more severe symptoms that can affect everyday life and even be life-threatening. Many people with TSC show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.

The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify with age and becomes hard or sclerotic. TSC occurs in all races and ethnic groups, and in both genders.

Causes of Tuberous Sclerosis Complex

TSC is caused by defects, or mutations, on two genes—TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene is on chromosome 9 and produces a protein called hamartin. The TSC2 gene is on chromosome 16 and produces the protein tuberin. Scientists believe these proteins act as growth suppressors by inhibiting the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.

Mutations in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins likely work together to help regulate cell growth and size. The proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way.

People with tuberous sclerosis complex are born with one mutated copy of the TSC1 or TSC2 gene in each cell. This mutation prevents the cell from making functional hamartin or tuberin from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For some types of tumors to develop, a second mutation involving the other copy of the TSC1 or TSC2 gene must occur in certain cells during a person’s lifetime.

When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin; cells with two altered copies of the TSC2 gene are unable to produce any functional tuberin. The loss of these proteins allows the cell to grow and divide in an uncontrolled way to form a tumor. In people with tuberous sclerosis complex, a second TSC1 or TSC2 mutation typically occurs in multiple cells over an affected person’s lifetime. The loss of hamartin or tuberin in different types of cells leads to the growth of tumors in many different organs and tissues.

Is TSC inherited?

Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2—meaning neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.

In cases where TSC is inherited, only one parent needs to have the faulty gene in order to pass it on to a child (called autosomal dominant inheritance). If a parent has TSC, each child has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and may have either a milder or a more severe form of the disorder.

In rare instances, people acquire TSC through a process called gonadal mosaicism. These individuals have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent’s reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved. In cases of gonadal mosaicism, genetic testing of a blood sample might not reveal the potential for passing the disease to offspring.

Symptoms of Tuberous Sclerosis Complex

TSC can affect many different systems of the body, causing a variety of signs and symptoms that range from very mild to quite severe. Common symptoms include:

Benign tumors are most common in the brain, kidneys, heart, lungs, and skin. Cancerous tumors are rare in TSC and those that do occur primarily affect the kidneys.

Three types of brain lesions are seen in TSC:

• Cortical tubers – for which the disease is named, generally form on the surface of the brain but may also appear in the deep areas of the brain
• Subependymal nodules (SEN) – which form in the walls of the ventricles—the fluid-filled cavities of the brain, and
• Subependymal giant-cell astrocytomas (SEGA) – which develop from SEN and grow such that they may block the flow of fluid within the brain—causing a buildup of fluid and pressure that can lead to headaches and blurred vision.

Tumors called cardiac rhabdomyomas are often found in the hearts of infants and young children with TSC, and they are often seen on prenatal fetus ultrasound exams. If the tumors are large or there are multiple tumors, they can block circulation and cause death. However, if they do not cause problems at birth—when in most cases they are at their largest size—they usually become smaller with time and do not affect the individual in later life.

Benign tumors called pakoras are sometimes found in the eyes of individuals with TSC, appearing as white patches on the retina. Generally, they do not cause vision loss or other vision problems, but they can be used to help diagnose the disease.

Additional tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas. Bone cysts, rectal polyps, gum fibromas, and dental pits may also occur.

Seizures affect most individuals with TSC at some point during their life. While some kinds of seizures caused by TSC result in obvious convulsive movements, others alter awareness, behavior, or postural tone without convulsions. Seizures also can be difficult to control by medication, and sometimes surgery or other measures are used.

Cognitive disabilities affect some people with TSC. Developmental delay occurs in about one-half to two-thirds of people with TSC. Delays range from mild learning disabilities to severe impairment.

Behavior problems, including aggression, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior occur in children with TSC and can be difficult to manage. About one-third of children with TSC meet the criteria for autism spectrum disorder.

Radiographic features

Tuberous sclerosis has a significant number of manifestations, involving many organ systems. The most common radiographic manifestations are:

• cortical or subependymal tubers and white matter abnormalities
• renal angiomyolipomas
• cardiac rhabdomyoma(s)

Neurological

• cortical/subcortical tubers: 50% are in the frontal lobe; high T2 and low T1 with only 10% of tubers showing enhancement; frequently calcify after two years of age
• subependymal hamartomas
  • 88% are associated with calcification, although calcification absent in early childhood
  • visible within the first six months of age ⁴
  • variable signal, frequently high T1 and iso to high T2
  • enhancement is variable and is not a useful feature in distinguishing them from subependymal giant cell astrocytomas (SGCA); only serial growth is reliable ^5,6
• subependymal giant cell astrocytomas (SGCA)
  • peak occurrence 8-18 years
  • tend to be large and demonstrate growth ^5,6
  • tend to have intense enhancement
• white matter abnormalities
  • variable appearance, with nodular, ill-defined, cystic and band-like lesions seen
  • radial bands are thought to be relatively specific for TS ⁷
• retinal phakomas
• rarer findings
  • cerebellar atrophy
  • infarcts (due to occlusive vascular disorders)
  • cerebral aneurysms
  • dysgenesis of the corpus callosum
  • Chiari malformations
  • microcephaly
  • arachnoid cysts
  • chordoma

Abdominal

• renal angiomyolipoma(s)
  • tuberous sclerosis accounts for 20% of all angiomyolipomas ³
  • angiomyolipomas are seen in 55-75% of patient with tuberous sclerosis
  • tend to be multiple, large and bilateral
  • tend to grow and require surgical treatment, as the probability of hemorrhage is proportional to the size
  • micro and macro aneurysms may be present ³
  • fat may not be visible in up to 4.5% ¹
• renal cysts: the TSC2 gene is located adjacent to the PCKD1 gene ³
  • 18-53% of patients with tuberous sclerosis ¹
• renal cell carcinoma and oncocytomas
  • although rates of renal cell carcinoma are the same as in the general population, in patients with tuberous sclerosis, renal cell carcinoma tends to occur at a younger age ¹
• retroperitoneal lymphangiomyomatosis (LAM)
  • histologically identical to pulmonary LAM
  • retroperitoneal cystic lesions
  • chylous ascites, enlarged lymph nodes, dilatation of the thoracic duct
• gastrointestinal polyps
• pancreatic neuroendocrine tumors ¹²
• hepatic angiomyolipoma(s)

Thoracic

• lymphangioleiomyomatosis (LAM)
  • rare (1%)
  • some studies have described a lymphangiomyomatosis-like change to be present in 25-40% of female patients with tuberous sclerosis
  • indistinguishable from sporadic LAM
  • pneumothorax and chylous pleural effusions common
  • ~80% 10-year survival
• multifocal micronodular pneumocyte hyperplasia (MMPH)
  • rare
  • characterized by multicentric well-demarcated nodular proliferation of type II pneumocytes
  • benign, non-progressive
  • differential diagnoses: miliary pulmonary opacities
• cardiac rhabdomyomas
  • benign striated muscle tumor characterized by the presence of spider cells
  • seen in 50-65% of patients with tuberous sclerosis
  • 40-80% of patients with cardiac rhabdomyomas have tuberous sclerosis
  • multiple or single
  • typically involve the ventricular septum
  • occur before the age of 1 year (75% of cases) ¹
  • typically regress before birth with spontaneous regression in 70% of children by age 4
• thoracic duct and aortic/pulmonary artery aneurysm
• myocardial fatty foci ¹⁴

Musculoskeletal

• sclerotic bone lesions: 40-66% ¹
• hyperostosis of the inner table of the calvaria
• periosteal new bone
• scoliosis
• bone cysts ⁸

Skin

Cutaneous lesions are present in ~95% of cases, but are rarely appreciated radiographically ⁸:

• hypopigmented macules (ash leaf spots): seen in 90% of patients ¹
• facial angiofibromas (Pringle nodules or adenoma sebaceum); seen in 75% of patients
• fibrous plaques of the forehead (15-20%)
• confetti lesions: variant of leukoderma spots
• shagreen patches: seen in 20-30% of patients
• periungual fibroma (Koenen tumors): 20% of patients

Skin abnormalities vary widely in individuals with TSC. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:

• Hypomanic macules – (“ash leaf spots”), which are white or lighter patches of skin that may appear anywhere on the body and are caused by a lack of skin pigment or melanin—the substance that gives skin its color.

• Facial angiofibromas (also called adenoma sebaceous) – are reddish spots or bumps which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.

• Forehead plaques – are raised, discolored areas on the forehead which are common and unique to TSC and may help doctors diagnose the disorder.

• Shagreen patches – are areas of thick leathery, pebbly skin, usually found on the lower back or nape of the neck.

• Ungual or subungual fibromas – are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These usually appear later in life, ages 20-50.

• Other skin features – that are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders; café au lait spots or flat brown marks; and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.

Kidney problems such as cysts and angiomyolipomas (benign growths of fatty tissue and muscle cells) occur in an estimated 70 to 80 percent of individuals with TSC. They usually occur between ages 15 and 30.

• Cysts are usually small, appear in limited numbers, and most often cause no serious problems. A very small percent of individuals with TSC develop large numbers of cysts during childhood, which may lead to bleeding, anemia, and kidney failure.
• Angiomyolipomas are the most common kidney lesions in TSC and can be found in people without TSC. Angiomyolipomas caused by TSC are usually found in both kidneys and in most cases do not produce symptoms. However, they can sometimes grow so large that they cause pain or kidney failure. Bleeding from angiomyolipomas may also occur, causing both pain and weakness. If severe bleeding does not stop naturally, there may be severe blood loss, resulting in profound anemia and a life-threatening drop in blood pressure, warranting urgent medical attention.
• Other rare kidney problems include renal cell carcinoma, developing from an angiomyolipoma, and oncocytomas, benign tumors unique to individuals with TSC.

Lung lesions are present in about one-third of adult women with TSC and are much less commonly seen in men.  Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH).  LAM is a tumor-like disorder in which cells proliferate in the lungs, and there is lung destruction with cyst formation. A range of symptoms can occur with LAM, with many TSC individuals having no symptoms, while others suffer with breathlessness, which can progress and be severe. MMPH is a more benign tumor that occurs in men and women equally.

As per the recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference, the diagnostic criteria for tuberous sclerosis include the following major and minor features[rx][rx]:

Major Features

• Hypomelanotic macules (more than 2, and at least 5-mm in diameter)
• Angiofibromas (more than 2) or fibrous cephalic plaque
• Ungual fibromas (more than 1)
• Shagreen patch
• Multiple retinal hamartomas
• Cortical dysplasias
• Subependymal nodules
• Subependymal giant cell astrocytoma
• Cardiac rhabdomyoma
• Lymphangioleiomyomatosis
• Angiomyolipomas (more than 1)
• More than 2 angiofibromas, which are skin-colored growths of blood vessels in the skin or a thick (fibrous) patch of skin on the forehead
• 2 or more periungual fibromas or hard growths, around or under the fingernails or toenails
• More than 3 light-colored areas on the skin, known as hypomelanotic macules or ash leaf spots
• Shagreen patch, meaning a rough growth of tissue on the surface of the skin
• Tubers, or thickened areas, found in the brain
• Nodules (round growths) found in the brain
• Subependymal giant cell astrocytoma (SEGA), a type of brain cancer
• Cardiac rhabdomyoma, which is a benign, noncancerous heart growth
• Angiomyolipoma of the kidney, which are benign growths that can cause serious medical problems; there is a low risk that these tumors could become cancerous
• Lymphangiomyomatosis, which are multiple cysts or fluid-filled growths along the lymphatic system under the skin
• Multiple hemangioblastomas, which are growths of newly formed blood vessels, of the brain, spinal cord, or eye
• One or more hemangioblastomas in addition to kidney cysts, pancreatic cysts, pheochromocytoma, which is a rare growth in the cells of one of the adrenal glands, or kidney cancer

Minor Features

• Confetti skin lesions
• Dental enamel Pitts (more than 3)
• Intraoral fibromas (more than 1)
• Retinal achromic patch
• Multiple renal cysts
• Nonrenal hamartomas
• Multiple pits or dents in the teeth
• Fibromas (growths) of the gums inside the mouth
• Multiple kidney cysts
• Pale discolorations in the skin, called “confetti.”
• Changes in the retina inside the eye
• Hamartomas, which are benign tissue growths

Definitive diagnosis is established in patients with two major features or one major feature with at least 2 minor features, while “possible diagnosis” is recognized in patients with one major feature or at least 2 minor features.[rx][rx]

Diagnosis of Tuberous Sclerosis Complex

Diagnosing TSC is based upon clinical criteria.  The first clue may be the presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules) or the identification of cardiac tumor rhabdomyoma.

Diagnosis of the disorder is based on a careful clinical exam in combination with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain—which may show tubers in the brain, and an ultrasound of the heart, liver, and kidneys, which may show tumors in those organs. Doctors should carefully examine the skin for a wide variety of skin features, the fingernails, and toenails for ungual fibromas; the teeth and gums for dental pits and/or gum fibromas; and the eyes for retinal lesions. A small hand-help lamp that uses black light, otherwise known as ultraviolet light, may show hypomelanotic macules which are sometimes hard to see on infants and individuals with pale or fair skin. A doctor experienced in the diagnosis of TSC should evaluate a potential patient.

In infants, TSC may be suspected if the child has cardiac rhabdomyomas at birth or seizures (especially the kind called infantile spasms) in the first six months of life. With a careful examination of the skin and brain, it may be possible to diagnose TSC in a very young infant. However, many children are not diagnosed until later in life when their seizures begin and other symptoms such as facial angiofibromas appear.

Treatment of Tuberous Sclerosis Complex

Treatment is

• mTOR inhibitor medicines – can be used to treat brain tumours, kidney tumours and epilepsy caused by TSC

• anti-epileptic medicines – to treat the associated seizures. Medication needs to be carefully monitored to make sure the child isn’t over-sedated

• brain surgery – if seizures cannot be controlled, it may be possible to remove lesions in the brain to reduce seizures

• skin treatments – dermatologists can provide advice on both surgical and medical treatment for the skin signs of TSC, including mTOR inhibitor creams.

• occupational therapy – can help children acquire skills and strategies

• speech therapy – can assist communication skills.

There is no cure for TSC, although treatment is available for a number of the symptoms. Antiepileptic drugs may be used to control seizures. Vigabatrin is a particularly useful medication in TSC and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of infantile spasms in TSC, although it has significant side effects. The FDA has approved the drug everolimus (Afinitor®) to treat subependymal giant cell astrocytomas (SEGA brain tumors) and angiomyolipoma kidney tumors, in addition to intractable seizures (seizures not controlled well by medicine). Specific medications may be prescribed for behavior problems. Intervention programs including special school programs and various therapies (such as physical, occupational, and speech therapies) may benefit individuals with special needs and developmental issues. Surgery may be needed in case of complications connected to tubers, subependymal nodules, or SEGA, as well as in risk of hemorrhage from kidney tumors. Respiratory insufficiency due to LAM can be treated with supplemental oxygen therapy or lung transplantation, if severe.

Skin lesions, particularly facial angiofibromas, may be psychologically distressing for some patients. Laser treatment or electrosurgery can be used to remove angiofibroma.

The topical mTOR inhibitor sirolimus 0.2% gel (also called rapamycin) has proved helpful in reducing angiofibromas in a clinical trial involving 36 adults and children. One study has also reported improvement in hypopigmented macules. A larger prospective, multicentre, randomized, double-blind, vehicle-controlled trial enrolled 179 patients with tuberous sclerosis-related facial angiofibromas and found improvement in more than 80% of patients treated with topical 1% rapamycin with most occurring in the first month.

Infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).

Treatment may require the coordinated efforts of a team of specialists. Pediatricians and general internists, neurologists, dermatologists, cardiologists, dental specialists, eye specialists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.

The treatment for tuberous sclerosis is supportive and symptomatic. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.

Anti-seizure drugs (anticonvulsants) may be prescribed to control seizures. The specific drug that is used will depend on several factors including the specific type of seizure, an affected individual’s age, other organ systems that are affected, and the severity of symptoms. Conventional anticonvulsants drugs that may be administered include phenobarbital, Dilantin (phenytoin), Klonopin (clonazepam), Depakene/Depakote (valproic acid/divalproex sodium), Tegretol (carbamazepine), Trileptal (oxcarbazepine), Topamax (topiramate), Lamictal (lamotrigine), Zonegran (zonisemide), Vimpat (lacosamide), Banzel (rufinamide), Onfi (clobazam), and others. All these anticonvulsants have potential side effects and require careful monitoring by a physician.

Two drugs have been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of seizures associated with tuberous sclerosis. FDA approved Afinitor (everolimus) for the treatment of seizures in adult and pediatric patients aged 2 years and older with tuberous sclerosis in 2018, and Epidiolex (cannabidiol) for patients one year and older in 2020.

Sabril (vigabatrin) was approved in 2009 by the FDA to treat infantile spasms in children ages 1 month to 2 years. Treatment of children with tuberous sclerosis and infantile spasms with vigabatrin has been found to be effective. Visual field loss is an important safety concern with the use of this medication. The FDA has also approved adreno-corticotrophic hormone or ACTH (Acthar gel) for the treatment of infantile spasms. This medication has also been used to treat infants with tuberous sclerosis. These medications are used cautiously because of their side effects.

No specific anti-seizure medication works for all affected individuals. Often, a combination of different drugs may be required to treat some individuals. Alternative treatments include the ketogenic diet or the glycemic diet. Sometimes, seizures can be difficult to treat and medications or diets that initially worked will no longer provide benefit (refractory seizures). In some instances, seizure surgery to remove areas of brain dysplasia may be necessary to help to control seizures that don’t respond or stop responding to medications. Less invasive surgical options to control seizures include the implanting of a vagal nerve stimulator (VNS device). This is a small electrical stimulator placed under the skin over the upper chest and connected to one vagal nerve in order to provide intermittent electrical stimulus, like a pacemaker to the brain.

Surgery of other organs may be necessary if the ability of a particular organ to function properly is impaired by the presence of a tumor. For example, the obstruction of cerebrospinal fluid (CSF) circulation inside the brain (intracranial hypertension) because of a benign tumor may require a shunting procedure to drain the liquid or the surgical removal of the tumor.

In 2012, the FDA approved the use of Afinitor (everolimus) for the treatment of children and adults with tuberous sclerosis who have a subependymal giant cell astrocytoma that cannot be removed or can be only partially removed by surgery. The FDA also approved everolimus for the treatment of adults with tuberous sclerosis who have an angiomyolipoma of the kidney that does not require surgery right away. In some instances, angiomyolipomas will require surgery or embolization therapy. Cutting off the blood supply (arterial embolization) to a kidney tumor may be used to shrink down the size of the tumor. Embolization is usually followed by treatment with corticosteroids and surgical removal (resection) of the tumor that spares the kidney or by destruction (ablation) of the tumor. Large cystic lesions of the kidneys may also require surgical decompression or removal.

In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.^[rx]

• Take a personal and family history covering three generations. Genetic counseling and tests determine if other individuals are at risk.

• A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).

• Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.

• Assess children for behavioral issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.

• Scan the abdomen for tumors in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.

• In adult women, test pulmonary function and perform a high-resolution computed tomography (HRCT) of the chest.

• Examine the skin under a Wood’s lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas).

• In infants under three, perform an echocardiogram to spot rhabdomyoma, and electrocardiogram (ECG) for any arrhythmia.

• Use a fundoscopy to spot retinal hamartomas or achromic patches.

A benign tumor inside the heart (rhabdomyoma) may not cause symptoms and generally does not require treatment as they often regress on their own within the first several years after birth. If symptomatic, however, surgical removal (resection) may be necessary. Reports in the medical literature have detailed the off-label use of mTOR inhibitors to treat these tumors with positive results. Some affected individuals may be prescribed certain medications to treat irregular heartbeats (arrhythmias).

Individuals taking mTOR inhibitors for internal tumors (e.g. SEGAs or angiomyolipomas) may see improvement in skin lesions. Topical formulations of mTOR inhibitors have shown promise in treating facial angiofibromas. Individuals with no immediate indication for mTOR inhibitor treatment may undergo certain procedures to improve the appearance of skin lesions including dermabrasion, laser therapy, or surgical removal (excision) of a lesion.

In 2015, the FDA approved the use of mTOR inhibitors for the treatment of lung complications such as LAM in individuals with tuberous sclerosis. Because LAM occurs most often in young women of childbearing age, researchers have speculated that female hormones such as estrogen play a role in the development of the disorder. A link between LAM and female hormones has not been proven. However, many physicians have explored the use of agents that lower the production or effects of estrogen in the body. The results have varied greatly among individuals. Such agents may include medroxyprogesterone acetate. Estrogen-containing medications and dietary supplements should be discontinued in patients with LAM.

Supplemental oxygen therapy may be necessary for some individuals with impaired lung function. In individuals with severe lung disease that is resistant to treatment, a lung transplant may ultimately become necessary.

Because TSC is a lifelong condition, individuals need to be regularly monitored by a doctor to make sure they are receiving the best possible treatments. Due to the many varied symptoms of TSC, care by a clinician experienced with the disorder is recommended.

Basic laboratory studies have revealed insight into the function of the TSC genes and have led to use of rapamycin (mTOR) inhibitors and related drugs for treating some of the manifestations of TSC.

Associate Treatment

• Surgery. If a growth affects the ability of a specific organ — such as the kidney or heart — to function, the growth may be surgically removed. Sometimes surgery helps control seizures caused by brain growths that don’t respond to medication. Surgical procedures such as dermabrasion or laser treatment may improve the appearance of skin growths.
• Various types of therapy. Early intervention services, such as occupational, physical or speech therapy, can help children with tuberous sclerosis who have special needs in these areas improve their ability to manage daily tasks and activities.
• Educational and vocational services. Early intervention and special needs services can help children with developmental delays and behavior issues adapt to the classroom so that they can meet their full potential. When needed, social, vocational and rehabilitation services may continue throughout life.
• Psychiatric and behavior management. Talking with a mental health provider may help children accept and adjust to living with this disorder. A mental health provider can also help address behavioral, social or emotional issues and recommend resources.

Ongoing monitoring

Tuberous sclerosis is a lifelong condition that requires careful monitoring and follow-up because many signs and symptoms may take years to develop. A schedule of regular follow-up monitoring throughout life may include tests similar to those done during diagnosis. Early identification of problems can help prevent complications.

What is the prognosis?

The prognosis for individuals with TSC is highly variable and depends on the severity of symptoms. Those individuals with mild symptoms usually do well and have a normal life expectancy, while paying attention to TSC-specific issues. Individuals who are severely affected can suffer from severe mental retardation and persistent epilepsy.

All individuals with TSC are at risk for life-threatening conditions related to brain tumors, kidney lesions, or LAM. Continued monitoring by a physician experienced with TSC is important. With appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.

QUESTIONS

1. Tuberous sclerosis complex is a genodermatosis:

   1. Autosomal dominant with hamartomas that affect multiple organs.

   2. Autosomal recessive with hamartomas that affect multiple organs.

   3. Autosomal dominant predominantly affecting females, and the most commonly affected organs are skin, central nervous system, heart, lungs and kidneys.

   4. Autosomal recessive with vascular malformations in many organs, being the most affected skin and central nervous system.

2. The classical tuberous sclerosis triad is characterized by:

   1. Shagreen patch, facial angiofibromas and mental retardation.

   2. Epilepsy, sebaceous adenoma and shagreen patch.

   3. Facial angiofibromas, fibrous cephalic plaque and epilepsy.

   4. Mental retardation, epilepsy and sebaceous adenoma (angiofibroma).

3. Choose the sentence with the correct sequence:

   • ( ) Skin lesions are found in more than 90% of cases, the majority appearing in the 3^rd decade of life.

   • ( ) “Ash-leaf” lesions tend to follow Blaschko lines when on the trunk, typical for type 3 mosaicism.

   • ( ) Hypopigmented macules in “confetti” or guttate leukoderma are hypopigmented macules that appear over the years.

   • ( ) Hypopigmented macules are many times found since birth, allowing for the early diagnosis of the disease when associated to other clinical findings.

     1. F T T F

     2. F F F T

     3. T T F T

     4. F T F T

4. About connective tissue nevi and ungual fibromas or Koenen tumors, it is correct to say that:

   1. Connective tissue nevi seen in TSC are normal-colored to brown plaques restricted to the lumbosacral region.

   2. Shagreen patch many times have the aspect of orange peel and are found on the upper back.

   3. Fibrous cephalic plaque is present in more than 80% of cases, being most commonly found on one side of the forehead.

   4. Koenen tumor usually appears during adolescence and has a predilection for females and the toes.

5. According to the systemic manifestations of TSC, we can affirm that the correct items are:

   1. Angiomyolipomas increase progressively from infancy and stop growing in the elderly.

   2. Renal lesions have an indolent, clinically asymptomatic course, with no potentially severe repercussions in the patient’s life.

   3. In cases of patients that evolve with hematuria in adulthood, the possibility of malignant transformation of the angiomyolipomas must be kept in mind, since they are usually asymptomatic.

   4. Lymphangioleiomyomatosis affects predominantly younger women with the first manifestations after early adolescence.

   5. Rhabdomyoma is the most common cardiac tumor and tends to grow progressively in the first year, when it stabilizes and continues until adulthood.

      1. 1 – 3

      2. 2 – 4

      3. 3 – 5

      4. 1 – 4

   6. Choose the INCORRECT option:

      1. The identification of the pathogenic TSC1 or TSC2 DNA mutation is not enough to establish the diagnosis of TSC.

      2. Molecular testing yields a positive result in 75% to 90% of TSC patients.

      3. In 10% to 25% of patients, conventional genetic testing does not identify the pathogenic TSC1 or TSC2 mutation.

      4. The identification of the pathogenic mutation for TSC in conventional genetic testing configures an independent diagnostic criterion.

6. About the diagnostic criteria for the tuberous sclerosis complex, reviewed in 2012, in the second International Tuberous Sclerosis Complex Consensus Conference, all are included as extracutaneous manifestations, EXCEPT:

   1. Subependymal giant cell astrocytoma.

   2. Cardiac rhabdomyoma.

   3. Lymphangioleiomyomatosis.

   4. Pigmented hamartomas of the iris.

7. It is a MAJOR clinical criterion for the diagnosis of TSC:

   1. ≥ 5 hypopigmented macules with at least 3mm diameter.

   2. ≥ 3 facial angiofibromas.

   3. ≥ 2 intraoral fibromas.

   4. > 3 dental enamel pits.

8. From the dermatological point of view, many destructive or surgical treatment options are used to reduce the development of and remove facial angiofibromas. It is correct to say that:

   1. The destructive procedures are usually comfortable for the patient and can be performed at any age.

   2. It usually is not necessary to repeat laser treatments periodically because the lesions tend not to recur.

   3. Are therapeutic options for facial angiofibromas dermabrasion, surgical excision, electrocautery and laser.

   4. It is not necessary to combine therapeutic methods to optimize results since that regardless of the treatment chosen, all provide satisfactory results.

9. Diagnostic suspicion of TSC comes from the following findings, EXCEPT:

   1. Antenatal detection of cardiac rhabdomyomas.

   2. Post-natal identification of hypopigmented patches on the skin.

   3. Visualization of ephelis on the axillary or inguinal regions.

   4. Seizures in childhood, particularly with spasms.

References

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Cerebral sclerosis is also known as Bourneville Phakomatosis, Bourneville disease, Tuberous sclerosis, tuberous sclerosis complex is a neurocutaneous disorder (phakomatosis) characterized by the development of multiple benign tumors of the embryonic ectoderm (e.g. skin, eyes, and nervous system).

Tuberous sclerosis complex is a multisystemic, autosomal dominant neurocutaneous genetic disorder with complete penetrance, hamartomatous growths in multiple organ systems that can evolve with hamartomas in multiple organs, by causing the growth of benign tumors, so-called hamartomas. As brain, skin, kidneys, heart, liver, lungs, and less frequently retina, gingiva, bones, and gastrointestinal tract can be affected, TSC patients require coordinated care of many specialties.

Hamartomas – plural of hamartoma; benign overgrowths of a mature cell type normal to the site or organ. They may be congenital or acquired

Tuberous sclerosis (also called tuberous sclerosis complex, or TSC) is a rare, multi-system genetic disease that causes non-cancerous (benign) tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and can result in a combination of symptoms including seizures, impaired intellectual development, autism, behavioral problems, skin abnormalities, and kidney disease.

The severity of symptoms varies widely. Symptoms range from mild—allowing people to live independent, productive lives—to more severe symptoms that can affect everyday life and even be life-threatening. Many people with TSC show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.

The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify with age and becomes hard or sclerotic. TSC occurs in all races and ethnic groups, and in both genders.

Causes of Tuberous Sclerosis Complex

TSC is caused by defects, or mutations, on two genes—TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene is on chromosome 9 and produces a protein called hamartin. The TSC2 gene is on chromosome 16 and produces the protein tuberin. Scientists believe these proteins act as growth suppressors by inhibiting the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.

Mutations in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins likely work together to help regulate cell growth and size. The proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way.

People with tuberous sclerosis complex are born with one mutated copy of the TSC1 or TSC2 gene in each cell. This mutation prevents the cell from making functional hamartin or tuberin from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For some types of tumors to develop, a second mutation involving the other copy of the TSC1 or TSC2 gene must occur in certain cells during a person’s lifetime.

When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin; cells with two altered copies of the TSC2 gene are unable to produce any functional tuberin. The loss of these proteins allows the cell to grow and divide in an uncontrolled way to form a tumor. In people with tuberous sclerosis complex, a second TSC1 or TSC2 mutation typically occurs in multiple cells over an affected person’s lifetime. The loss of hamartin or tuberin in different types of cells leads to the growth of tumors in many different organs and tissues.

Is TSC inherited?

Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2—meaning neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.

In cases where TSC is inherited, only one parent needs to have the faulty gene in order to pass it on to a child (called autosomal dominant inheritance). If a parent has TSC, each child has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and may have either a milder or a more severe form of the disorder.

In rare instances, people acquire TSC through a process called gonadal mosaicism. These individuals have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent’s reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved. In cases of gonadal mosaicism, genetic testing of a blood sample might not reveal the potential for passing the disease to offspring.

Symptoms of Tuberous Sclerosis Complex

TSC can affect many different systems of the body, causing a variety of signs and symptoms that range from very mild to quite severe. Common symptoms include:

Benign tumors are most common in the brain, kidneys, heart, lungs, and skin. Cancerous tumors are rare in TSC and those that do occur primarily affect the kidneys.

Three types of brain lesions are seen in TSC:

• Cortical tubers – for which the disease is named, generally form on the surface of the brain but may also appear in the deep areas of the brain
• Subependymal nodules (SEN) – which form in the walls of the ventricles—the fluid-filled cavities of the brain, and
• Subependymal giant-cell astrocytomas (SEGA) – which develop from SEN and grow such that they may block the flow of fluid within the brain—causing a buildup of fluid and pressure that can lead to headaches and blurred vision.

Tumors called cardiac rhabdomyomas are often found in the hearts of infants and young children with TSC, and they are often seen on prenatal fetus ultrasound exams. If the tumors are large or there are multiple tumors, they can block circulation and cause death. However, if they do not cause problems at birth—when in most cases they are at their largest size—they usually become smaller with time and do not affect the individual in later life.

Benign tumors called pakoras are sometimes found in the eyes of individuals with TSC, appearing as white patches on the retina. Generally, they do not cause vision loss or other vision problems, but they can be used to help diagnose the disease.

Additional tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas. Bone cysts, rectal polyps, gum fibromas, and dental pits may also occur.

Seizures affect most individuals with TSC at some point during their life. While some kinds of seizures caused by TSC result in obvious convulsive movements, others alter awareness, behavior, or postural tone without convulsions. Seizures also can be difficult to control by medication, and sometimes surgery or other measures are used.

Cognitive disabilities affect some people with TSC. Developmental delay occurs in about one-half to two-thirds of people with TSC. Delays range from mild learning disabilities to severe impairment.

Behavior problems, including aggression, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior occur in children with TSC and can be difficult to manage. About one-third of children with TSC meet the criteria for autism spectrum disorder.

Skin abnormalities vary widely in individuals with TSC. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:

• Hypomanic macules (“ash leaf spots”), which are white or lighter patches of skin that may appear anywhere on the body and are caused by a lack of skin pigment or melanin—the substance that gives skin its color.
• Facial angiofibromas (also called adenoma sebaceous) are reddish spots or bumps which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.
• Forehead plaques are raised, discolored areas on the forehead which are common and unique to TSC and may help doctors diagnose the disorder.
• Shagreen patches are areas of thick leathery, pebbly skin, usually found on the lower back or nape of the neck.
• Ungual or subungual fibromas are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These usually appear later in life, ages 20-50.
• Other skin features that are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders; café au lait spots or flat brown marks; and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.

Kidney problems such as cysts and angiomyolipomas (benign growths of fatty tissue and muscle cells) occur in an estimated 70 to 80 percent of individuals with TSC. They usually occur between ages 15 and 30.

• Cysts are usually small, appear in limited numbers, and most often cause no serious problems. A very small percent of individuals with TSC develop large numbers of cysts during childhood, which may lead to bleeding, anemia, and kidney failure.
• Angiomyolipomas are the most common kidney lesions in TSC and can be found in people without TSC. Angiomyolipomas caused by TSC are usually found in both kidneys and in most cases do not produce symptoms. However, they can sometimes grow so large that they cause pain or kidney failure. Bleeding from angiomyolipomas may also occur, causing both pain and weakness. If severe bleeding does not stop naturally, there may be severe blood loss, resulting in profound anemia and a life-threatening drop in blood pressure, warranting urgent medical attention.
• Other rare kidney problems include renal cell carcinoma, developing from an angiomyolipoma, and oncocytomas, benign tumors unique to individuals with TSC.

Associate signs of tuberous sclerosis can appear later in childhood or even into adulthood. These symptoms may include:

• White spots on the skin (called hypopigmented macules) that glow under a special lamp

• A rash on the face (called facial angiofibromas) that may look like acne

• Problems with the kidneys (associated with growths in the kidneys)

• Areas of very thick skin, often on the back

• Growths under or around the nails

• Pitted teeth

• Coughing or shortness of breath

• Mental disabilities.

• Developmental delays

• Autism spectrum disorder

Lung lesions are present in about one-third of adult women with TSC and are much less commonly seen in men.  Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH).  LAM is a tumor-like disorder in which cells proliferate in the lungs, and there is lung destruction with cyst formation. A range of symptoms can occur with LAM, with many TSC individuals having no symptoms, while others suffer with breathlessness, which can progress and be severe. MMPH is a more benign tumor that occurs in men and women equally.

As per the recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference, the diagnostic criteria for tuberous sclerosis include the following major and minor features[rx][rx]:

Major Features

• Hypomelanotic macules (more than 2, and at least 5-mm in diameter)
• Angiofibromas (more than 2) or fibrous cephalic plaque
• Ungual fibromas (more than 1)
• Shagreen patch
• Multiple retinal hamartomas
• Cortical dysplasias
• Subependymal nodules
• Subependymal giant cell astrocytoma
• Cardiac rhabdomyoma
• Lymphangioleiomyomatosis
• Angiomyolipomas (more than 1)
• More than 2 angiofibromas, which are skin-colored growths of blood vessels in the skin or a thick (fibrous) patch of skin on the forehead
• 2 or more periungual fibromas or hard growths, around or under the fingernails or toenails
• More than 3 light-colored areas on the skin, known as hypomelanotic macules or ash leaf spots
• Shagreen patch, meaning a rough growth of tissue on the surface of the skin
• Tubers, or thickened areas, found in the brain
• Nodules (round growths) found in the brain
• Subependymal giant cell astrocytoma (SEGA), a type of brain cancer
• Cardiac rhabdomyoma, which is a benign, noncancerous heart growth
• Angiomyolipoma of the kidney, which are benign growths that can cause serious medical problems; there is a low risk that these tumors could become cancerous
• Lymphangiomyomatosis, which are multiple cysts or fluid-filled growths along the lymphatic system under the skin
• Multiple hemangioblastomas, which are growths of newly formed blood vessels, of the brain, spinal cord, or eye
• One or more hemangioblastomas in addition to kidney cysts, pancreatic cysts, pheochromocytoma, which is a rare growth in the cells of one of the adrenal glands, or kidney cancer

Minor Features

• Confetti skin lesions
• Dental enamel Pitts (more than 3)
• Intraoral fibromas (more than 1)
• Retinal achromic patch
• Multiple renal cysts
• Nonrenal hamartomas
• Multiple pits or dents in the teeth
• Fibromas (growths) of the gums inside the mouth
• Multiple kidney cysts
• Pale discolorations in the skin, called “confetti.”
• Changes in the retina inside the eye
• Hamartomas, which are benign tissue growths

Definitive diagnosis is established in patients with two major features or one major feature with at least 2 minor features, while “possible diagnosis” is recognized in patients with one major feature or at least 2 minor features.[rx][rx]

Diagnosis of Tuberous Sclerosis Complex

Diagnosing TSC is based upon clinical criteria.  The first clue may be the presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules) or the identification of cardiac tumor rhabdomyoma.

Diagnosis of the disorder is based on a careful clinical exam in combination with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain—which may show tubers in the brain, and an ultrasound of the heart, liver, and kidneys, which may show tumors in those organs. Doctors should carefully examine the skin for a wide variety of skin features, the fingernails, and toenails for ungual fibromas; the teeth and gums for dental pits and/or gum fibromas; and the eyes for retinal lesions. A small hand-help lamp that uses black light, otherwise known as ultraviolet light, may show hypomelanotic macules which are sometimes hard to see on infants and individuals with pale or fair skin. A doctor experienced in the diagnosis of TSC should evaluate a potential patient.

In infants, TSC may be suspected if the child has cardiac rhabdomyomas at birth or seizures (especially the kind called infantile spasms) in the first six months of life. With a careful examination of the skin and brain, it may be possible to diagnose TSC in a very young infant. However, many children are not diagnosed until later in life when their seizures begin and other symptoms such as facial angiofibromas appear.

Treatment of Tuberous Sclerosis Complex

Treatment is

• mTOR inhibitor medicines – can be used to treat brain tumours, kidney tumours and epilepsy caused by TSC

• anti-epileptic medicines – to treat the associated seizures. Medication needs to be carefully monitored to make sure the child isn’t over-sedated

• brain surgery – if seizures cannot be controlled, it may be possible to remove lesions in the brain to reduce seizures

• skin treatments – dermatologists can provide advice on both surgical and medical treatment for the skin signs of TSC, including mTOR inhibitor creams.

• occupational therapy – can help children acquire skills and strategies

• speech therapy – can assist communication skills.

There is no cure for TSC, although treatment is available for a number of the symptoms. Antiepileptic drugs may be used to control seizures. Vigabatrin is a particularly useful medication in TSC and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of infantile spasms in TSC, although it has significant side effects. The FDA has approved the drug everolimus (Afinitor®) to treat subependymal giant cell astrocytomas (SEGA brain tumors) and angiomyolipoma kidney tumors, in addition to intractable seizures (seizures not controlled well by medicine). Specific medications may be prescribed for behavior problems. Intervention programs including special school programs and various therapies (such as physical, occupational, and speech therapies) may benefit individuals with special needs and developmental issues. Surgery may be needed in case of complications connected to tubers, subependymal nodules, or SEGA, as well as in risk of hemorrhage from kidney tumors. Respiratory insufficiency due to LAM can be treated with supplemental oxygen therapy or lung transplantation, if severe.

Skin lesions, particularly facial angiofibromas, may be psychologically distressing for some patients. Laser treatment or electrosurgery can be used to remove angiofibroma.

The topical mTOR inhibitor sirolimus 0.2% gel (also called rapamycin) has proved helpful in reducing angiofibromas in a clinical trial involving 36 adults and children. One study has also reported improvement in hypopigmented macules. A larger prospective, multicentre, randomized, double-blind, vehicle-controlled trial enrolled 179 patients with tuberous sclerosis-related facial angiofibromas and found improvement in more than 80% of patients treated with topical 1% rapamycin with most occurring in the first month.

Infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).

Treatment may require the coordinated efforts of a team of specialists. Pediatricians and general internists, neurologists, dermatologists, cardiologists, dental specialists, eye specialists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.

The treatment for tuberous sclerosis is supportive and symptomatic. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.

Anti-seizure drugs (anticonvulsants) may be prescribed to control seizures. The specific drug that is used will depend on several factors including the specific type of seizure, an affected individual’s age, other organ systems that are affected, and the severity of symptoms. Conventional anticonvulsants drugs that may be administered include phenobarbital, Dilantin (phenytoin), Klonopin (clonazepam), Depakene/Depakote (valproic acid/divalproex sodium), Tegretol (carbamazepine), Trileptal (oxcarbazepine), Topamax (topiramate), Lamictal (lamotrigine), Zonegran (zonisemide), Vimpat (lacosamide), Banzel (rufinamide), Onfi (clobazam), and others. All these anticonvulsants have potential side effects and require careful monitoring by a physician.

Two drugs have been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of seizures associated with tuberous sclerosis. FDA approved Afinitor (everolimus) for the treatment of seizures in adult and pediatric patients aged 2 years and older with tuberous sclerosis in 2018, and Epidiolex (cannabidiol) for patients one year and older in 2020.

Sabril (vigabatrin) was approved in 2009 by the FDA to treat infantile spasms in children ages 1 month to 2 years. Treatment of children with tuberous sclerosis and infantile spasms with vigabatrin has been found to be effective. Visual field loss is an important safety concern with the use of this medication. The FDA has also approved adreno-corticotrophic hormone or ACTH (Acthar gel) for the treatment of infantile spasms. This medication has also been used to treat infants with tuberous sclerosis. These medications are used cautiously because of their side effects.

No specific anti-seizure medication works for all affected individuals. Often, a combination of different drugs may be required to treat some individuals. Alternative treatments include the ketogenic diet or the glycemic diet. Sometimes, seizures can be difficult to treat and medications or diets that initially worked will no longer provide benefit (refractory seizures). In some instances, seizure surgery to remove areas of brain dysplasia may be necessary to help to control seizures that don’t respond or stop responding to medications. Less invasive surgical options to control seizures include the implanting of a vagal nerve stimulator (VNS device). This is a small electrical stimulator placed under the skin over the upper chest and connected to one vagal nerve in order to provide intermittent electrical stimulus, like a pacemaker to the brain.

Surgery of other organs may be necessary if the ability of a particular organ to function properly is impaired by the presence of a tumor. For example, the obstruction of cerebrospinal fluid (CSF) circulation inside the brain (intracranial hypertension) because of a benign tumor may require a shunting procedure to drain the liquid or the surgical removal of the tumor.

In 2012, the FDA approved the use of Afinitor (everolimus) for the treatment of children and adults with tuberous sclerosis who have a subependymal giant cell astrocytoma that cannot be removed or can be only partially removed by surgery. The FDA also approved everolimus for the treatment of adults with tuberous sclerosis who have an angiomyolipoma of the kidney that does not require surgery right away. In some instances, angiomyolipomas will require surgery or embolization therapy. Cutting off the blood supply (arterial embolization) to a kidney tumor may be used to shrink down the size of the tumor. Embolization is usually followed by treatment with corticosteroids and surgical removal (resection) of the tumor that spares the kidney or by destruction (ablation) of the tumor. Large cystic lesions of the kidneys may also require surgical decompression or removal.

In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.^[rx]

• Take a personal and family history covering three generations. Genetic counseling and tests determine if other individuals are at risk.

• A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).

• Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.

• Assess children for behavioral issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.

• Scan the abdomen for tumors in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.

• In adult women, test pulmonary function and perform a high-resolution computed tomography (HRCT) of the chest.

• Examine the skin under a Wood’s lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas).

• In infants under three, perform an echocardiogram to spot rhabdomyoma, and electrocardiogram (ECG) for any arrhythmia.

• Use a fundoscopy to spot retinal hamartomas or achromic patches.

A benign tumor inside the heart (rhabdomyoma) may not cause symptoms and generally does not require treatment as they often regress on their own within the first several years after birth. If symptomatic, however, surgical removal (resection) may be necessary. Reports in the medical literature have detailed the off-label use of mTOR inhibitors to treat these tumors with positive results. Some affected individuals may be prescribed certain medications to treat irregular heartbeats (arrhythmias).

Individuals taking mTOR inhibitors for internal tumors (e.g. SEGAs or angiomyolipomas) may see improvement in skin lesions. Topical formulations of mTOR inhibitors have shown promise in treating facial angiofibromas. Individuals with no immediate indication for mTOR inhibitor treatment may undergo certain procedures to improve the appearance of skin lesions including dermabrasion, laser therapy, or surgical removal (excision) of a lesion.

In 2015, the FDA approved the use of mTOR inhibitors for the treatment of lung complications such as LAM in individuals with tuberous sclerosis. Because LAM occurs most often in young women of childbearing age, researchers have speculated that female hormones such as estrogen play a role in the development of the disorder. A link between LAM and female hormones has not been proven. However, many physicians have explored the use of agents that lower the production or effects of estrogen in the body. The results have varied greatly among individuals. Such agents may include medroxyprogesterone acetate. Estrogen-containing medications and dietary supplements should be discontinued in patients with LAM.

Supplemental oxygen therapy may be necessary for some individuals with impaired lung function. In individuals with severe lung disease that is resistant to treatment, a lung transplant may ultimately become necessary.

Because TSC is a lifelong condition, individuals need to be regularly monitored by a doctor to make sure they are receiving the best possible treatments. Due to the many varied symptoms of TSC, care by a clinician experienced with the disorder is recommended.

Basic laboratory studies have revealed insight into the function of the TSC genes and have led to use of rapamycin (mTOR) inhibitors and related drugs for treating some of the manifestations of TSC.

Associate Treatment

• Surgery. If a growth affects the ability of a specific organ — such as the kidney or heart — to function, the growth may be surgically removed. Sometimes surgery helps control seizures caused by brain growths that don’t respond to medication. Surgical procedures such as dermabrasion or laser treatment may improve the appearance of skin growths.
• Various types of therapy. Early intervention services, such as occupational, physical or speech therapy, can help children with tuberous sclerosis who have special needs in these areas improve their ability to manage daily tasks and activities.
• Educational and vocational services. Early intervention and special needs services can help children with developmental delays and behavior issues adapt to the classroom so that they can meet their full potential. When needed, social, vocational and rehabilitation services may continue throughout life.
• Psychiatric and behavior management. Talking with a mental health provider may help children accept and adjust to living with this disorder. A mental health provider can also help address behavioral, social or emotional issues and recommend resources.

Ongoing monitoring

Tuberous sclerosis is a lifelong condition that requires careful monitoring and follow-up because many signs and symptoms may take years to develop. A schedule of regular follow-up monitoring throughout life may include tests similar to those done during diagnosis. Early identification of problems can help prevent complications.

What is the prognosis?

The prognosis for individuals with TSC is highly variable and depends on the severity of symptoms. Those individuals with mild symptoms usually do well and have a normal life expectancy, while paying attention to TSC-specific issues. Individuals who are severely affected can suffer from severe mental retardation and persistent epilepsy.

All individuals with TSC are at risk for life-threatening conditions related to brain tumors, kidney lesions, or LAM. Continued monitoring by a physician experienced with TSC is important. With appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.

QUESTIONS

1. Tuberous sclerosis complex is a genodermatosis:

   1. Autosomal dominant with hamartomas that affect multiple organs.

   2. Autosomal recessive with hamartomas that affect multiple organs.

   3. Autosomal dominant predominantly affecting females, and the most commonly affected organs are skin, central nervous system, heart, lungs and kidneys.

   4. Autosomal recessive with vascular malformations in many organs, being the most affected skin and central nervous system.

2. The classical tuberous sclerosis triad is characterized by:

   1. Shagreen patch, facial angiofibromas and mental retardation.

   2. Epilepsy, sebaceous adenoma and shagreen patch.

   3. Facial angiofibromas, fibrous cephalic plaque and epilepsy.

   4. Mental retardation, epilepsy and sebaceous adenoma (angiofibroma).

3. Choose the sentence with the correct sequence:

   • ( ) Skin lesions are found in more than 90% of cases, the majority appearing in the 3^rd decade of life.

   • ( ) “Ash-leaf” lesions tend to follow Blaschko lines when on the trunk, typical for type 3 mosaicism.

   • ( ) Hypopigmented macules in “confetti” or guttate leukoderma are hypopigmented macules that appear over the years.

   • ( ) Hypopigmented macules are many times found since birth, allowing for the early diagnosis of the disease when associated to other clinical findings.

     1. F T T F

     2. F F F T

     3. T T F T

     4. F T F T

4. About connective tissue nevi and ungual fibromas or Koenen tumors, it is correct to say that:

   1. Connective tissue nevi seen in TSC are normal-colored to brown plaques restricted to the lumbosacral region.

   2. Shagreen patch many times have the aspect of orange peel and are found on the upper back.

   3. Fibrous cephalic plaque is present in more than 80% of cases, being most commonly found on one side of the forehead.

   4. Koenen tumor usually appears during adolescence and has a predilection for females and the toes.

5. According to the systemic manifestations of TSC, we can affirm that the correct items are:

   1. Angiomyolipomas increase progressively from infancy and stop growing in the elderly.

   2. Renal lesions have an indolent, clinically asymptomatic course, with no potentially severe repercussions in the patient’s life.

   3. In cases of patients that evolve with hematuria in adulthood, the possibility of malignant transformation of the angiomyolipomas must be kept in mind, since they are usually asymptomatic.

   4. Lymphangioleiomyomatosis affects predominantly younger women with the first manifestations after early adolescence.

   5. Rhabdomyoma is the most common cardiac tumor and tends to grow progressively in the first year, when it stabilizes and continues until adulthood.

      1. 1 – 3

      2. 2 – 4

      3. 3 – 5

      4. 1 – 4

   6. Choose the INCORRECT option:

      1. The identification of the pathogenic TSC1 or TSC2 DNA mutation is not enough to establish the diagnosis of TSC.

      2. Molecular testing yields a positive result in 75% to 90% of TSC patients.

      3. In 10% to 25% of patients, conventional genetic testing does not identify the pathogenic TSC1 or TSC2 mutation.

      4. The identification of the pathogenic mutation for TSC in conventional genetic testing configures an independent diagnostic criterion.

6. About the diagnostic criteria for the tuberous sclerosis complex, reviewed in 2012, in the second International Tuberous Sclerosis Complex Consensus Conference, all are included as extracutaneous manifestations, EXCEPT:

   1. Subependymal giant cell astrocytoma.

   2. Cardiac rhabdomyoma.

   3. Lymphangioleiomyomatosis.

   4. Pigmented hamartomas of the iris.

7. It is a MAJOR clinical criterion for the diagnosis of TSC:

   1. ≥ 5 hypopigmented macules with at least 3mm diameter.

   2. ≥ 3 facial angiofibromas.

   3. ≥ 2 intraoral fibromas.

   4. > 3 dental enamel pits.

8. From the dermatological point of view, many destructive or surgical treatment options are used to reduce the development of and remove facial angiofibromas. It is correct to say that:

   1. The destructive procedures are usually comfortable for the patient and can be performed at any age.

   2. It usually is not necessary to repeat laser treatments periodically because the lesions tend not to recur.

   3. Are therapeutic options for facial angiofibromas dermabrasion, surgical excision, electrocautery and laser.

   4. It is not necessary to combine therapeutic methods to optimize results since that regardless of the treatment chosen, all provide satisfactory results.

9. Diagnostic suspicion of TSC comes from the following findings, EXCEPT:

   1. Antenatal detection of cardiac rhabdomyomas.

   2. Post-natal identification of hypopigmented patches on the skin.

   3. Visualization of ephelis on the axillary or inguinal regions.

   4. Seizures in childhood, particularly with spasms.

References

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Bourneville Phakomatosis is also known as Bourneville disease,  Tuberous sclerosis, tuberous sclerosis complex is a neurocutaneous disorder (phakomatosis) characterized by the development of multiple benign tumors of the embryonic ectoderm (e.g. skin, eyes, and nervous system).

Tuberous sclerosis complex is a multisystemic, autosomal dominant neurocutaneous genetic disorder with complete penetrance, hamartomatous growths in multiple organ systems that can evolve with hamartomas in multiple organs, by causing the growth of benign tumors, so-called hamartomas. As brain, skin, kidneys, heart, liver, lungs, and less frequently retina, gingiva, bones, and gastrointestinal tract can be affected, TSC patients require coordinated care of many specialties.

Hamartomas – plural of hamartoma; benign overgrowths of a mature cell type normal to the site or organ. They may be congenital or acquired

Tuberous sclerosis (also called tuberous sclerosis complex, or TSC) is a rare, multi-system genetic disease that causes non-cancerous (benign) tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and can result in a combination of symptoms including seizures, impaired intellectual development, autism, behavioral problems, skin abnormalities, and kidney disease.

The severity of symptoms varies widely. Symptoms range from mild—allowing people to live independent, productive lives—to more severe symptoms that can affect everyday life and even be life-threatening. Many people with TSC show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.

The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify with age and becomes hard or sclerotic. TSC occurs in all races and ethnic groups, and in both genders.

Causes of Tuberous Sclerosis Complex

TSC is caused by defects, or mutations, on two genes—TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene is on chromosome 9 and produces a protein called hamartin. The TSC2 gene is on chromosome 16 and produces the protein tuberin. Scientists believe these proteins act as growth suppressors by inhibiting the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.

Mutations in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins likely work together to help regulate cell growth and size. The proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way.

People with tuberous sclerosis complex are born with one mutated copy of the TSC1 or TSC2 gene in each cell. This mutation prevents the cell from making functional hamartin or tuberin from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For some types of tumors to develop, a second mutation involving the other copy of the TSC1 or TSC2 gene must occur in certain cells during a person’s lifetime.

When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin; cells with two altered copies of the TSC2 gene are unable to produce any functional tuberin. The loss of these proteins allows the cell to grow and divide in an uncontrolled way to form a tumor. In people with tuberous sclerosis complex, a second TSC1 or TSC2 mutation typically occurs in multiple cells over an affected person’s lifetime. The loss of hamartin or tuberin in different types of cells leads to the growth of tumors in many different organs and tissues.

Is TSC inherited?

Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2—meaning neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.

In cases where TSC is inherited, only one parent needs to have the faulty gene in order to pass it on to a child (called autosomal dominant inheritance). If a parent has TSC, each child has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and may have either a milder or a more severe form of the disorder.

In rare instances, people acquire TSC through a process called gonadal mosaicism. These individuals have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent’s reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved. In cases of gonadal mosaicism, genetic testing of a blood sample might not reveal the potential for passing the disease to offspring.

Symptoms of Tuberous Sclerosis Complex

TSC can affect many different systems of the body, causing a variety of signs and symptoms that range from very mild to quite severe. Common symptoms include:

Benign tumors are most common in the brain, kidneys, heart, lungs, and skin. Cancerous tumors are rare in TSC and those that do occur primarily affect the kidneys.

Three types of brain lesions are seen in TSC:

• Cortical tubers – for which the disease is named, generally form on the surface of the brain but may also appear in the deep areas of the brain
• Subependymal nodules (SEN) – which form in the walls of the ventricles—the fluid-filled cavities of the brain, and
• Subependymal giant-cell astrocytomas (SEGA) – which develop from SEN and grow such that they may block the flow of fluid within the brain—causing a buildup of fluid and pressure that can lead to headaches and blurred vision.

Tumors called cardiac rhabdomyomas are often found in the hearts of infants and young children with TSC, and they are often seen on prenatal fetus ultrasound exams. If the tumors are large or there are multiple tumors, they can block circulation and cause death. However, if they do not cause problems at birth—when in most cases they are at their largest size—they usually become smaller with time and do not affect the individual in later life.

Benign tumors called pakoras are sometimes found in the eyes of individuals with TSC, appearing as white patches on the retina. Generally, they do not cause vision loss or other vision problems, but they can be used to help diagnose the disease.

Additional tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas. Bone cysts, rectal polyps, gum fibromas, and dental pits may also occur.

Seizures affect most individuals with TSC at some point during their life. While some kinds of seizures caused by TSC result in obvious convulsive movements, others alter awareness, behavior, or postural tone without convulsions. Seizures also can be difficult to control by medication, and sometimes surgery or other measures are used.

Cognitive disabilities affect some people with TSC. Developmental delay occurs in about one-half to two-thirds of people with TSC. Delays range from mild learning disabilities to severe impairment.

Behavior problems, including aggression, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior occur in children with TSC and can be difficult to manage. About one-third of children with TSC meet the criteria for autism spectrum disorder.

Skin abnormalities vary widely in individuals with TSC. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:

• Hypomanic macules (“ash leaf spots”), which are white or lighter patches of skin that may appear anywhere on the body and are caused by a lack of skin pigment or melanin—the substance that gives skin its color.
• Facial angiofibromas (also called adenoma sebaceous) are reddish spots or bumps which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.
• Forehead plaques are raised, discolored areas on the forehead which are common and unique to TSC and may help doctors diagnose the disorder.
• Shagreen patches are areas of thick leathery, pebbly skin, usually found on the lower back or nape of the neck.
• Ungual or subungual fibromas are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These usually appear later in life, ages 20-50.
• Other skin features that are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders; café au lait spots or flat brown marks; and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.

Kidney problems such as cysts and angiomyolipomas (benign growths of fatty tissue and muscle cells) occur in an estimated 70 to 80 percent of individuals with TSC. They usually occur between ages 15 and 30.

• Cysts are usually small, appear in limited numbers, and most often cause no serious problems. A very small percent of individuals with TSC develop large numbers of cysts during childhood, which may lead to bleeding, anemia, and kidney failure.
• Angiomyolipomas are the most common kidney lesions in TSC and can be found in people without TSC. Angiomyolipomas caused by TSC are usually found in both kidneys and in most cases do not produce symptoms. However, they can sometimes grow so large that they cause pain or kidney failure. Bleeding from angiomyolipomas may also occur, causing both pain and weakness. If severe bleeding does not stop naturally, there may be severe blood loss, resulting in profound anemia and a life-threatening drop in blood pressure, warranting urgent medical attention.
• Other rare kidney problems include renal cell carcinoma, developing from an angiomyolipoma, and oncocytomas, benign tumors unique to individuals with TSC.

Associate signs of tuberous sclerosis can appear later in childhood or even into adulthood. These symptoms may include:

• White spots on the skin (called hypopigmented macules) that glow under a special lamp

• A rash on the face (called facial angiofibromas) that may look like acne

• Problems with the kidneys (associated with growths in the kidneys)

• Areas of very thick skin, often on the back

• Growths under or around the nails

• Pitted teeth

• Coughing or shortness of breath

• Mental disabilities.

• Developmental delays

• Autism spectrum disorder

Lung lesions are present in about one-third of adult women with TSC and are much less commonly seen in men.  Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH).  LAM is a tumor-like disorder in which cells proliferate in the lungs, and there is lung destruction with cyst formation. A range of symptoms can occur with LAM, with many TSC individuals having no symptoms, while others suffer with breathlessness, which can progress and be severe. MMPH is a more benign tumor that occurs in men and women equally.

As per the recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference, the diagnostic criteria for tuberous sclerosis include the following major and minor features[rx][rx]:

Major Features

• Hypomelanotic macules (more than 2, and at least 5-mm in diameter)
• Angiofibromas (more than 2) or fibrous cephalic plaque
• Ungual fibromas (more than 1)
• Shagreen patch
• Multiple retinal hamartomas
• Cortical dysplasias
• Subependymal nodules
• Subependymal giant cell astrocytoma
• Cardiac rhabdomyoma
• Lymphangioleiomyomatosis
• Angiomyolipomas (more than 1)
• More than 2 angiofibromas, which are skin-colored growths of blood vessels in the skin or a thick (fibrous) patch of skin on the forehead
• 2 or more periungual fibromas or hard growths, around or under the fingernails or toenails
• More than 3 light-colored areas on the skin, known as hypomelanotic macules or ash leaf spots
• Shagreen patch, meaning a rough growth of tissue on the surface of the skin
• Tubers, or thickened areas, found in the brain
• Nodules (round growths) found in the brain
• Subependymal giant cell astrocytoma (SEGA), a type of brain cancer
• Cardiac rhabdomyoma, which is a benign, noncancerous heart growth
• Angiomyolipoma of the kidney, which are benign growths that can cause serious medical problems; there is a low risk that these tumors could become cancerous
• Lymphangiomyomatosis, which are multiple cysts or fluid-filled growths along the lymphatic system under the skin
• Multiple hemangioblastomas, which are growths of newly formed blood vessels, of the brain, spinal cord, or eye
• One or more hemangioblastomas in addition to kidney cysts, pancreatic cysts, pheochromocytoma, which is a rare growth in the cells of one of the adrenal glands, or kidney cancer

Minor Features

• Confetti skin lesions
• Dental enamel Pitts (more than 3)
• Intraoral fibromas (more than 1)
• Retinal achromic patch
• Multiple renal cysts
• Nonrenal hamartomas
• Multiple pits or dents in the teeth
• Fibromas (growths) of the gums inside the mouth
• Multiple kidney cysts
• Pale discolorations in the skin, called “confetti.”
• Changes in the retina inside the eye
• Hamartomas, which are benign tissue growths

Definitive diagnosis is established in patients with two major features or one major feature with at least 2 minor features, while “possible diagnosis” is recognized in patients with one major feature or at least 2 minor features.[rx][rx]

Diagnosis of Tuberous Sclerosis Complex

Diagnosing TSC is based upon clinical criteria.  The first clue may be the presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules) or the identification of cardiac tumor rhabdomyoma.

Diagnosis of the disorder is based on a careful clinical exam in combination with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain—which may show tubers in the brain, and an ultrasound of the heart, liver, and kidneys, which may show tumors in those organs. Doctors should carefully examine the skin for a wide variety of skin features, the fingernails, and toenails for ungual fibromas; the teeth and gums for dental pits and/or gum fibromas; and the eyes for retinal lesions. A small hand-help lamp that uses black light, otherwise known as ultraviolet light, may show hypomelanotic macules which are sometimes hard to see on infants and individuals with pale or fair skin. A doctor experienced in the diagnosis of TSC should evaluate a potential patient.

In infants, TSC may be suspected if the child has cardiac rhabdomyomas at birth or seizures (especially the kind called infantile spasms) in the first six months of life. With a careful examination of the skin and brain, it may be possible to diagnose TSC in a very young infant. However, many children are not diagnosed until later in life when their seizures begin and other symptoms such as facial angiofibromas appear.

Treatment of Tuberous Sclerosis Complex

Treatment is

• mTOR inhibitor medicines – can be used to treat brain tumours, kidney tumours and epilepsy caused by TSC

• anti-epileptic medicines – to treat the associated seizures. Medication needs to be carefully monitored to make sure the child isn’t over-sedated

• brain surgery – if seizures cannot be controlled, it may be possible to remove lesions in the brain to reduce seizures

• skin treatments – dermatologists can provide advice on both surgical and medical treatment for the skin signs of TSC, including mTOR inhibitor creams.

• occupational therapy – can help children acquire skills and strategies

• speech therapy – can assist communication skills.

There is no cure for TSC, although treatment is available for a number of the symptoms. Antiepileptic drugs may be used to control seizures. Vigabatrin is a particularly useful medication in TSC and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of infantile spasms in TSC, although it has significant side effects. The FDA has approved the drug everolimus (Afinitor®) to treat subependymal giant cell astrocytomas (SEGA brain tumors) and angiomyolipoma kidney tumors, in addition to intractable seizures (seizures not controlled well by medicine). Specific medications may be prescribed for behavior problems. Intervention programs including special school programs and various therapies (such as physical, occupational, and speech therapies) may benefit individuals with special needs and developmental issues. Surgery may be needed in case of complications connected to tubers, subependymal nodules, or SEGA, as well as in risk of hemorrhage from kidney tumors. Respiratory insufficiency due to LAM can be treated with supplemental oxygen therapy or lung transplantation, if severe.

Skin lesions, particularly facial angiofibromas, may be psychologically distressing for some patients. Laser treatment or electrosurgery can be used to remove angiofibroma.

The topical mTOR inhibitor sirolimus 0.2% gel (also called rapamycin) has proved helpful in reducing angiofibromas in a clinical trial involving 36 adults and children. One study has also reported improvement in hypopigmented macules. A larger prospective, multicentre, randomized, double-blind, vehicle-controlled trial enrolled 179 patients with tuberous sclerosis-related facial angiofibromas and found improvement in more than 80% of patients treated with topical 1% rapamycin with most occurring in the first month.

Infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).

Treatment may require the coordinated efforts of a team of specialists. Pediatricians and general internists, neurologists, dermatologists, cardiologists, dental specialists, eye specialists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.

The treatment for tuberous sclerosis is supportive and symptomatic. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.

Anti-seizure drugs (anticonvulsants) may be prescribed to control seizures. The specific drug that is used will depend on several factors including the specific type of seizure, an affected individual’s age, other organ systems that are affected, and the severity of symptoms. Conventional anticonvulsants drugs that may be administered include phenobarbital, Dilantin (phenytoin), Klonopin (clonazepam), Depakene/Depakote (valproic acid/divalproex sodium), Tegretol (carbamazepine), Trileptal (oxcarbazepine), Topamax (topiramate), Lamictal (lamotrigine), Zonegran (zonisemide), Vimpat (lacosamide), Banzel (rufinamide), Onfi (clobazam), and others. All these anticonvulsants have potential side effects and require careful monitoring by a physician.

Two drugs have been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of seizures associated with tuberous sclerosis. FDA approved Afinitor (everolimus) for the treatment of seizures in adult and pediatric patients aged 2 years and older with tuberous sclerosis in 2018, and Epidiolex (cannabidiol) for patients one year and older in 2020.

Sabril (vigabatrin) was approved in 2009 by the FDA to treat infantile spasms in children ages 1 month to 2 years. Treatment of children with tuberous sclerosis and infantile spasms with vigabatrin has been found to be effective. Visual field loss is an important safety concern with the use of this medication. The FDA has also approved adreno-corticotrophic hormone or ACTH (Acthar gel) for the treatment of infantile spasms. This medication has also been used to treat infants with tuberous sclerosis. These medications are used cautiously because of their side effects.

No specific anti-seizure medication works for all affected individuals. Often, a combination of different drugs may be required to treat some individuals. Alternative treatments include the ketogenic diet or the glycemic diet. Sometimes, seizures can be difficult to treat and medications or diets that initially worked will no longer provide benefit (refractory seizures). In some instances, seizure surgery to remove areas of brain dysplasia may be necessary to help to control seizures that don’t respond or stop responding to medications. Less invasive surgical options to control seizures include the implanting of a vagal nerve stimulator (VNS device). This is a small electrical stimulator placed under the skin over the upper chest and connected to one vagal nerve in order to provide intermittent electrical stimulus, like a pacemaker to the brain.

Surgery of other organs may be necessary if the ability of a particular organ to function properly is impaired by the presence of a tumor. For example, the obstruction of cerebrospinal fluid (CSF) circulation inside the brain (intracranial hypertension) because of a benign tumor may require a shunting procedure to drain the liquid or the surgical removal of the tumor.

In 2012, the FDA approved the use of Afinitor (everolimus) for the treatment of children and adults with tuberous sclerosis who have a subependymal giant cell astrocytoma that cannot be removed or can be only partially removed by surgery. The FDA also approved everolimus for the treatment of adults with tuberous sclerosis who have an angiomyolipoma of the kidney that does not require surgery right away. In some instances, angiomyolipomas will require surgery or embolization therapy. Cutting off the blood supply (arterial embolization) to a kidney tumor may be used to shrink down the size of the tumor. Embolization is usually followed by treatment with corticosteroids and surgical removal (resection) of the tumor that spares the kidney or by destruction (ablation) of the tumor. Large cystic lesions of the kidneys may also require surgical decompression or removal.

In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.^[rx]

• Take a personal and family history covering three generations. Genetic counseling and tests determine if other individuals are at risk.

• A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).

• Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.

• Assess children for behavioral issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.

• Scan the abdomen for tumors in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.

• In adult women, test pulmonary function and perform a high-resolution computed tomography (HRCT) of the chest.

• Examine the skin under a Wood’s lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas).

• In infants under three, perform an echocardiogram to spot rhabdomyoma, and electrocardiogram (ECG) for any arrhythmia.

• Use a fundoscopy to spot retinal hamartomas or achromic patches.

A benign tumor inside the heart (rhabdomyoma) may not cause symptoms and generally does not require treatment as they often regress on their own within the first several years after birth. If symptomatic, however, surgical removal (resection) may be necessary. Reports in the medical literature have detailed the off-label use of mTOR inhibitors to treat these tumors with positive results. Some affected individuals may be prescribed certain medications to treat irregular heartbeats (arrhythmias).

Individuals taking mTOR inhibitors for internal tumors (e.g. SEGAs or angiomyolipomas) may see improvement in skin lesions. Topical formulations of mTOR inhibitors have shown promise in treating facial angiofibromas. Individuals with no immediate indication for mTOR inhibitor treatment may undergo certain procedures to improve the appearance of skin lesions including dermabrasion, laser therapy, or surgical removal (excision) of a lesion.

In 2015, the FDA approved the use of mTOR inhibitors for the treatment of lung complications such as LAM in individuals with tuberous sclerosis. Because LAM occurs most often in young women of childbearing age, researchers have speculated that female hormones such as estrogen play a role in the development of the disorder. A link between LAM and female hormones has not been proven. However, many physicians have explored the use of agents that lower the production or effects of estrogen in the body. The results have varied greatly among individuals. Such agents may include medroxyprogesterone acetate. Estrogen-containing medications and dietary supplements should be discontinued in patients with LAM.

Supplemental oxygen therapy may be necessary for some individuals with impaired lung function. In individuals with severe lung disease that is resistant to treatment, a lung transplant may ultimately become necessary.

Because TSC is a lifelong condition, individuals need to be regularly monitored by a doctor to make sure they are receiving the best possible treatments. Due to the many varied symptoms of TSC, care by a clinician experienced with the disorder is recommended.

Basic laboratory studies have revealed insight into the function of the TSC genes and have led to use of rapamycin (mTOR) inhibitors and related drugs for treating some of the manifestations of TSC.

Associate Treatment

• Surgery. If a growth affects the ability of a specific organ — such as the kidney or heart — to function, the growth may be surgically removed. Sometimes surgery helps control seizures caused by brain growths that don’t respond to medication. Surgical procedures such as dermabrasion or laser treatment may improve the appearance of skin growths.
• Various types of therapy. Early intervention services, such as occupational, physical or speech therapy, can help children with tuberous sclerosis who have special needs in these areas improve their ability to manage daily tasks and activities.
• Educational and vocational services. Early intervention and special needs services can help children with developmental delays and behavior issues adapt to the classroom so that they can meet their full potential. When needed, social, vocational and rehabilitation services may continue throughout life.
• Psychiatric and behavior management. Talking with a mental health provider may help children accept and adjust to living with this disorder. A mental health provider can also help address behavioral, social or emotional issues and recommend resources.

Ongoing monitoring

Tuberous sclerosis is a lifelong condition that requires careful monitoring and follow-up because many signs and symptoms may take years to develop. A schedule of regular follow-up monitoring throughout life may include tests similar to those done during diagnosis. Early identification of problems can help prevent complications.

What is the prognosis?

The prognosis for individuals with TSC is highly variable and depends on the severity of symptoms. Those individuals with mild symptoms usually do well and have a normal life expectancy, while paying attention to TSC-specific issues. Individuals who are severely affected can suffer from severe mental retardation and persistent epilepsy.

All individuals with TSC are at risk for life-threatening conditions related to brain tumors, kidney lesions, or LAM. Continued monitoring by a physician experienced with TSC is important. With appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.

QUESTIONS

1. Tuberous sclerosis complex is a genodermatosis:

   1. Autosomal dominant with hamartomas that affect multiple organs.

   2. Autosomal recessive with hamartomas that affect multiple organs.

   3. Autosomal dominant predominantly affecting females, and the most commonly affected organs are skin, central nervous system, heart, lungs and kidneys.

   4. Autosomal recessive with vascular malformations in many organs, being the most affected skin and central nervous system.

2. The classical tuberous sclerosis triad is characterized by:

   1. Shagreen patch, facial angiofibromas and mental retardation.

   2. Epilepsy, sebaceous adenoma and shagreen patch.

   3. Facial angiofibromas, fibrous cephalic plaque and epilepsy.

   4. Mental retardation, epilepsy and sebaceous adenoma (angiofibroma).

3. Choose the sentence with the correct sequence:

   • ( ) Skin lesions are found in more than 90% of cases, the majority appearing in the 3^rd decade of life.

   • ( ) “Ash-leaf” lesions tend to follow Blaschko lines when on the trunk, typical for type 3 mosaicism.

   • ( ) Hypopigmented macules in “confetti” or guttate leukoderma are hypopigmented macules that appear over the years.

   • ( ) Hypopigmented macules are many times found since birth, allowing for the early diagnosis of the disease when associated to other clinical findings.

     1. F T T F

     2. F F F T

     3. T T F T

     4. F T F T

4. About connective tissue nevi and ungual fibromas or Koenen tumors, it is correct to say that:

   1. Connective tissue nevi seen in TSC are normal-colored to brown plaques restricted to the lumbosacral region.

   2. Shagreen patch many times have the aspect of orange peel and are found on the upper back.

   3. Fibrous cephalic plaque is present in more than 80% of cases, being most commonly found on one side of the forehead.

   4. Koenen tumor usually appears during adolescence and has a predilection for females and the toes.

5. According to the systemic manifestations of TSC, we can affirm that the correct items are:

   1. Angiomyolipomas increase progressively from infancy and stop growing in the elderly.

   2. Renal lesions have an indolent, clinically asymptomatic course, with no potentially severe repercussions in the patient’s life.

   3. In cases of patients that evolve with hematuria in adulthood, the possibility of malignant transformation of the angiomyolipomas must be kept in mind, since they are usually asymptomatic.

   4. Lymphangioleiomyomatosis affects predominantly younger women with the first manifestations after early adolescence.

   5. Rhabdomyoma is the most common cardiac tumor and tends to grow progressively in the first year, when it stabilizes and continues until adulthood.

      1. 1 – 3

      2. 2 – 4

      3. 3 – 5

      4. 1 – 4

   6. Choose the INCORRECT option:

      1. The identification of the pathogenic TSC1 or TSC2 DNA mutation is not enough to establish the diagnosis of TSC.

      2. Molecular testing yields a positive result in 75% to 90% of TSC patients.

      3. In 10% to 25% of patients, conventional genetic testing does not identify the pathogenic TSC1 or TSC2 mutation.

      4. The identification of the pathogenic mutation for TSC in conventional genetic testing configures an independent diagnostic criterion.

6. About the diagnostic criteria for the tuberous sclerosis complex, reviewed in 2012, in the second International Tuberous Sclerosis Complex Consensus Conference, all are included as extracutaneous manifestations, EXCEPT:

   1. Subependymal giant cell astrocytoma.

   2. Cardiac rhabdomyoma.

   3. Lymphangioleiomyomatosis.

   4. Pigmented hamartomas of the iris.

7. It is a MAJOR clinical criterion for the diagnosis of TSC:

   1. ≥ 5 hypopigmented macules with at least 3mm diameter.

   2. ≥ 3 facial angiofibromas.

   3. ≥ 2 intraoral fibromas.

   4. > 3 dental enamel pits.

8. From the dermatological point of view, many destructive or surgical treatment options are used to reduce the development of and remove facial angiofibromas. It is correct to say that:

   1. The destructive procedures are usually comfortable for the patient and can be performed at any age.

   2. It usually is not necessary to repeat laser treatments periodically because the lesions tend not to recur.

   3. Are therapeutic options for facial angiofibromas dermabrasion, surgical excision, electrocautery and laser.

   4. It is not necessary to combine therapeutic methods to optimize results since that regardless of the treatment chosen, all provide satisfactory results.

9. Diagnostic suspicion of TSC comes from the following findings, EXCEPT:

   1. Antenatal detection of cardiac rhabdomyomas.

   2. Post-natal identification of hypopigmented patches on the skin.

   3. Visualization of ephelis on the axillary or inguinal regions.

   4. Seizures in childhood, particularly with spasms.

References

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Bourneville disease, also known as Tuberous sclerosis, tuberous sclerosis complex is a neurocutaneous disorder (phakomatosis) characterized by the development of multiple benign tumors of the embryonic ectoderm (e.g. skin, eyes, and nervous system).

Tuberous sclerosis complex is a multisystemic, autosomal dominant neurocutaneous genetic disorder with complete penetrance, hamartomatous growths in multiple organ systems that can evolve with hamartomas in multiple organs, by causing the growth of benign tumors, so-called hamartomas. As brain, skin, kidneys, heart, liver, lungs, and less frequently retina, gingiva, bones, and gastrointestinal tract can be affected, TSC patients require coordinated care of many specialties.

Hamartomas – plural of hamartoma; benign overgrowths of a mature cell type normal to the site or organ. They may be congenital or acquired

Tuberous sclerosis (also called tuberous sclerosis complex, or TSC) is a rare, multi-system genetic disease that causes non-cancerous (benign) tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and can result in a combination of symptoms including seizures, impaired intellectual development, autism, behavioral problems, skin abnormalities, and kidney disease.

The severity of symptoms varies widely. Symptoms range from mild—allowing people to live independent, productive lives—to more severe symptoms that can affect everyday life and even be life-threatening. Many people with TSC show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.

The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify with age and becomes hard or sclerotic. TSC occurs in all races and ethnic groups, and in both genders.

Causes of Tuberous Sclerosis Complex

TSC is caused by defects, or mutations, on two genes—TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene is on chromosome 9 and produces a protein called hamartin. The TSC2 gene is on chromosome 16 and produces the protein tuberin. Scientists believe these proteins act as growth suppressors by inhibiting the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.

Mutations in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins likely work together to help regulate cell growth and size. The proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way.

People with tuberous sclerosis complex are born with one mutated copy of the TSC1 or TSC2 gene in each cell. This mutation prevents the cell from making functional hamartin or tuberin from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For some types of tumors to develop, a second mutation involving the other copy of the TSC1 or TSC2 gene must occur in certain cells during a person’s lifetime.

When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin; cells with two altered copies of the TSC2 gene are unable to produce any functional tuberin. The loss of these proteins allows the cell to grow and divide in an uncontrolled way to form a tumor. In people with tuberous sclerosis complex, a second TSC1 or TSC2 mutation typically occurs in multiple cells over an affected person’s lifetime. The loss of hamartin or tuberin in different types of cells leads to the growth of tumors in many different organs and tissues.

Is TSC inherited?

Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2—meaning neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.

In cases where TSC is inherited, only one parent needs to have the faulty gene in order to pass it on to a child (called autosomal dominant inheritance). If a parent has TSC, each child has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and may have either a milder or a more severe form of the disorder.

In rare instances, people acquire TSC through a process called gonadal mosaicism. These individuals have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent’s reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved. In cases of gonadal mosaicism, genetic testing of a blood sample might not reveal the potential for passing the disease to offspring.

Symptoms of Tuberous Sclerosis Complex

TSC can affect many different systems of the body, causing a variety of signs and symptoms that range from very mild to quite severe. Common symptoms include:

Benign tumors are most common in the brain, kidneys, heart, lungs, and skin. Cancerous tumors are rare in TSC and those that do occur primarily affect the kidneys.

Three types of brain lesions are seen in TSC:

• Cortical tubers – for which the disease is named, generally form on the surface of the brain but may also appear in the deep areas of the brain
• Subependymal nodules (SEN) – which form in the walls of the ventricles—the fluid-filled cavities of the brain, and
• Subependymal giant-cell astrocytomas (SEGA) – which develop from SEN and grow such that they may block the flow of fluid within the brain—causing a buildup of fluid and pressure that can lead to headaches and blurred vision.

Tumors called cardiac rhabdomyomas are often found in the hearts of infants and young children with TSC, and they are often seen on prenatal fetus ultrasound exams. If the tumors are large or there are multiple tumors, they can block circulation and cause death. However, if they do not cause problems at birth—when in most cases they are at their largest size—they usually become smaller with time and do not affect the individual in later life.

Benign tumors called pakoras are sometimes found in the eyes of individuals with TSC, appearing as white patches on the retina. Generally, they do not cause vision loss or other vision problems, but they can be used to help diagnose the disease.

Additional tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas. Bone cysts, rectal polyps, gum fibromas, and dental pits may also occur.

Seizures affect most individuals with TSC at some point during their life. While some kinds of seizures caused by TSC result in obvious convulsive movements, others alter awareness, behavior, or postural tone without convulsions. Seizures also can be difficult to control by medication, and sometimes surgery or other measures are used.

Cognitive disabilities affect some people with TSC. Developmental delay occurs in about one-half to two-thirds of people with TSC. Delays range from mild learning disabilities to severe impairment.

Behavior problems, including aggression, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior occur in children with TSC and can be difficult to manage. About one-third of children with TSC meet the criteria for autism spectrum disorder.

Skin abnormalities vary widely in individuals with TSC. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:

• Hypomanic macules (“ash leaf spots”), which are white or lighter patches of skin that may appear anywhere on the body and are caused by a lack of skin pigment or melanin—the substance that gives skin its color.
• Facial angiofibromas (also called adenoma sebaceous) are reddish spots or bumps which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.
• Forehead plaques are raised, discolored areas on the forehead which are common and unique to TSC and may help doctors diagnose the disorder.
• Shagreen patches are areas of thick leathery, pebbly skin, usually found on the lower back or nape of the neck.
• Ungual or subungual fibromas are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These usually appear later in life, ages 20-50.
• Other skin features that are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders; café au lait spots or flat brown marks; and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.

Kidney problems such as cysts and angiomyolipomas (benign growths of fatty tissue and muscle cells) occur in an estimated 70 to 80 percent of individuals with TSC. They usually occur between ages 15 and 30.

• Cysts are usually small, appear in limited numbers, and most often cause no serious problems. A very small percent of individuals with TSC develop large numbers of cysts during childhood, which may lead to bleeding, anemia, and kidney failure.
• Angiomyolipomas are the most common kidney lesions in TSC and can be found in people without TSC. Angiomyolipomas caused by TSC are usually found in both kidneys and in most cases do not produce symptoms. However, they can sometimes grow so large that they cause pain or kidney failure. Bleeding from angiomyolipomas may also occur, causing both pain and weakness. If severe bleeding does not stop naturally, there may be severe blood loss, resulting in profound anemia and a life-threatening drop in blood pressure, warranting urgent medical attention.
• Other rare kidney problems include renal cell carcinoma, developing from an angiomyolipoma, and oncocytomas, benign tumors unique to individuals with TSC.

Associate signs of tuberous sclerosis can appear later in childhood or even into adulthood. These symptoms may include:

• White spots on the skin (called hypopigmented macules) that glow under a special lamp

• A rash on the face (called facial angiofibromas) that may look like acne

• Problems with the kidneys (associated with growths in the kidneys)

• Areas of very thick skin, often on the back

• Growths under or around the nails

• Pitted teeth

• Coughing or shortness of breath

• Mental disabilities.

• Developmental delays

• Autism spectrum disorder

Lung lesions are present in about one-third of adult women with TSC and are much less commonly seen in men.  Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH).  LAM is a tumor-like disorder in which cells proliferate in the lungs, and there is lung destruction with cyst formation. A range of symptoms can occur with LAM, with many TSC individuals having no symptoms, while others suffer with breathlessness, which can progress and be severe. MMPH is a more benign tumor that occurs in men and women equally.

As per the recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference, the diagnostic criteria for tuberous sclerosis include the following major and minor features[rx][rx]:

Major Features

• Hypomelanotic macules (more than 2, and at least 5-mm in diameter)
• Angiofibromas (more than 2) or fibrous cephalic plaque
• Ungual fibromas (more than 1)
• Shagreen patch
• Multiple retinal hamartomas
• Cortical dysplasias
• Subependymal nodules
• Subependymal giant cell astrocytoma
• Cardiac rhabdomyoma
• Lymphangioleiomyomatosis
• Angiomyolipomas (more than 1)
• More than 2 angiofibromas, which are skin-colored growths of blood vessels in the skin or a thick (fibrous) patch of skin on the forehead
• 2 or more periungual fibromas or hard growths, around or under the fingernails or toenails
• More than 3 light-colored areas on the skin, known as hypomelanotic macules or ash leaf spots
• Shagreen patch, meaning a rough growth of tissue on the surface of the skin
• Tubers, or thickened areas, found in the brain
• Nodules (round growths) found in the brain
• Subependymal giant cell astrocytoma (SEGA), a type of brain cancer
• Cardiac rhabdomyoma, which is a benign, noncancerous heart growth
• Angiomyolipoma of the kidney, which are benign growths that can cause serious medical problems; there is a low risk that these tumors could become cancerous
• Lymphangiomyomatosis, which are multiple cysts or fluid-filled growths along the lymphatic system under the skin
• Multiple hemangioblastomas, which are growths of newly formed blood vessels, of the brain, spinal cord, or eye
• One or more hemangioblastomas in addition to kidney cysts, pancreatic cysts, pheochromocytoma, which is a rare growth in the cells of one of the adrenal glands, or kidney cancer

Minor Features

• Confetti skin lesions
• Dental enamel Pitts (more than 3)
• Intraoral fibromas (more than 1)
• Retinal achromic patch
• Multiple renal cysts
• Nonrenal hamartomas
• Multiple pits or dents in the teeth
• Fibromas (growths) of the gums inside the mouth
• Multiple kidney cysts
• Pale discolorations in the skin, called “confetti.”
• Changes in the retina inside the eye
• Hamartomas, which are benign tissue growths

Definitive diagnosis is established in patients with two major features or one major feature with at least 2 minor features, while “possible diagnosis” is recognized in patients with one major feature or at least 2 minor features.[rx][rx]

Diagnosis of Tuberous Sclerosis Complex

Diagnosing TSC is based upon clinical criteria.  The first clue may be the presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules) or the identification of cardiac tumor rhabdomyoma.

Diagnosis of the disorder is based on a careful clinical exam in combination with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain—which may show tubers in the brain, and an ultrasound of the heart, liver, and kidneys, which may show tumors in those organs. Doctors should carefully examine the skin for a wide variety of skin features, the fingernails, and toenails for ungual fibromas; the teeth and gums for dental pits and/or gum fibromas; and the eyes for retinal lesions. A small hand-help lamp that uses black light, otherwise known as ultraviolet light, may show hypomelanotic macules which are sometimes hard to see on infants and individuals with pale or fair skin. A doctor experienced in the diagnosis of TSC should evaluate a potential patient.

In infants, TSC may be suspected if the child has cardiac rhabdomyomas at birth or seizures (especially the kind called infantile spasms) in the first six months of life. With a careful examination of the skin and brain, it may be possible to diagnose TSC in a very young infant. However, many children are not diagnosed until later in life when their seizures begin and other symptoms such as facial angiofibromas appear.

Treatment of Tuberous Sclerosis Complex

Treatment is

• mTOR inhibitor medicines – can be used to treat brain tumours, kidney tumours and epilepsy caused by TSC

• anti-epileptic medicines – to treat the associated seizures. Medication needs to be carefully monitored to make sure the child isn’t over-sedated

• brain surgery – if seizures cannot be controlled, it may be possible to remove lesions in the brain to reduce seizures

• skin treatments – dermatologists can provide advice on both surgical and medical treatment for the skin signs of TSC, including mTOR inhibitor creams.

• occupational therapy – can help children acquire skills and strategies

• speech therapy – can assist communication skills.

There is no cure for TSC, although treatment is available for a number of the symptoms. Antiepileptic drugs may be used to control seizures. Vigabatrin is a particularly useful medication in TSC and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of infantile spasms in TSC, although it has significant side effects. The FDA has approved the drug everolimus (Afinitor®) to treat subependymal giant cell astrocytomas (SEGA brain tumors) and angiomyolipoma kidney tumors, in addition to intractable seizures (seizures not controlled well by medicine). Specific medications may be prescribed for behavior problems. Intervention programs including special school programs and various therapies (such as physical, occupational, and speech therapies) may benefit individuals with special needs and developmental issues. Surgery may be needed in case of complications connected to tubers, subependymal nodules, or SEGA, as well as in risk of hemorrhage from kidney tumors. Respiratory insufficiency due to LAM can be treated with supplemental oxygen therapy or lung transplantation, if severe.

Skin lesions, particularly facial angiofibromas, may be psychologically distressing for some patients. Laser treatment or electrosurgery can be used to remove angiofibroma.

The topical mTOR inhibitor sirolimus 0.2% gel (also called rapamycin) has proved helpful in reducing angiofibromas in a clinical trial involving 36 adults and children. One study has also reported improvement in hypopigmented macules. A larger prospective, multicentre, randomized, double-blind, vehicle-controlled trial enrolled 179 patients with tuberous sclerosis-related facial angiofibromas and found improvement in more than 80% of patients treated with topical 1% rapamycin with most occurring in the first month.

Infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).

Treatment may require the coordinated efforts of a team of specialists. Pediatricians and general internists, neurologists, dermatologists, cardiologists, dental specialists, eye specialists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.

The treatment for tuberous sclerosis is supportive and symptomatic. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.

Anti-seizure drugs (anticonvulsants) may be prescribed to control seizures. The specific drug that is used will depend on several factors including the specific type of seizure, an affected individual’s age, other organ systems that are affected, and the severity of symptoms. Conventional anticonvulsants drugs that may be administered include phenobarbital, Dilantin (phenytoin), Klonopin (clonazepam), Depakene/Depakote (valproic acid/divalproex sodium), Tegretol (carbamazepine), Trileptal (oxcarbazepine), Topamax (topiramate), Lamictal (lamotrigine), Zonegran (zonisemide), Vimpat (lacosamide), Banzel (rufinamide), Onfi (clobazam), and others. All these anticonvulsants have potential side effects and require careful monitoring by a physician.

Two drugs have been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of seizures associated with tuberous sclerosis. FDA approved Afinitor (everolimus) for the treatment of seizures in adult and pediatric patients aged 2 years and older with tuberous sclerosis in 2018, and Epidiolex (cannabidiol) for patients one year and older in 2020.

Sabril (vigabatrin) was approved in 2009 by the FDA to treat infantile spasms in children ages 1 month to 2 years. Treatment of children with tuberous sclerosis and infantile spasms with vigabatrin has been found to be effective. Visual field loss is an important safety concern with the use of this medication. The FDA has also approved adreno-corticotrophic hormone or ACTH (Acthar gel) for the treatment of infantile spasms. This medication has also been used to treat infants with tuberous sclerosis. These medications are used cautiously because of their side effects.

No specific anti-seizure medication works for all affected individuals. Often, a combination of different drugs may be required to treat some individuals. Alternative treatments include the ketogenic diet or the glycemic diet. Sometimes, seizures can be difficult to treat and medications or diets that initially worked will no longer provide benefit (refractory seizures). In some instances, seizure surgery to remove areas of brain dysplasia may be necessary to help to control seizures that don’t respond or stop responding to medications. Less invasive surgical options to control seizures include the implanting of a vagal nerve stimulator (VNS device). This is a small electrical stimulator placed under the skin over the upper chest and connected to one vagal nerve in order to provide intermittent electrical stimulus, like a pacemaker to the brain.

Surgery of other organs may be necessary if the ability of a particular organ to function properly is impaired by the presence of a tumor. For example, the obstruction of cerebrospinal fluid (CSF) circulation inside the brain (intracranial hypertension) because of a benign tumor may require a shunting procedure to drain the liquid or the surgical removal of the tumor.

In 2012, the FDA approved the use of Afinitor (everolimus) for the treatment of children and adults with tuberous sclerosis who have a subependymal giant cell astrocytoma that cannot be removed or can be only partially removed by surgery. The FDA also approved everolimus for the treatment of adults with tuberous sclerosis who have an angiomyolipoma of the kidney that does not require surgery right away. In some instances, angiomyolipomas will require surgery or embolization therapy. Cutting off the blood supply (arterial embolization) to a kidney tumor may be used to shrink down the size of the tumor. Embolization is usually followed by treatment with corticosteroids and surgical removal (resection) of the tumor that spares the kidney or by destruction (ablation) of the tumor. Large cystic lesions of the kidneys may also require surgical decompression or removal.

In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.^[rx]

• Take a personal and family history covering three generations. Genetic counseling and tests determine if other individuals are at risk.

• A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).

• Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.

• Assess children for behavioral issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.

• Scan the abdomen for tumors in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.

• In adult women, test pulmonary function and perform a high-resolution computed tomography (HRCT) of the chest.

• Examine the skin under a Wood’s lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas).

• In infants under three, perform an echocardiogram to spot rhabdomyoma, and electrocardiogram (ECG) for any arrhythmia.

• Use a fundoscopy to spot retinal hamartomas or achromic patches.

A benign tumor inside the heart (rhabdomyoma) may not cause symptoms and generally does not require treatment as they often regress on their own within the first several years after birth. If symptomatic, however, surgical removal (resection) may be necessary. Reports in the medical literature have detailed the off-label use of mTOR inhibitors to treat these tumors with positive results. Some affected individuals may be prescribed certain medications to treat irregular heartbeats (arrhythmias).

Individuals taking mTOR inhibitors for internal tumors (e.g. SEGAs or angiomyolipomas) may see improvement in skin lesions. Topical formulations of mTOR inhibitors have shown promise in treating facial angiofibromas. Individuals with no immediate indication for mTOR inhibitor treatment may undergo certain procedures to improve the appearance of skin lesions including dermabrasion, laser therapy, or surgical removal (excision) of a lesion.

In 2015, the FDA approved the use of mTOR inhibitors for the treatment of lung complications such as LAM in individuals with tuberous sclerosis. Because LAM occurs most often in young women of childbearing age, researchers have speculated that female hormones such as estrogen play a role in the development of the disorder. A link between LAM and female hormones has not been proven. However, many physicians have explored the use of agents that lower the production or effects of estrogen in the body. The results have varied greatly among individuals. Such agents may include medroxyprogesterone acetate. Estrogen-containing medications and dietary supplements should be discontinued in patients with LAM.

Supplemental oxygen therapy may be necessary for some individuals with impaired lung function. In individuals with severe lung disease that is resistant to treatment, a lung transplant may ultimately become necessary.

Because TSC is a lifelong condition, individuals need to be regularly monitored by a doctor to make sure they are receiving the best possible treatments. Due to the many varied symptoms of TSC, care by a clinician experienced with the disorder is recommended.

Basic laboratory studies have revealed insight into the function of the TSC genes and have led to use of rapamycin (mTOR) inhibitors and related drugs for treating some of the manifestations of TSC.

Associate Treatment

• Surgery. If a growth affects the ability of a specific organ — such as the kidney or heart — to function, the growth may be surgically removed. Sometimes surgery helps control seizures caused by brain growths that don’t respond to medication. Surgical procedures such as dermabrasion or laser treatment may improve the appearance of skin growths.
• Various types of therapy. Early intervention services, such as occupational, physical or speech therapy, can help children with tuberous sclerosis who have special needs in these areas improve their ability to manage daily tasks and activities.
• Educational and vocational services. Early intervention and special needs services can help children with developmental delays and behavior issues adapt to the classroom so that they can meet their full potential. When needed, social, vocational and rehabilitation services may continue throughout life.
• Psychiatric and behavior management. Talking with a mental health provider may help children accept and adjust to living with this disorder. A mental health provider can also help address behavioral, social or emotional issues and recommend resources.

Ongoing monitoring

Tuberous sclerosis is a lifelong condition that requires careful monitoring and follow-up because many signs and symptoms may take years to develop. A schedule of regular follow-up monitoring throughout life may include tests similar to those done during diagnosis. Early identification of problems can help prevent complications.

What is the prognosis?

The prognosis for individuals with TSC is highly variable and depends on the severity of symptoms. Those individuals with mild symptoms usually do well and have a normal life expectancy, while paying attention to TSC-specific issues. Individuals who are severely affected can suffer from severe mental retardation and persistent epilepsy.

All individuals with TSC are at risk for life-threatening conditions related to brain tumors, kidney lesions, or LAM. Continued monitoring by a physician experienced with TSC is important. With appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.

QUESTIONS

1. Tuberous sclerosis complex is a genodermatosis:

   1. Autosomal dominant with hamartomas that affect multiple organs.

   2. Autosomal recessive with hamartomas that affect multiple organs.

   3. Autosomal dominant predominantly affecting females, and the most commonly affected organs are skin, central nervous system, heart, lungs and kidneys.

   4. Autosomal recessive with vascular malformations in many organs, being the most affected skin and central nervous system.

2. The classical tuberous sclerosis triad is characterized by:

   1. Shagreen patch, facial angiofibromas and mental retardation.

   2. Epilepsy, sebaceous adenoma and shagreen patch.

   3. Facial angiofibromas, fibrous cephalic plaque and epilepsy.

   4. Mental retardation, epilepsy and sebaceous adenoma (angiofibroma).

3. Choose the sentence with the correct sequence:

   • ( ) Skin lesions are found in more than 90% of cases, the majority appearing in the 3^rd decade of life.

   • ( ) “Ash-leaf” lesions tend to follow Blaschko lines when on the trunk, typical for type 3 mosaicism.

   • ( ) Hypopigmented macules in “confetti” or guttate leukoderma are hypopigmented macules that appear over the years.

   • ( ) Hypopigmented macules are many times found since birth, allowing for the early diagnosis of the disease when associated to other clinical findings.

     1. F T T F

     2. F F F T

     3. T T F T

     4. F T F T

4. About connective tissue nevi and ungual fibromas or Koenen tumors, it is correct to say that:

   1. Connective tissue nevi seen in TSC are normal-colored to brown plaques restricted to the lumbosacral region.

   2. Shagreen patch many times have the aspect of orange peel and are found on the upper back.

   3. Fibrous cephalic plaque is present in more than 80% of cases, being most commonly found on one side of the forehead.

   4. Koenen tumor usually appears during adolescence and has a predilection for females and the toes.

5. According to the systemic manifestations of TSC, we can affirm that the correct items are:

   1. Angiomyolipomas increase progressively from infancy and stop growing in the elderly.

   2. Renal lesions have an indolent, clinically asymptomatic course, with no potentially severe repercussions in the patient’s life.

   3. In cases of patients that evolve with hematuria in adulthood, the possibility of malignant transformation of the angiomyolipomas must be kept in mind, since they are usually asymptomatic.

   4. Lymphangioleiomyomatosis affects predominantly younger women with the first manifestations after early adolescence.

   5. Rhabdomyoma is the most common cardiac tumor and tends to grow progressively in the first year, when it stabilizes and continues until adulthood.

      1. 1 – 3

      2. 2 – 4

      3. 3 – 5

      4. 1 – 4

   6. Choose the INCORRECT option:

      1. The identification of the pathogenic TSC1 or TSC2 DNA mutation is not enough to establish the diagnosis of TSC.

      2. Molecular testing yields a positive result in 75% to 90% of TSC patients.

      3. In 10% to 25% of patients, conventional genetic testing does not identify the pathogenic TSC1 or TSC2 mutation.

      4. The identification of the pathogenic mutation for TSC in conventional genetic testing configures an independent diagnostic criterion.

6. About the diagnostic criteria for the tuberous sclerosis complex, reviewed in 2012, in the second International Tuberous Sclerosis Complex Consensus Conference, all are included as extracutaneous manifestations, EXCEPT:

   1. Subependymal giant cell astrocytoma.

   2. Cardiac rhabdomyoma.

   3. Lymphangioleiomyomatosis.

   4. Pigmented hamartomas of the iris.

7. It is a MAJOR clinical criterion for the diagnosis of TSC:

   1. ≥ 5 hypopigmented macules with at least 3mm diameter.

   2. ≥ 3 facial angiofibromas.

   3. ≥ 2 intraoral fibromas.

   4. > 3 dental enamel pits.

8. From the dermatological point of view, many destructive or surgical treatment options are used to reduce the development of and remove facial angiofibromas. It is correct to say that:

   1. The destructive procedures are usually comfortable for the patient and can be performed at any age.

   2. It usually is not necessary to repeat laser treatments periodically because the lesions tend not to recur.

   3. Are therapeutic options for facial angiofibromas dermabrasion, surgical excision, electrocautery and laser.

   4. It is not necessary to combine therapeutic methods to optimize results since that regardless of the treatment chosen, all provide satisfactory results.

9. Diagnostic suspicion of TSC comes from the following findings, EXCEPT:

   1. Antenatal detection of cardiac rhabdomyomas.

   2. Post-natal identification of hypopigmented patches on the skin.

   3. Visualization of ephelis on the axillary or inguinal regions.

   4. Seizures in childhood, particularly with spasms.

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Tuberous sclerosis complex is a multisystemic, autosomal dominant neurocutaneous genetic disorder with complete penetrance, hamartomatous growths in multiple organ systems that can evolve with hamartomas in multiple organs, by causing the growth of benign tumors, so-called hamartomas. As brain, skin, kidneys, heart, liver, lungs, and less frequently retina, gingiva, bones, and gastrointestinal tract can be affected, TSC patients require coordinated care of many specialties.

Hamartomas – plural of hamartoma; benign overgrowths of a mature cell type normal to the site or organ. They may be congenital or acquired

Tuberous sclerosis (also called tuberous sclerosis complex, or TSC) is a rare, multi-system genetic disease that causes non-cancerous (benign) tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and can result in a combination of symptoms including seizures, impaired intellectual development, autism, behavioral problems, skin abnormalities, and kidney disease.

The severity of symptoms varies widely. Symptoms range from mild—allowing people to live independent, productive lives—to more severe symptoms that can affect everyday life and even be life-threatening. Many people with TSC show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.

The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify with age and becomes hard or sclerotic. TSC occurs in all races and ethnic groups, and in both genders.

Causes of Tuberous Sclerosis Complex

TSC is caused by defects, or mutations, on two genes—TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene is on chromosome 9 and produces a protein called hamartin. The TSC2 gene is on chromosome 16 and produces the protein tuberin. Scientists believe these proteins act as growth suppressors by inhibiting the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.

Mutations in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins likely work together to help regulate cell growth and size. The proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way.

People with tuberous sclerosis complex are born with one mutated copy of the TSC1 or TSC2 gene in each cell. This mutation prevents the cell from making functional hamartin or tuberin from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For some types of tumors to develop, a second mutation involving the other copy of the TSC1 or TSC2 gene must occur in certain cells during a person’s lifetime.

When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin; cells with two altered copies of the TSC2 gene are unable to produce any functional tuberin. The loss of these proteins allows the cell to grow and divide in an uncontrolled way to form a tumor. In people with tuberous sclerosis complex, a second TSC1 or TSC2 mutation typically occurs in multiple cells over an affected person’s lifetime. The loss of hamartin or tuberin in different types of cells leads to the growth of tumors in many different organs and tissues.

Is TSC inherited?

Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2—meaning neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.

In cases where TSC is inherited, only one parent needs to have the faulty gene in order to pass it on to a child (called autosomal dominant inheritance). If a parent has TSC, each child has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and may have either a milder or a more severe form of the disorder.

In rare instances, people acquire TSC through a process called gonadal mosaicism. These individuals have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent’s reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved. In cases of gonadal mosaicism, genetic testing of a blood sample might not reveal the potential for passing the disease to offspring.

Symptoms of Tuberous Sclerosis Complex

TSC can affect many different systems of the body, causing a variety of signs and symptoms that range from very mild to quite severe. Common symptoms include:

Benign tumors are most common in the brain, kidneys, heart, lungs, and skin. Cancerous tumors are rare in TSC and those that do occur primarily affect the kidneys.

Three types of brain lesions are seen in TSC:

• Cortical tubers – for which the disease is named, generally form on the surface of the brain but may also appear in the deep areas of the brain
• Subependymal nodules (SEN) – which form in the walls of the ventricles—the fluid-filled cavities of the brain, and
• Subependymal giant-cell astrocytomas (SEGA) – which develop from SEN and grow such that they may block the flow of fluid within the brain—causing a buildup of fluid and pressure that can lead to headaches and blurred vision.

Tumors called cardiac rhabdomyomas are often found in the hearts of infants and young children with TSC, and they are often seen on prenatal fetus ultrasound exams. If the tumors are large or there are multiple tumors, they can block circulation and cause death. However, if they do not cause problems at birth—when in most cases they are at their largest size—they usually become smaller with time and do not affect the individual in later life.

Benign tumors called pakoras are sometimes found in the eyes of individuals with TSC, appearing as white patches on the retina. Generally, they do not cause vision loss or other vision problems, but they can be used to help diagnose the disease.

Additional tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas. Bone cysts, rectal polyps, gum fibromas, and dental pits may also occur.

Radiographic features

Tuberous sclerosis has a significant number of manifestations, involving many organ systems. The most common radiographic manifestations are:

• cortical or subependymal tubers and white matter abnormalities
• renal angiomyolipomas
• cardiac rhabdomyoma(s)

Neurological

• cortical/subcortical tubers: 50% are in the frontal lobe; high T2 and low T1 with only 10% of tubers showing enhancement; frequently calcify after two years of age
• subependymal hamartomas
  • 88% are associated with calcification, although calcification absent in early childhood
  • visible within the first six months of age ⁴
  • variable signal, frequently high T1 and iso to high T2
  • enhancement is variable and is not a useful feature in distinguishing them from subependymal giant cell astrocytomas (SGCA); only serial growth is reliable ^5,6
• subependymal giant cell astrocytomas (SGCA)
  • peak occurrence 8-18 years
  • tend to be large and demonstrate growth ^5,6
  • tend to have intense enhancement
• white matter abnormalities
  • variable appearance, with nodular, ill-defined, cystic and band-like lesions seen
  • radial bands are thought to be relatively specific for TS ⁷
• retinal phakomas
• rarer findings
  • cerebellar atrophy
  • infarcts (due to occlusive vascular disorders)
  • cerebral aneurysms
  • dysgenesis of the corpus callosum
  • Chiari malformations
  • microcephaly
  • arachnoid cysts
  • chordoma

Abdominal

• renal angiomyolipoma(s)
  • tuberous sclerosis accounts for 20% of all angiomyolipomas ³
  • angiomyolipomas are seen in 55-75% of patient with tuberous sclerosis
  • tend to be multiple, large and bilateral
  • tend to grow and require surgical treatment, as the probability of hemorrhage is proportional to the size
  • micro and macro aneurysms may be present ³
  • fat may not be visible in up to 4.5% ¹
• renal cysts: the TSC2 gene is located adjacent to the PCKD1 gene ³
  • 18-53% of patients with tuberous sclerosis ¹
• renal cell carcinoma and oncocytomas
  • although rates of renal cell carcinoma are the same as in the general population, in patients with tuberous sclerosis, renal cell carcinoma tends to occur at a younger age ¹
• retroperitoneal lymphangiomyomatosis (LAM)
  • histologically identical to pulmonary LAM
  • retroperitoneal cystic lesions
  • chylous ascites, enlarged lymph nodes, dilatation of the thoracic duct
• gastrointestinal polyps
• pancreatic neuroendocrine tumors ¹²
• hepatic angiomyolipoma(s)

Thoracic

• lymphangioleiomyomatosis (LAM)
  • rare (1%)
  • some studies have described a lymphangiomyomatosis-like change to be present in 25-40% of female patients with tuberous sclerosis
  • indistinguishable from sporadic LAM
  • pneumothorax and chylous pleural effusions common
  • ~80% 10-year survival
• multifocal micronodular pneumocyte hyperplasia (MMPH)
  • rare
  • characterized by multicentric well-demarcated nodular proliferation of type II pneumocytes
  • benign, non-progressive
  • differential diagnoses: miliary pulmonary opacities
• cardiac rhabdomyomas
  • benign striated muscle tumor characterized by the presence of spider cells
  • seen in 50-65% of patients with tuberous sclerosis
  • 40-80% of patients with cardiac rhabdomyomas have tuberous sclerosis
  • multiple or single
  • typically involve the ventricular septum
  • occur before the age of 1 year (75% of cases) ¹
  • typically regress before birth with spontaneous regression in 70% of children by age 4
• thoracic duct and aortic/pulmonary artery aneurysm
• myocardial fatty foci ¹⁴

Musculoskeletal

• sclerotic bone lesions: 40-66% ¹
• hyperostosis of the inner table of the calvaria
• periosteal new bone
• scoliosis
• bone cysts ⁸

Skin

Cutaneous lesions are present in ~95% of cases, but are rarely appreciated radiographically ⁸:

• hypopigmented macules (ash leaf spots): seen in 90% of patients ¹
• facial angiofibromas (Pringle nodules or adenoma sebaceum); seen in 75% of patients
• fibrous plaques of the forehead (15-20%)
• confetti lesions: variant of leukoderma spots
• shagreen patches: seen in 20-30% of patients
• periungual fibroma (Koenen tumors): 20% of patients

Seizures affect most individuals with TSC at some point during their life. While some kinds of seizures caused by TSC result in obvious convulsive movements, others alter awareness, behavior, or postural tone without convulsions. Seizures also can be difficult to control by medication, and sometimes surgery or other measures are used.

Cognitive disabilities affect some people with TSC. Developmental delay occurs in about one-half to two-thirds of people with TSC. Delays range from mild learning disabilities to severe impairment.

Behavior problems, including aggression, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior occur in children with TSC and can be difficult to manage. About one-third of children with TSC meet the criteria for autism spectrum disorder.

Skin abnormalities vary widely in individuals with TSC. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:

• Hypomanic macules (“ash leaf spots”), which are white or lighter patches of skin that may appear anywhere on the body and are caused by a lack of skin pigment or melanin—the substance that gives skin its color.
• Facial angiofibromas (also called adenoma sebaceous) are reddish spots or bumps which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.
• Forehead plaques are raised, discolored areas on the forehead which are common and unique to TSC and may help doctors diagnose the disorder.
• Shagreen patches are areas of thick leathery, pebbly skin, usually found on the lower back or nape of the neck.
• Ungual or subungual fibromas are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These usually appear later in life, ages 20-50.
• Other skin features that are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders; café au lait spots or flat brown marks; and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.

Kidney problems such as cysts and angiomyolipomas (benign growths of fatty tissue and muscle cells) occur in an estimated 70 to 80 percent of individuals with TSC. They usually occur between ages 15 and 30.

• Cysts are usually small, appear in limited numbers, and most often cause no serious problems. A very small percent of individuals with TSC develop large numbers of cysts during childhood, which may lead to bleeding, anemia, and kidney failure.
• Angiomyolipomas are the most common kidney lesions in TSC and can be found in people without TSC. Angiomyolipomas caused by TSC are usually found in both kidneys and in most cases do not produce symptoms. However, they can sometimes grow so large that they cause pain or kidney failure. Bleeding from angiomyolipomas may also occur, causing both pain and weakness. If severe bleeding does not stop naturally, there may be severe blood loss, resulting in profound anemia and a life-threatening drop in blood pressure, warranting urgent medical attention.
• Other rare kidney problems include renal cell carcinoma, developing from an angiomyolipoma, and oncocytomas, benign tumors unique to individuals with TSC.

Associate signs of tuberous sclerosis can appear later in childhood or even into adulthood. These symptoms may include:

• White spots on the skin (called hypopigmented macules) that glow under a special lamp

• A rash on the face (called facial angiofibromas) that may look like acne

• Problems with the kidneys (associated with growths in the kidneys)

• Areas of very thick skin, often on the back

• Growths under or around the nails

• Pitted teeth

• Coughing or shortness of breath

• Mental disabilities.

• Developmental delays

• Autism spectrum disorder

Lung lesions are present in about one-third of adult women with TSC and are much less commonly seen in men.  Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH).  LAM is a tumor-like disorder in which cells proliferate in the lungs, and there is lung destruction with cyst formation. A range of symptoms can occur with LAM, with many TSC individuals having no symptoms, while others suffer with breathlessness, which can progress and be severe. MMPH is a more benign tumor that occurs in men and women equally.

As per the recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference, the diagnostic criteria for tuberous sclerosis include the following major and minor features[rx][rx]:

Major Features

• Hypomelanotic macules (more than 2, and at least 5-mm in diameter)
• Angiofibromas (more than 2) or fibrous cephalic plaque
• Ungual fibromas (more than 1)
• Shagreen patch
• Multiple retinal hamartomas
• Cortical dysplasias
• Subependymal nodules
• Subependymal giant cell astrocytoma
• Cardiac rhabdomyoma
• Lymphangioleiomyomatosis
• Angiomyolipomas (more than 1)
• More than 2 angiofibromas, which are skin-colored growths of blood vessels in the skin or a thick (fibrous) patch of skin on the forehead
• 2 or more periungual fibromas or hard growths, around or under the fingernails or toenails
• More than 3 light-colored areas on the skin, known as hypomelanotic macules or ash leaf spots
• Shagreen patch, meaning a rough growth of tissue on the surface of the skin
• Tubers, or thickened areas, found in the brain
• Nodules (round growths) found in the brain
• Subependymal giant cell astrocytoma (SEGA), a type of brain cancer
• Cardiac rhabdomyoma, which is a benign, noncancerous heart growth
• Angiomyolipoma of the kidney, which are benign growths that can cause serious medical problems; there is a low risk that these tumors could become cancerous
• Lymphangiomyomatosis, which are multiple cysts or fluid-filled growths along the lymphatic system under the skin
• Multiple hemangioblastomas, which are growths of newly formed blood vessels, of the brain, spinal cord, or eye
• One or more hemangioblastomas in addition to kidney cysts, pancreatic cysts, pheochromocytoma, which is a rare growth in the cells of one of the adrenal glands, or kidney cancer

Minor Features

• Confetti skin lesions
• Dental enamel Pitts (more than 3)
• Intraoral fibromas (more than 1)
• Retinal achromic patch
• Multiple renal cysts
• Nonrenal hamartomas
• Multiple pits or dents in the teeth
• Fibromas (growths) of the gums inside the mouth
• Multiple kidney cysts
• Pale discolorations in the skin, called “confetti.”
• Changes in the retina inside the eye
• Hamartomas, which are benign tissue growths

Definitive diagnosis is established in patients with two major features or one major feature with at least 2 minor features, while “possible diagnosis” is recognized in patients with one major feature or at least 2 minor features.[rx][rx]

Diagnosis of Tuberous Sclerosis Complex

Diagnosing TSC is based upon clinical criteria.  The first clue may be the presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules) or the identification of cardiac tumor rhabdomyoma.

Diagnosis of the disorder is based on a careful clinical exam in combination with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain—which may show tubers in the brain, and an ultrasound of the heart, liver, and kidneys, which may show tumors in those organs. Doctors should carefully examine the skin for a wide variety of skin features, the fingernails, and toenails for ungual fibromas; the teeth and gums for dental pits and/or gum fibromas; and the eyes for retinal lesions. A small hand-help lamp that uses black light, otherwise known as ultraviolet light, may show hypomelanotic macules which are sometimes hard to see on infants and individuals with pale or fair skin. A doctor experienced in the diagnosis of TSC should evaluate a potential patient.

In infants, TSC may be suspected if the child has cardiac rhabdomyomas at birth or seizures (especially the kind called infantile spasms) in the first six months of life. With a careful examination of the skin and brain, it may be possible to diagnose TSC in a very young infant. However, many children are not diagnosed until later in life when their seizures begin and other symptoms such as facial angiofibromas appear.

Treatment of Tuberous Sclerosis Complex

Treatment is

• mTOR inhibitor medicines – can be used to treat brain tumours, kidney tumours and epilepsy caused by TSC

• anti-epileptic medicines – to treat the associated seizures. Medication needs to be carefully monitored to make sure the child isn’t over-sedated

• brain surgery – if seizures cannot be controlled, it may be possible to remove lesions in the brain to reduce seizures

• skin treatments – dermatologists can provide advice on both surgical and medical treatment for the skin signs of TSC, including mTOR inhibitor creams.

• occupational therapy – can help children acquire skills and strategies

• speech therapy – can assist communication skills.

There is no cure for TSC, although treatment is available for a number of the symptoms. Antiepileptic drugs may be used to control seizures. Vigabatrin is a particularly useful medication in TSC and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of infantile spasms in TSC, although it has significant side effects. The FDA has approved the drug everolimus (Afinitor®) to treat subependymal giant cell astrocytomas (SEGA brain tumors) and angiomyolipoma kidney tumors, in addition to intractable seizures (seizures not controlled well by medicine). Specific medications may be prescribed for behavior problems. Intervention programs including special school programs and various therapies (such as physical, occupational, and speech therapies) may benefit individuals with special needs and developmental issues. Surgery may be needed in case of complications connected to tubers, subependymal nodules, or SEGA, as well as in risk of hemorrhage from kidney tumors. Respiratory insufficiency due to LAM can be treated with supplemental oxygen therapy or lung transplantation, if severe.

Skin lesions, particularly facial angiofibromas, may be psychologically distressing for some patients. Laser treatment or electrosurgery can be used to remove angiofibroma.

The topical mTOR inhibitor sirolimus 0.2% gel (also called rapamycin) has proved helpful in reducing angiofibromas in a clinical trial involving 36 adults and children. One study has also reported improvement in hypopigmented macules. A larger prospective, multicentre, randomized, double-blind, vehicle-controlled trial enrolled 179 patients with tuberous sclerosis-related facial angiofibromas and found improvement in more than 80% of patients treated with topical 1% rapamycin with most occurring in the first month.

Infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).

Treatment may require the coordinated efforts of a team of specialists. Pediatricians and general internists, neurologists, dermatologists, cardiologists, dental specialists, eye specialists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.

The treatment for tuberous sclerosis is supportive and symptomatic. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.

Anti-seizure drugs (anticonvulsants) may be prescribed to control seizures. The specific drug that is used will depend on several factors including the specific type of seizure, an affected individual’s age, other organ systems that are affected, and the severity of symptoms. Conventional anticonvulsants drugs that may be administered include phenobarbital, Dilantin (phenytoin), Klonopin (clonazepam), Depakene/Depakote (valproic acid/divalproex sodium), Tegretol (carbamazepine), Trileptal (oxcarbazepine), Topamax (topiramate), Lamictal (lamotrigine), Zonegran (zonisemide), Vimpat (lacosamide), Banzel (rufinamide), Onfi (clobazam), and others. All these anticonvulsants have potential side effects and require careful monitoring by a physician.

Two drugs have been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of seizures associated with tuberous sclerosis. FDA approved Afinitor (everolimus) for the treatment of seizures in adult and pediatric patients aged 2 years and older with tuberous sclerosis in 2018, and Epidiolex (cannabidiol) for patients one year and older in 2020.

Sabril (vigabatrin) was approved in 2009 by the FDA to treat infantile spasms in children ages 1 month to 2 years. Treatment of children with tuberous sclerosis and infantile spasms with vigabatrin has been found to be effective. Visual field loss is an important safety concern with the use of this medication. The FDA has also approved adreno-corticotrophic hormone or ACTH (Acthar gel) for the treatment of infantile spasms. This medication has also been used to treat infants with tuberous sclerosis. These medications are used cautiously because of their side effects.

No specific anti-seizure medication works for all affected individuals. Often, a combination of different drugs may be required to treat some individuals. Alternative treatments include the ketogenic diet or the glycemic diet. Sometimes, seizures can be difficult to treat and medications or diets that initially worked will no longer provide benefit (refractory seizures). In some instances, seizure surgery to remove areas of brain dysplasia may be necessary to help to control seizures that don’t respond or stop responding to medications. Less invasive surgical options to control seizures include the implanting of a vagal nerve stimulator (VNS device). This is a small electrical stimulator placed under the skin over the upper chest and connected to one vagal nerve in order to provide intermittent electrical stimulus, like a pacemaker to the brain.

Surgery of other organs may be necessary if the ability of a particular organ to function properly is impaired by the presence of a tumor. For example, the obstruction of cerebrospinal fluid (CSF) circulation inside the brain (intracranial hypertension) because of a benign tumor may require a shunting procedure to drain the liquid or the surgical removal of the tumor.

In 2012, the FDA approved the use of Afinitor (everolimus) for the treatment of children and adults with tuberous sclerosis who have a subependymal giant cell astrocytoma that cannot be removed or can be only partially removed by surgery. The FDA also approved everolimus for the treatment of adults with tuberous sclerosis who have an angiomyolipoma of the kidney that does not require surgery right away. In some instances, angiomyolipomas will require surgery or embolization therapy. Cutting off the blood supply (arterial embolization) to a kidney tumor may be used to shrink down the size of the tumor. Embolization is usually followed by treatment with corticosteroids and surgical removal (resection) of the tumor that spares the kidney or by destruction (ablation) of the tumor. Large cystic lesions of the kidneys may also require surgical decompression or removal.

In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.^[rx]

• Take a personal and family history covering three generations. Genetic counseling and tests determine if other individuals are at risk.

• A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).

• Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.

• Assess children for behavioral issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.

• Scan the abdomen for tumors in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.

• In adult women, test pulmonary function and perform a high-resolution computed tomography (HRCT) of the chest.

• Examine the skin under a Wood’s lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas).

• In infants under three, perform an echocardiogram to spot rhabdomyoma, and electrocardiogram (ECG) for any arrhythmia.

• Use a fundoscopy to spot retinal hamartomas or achromic patches.

A benign tumor inside the heart (rhabdomyoma) may not cause symptoms and generally does not require treatment as they often regress on their own within the first several years after birth. If symptomatic, however, surgical removal (resection) may be necessary. Reports in the medical literature have detailed the off-label use of mTOR inhibitors to treat these tumors with positive results. Some affected individuals may be prescribed certain medications to treat irregular heartbeats (arrhythmias).

Individuals taking mTOR inhibitors for internal tumors (e.g. SEGAs or angiomyolipomas) may see improvement in skin lesions. Topical formulations of mTOR inhibitors have shown promise in treating facial angiofibromas. Individuals with no immediate indication for mTOR inhibitor treatment may undergo certain procedures to improve the appearance of skin lesions including dermabrasion, laser therapy, or surgical removal (excision) of a lesion.

In 2015, the FDA approved the use of mTOR inhibitors for the treatment of lung complications such as LAM in individuals with tuberous sclerosis. Because LAM occurs most often in young women of childbearing age, researchers have speculated that female hormones such as estrogen play a role in the development of the disorder. A link between LAM and female hormones has not been proven. However, many physicians have explored the use of agents that lower the production or effects of estrogen in the body. The results have varied greatly among individuals. Such agents may include medroxyprogesterone acetate. Estrogen-containing medications and dietary supplements should be discontinued in patients with LAM.

Supplemental oxygen therapy may be necessary for some individuals with impaired lung function. In individuals with severe lung disease that is resistant to treatment, a lung transplant may ultimately become necessary.

Because TSC is a lifelong condition, individuals need to be regularly monitored by a doctor to make sure they are receiving the best possible treatments. Due to the many varied symptoms of TSC, care by a clinician experienced with the disorder is recommended.

Basic laboratory studies have revealed insight into the function of the TSC genes and have led to use of rapamycin (mTOR) inhibitors and related drugs for treating some of the manifestations of TSC.

Associate Treatment

• Surgery. If a growth affects the ability of a specific organ — such as the kidney or heart — to function, the growth may be surgically removed. Sometimes surgery helps control seizures caused by brain growths that don’t respond to medication. Surgical procedures such as dermabrasion or laser treatment may improve the appearance of skin growths.
• Various types of therapy. Early intervention services, such as occupational, physical or speech therapy, can help children with tuberous sclerosis who have special needs in these areas improve their ability to manage daily tasks and activities.
• Educational and vocational services. Early intervention and special needs services can help children with developmental delays and behavior issues adapt to the classroom so that they can meet their full potential. When needed, social, vocational and rehabilitation services may continue throughout life.
• Psychiatric and behavior management. Talking with a mental health provider may help children accept and adjust to living with this disorder. A mental health provider can also help address behavioral, social or emotional issues and recommend resources.

Ongoing monitoring

Tuberous sclerosis is a lifelong condition that requires careful monitoring and follow-up because many signs and symptoms may take years to develop. A schedule of regular follow-up monitoring throughout life may include tests similar to those done during diagnosis. Early identification of problems can help prevent complications.

What is the prognosis?

The prognosis for individuals with TSC is highly variable and depends on the severity of symptoms. Those individuals with mild symptoms usually do well and have a normal life expectancy, while paying attention to TSC-specific issues. Individuals who are severely affected can suffer from severe mental retardation and persistent epilepsy.

All individuals with TSC are at risk for life-threatening conditions related to brain tumors, kidney lesions, or LAM. Continued monitoring by a physician experienced with TSC is important. With appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.

QUESTIONS

1. Tuberous sclerosis complex is a genodermatosis:

   1. Autosomal dominant with hamartomas that affect multiple organs.

   2. Autosomal recessive with hamartomas that affect multiple organs.

   3. Autosomal dominant predominantly affecting females, and the most commonly affected organs are skin, central nervous system, heart, lungs and kidneys.

   4. Autosomal recessive with vascular malformations in many organs, being the most affected skin and central nervous system.

2. The classical tuberous sclerosis triad is characterized by:

   1. Shagreen patch, facial angiofibromas and mental retardation.

   2. Epilepsy, sebaceous adenoma and shagreen patch.

   3. Facial angiofibromas, fibrous cephalic plaque and epilepsy.

   4. Mental retardation, epilepsy and sebaceous adenoma (angiofibroma).

3. Choose the sentence with the correct sequence:

   • ( ) Skin lesions are found in more than 90% of cases, the majority appearing in the 3^rd decade of life.

   • ( ) “Ash-leaf” lesions tend to follow Blaschko lines when on the trunk, typical for type 3 mosaicism.

   • ( ) Hypopigmented macules in “confetti” or guttate leukoderma are hypopigmented macules that appear over the years.

   • ( ) Hypopigmented macules are many times found since birth, allowing for the early diagnosis of the disease when associated to other clinical findings.

     1. F T T F

     2. F F F T

     3. T T F T

     4. F T F T

4. About connective tissue nevi and ungual fibromas or Koenen tumors, it is correct to say that:

   1. Connective tissue nevi seen in TSC are normal-colored to brown plaques restricted to the lumbosacral region.

   2. Shagreen patch many times have the aspect of orange peel and are found on the upper back.

   3. Fibrous cephalic plaque is present in more than 80% of cases, being most commonly found on one side of the forehead.

   4. Koenen tumor usually appears during adolescence and has a predilection for females and the toes.

5. According to the systemic manifestations of TSC, we can affirm that the correct items are:

   1. Angiomyolipomas increase progressively from infancy and stop growing in the elderly.

   2. Renal lesions have an indolent, clinically asymptomatic course, with no potentially severe repercussions in the patient’s life.

   3. In cases of patients that evolve with hematuria in adulthood, the possibility of malignant transformation of the angiomyolipomas must be kept in mind, since they are usually asymptomatic.

   4. Lymphangioleiomyomatosis affects predominantly younger women with the first manifestations after early adolescence.

   5. Rhabdomyoma is the most common cardiac tumor and tends to grow progressively in the first year, when it stabilizes and continues until adulthood.

      1. 1 – 3

      2. 2 – 4

      3. 3 – 5

      4. 1 – 4

   6. Choose the INCORRECT option:

      1. The identification of the pathogenic TSC1 or TSC2 DNA mutation is not enough to establish the diagnosis of TSC.

      2. Molecular testing yields a positive result in 75% to 90% of TSC patients.

      3. In 10% to 25% of patients, conventional genetic testing does not identify the pathogenic TSC1 or TSC2 mutation.

      4. The identification of the pathogenic mutation for TSC in conventional genetic testing configures an independent diagnostic criterion.

6. About the diagnostic criteria for the tuberous sclerosis complex, reviewed in 2012, in the second International Tuberous Sclerosis Complex Consensus Conference, all are included as extracutaneous manifestations, EXCEPT:

   1. Subependymal giant cell astrocytoma.

   2. Cardiac rhabdomyoma.

   3. Lymphangioleiomyomatosis.

   4. Pigmented hamartomas of the iris.

7. It is a MAJOR clinical criterion for the diagnosis of TSC:

   1. ≥ 5 hypopigmented macules with at least 3mm diameter.

   2. ≥ 3 facial angiofibromas.

   3. ≥ 2 intraoral fibromas.

   4. > 3 dental enamel pits.

8. From the dermatological point of view, many destructive or surgical treatment options are used to reduce the development of and remove facial angiofibromas. It is correct to say that:

   1. The destructive procedures are usually comfortable for the patient and can be performed at any age.

   2. It usually is not necessary to repeat laser treatments periodically because the lesions tend not to recur.

   3. Are therapeutic options for facial angiofibromas dermabrasion, surgical excision, electrocautery and laser.

   4. It is not necessary to combine therapeutic methods to optimize results since that regardless of the treatment chosen, all provide satisfactory results.

9. Diagnostic suspicion of TSC comes from the following findings, EXCEPT:

   1. Antenatal detection of cardiac rhabdomyomas.

   2. Post-natal identification of hypopigmented patches on the skin.

   3. Visualization of ephelis on the axillary or inguinal regions.

   4. Seizures in childhood, particularly with spasms.

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