Category Archive Research

Diseases of the Cranial Nerves – Test and Examination

Diseases of the Cranial Nerves 12 mean the specific abnormality that is happening in cranial nerves are peripheral nerves except for the optic nerve which is a central nervous system tract. Disorders of particular note include the following: Olfactory (I) nerve—anosmia is most commonly encountered as a sequel to head injury.

Third, fourth, and sixth cranial nerves—complete lesions lead to the following deficits

  • (1) third nerve—a dilated and unreactive pupil, complete ptosis, and loss of upward, downward, and medial movement of the eye;
  • (2) fourth nerve—extorsion of the eye when the patient looks outwards, with diplopia when the gaze is directed downwards and medially;
  • (3) sixth nerve—convergent strabismus, with the inability to abduct the affected eye and diplopia maximal on lateral gaze to the affected side. The third, fourth, and sixth nerves may be affected singly or in combination: in older patients, the commonest cause is a vascular disease of the nerves themselves or their nuclei in the brainstem.
  • Other causes of lesions include (1) false localizing signs—third or sixth nerve palsies related to the displacement of the brainstem produced by supratentorial space-occupying lesions; (2) intracavernous aneurysm of the internal carotid artery—third, fourth, and sixth nerve lesions. Lesions of these nerves can be mimicked by myasthenia gravis

Diseases of the Cranial Nerves – Test and Examination

Facial nerve palsy is paresis of the muscles supplied by the facial nerve (VII) on 1 side of the face due to a lesion of the facial nerve. The paresis generally only occurs on 1 side, but it may also occur on both sides. Usually, it is temporary. Initially, the patient suffers from non-specific dragging pain in the region of the ear before the paresis develops over several hours or days.

This occurs in 10–35 cases/100,000 inhabitants. During pregnancy, the prevalence increases 3 times, especially in the 1st trimester. This condition has a universal distribution and has no predilection for ethnicity or age.

cranial nerve VII 7

Possible causes for facial nerve paresis:

  • Viral and bacterial infections
  • Stroke/ischemic lesions
  • Basal skull fracture
  • Tumors in the petrous bone or the parotid gland
  • Intracranial injury
  • Toxic causes
  • Idiopathic causes
  • Chromosomal damage

Depending on the location of the lesion, one distinguishes between central and peripheral facial nerve palsy.

In both, rehabilitation must be started as soon as possible to avoid complications.

Peripheral facial nerve paresis

Peripheral facial nerve paresis involves lesions of the 2nd motor neuron, the anterior motor horn, the peripheral nerves, or the muscles outside the central nervous system. Peripheral facial nerve palsy is characterized by a weakened myotatic reflex, negative pyramidal tract signs, a slack tone, and atrophy of the affected muscles.

Idiopathic facial nerve palsy (Bell’s palsy) is the most frequent peripheral cranial nerve lesion, and it is accompanied by a single-sided and acute occurrence of peripheral facial nerve palsy. This disease can occur at any age, often between the ages of 10–20 and 30–40 years. Women seem to be affected more frequently than men.

Bell’s palsy heals in approx. 70% of cases without any consequences, but persistent defects after re-innervation may remain.

As a consequence of 1-sided peripheral facial palsy, the following actions are no longer possible:

  • Frowning
  • Raising eyebrows
  • Closing the eyes
  • Puffing out the cheeks
  • Whistling
  • Showing the teeth

These symptoms also suggest the failure of the nerve, and weakness or complete paresis of the mimic muscles may result. Symptoms include:

  • Bell’s phenomenon (incomplete closure of the eyelid)
  • Upward rotation of the eyeball becomes visible
  • Drooping of the labial angle and the lower eyelid
  • Elapsed nasolabial fold
  • Slackened platysma

Disorders of lacrimation, headache, gustatory disturbances in the anterior 3rd of the tongue, ear pain, and increased hearing sensation are other accompanying symptoms.

Causes of Bell’s palsy are:

  1. Herpes zoster infections
  2. Otitis media
  3. Guillain-Barré syndrome
  4. HIV infection tumor
  5. Ischemic stroke
  6. Autoimmune disease
  7. Lyme disease
  8. Among others.

Central facial palsy

Central facial palsy is due to a lesion of the 1st motor neuron in the region of the brain or its descending projections to the spinal cord.

Central facial palsy involves increased myotatic reflexes, weakened multisynaptic reflexes, and positive pyramidal tract signs; a cramp-like increase in the tone of the affected muscles also occurs, without any relevant atrophy. Frequently, central facial palsies are caused by cerebral circulatory impairments or brain tumors.

In contrast to peripheral facial palsy, a patient with central facial palsy can frown and close his eyelid since the peripheral nuclear areas (facial nucleus) lead to the fibers of the facial nerve and are interconnected to finally reach the forehead and the eye, which also receive fibers from the other side.

The musculature is no longer mobile – especially in the area of the mouth – and it is flaccid, as with peripheral facial palsy. Also, the labial angle droops are immobile and are partially open on the affected side.

picture of a man suffering from right facial palsy

Note: A distinguishing feature of peripheral and central facial palsy: with central facial palsy, the patient can frown and close his eyelid.

Trigeminal Neuralgia

Trigeminal neuralgia occurs in the innervation area of the trigeminal nerve in the form of a severe, acute, and recurrent attack-like facial pain that is generally single-sided. Three forms are distinguished:

  • Classic trigeminal neuralgia: in patients with compression of the trigeminal nerve by a presumed or demonstrated vascular loop
  • Secondary trigeminal neuralgia: associated with another disease such as multiple sclerosis and tumors
  • Idiopathic trigeminal neuralgia: when the cause is unknown

Other categories include several causes of facial pain such as painful trigeminal neuropathy due to herpes zoster virus, post-traumatic trigeminal neuropathy, painful trigeminal neuropathy attributed to other disorders, and idiopathic painful trigeminal neuropathy.

Classic trigeminal neuralgia

Previously called tic douloureux. The principal cause of this pain is the compression or mechanical irritation of the trigeminal nerve by blood vessel loops at the point where it exits the brainstem. The average age of onset is between 50–79 years.

Symptomatic trigeminal neuralgia

This form of trigeminal neuralgia accompanies demyelination diseases such as multiple sclerosis, which occurs as a consequence of either tumors or Costen’s syndrome (e.g., a facial pain that originates from the facial muscles due to malfunction of the mandibular joint). Inflammatory processes and, in rare cases, medical interventions can result in trigeminal neuralgia.

Symptomatic trigeminal neuralgia may be accompanied by hypoesthesia, i.e. reduced sensitivity towards tactile stimuli, in the form of numbness or tingling, in the region of the 1st trigeminal branch. Furthermore, the corneal reflex is weakened.

Patients with symptomatic trigeminal neuralgia are, on average, younger than patients with the classical form of the disease (tic doulourex). Double-sided facial pain often also occurs in such patients. The goal of therapy is to treat the underlying cause.

Symptoms of trigeminal neuralgia:

  • Attacks of shooting and severe pain, which occurs repeatedly, up to 100 times a day
  • Mostly, the supply area of the 2nd branch of the trigeminal nerve is affected
  • It can be triggered by touch, coldness, speaking, swallowing, chewing, combing hair, touching or washing the face, spicy food, vibration at walking, etc.
  • Due to the pain, patients are sad, powerless, anorexic, they sleep badly, and they feel weak

The patients try to avoid the trigger by reducing their mimic movement, not speaking, and not eating. Often, only fluid foods are taken in with a straw. In the cold seasons, most patients protect themselves from the cold and the wind with a scarf.

trigeminal distribution

Eye muscle paresis

Oculomotor nerve palsy

The oculomotor nerve (the eye movement nerve) innervates several eye muscles and – along with the trochlear nerve (IV) and the abducens nerve (VI) – is responsible for the movement of the eyeball.

Roughly/3rd of all eye muscle pareses are caused by oculomotor nerve palsy, which is overall slightly rarer than abducens nerve palsy. In 60–70% of cases, oculomotor nerve palsy occurs as an isolated loss.

Lesions of this nerve can result in various types of paresis: complete (inner and outer) oculomotor nerve palsy.

Complete loss of the function of the nerve leads to the following clinical picture:

  • Ptosis (drooping of the upper eyelid)
  • The eyeball deviates to the outside and downwards
  • Widened pupil (mydriasis) and pupils unresponsive to light (totally unresponsive pupil)
  • Diplopia (double vision)

In cases of complete oculomotor nerve palsy, the consensual reaction of the opposite eye remains, i.e. a reflex-triggered concordant reaction occurs on the opposite side of the body. The opening of the eyelid may be possible through contraction of the frontal muscle since double vision only occurs following the elevation of the eyelid.

Causes of oculomotor nerve palsy are:

  1. Tumor
  2. Stroke
  3. Infections of the central nervous system (meningitis or encephalitis)
  4. Aneurysm
  5. A local lesion in the base of the eye.

Ophthalmoplegia interna

Ophthalmoplegia interna involves completely unresponsive pupils accompanied by the free movement of the eyeball; the pupil does not react to either direct or indirect light nor convergence. As a result, the patient does not have a clear vision in the affected eye when looking at close objects. There is also paresis of accommodation.

Ophthalmoplegia externa

In cases of ophthalmoplegia externa, however, the motility of the eyeball is impaired, yet autonomous innervation of the pupil and the ciliary muscle is intact. If pupil function has been preserved, complete paresis of all the muscles innervated by the oculomotor nerve is quite rare.

Anisocoria

Another disease or deficit of the oculomotor nerve would be pupils of unequal width, which is referred to as anisocoria. Anisocoria is present in Claude-Bernard- Horner syndrome, which is characterized by constriction of the pupil (miosis), a drooping eyelid (ptosis), anhidrosis (decreased sweating), and posterior displacement of the eyeball (enophthalmos).

Anisocoria can also occur alongside intracranial pressure involving compression of the oculomotor nerve.

anisocoria

Trochlear Nerve Palsy

Trochlear nerve palsies are rarer than oculomotor or abducens nerve palsies. The most frequent cause of monosymptomatic trochlear nerve palsy is a traumatic brain injury.

Trochlear nerve palsy is characterized by isolated paresis of the superior oblique muscle. The function of this muscle is to depress the eyeball. In cases of paresis, the symptom increases during adduction and is virtually absent during abduction, i.e. the eye of the patient faces towards the nose and upwards, and the patient experiences double vision (diplopia), just as in cases of oculomotor nerve palsy.

Causes of trochlear nerve palsy are tumor, demyelination, meningitis, and other.

trochlear and frontal nerves

A distinction is made between double and single-sided trochlear nerve palsy.

Double-sided trochlear nerve palsy

In cases of double-sided trochlear nerve palsy, the Bielschowsky phenomenon is often positive on both sides. In this case, the diseased eye stands higher, is rotated outwards to the temple, and has a squint deviation to the nose, which creates oblique double vision. To compensate, the patient tries to rotate and lower the chin and to tilt the head to the healthy side.

Compensatory head-turning and tilting are usually not present, in contrast to 1-sided trochlear nerve palsy.

One-sided trochlear nerve palsy

One-sided trochlear nerve palsy is accompanied by a compensatory head posture with turning and tilting towards the healthy shoulder and lowering of the chin. The affected eye is in an abduction position and is rotated outwards. An annoying pathological rolling image is avoided since the slackened internal rotator is not utilized this way.

Abducens nerve palsy

The abducens nerve palsy is characterized by an isolated paresis of the rectus lateralis muscle (an externally turning muscle), which often occurs without identifiable intracranial lesions. In a high percentage of cases, the cause of these palsies remains idiopathic. However, trauma, a diabetic metabolic state, and increased intracranial pressure due to tumor or meningitis are some causes of abducens nerve palsy.

isolated paresis of the rectur lateralis muscle

In cases of abducens nerve palsy, convergent paralytic strabismus occurs even in the primary position, i.e. the affected eye deviates towards the inside and the paralyzed eye is impaired or inhibited if it tries to turn to look to the side or to look up.

Furthermore, a slight adduction position can occur when looking up or down. Undisturbed binocular movement is, however, observed when looking to the healthy side.

Horizontally parallel double images (i.e. double vision) are usually perceived even in the primary position. The deviation of the images of objects on the retina increases on the paralyzed side, but when the affected eye is covered, the image corresponding to the respective side disappears.

However, the annoying phenomenon of double vision causes a compensatory head posture, which leads to the head being turned towards the side of the paralyzed muscle – a position that does not require the rectus lateralis muscle.

Lesions of the visual pathway

Each optic tract consists of ‘2 half, former’ optical nerves. They conduct the lateral part of the visual information coming from the same side and also the medial sensations of the opposite side.

The visual pathway crosses the whole brain. Very differing deficits in the visual field may arise depending on the location of the lesion. Therefore, when there is a lesion in the visual pathway, the visual field is examined, and pupil reaction and the appearance of the papilla are examined.

The following deficits in the visual field can occur as a result of nerve lesions:

  • If the optic nerve is severely damaged on 1 side, the patient is blind on the affected eye, and their sight is not impaired on the other side.
  • When there is a lesion of the medial part of the optic chiasm, it is mainly the fibers that cross to the other side that are damaged. The patient can suffer from a bitemporal (heteronymous) hemianopsia, i.e the patient does not get any visual information relating to what happens in his lateral field of vision. This is referred to as hemianopsia, or ‘blinker vision.’ The lateral section, which does not cross and leads to the optic tract, remains intact, meaning sight in this part of the visual field is not impaired.
  • Visual loss can also affect the optic tract. For example, the patient may have a lesion in the right optic tract which leads to a deficit in the left half of the visual field of both eyes. This failure is referred to as bilateral homonymous hemianopsia (left). A lesion of the left optic tract would lead to a corresponding opposite deficit in the right half of the visual field. Depending on where the optic tract is damaged, this may lead to a complete or an incomplete deficit. Once such deficits have arisen, they do not usually disappear.

Further lesions can arise in the realm of visual radiation, and such lesions have diverse consequences since visual radiation spreads a fan-like manner. Tumors and strokes are the most frequent triggers for this visual disorder.

Deficits in the visual field can be observed in the following form:

  • First: Pathology to the right part of the visual radiation produces left homonymous hemianopsia
  • Second: Pathology to the leftward side of the visual radiation produces right homonymous hemianopsia
homonyme hemianopsie

Quadrantanopsia occurs whenever there is only partial damage to the visual radiation such that a quadrant of the visual field is missing rather than an entire half.

Deficits in the upper part of the visual radiation are more severe than in the lower part. Deficits in the area of the visual radiation likewise do not regress either.

Amaurosis

This term refers to a complete loss of vision without apparent lesions in the eye; it can occur in 1 or 2 eyes. Amaurosis can be congenital (Leber’s congenital amaurosis) or secondary. What this means for the optic nerve is that injury is commonly secondary to compression of the nerve by tumor (commonly from the pituitary), trauma, or ischemic events.

Summary of the Important Diseases of All 12 Pairs of Cranial Nerves

Olfactory nerve (I)

  • Anosmia (inability to smell)
  • Hyposmia (weakened ability to smell)

Optical nerve (II)

  • Anopsia or amaurosis (blindness in 1 or both eyes)
  • Hemianopsia
  • Quadrant anopsia
  • Blinker-phenomenon
  • Papilledema

Oculomotor nerve (III)

  • Anisocoria (unequally wide pupils)
  • Miosis (narrow pupils)
  • Mydriasis (wide pupils)
  • Gaze palsy
  • Diplopia (double vision)
  • Ptosis (drooping upper eyelid)

Trochlear nerve (IV)

  • Strabismus
  • Diplopia

Trigeminal nerve (V)

  • Trigeminal neuralgia/tic doulourex
  • Paresis of the muscles of mastication
  • Loss of the sensation of touch and temperature

Abducens nerve (VI)

  • Diplopia

Facial nerve (VII)

  • Bell’s palsy (paralysis of the the facial muscles)
  • Hyperacusis (sounds are perceived too loud)
  • Loss of gustatory sensation in the anterior tongue
  • Burning eye sensation due to dehydration of the conjunctiva/cornea

Vestibulocochlear nerve (VIII)

  • Hypacusis (hearing loss)
  • Deafness
  • Tinnitus (permanent aural noises)
  • Ataxia (instability regarding movement)
  • Rotatory vertigo
  • Nystagmus (eye twitching)

Glossopharyngeal nerve (IX)

  • Difficulty swallowing
  • Diminished salivation
  • Loss of gustatory sensation in the posterior part of the tongue
  • Loss of sensation in the throat

Vagus nerve (X)

  • Hoarseness
  • Difficulties with swallowing and at phonation
  • Posticus paralysis (severe respiratory distress when a particular muscle of the larynx fails)
  • Changes in heart rate (quicker or slower)
  • Less gastric acid and intestinal peristalsis

Accessory nerve (XI)

  • Inability to lift the shoulder
  • Weakness in turning the head

The hypoglossal nerve (XII)

  • Speech disorders
  • Difficulty swallowing

Cranial nerve examination frequently appears in OSCEs. You’ll be expected to assess a subset of the twelve cranial nerves and identify abnormalities using your clinical skills. This cranial nerve examination OSCE guide provides a clear step-by-step approach to examining the cranial nerves, with an included video demonstration.

Cranial Nerves – Test and Examination

Gather equipment

Gather the appropriate equipment to perform cranial nerve examination:

  • Pen torch
  • Snellen chart
  • Ishihara plates
  • Ophthalmoscope and mydriatic eye drops (if necessary)
  • Cotton wool
  • Neuro-tip
  • Tuning fork (512hz)
  • Glass of water

Introduction

Wash your hands and don PPE if appropriate.

Introduce yourself to the patient including your name and role.

Confirm the patient’s name and date of birth.

Briefly explain what the examination will involve using patient-friendly language.

Gain consent to proceed with the examination.

Ask the patient to sit on a chair, approximately one arm’s length away.

Ask the patient if they have any pain before proceeding with the clinical examination.

General inspection

Perform a brief general inspection of the patient, looking for clinical signs suggestive of underlying pathology:

  • Speech abnormalities: may indicate glossopharyngeal or vagus nerve pathology.
  • Facial asymmetry: suggestive of facial nerve palsy.
  • Eyelid abnormalities: ptosis may indicate oculomotor nerve pathology.
  • Pupillary abnormalities: mydriasis occurs in oculomotor nerve palsy.
  • Strabismus: may indicate oculomotor, trochlear or abducens nerve palsy.
  • Limbs: pay attention to the patient’s arms and legs as they enter the room and take a seat noting any abnormalities (e.g. spasticity, weakness, wasting, tremor, fasciculation) which may suggest the presence of a neurological syndrome).

Look for objects or equipment on or around the patient that may provide useful insights into their medical history and current clinical status:

  • Walking aids: gait issues are associated with a wide range of neurological pathology including Parkinson’s disease, stroke, cerebellar disease and myasthenia gravis.
  • Hearing aids: often worn by patients with vestibulocochlear nerve issues (e.g. Ménière’s disease).
  • Visual aids: the use of visual prisms or occluders may indicate underlying strabismus.
  • Prescriptions: prescribing charts or personal prescriptions can provide useful information about the patient’s recent medications.

Olfactory nerve (CN I)

The olfactory nerve (CN I) transmits sensory information about odors to the central nervous system where they are perceived as smell (olfaction). There is no motor component to the olfactory nerve.

Ask the patient if they have noticed any recent changes to their sense of smell.

Olfaction can be tested more formally using different odors (e.g. lemon, peppermint), or most formally using the University of Pennsylvania smell identification test. However, this is unlikely to be required in an OSCE.

Causes of anosmia

There are many potential causes of anosmia including:

  • Mucous blockage of the nose: preventing odors from reaching the olfactory nerve receptors.
  • Head trauma: can result in shearing of the olfactory nerve fibers leading to anosmia.
  • Genetics: some individuals have congenital anosmia.
  • Parkinson’s disease: anosmia is an early feature of Parkinson’s disease.
  • COVID-19: transient anosmia is a common feature of COVID-19.

Optic nerve (CN II)

The optic nerve (CN II) transmits sensory visual information from the retina to the brain. There is no motor component to the optic nerve.

Inspect the pupils

The pupil is the hole in the centre of the iris that allows light to enter the eye and reach the retina.

Assess pupil size:

  • Normal pupil size varies between individuals and depends on lighting conditions (i.e. smaller in bright light, larger in the dark).
  • Pupils are usually smaller in infancy and larger in adolescence.

Assess pupil shape:

  • Pupils should be round, abnormal shapes can be congenital or due to pathology (e.g. posterior synechiae associated with uveitis).
  • Peaked pupils in the context of trauma are suggestive of globe injury.

Assess pupil symmetry:

  • Note any asymmetry in pupil size between the pupils (anisocoria). This may be longstanding and non-pathological or relate to actual pathology. If the pupil is more pronounced in bright light this would suggest that the larger pupil is the abnormal pupil, if more pronounced in dark this would suggest the smaller pupil is abnormal.
  • Examples of asymmetry include a large pupil in oculomotor nerve palsy and a small and reactive pupil in Horner’s syndrome.
  • Inspect the pupils
    Inspect the pupils

Visual acuity

Assessment of visual acuity (distance)

Begin by assessing the patient’s visual acuity using a Snellen chart. If the patient normally uses distance glasses, ensure these are worn for the assessment.

1. Stand the patient at 6 metres from the Snellen chart.

2. Ask the patient to cover one eye and read the lowest line they are able to.

3. Record the lowest line the patient was able to read (e.g. 6/6 (metric) which is equivalent to 20/20 (imperial)).

4. You can have the patient read through a pinhole to see if this improves vision (if vision is improved with a pinhole, it suggests there is a refractive component to the patient’s poor vision).

5. Repeat the above steps with the other eye.

Recording visual acuity

Visual acuity is recorded as chart distance (numerator) over the number of the lowest line read (denominator).

If the patient reads the 6/6 line but gets 2 letters incorrect, you would record as 6/6 (-2).

If the patient gets more than 2 letters wrong, then the previous line should be recorded as their acuity.

When recording the vision it should state whether this vision was unaided (UA), with glasses or with pinhole (PH).

Further steps for patients with poor vision

If the patient is unable to read the top line of the Snellen chart at 6 metres (even with pinhole) move through the following steps as necessary:

1. Reduce the distance to 3 metres from the Snellen chart (the acuity would then be recorded as 3/denominator).

2. Reduce the distance to 1 metre from the Snellen chart (1/denominator).

3. Assess if they can count the number of fingers you’re holding up (recorded as “Counting Fingers” or “CF”).

4. Assess if they can see gross hand movements (recorded as “Hand Movements” or “HM”).

5. Assess if they can detect light from a pen torch shone into each eye (“Perception of Light”/”PL” or “No Perception of Light”/”NPL”).

Causes of decreased visual acuity

Decreased visual acuity has many potential causes including:

  • Refractive errors
  • Amblyopia
  • Ocular media opacities such as cataract or corneal scarring
  • Retinal diseases such as age-related macular degeneration
  • Optic nerve (CN II) pathology such as optic neuritis
  • Lesions higher in the visual pathways

Optic nerve (CN II) pathology usually causes a decrease in acuity in the affected eye. In comparison, papilloedema (optic disc swelling from raised intracranial pressure), does not usually affect visual acuity until it is at a late stage.

Pupillary reflexes

With the patient seateddim the lights in the assessment room to allow you to assess pupillary reflexes effectively.

Direct pupillary reflex

Assess the direct pupillary reflex:

  • Shine the light from your pen torch into the patient’s pupil and observe for pupillary restriction in the ipsilateral eye.
  • A normal direct pupillary reflex involves constriction of the pupil that the light is being shone into.

Consensual pupillary reflex

Assess the consensual pupillary reflex:

  • Once again shine the light from your pen torch into the same pupil, but this time observe for pupillary restriction in the contralateral eye.
  • A normal consensual pupillary reflex involves the contralateral pupil constricting as a response to light entering the eye being tested.
  • Assess direct and consensual pupillary light reflexes
    Assess direct and consensual pupillary light reflexes

Swinging light test

Move the pen torch rapidly between the two pupils to check for a relative afferent pupillary defect (see more details below).

  • Perform the swinging light test
    Perform the swinging light test

Accommodation reflex

1. Ask the patient to focus on a distant object (clock on the wall/light switch).

2. Place your finger approximately 20-30cm in front of their eyes (alternatively, use the patient’s own thumb).

3. Ask the patient to switch from looking at the distant object to the nearby finger/thumb.

4. Observe the pupils, you should see constriction and convergence bilaterally.

  • Assess the accommodation reflex
    Assess the accommodation reflex
Pupillary light reflex

Each afferent limb of the pupillary reflex has two efferent limbs, one ipsilateral and one contralateral.

The afferent limb functions as follows:

  • Sensory input (e.g. light being shone into the eye) is transmitted from the retina, along the optic nerve to the ipsilateral pretectal nucleus in the midbrain.

The two efferent limbs function as follows:

  • Motor output is transmitted from the pretectal nucleus to the Edinger-Westphal nuclei on both sides of the brain (ipsilateral and contralateral).
  • Each Edinger-Westphal nucleus gives rise to efferent nerve fibres which travel in the oculomotor nerve to innervate the ciliary sphincter and enable pupillary constriction.

Normal pupillary light reflexes rely on the afferent and efferent pathways of the reflex arc being intact and therefore provide an indirect way of assessing their function:

  • The direct pupillary reflex assesses the ipsilateral afferent limb and the ipsilateral efferent limb of the pathway.
  • The consensual pupillary reflex assesses the contralateral efferent limb of the pathway.
  • The swinging light test is used to detect relative afferent limb defects.
Abnormal pupillary responses
  • Relative afferent pupillary defect (Marcus-Gunn pupil): normally light shone into either eye should constrict both pupils equally (due to the dual efferent pathways described above). When the afferent limb in one of the optic nerves is damaged, partially or completely, both pupils will constrict less when light is shone into the affected eye compared to the healthy eye. The pupils, therefore, appear to relatively dilate when swinging the torch from the healthy to the affected eye. This is termed a relative…. afferent… pupillary defect. This can be due to significant retinal damage in the affected eye secondary to central retinal artery or vein occlusion and large retinal detachment; or due to significant optic neuropathy such as optic neuritis, unilateral advanced glaucoma and compression secondary to tumour or abscess.
  • Unilateral efferent defect: commonly caused by extrinsic compression of the oculomotor nerve, resulting in the loss of the efferent limb of the ipsilateral pupillary reflexes. As a result, the ipsilateral pupil is dilated and non-responsive to light entering either eye (due to loss of ciliary sphincter function). The consensual light reflex in the unaffected eye would still be present as the afferent pathway (i.e. optic nerve) of the affected eye and the efferent pathway (i.e. oculomotor nerve) of the unaffected eye remain intact.
  • Relative afferent pupillary defect (RAPD)
    Relative afferent pupillary defect (RAPD) 1

Colour vision assessment

Colour vision can be assessed using Ishihara plates, each of which contains a colored circle of dots. Within the pattern of each circle are dots that form a number or shape that is clearly visible to those with normal color vision and difficult or impossible to see for those with a red-green color vision defect.

How to use Ishihara plates

If the patient normally wears glasses for reading, ensure these are worn for the assessment.

1. Ask the patient to cover one of their eyes.

2. Then ask the patient to read the numbers on the Ishihara plates. The first page is usually the ‘test plate’ which does not test color vision and instead assesses contrast sensitivity. If the patient is unable to read the test plate, you should document this.

3. If the patient is able to read the test plate, you should move through all of the Ishihara plates, asking the patient to identify the number on each. Once the test is complete, you should document the number of plates the patient identified correctly, including the test plate (e.g. 13/13).

4. Repeat the assessment on the other eye.

  • Assess colour vision using an Ishihara chart at arms length
    Assess colour vision using an Ishihara chart at arms length
Colour vision deficiencies

Colour vision deficiencies can be congenital or acquired. Some causes of acquired colour vision deficiency include:

  • Optic neuritis: results in a reduction of colour vision (typically red).
  • Vitamin A deficiency
  • Chronic solvent exposure

Visual neglect/inattention

Visual neglect (also known as visual inattention) is a condition in which an individual develops a deficit in their awareness of one side of their visual field. This typically occurs in the context of parietal lobe injury after stroke, which results in an inability to perceive or process stimuli on one side of the body. The side of the visual field that is affected is contralateral to the location of the parietal lesion. It should be noted that visual neglect is not caused by optic nerve pathology and therefore this test is often not included in a cranial nerve exam.

Assessment

To assess for visual neglect:

1.  Position yourself sitting opposite the patient approximately 1 metre away.

2. Ask the patient to remain focused on a fixed point on your face (e.g. nose) and to state if they see your left, right or both hands moving.

3. Hold your hands out laterally with each occupying one side of the patient’s visual field (i.e. left and right).

4. Take turns wiggling a finger on each hand to see if the patient is able to correctly identify which hand has moved.

5. Finally wiggle both fingers simultaneously to see if the patient is able to correctly identify this (often patients with visual neglect will only report the hand moving in the unaffected visual field – i.e. ipsilateral to the primary brain lesion).

  • Visual inattention
    Assess for visual inattention

Visual fields

This method of assessment relies on comparing the patient’s visual field with your own and therefore for it to work:

  • you need to position yourself, the patient and the target correctly (see details below).
  • you need to have normal visual fields and a normal-sized blindspot.

Visual field assessment

1. Sit directly opposite the patient, at a distance of around 1 metre.

2. Ask the patient to cover one eye with their hand.

3. If the patient covers their right eye, you should cover your left eye (mirroring the patient).

4. Ask the patient to focus on part of your face (e.g. nose) and not move their head or eyes during the assessment. You should do the same and focus your gaze on the patient’s face.

5. As a screen for central visual field loss or distortion, ask the patient if any part of your face is missing or distorted. A formal assessment can be completed with an Amsler chart.

6. Position the hatpin (or another visual target such as your finger) at an equal distance between you and the patient (this is essential for the assessment to work).

7. Assess the patient’s peripheral visual field by comparing to your own and using the target. Start from the periphery and slowly move the target towards the centre, asking the patient to report when they first see it. If you are able to see the target but the patient cannot, this would suggest the patient has a reduced visual field.

8. Repeat this process for each visual field quadrant, then repeat the entire process for the other eye.

9. Document your findings.

  • Assess the patient's peripheral visual fields
    Assess the patient’s peripheral visual fields
Types of visual field defects
  • Bitemporal hemianopia: loss of the temporal visual field in both eyes resulting in central tunnel vision. Bitemporal hemianopia typically occurs as a result of optic chiasm compression by a tumour (e.g. pituitary adenoma, craniopharyngioma).
  • Homonymous field defects: affect the same side of the visual field in each eye and are commonly attributed to stroke, tumour, abscess (i.e. pathology affecting visual pathways posterior to the optic chiasm). These are deemed hemianopias if half the vision is affected and quadrantanopias if a quarter of the vision is affected.
  • Scotoma: an area of absent or reduced vision surrounded by areas of normal vision. There is a wide range of possible aetiologies including demyelinating disease (e.g. multiple sclerosis) and diabetic maculopathy.
  • Monocular vision loss: total loss of vision in one eye secondary to optic nerve pathology (e.g. anterior ischaemic optic neuropathy) or ocular diseases (e.g. central retinal artery occlusion, total retinal detachment).

Blind spot

A physiological blind spot exists in all healthy individuals as a result of the lack of photoreceptor cells in the area where the optic nerve passes through the optic disc. In day to day life, the brain does an excellent job of reducing our awareness of the blind spot by using information from other areas of the retina and the other eye to mask the defect.

Blind spot assessment

1. Sit directly opposite the patient, at a distance of around 1 metre.

2. Ask the patient to cover one eye with their hand.

3. If the patient covers their right eye, you should cover your left eye (mirroring the patient).

4. Ask the patient to focus on part of your face (e.g. nose) and not move their head or eyes during the assessment. You should do the same and focus your gaze on the patient’s face.

5. Using a red hatpin (or alternatively, a cotton bud stained with fluorescein/pen with a red base) start by identifying and assessing the patient’s blind spot in comparison to the size of your own. The red hatpin needs to be positioned at an equal distance between you and the patient for this to work.

6. Ask the patient to say when the red part of the hatpin disappears, whilst continuing to focus on the same point on your face.

7. With the red hatpin positioned equidistant between you and the patient, slowly move it laterally until the patient reports the disappearance of the top of the hatpin. The blind spot is normally found just temporal to central vision at eye level. The disappearance of the hatpin should occur at a similar point for you and the patient.

8. After the hatpin has disappeared for the patient, continue to move it laterally and ask the patient to let you know when they can see it again. The point at which the patient reports the hatpin re-appearing should be similar to the point at which it re-appears for you (presuming the patient and you have a normal blind spot).

9. You can further assess the superior and inferior borders of the blind spot using the same process.

  • Assess the patient's blind spot
    Assess the patient’s blind spot

Fundoscopy

In the context of a cranial nerve examination, fundoscopy is performed to assess the optic disc for signs of pathology (e.g. papilloedema). You should offer to perform fundoscopy in your OSCE, however, it may not be required. See our dedicated fundoscopy guide for more details.

Oculomotor (CN III), trochlear (CN IV) and abducens (CN VI) nerves

The oculomotor (CN III), trochlear (CN IV) and abducens (CN VI) nerves transmit motor information to the extraocular muscles to control eye movement and eyelid function. The oculomotor nerve also carries parasympathetic fibres responsible for pupillary constriction.

Eyelids

Inspect the eyelids for evidence of ptosis which can be associated with:

  • Oculomotor nerve pathology
  • Horner’s syndrome
  • Neuromuscular pathology (e.g. myasthenia gravis)

Eye movements

Briefly assess for abnormalities of eye movements which may be caused by underlying cranial nerve palsy (e.g. oculomotor, trochlear, abducens, vestibular nerve pathology).

1. Hold your finger (or a pin) approximately 30cm in front of the patient’s eyes and ask them to focus on it. Look at the eyes in the primary position for any deviation or abnormal movements.

2. Ask the patient to keep their head still whilst following your finger with their eyes. Ask them to let you know if they experience any double vision or pain.

3. Move your finger through the various axes of eye movement in a ‘H’ pattern.

4. Observe for any restriction of eye movement and note any nystagmus (which may suggest vestibular nerve pathology or stroke).

  • Assess eye movements
    Assess eye movements
Actions of the extraocular muscles
  • Superior rectus: primary action is elevation, secondary actions include adduction and medial rotation of the eyeball.
  • Inferior rectus: primary action is depression, secondary actions include adduction and lateral rotation of the eyeball.
  • Medial rectus: adduction of the eyeball.
  • Lateral rectus: abduction of the eyeball.
  • Superior oblique: depresses, abducts and medially rotates the eyeball.
  • Inferior oblique: elevates, abducts and laterally rotates the eyeball.
Oculomotor, trochlear and abducens nerve palsy

Damage to any of the three cranial nerves innervating the extraocular muscles can result in paralysis of the corresponding muscles.

Oculomotor nerve palsy (CN III)

The oculomotor nerve supplies all extraocular muscles except the superior oblique (CNIV) and the lateral rectus (CNVI). Oculomotor palsy (a.k.a. ‘third nerve palsy’), therefore, results in the unopposed action of both the lateral rectus and superior oblique muscles, which pull the eye inferolateral. As a result, patients typically present with a ‘down and out’ appearance of the affected eye.

Oculomotor nerve palsy can also cause ptosis (due to a loss of innervation to levator palpebrae superioris) as well as mydriasis due to the loss of parasympathetic fibres responsible for innervating to the sphincter pupillae muscle.

Trochlear nerve palsy (CN IV)

The only muscle the trochlear nerve innervates is the superior oblique muscle. As a result, trochlear nerve palsy (‘fourth nerve palsy’) typically results in vertical diplopia when looking inferiorly, due to loss of the superior oblique’s action of pulling the eye downwards. Patients often try to compensate for this by tilting their heads forwards and tucking their chin in, which minimises vertical diplopia. Trochlear nerve palsy also causes torsional diplopia (as the superior oblique muscle assists with intorsion of the eye as the head tilts). To compensate for this, patients with trochlear nerve palsy tilt their head to the opposite side, in order to fuse the two images together.

Abducens nerve palsy (CN VI)

The abducens nerve (CN VI) innervates the lateral rectus muscle. Abducens nerve palsy (‘sixth nerve palsy’) results in unopposed adduction of the eye (by the medial rectus muscle), resulting in a convergent squint. Patients typically present with horizontal diplopia which is worsened when they attempt to look towards the affected side.

Assessment of strabismus

Strabismus is a condition in which the eyes do not properly align with each other when looking at an object. Pathology affecting the oculomotor, trochlear or abducens nerves can cause strabismus.

Light reflex test (a.k.a. corneal reflex test or Hirschberg test)

1. Ask the patient to focus on a target approximately half a metre away whilst you shine a pen torch towards both eyes.

2. Inspect the corneal reflex on each eye:

  • If the ocular alignment is normal, the light reflex will be positioned centrally and symmetrically in each pupil.
  • Deflection of the corneal light reflex in one eye suggests a misalignment.

Cover test

The cover test is used to determine if a heterotropia (i.e. manifest strabismus) is present.

1. Ask the patient to fixate on a target (e.g. light switch).

2. Occlude one of the patient’s eyes and observe the contralateral eye for a shift in fixation:

  • If there is no shift in fixation in the contralateral eye, while covering either eye, the patient is orthotropic (i.e. normal alignment).
  • If there is a shift in fixation in the contralateral eye, while covering the other eye, the patient has a heterotropia.

3. Repeat the cover test on the other eye.

The direction of the shift in fixation determines the type of tropia; the table below describes the appropriate interpretation.

Interpretation of the cover test

Direction of eye at rest The direction of shift in fixation of the unoccluded eye when the opposite eye is occluded Type of tropia present
Temporally (i.e. laterally or outwards) Nasally (i.e. medially or inwards) Exotropia
Nasally (i.e. medially or inwards) Temporally (i.e. laterally or outwards) Esotropia
Superiorly (i.e. upwards) Inferiorly (i.e. downwards) Hypertropia
Inferiorly (i.e. downwards) Superiorly (i.e. upwards) Hypotropia
Cover test interpretation
Cover test interpretation

Trigeminal nerve (CN V)

The trigeminal nerve (CN V) transmits both sensory information about facial sensation and motor information to the muscles of mastication.

The trigeminal nerve has three sub-divisions, each of which has its own broad set of functions (not all are covered below):

  • Ophthalmic (V1): carries sensory information from the scalp and forehead, nose, upper eyelid as well as the conjunctiva and cornea of the eye.
  • Maxillary (V2): carries sensory information from the lower eyelid, cheek, nares, upper lip, upper teeth and gums.
  • Mandibular (V3): carries sensory information from the chin, jaw, lower lip, mouth, lower teeth and gums. Also carries motor information to the muscles of mastication (masseter, temporal muscle and the medial/lateral pterygoids) as well as the tensor tympani, tensor veli palatini, mylohyoid and digastric muscles.

Sensory assessment

First, explain the modalities of sensation you are going to assess (e.g. light touch/pinprick) to the patient by demonstrating on their sternum. This provides them with a reference of what the sensation should feel like (assuming they have no sensory deficits in the region overlying the sternum).

Ask the patient to close their eyes and say ‘yes’ each time they feel you touch their face.

Assess the sensory component of V1V2 and V3 by testing light touch and pinprick sensation across regions of the face supplied by each branch:

  • Forehead (lateral aspect): ophthalmic (V1)
  • Cheek: maxillary (V2)
  • Lower jaw (avoid the angle of the mandible as it is supplied by C2/C3): mandibular branch (V3)

You should compare each region on both sides of the face to allow the patient to identify subtle differences in sensation.

Motor assessment

Use the muscles of mastication to assess the motor component of V3:

1. Inspect the temporalis (located in the temple region) and masseter muscles (located at the posterior jaw) for evidence of wasting. This is typically most noticeable in the temporalis muscles, where a hollowing effect in the temple region is observed.

2. Palpate the masseter muscle (located at the posterior jaw) bilaterally whilst asking the patient to clench their teeth to allow you to assess and compare muscle bulk.

3. Ask the patient to open their mouth whilst you apply resistance underneath the jaw to assess the lateral pterygoid muscles. An inability to open the jaw against resistance or deviation of the jaw (typically to the side of the lesion) may occur in trigeminal nerve palsy.

Reflexes

Jaw jerk reflex

The jaw jerk reflex is a stretch reflex that involves the slight jerking of the jaw upwards in response to a downward tap. This response is exaggerated in patients with an upper motor neuron lesion. Both afferent and efferent pathways of the jaw jerk reflex involve the trigeminal nerve.

To assess the jaw jerk reflex:

1. Clearly explain what the procedure will involve to the patient and gain consent to proceed.

2. Ask the patient to open their mouth.

3. Place your finger horizontally across the patient’s chin.

4. Tap your finger gently with the tendon hammer.

5. In healthy individuals, this should trigger a slight closure of the mouth. In patients with upper motor neuron lesions, the jaw may briskly move upwards causing the mouth to close completely.

Corneal reflex

The corneal reflex involves involuntary blinking of both eyelids in response to unilateral corneal stimulation (direct and consensual blinking). The afferent branch of the corneal reflex involves V1 of the trigeminal nerve whereas the efferent branch is mediated by the temporal and zygomatic branches of the facial nerve.

To assess the corneal reflex:

1. Clearly explain what the procedure will involve to the patient and gain consent to proceed.

2. Gently touch the edge of the cornea using a wisp of cotton wool.

3. In healthy individuals, you should observe both direct and consensual blinking. The absence of a blinking response suggests pathology involving either the trigeminal or facial nerve.

The corneal reflex is not usually assessed in an OSCE scenario, however, you should offer to test it and understand the purpose behind the test.

  • Trigeminal nerve sensation
    Assess light touch sensation (V1)

Facial nerve (CN VII)

The facial nerve (CN VII) transmits motor information to the muscles of facial expression and the stapedius muscle (involved in the regulation of hearing). The facial nerve also has a sensory component responsible for the conveyance of taste from the anterior two-thirds of the tongue.

Sensory assessment

Ask the patient if they have noticed any recent changes in their sense of taste.

Motor assessment

Hearing changes

Ask the patient if they have noticed any changes to their hearing (paralysis of the stapedius muscle can result in hyperacusis).

Inspection

Inspect the patient’s face at rest for asymmetry, paying particular attention to:

  • Forehead wrinkles
  • Nasolabial folds
  • Angles of the mouth

Facial movement

Ask the patient to carry out a sequence of facial expressions whilst again observing for asymmetry:

  • Raised eyebrows: assesses frontalis – “Raise your eyebrows as if you’re surprised.”
  • Closed eyes: assesses orbicular oculi – “Scrunch up your eyes and don’t let me open them.”
  • Blown out cheeks: assesses orbicularis oris – “Blow out your cheeks and don’t let me deflate them.”
  • Smiling: assesses levator anguli oris and zygomaticus major – “Can you do a big smile for me?”
  • Pursed lips: assesses orbicularis oris and buccinator – “Can you try to whistle?”
  • Assess facial nerve
    “Raise your eyebrows”
Facial nerve palsy

Facial nerve palsy presents with unilateral weakness of the muscles of facial expression and can be caused by both upper and lower motor neuron lesions.

Facial nerve palsy caused by a lower motor neuron lesion presents with weakness of all ipsilateral muscles of facial expression, due to the loss of innervation to all muscles on the affected side. The most common cause of lower motor neuron facial palsy is Bell’s palsy.

Facial nerve palsy caused by an upper motor neuron lesion also presents with unilateral facial muscle weakness, however, the upper facial muscles are partially spared because of bilateral cortical representation (resulting in forehead/frontalis function being somewhat maintained). The most common cause of upper motor neuron facial palsy is stroke.

  • Bell's palsy
    Bell’s palsy 2, 3

Vestibulocochlear nerve (CN VIII)

The vestibulocochlear nerve (CN VIII) transmits sensory information about sound and balance from the inner ear to the brain. The vestibulocochlear nerve has no motor component.

Gross hearing assessment

Preparation

Ask the patient if they have noticed any change in their hearing recently.

Explain that you’re going to say 3 words or 3 numbers and you’d like the patient to repeat them back to you (choose two-syllable words or bi-digit numbers).

Assessment

1. Position yourself approximately 60cm from the ear and then whisper a number or word.

2. Mask the ear not being tested by rubbing the tragus. Do not place your arm across the face of the patient when rubbing the tragus, it is far nicer to occlude the ear from behind the head. If possible shield the patient’s eyes to prevent any visual stimulus.

3. Ask the patient to repeat the number or word back to you. If they get two-thirds or more correct then their hearing level is 12db or better. If there is no response use a conversational voice (48db or worse) or loud voice (76db or worse).

4. If there is no response you can move closer and repeat the test at 15cm. Here the thresholds are 34db for a whisper and 56db for a conversational voice.

5. Assess the other ear in the same way.

  • Whisper a number 60cm from the ear
    Whisper a number 60cm from the ear

Rinne’s test

1. Place a vibrating 512 Hz tuning fork firmly on the mastoid process (apply pressure to the opposite side of the head to make sure the contact is firm). This tests bone conduction.

2. Confirm the patient can hear the sound of the tuning fork and then ask them to tell you when they can no longer hear it.

3. When the patient can no longer hear the sound, move the tuning fork in front of the external auditory meatus to test air conduction.

4. Ask the patient if they can now hear the sound again. If they can hear the sound, it suggests air conduction is better than bone conduction, which is what would be expected in a healthy individual (this is often confusingly referred to as a “Rinne’s positive” result).

Summary of Rinne’s test results

These results should be assessed in context with the results of Weber’s test before any diagnostic assumptions are made:

  • Normal result: air conduction > bone conduction (Rinne’s positive)
  • Sensorineural deafness: air conduction > bone conduction (Rinne’s positive) – due to both air and bone conduction being reduced equally
  • Conductive deafness: bone conduction > air conduction (Rinne’s negative)
  • Rinne's test
    Place a 512 Hz tuning fork on the mastoid process

Weber’s test

1. Tap a 512Hz tuning fork and place in the midline of the forehead. The tuning fork should be set in motion by striking it on your knee (not the patient’s knee or a table).

2. Ask the patient “Where do you hear the sound?”

These results should be assessed in context with the results of Rinne’s test before any diagnostic assumptions are made:

  • Normal: sound is heard equally in both ears.
  • Sensorineural deafness: sound is heard louder on the side of the intact ear.
  • Conductive deafness: sound is heard louder on the side of the affected ear.

A 512Hz tuning fork is used as it gives the best balance between time of decay and tactile vibration. Ideally, you want a tuning fork that has a long period of decay and cannot be detected by vibration sensation.

  • Weber's test
    Tap a 512Hz tuning fork and place in the midline of the forehead
Conductive vs sensorineural hearing loss

Conductive hearing loss occurs when sound is unable to effectively transfer at any point between the outer ear, external auditory canal, tympanic membrane and middle ear (ossicles). Causes of conductive hearing loss include excessive ear wax, otitis externa, otitis media, perforated tympanic membrane and otosclerosis.

Sensorineural hearing loss occurs due to dysfunction of the cochlea and/or vestibulocochlear nerve. Causes of sensorineural hearing loss include increasing age (presbycusis), excessive noise exposure, genetic mutations, viral infections (e.g. cytomegalovirus) and ototoxic agents (e.g. gentamicin).

Vestibular testing – “Unterberger” or “Turning test”

Ask the patient to march on the spot with their arms outstretched and their eyes closed:

  • Normal result: the patient remains in the same position.
  • Vestibular lesion: the patient will turn towards the side of the lesion

Vestibular testing – “Head thrust test” or “Vestibular-ocular reflex”

Before performing this test you need to check if the patient has any neck problems and if so you should not proceed.

1. Explain to the patient that the test will involve briskly turning their head and then gain consent to proceed.

2. Sit facing the patient and ask them to fixate on your nose at all times during the test.

3. Hold their head in your hands (one hand covering each ear) and rotate it rapidly to the left, at a medium amplitude.

4. Repeat this process, but this time turn the head to the right.

The normal response is that ocular fixation is maintained. In a patient with loss of vestibular function on one side, the eyes will first move in the direction of the head (losing fixation), before a corrective refixation saccade occurs towards your nose.

  • Turning test
    Turning test

Glossopharyngeal (CN IX) and vagus (CN X) nerves

The glossopharyngeal nerve transmits motor information to the stylopharyngeus muscle which elevates the pharynx during swallowing and speech. The glossopharyngeal nerve also transmits sensory information that conveys taste from the posterior third of the tongue. Visceral sensory fibres of CN IX also mediate the afferent limb of the gag reflex.

The vagus nerve transmits motor information to several muscles of the mouth which are involved in the production of speech and the efferent limb of the gag reflex.

The glossopharyngeal and vagus nerves are assessed together because of their closely related functions.

Assessment

Ask the patient if they have experienced any issues with swallowing, as well as any changes to their voice or cough.

Inspection

Ask the patient to open their mouth and inspect the soft palate and uvula:

  • Note the position of the uvula. Vagus nerve lesions result in deviation of the uvula towards the unaffected side.

Ask the patient to say “ahh“:

  • Inspect the palate and uvula which should elevate symmetrically, with the uvula remaining in the midline. A vagus nerve lesion will cause asymmetrical elevation of the palate and uvula deviation away from the lesion.

Ask the patient to cough:

  • Vagus nerve lesions can result in the presence of a weak, non-explosive sounding bovine cough caused by an inability to close the glottis.

Swallow assessment

Ask the patient to take a small sip of water (approximately 3 teaspoons) and observe the patient swallow. The presence of a cough or a change to the quality of their voice suggests an ineffective swallow which can be caused by both glossopharyngeal (afferent) and vagus (efferent) nerve pathology.

Gag reflex

The gag reflex involves both the glossopharyngeal nerve (afferent) and the vagus nerve (efferent). This test is highly unpleasant for patients and therefore the swallow test mentioned previously is preferred as an alternative. You should not perform this test in an OSCE, although you may be expected to have an understanding of what cranial nerves are involved in the reflex.

To perform the gag reflex:

1. Stimulate the posterior aspect of the tongue and oropharynx which in healthy individuals should trigger a gag reflex. The absence of a gag reflex can be caused by both glossopharyngeal and vagus nerve pathology.

  • Soft palate & uvula
    Assess soft palate and uvula

Accessory nerve (CN XI)

The accessory nerve (CN XI) transmits motor information to the sternocleidomastoid and trapezius muscles. It does not have a sensory component.

Assessment

To assess the accessory nerve:

1. First, inspect for evidence sternocleidomastoid or trapezius muscle wasting.

2. Ask the patient to raise their shoulders and resist you pushing them downwards: this assesses the trapezius muscle (accessory nerve palsy will result in weakness).

3. Ask the patient to turn their head left whilst you resist the movement and then repeat with the patient turning their head to the right: this assesses the sternocleidomastoid muscle (accessory nerve palsy will result in weakness).

  • Assess Trapezius strength.
    Assess trapezius strength

Hypoglossal nerve (CN XII)

The hypoglossal nerve (CN XII) transmits motor information to the extrinsic muscles of the tongue (except for palatoglossus which is innervated by the vagus nerve). It does not have a sensory component.

Assessment

To assess the hypoglossal nerve:

1. Ask the patient to open their mouth and inspect the tongue for wasting and fasciculations at rest (minor fasciculations can be normal).

2. Ask the patient to protrude their tongue and observe for any deviation (which occurs towards the side of a hypoglossal lesion).

3. Place your finger on the patient’s cheek and ask them to push their tongue against it. Repeat this on each cheek to assess and compare power (weakness would be present on the side of the lesion).

  • Inspect tongue at rest for fasciculations
    Inspect the tongue at rest
Hypoglossal nerve palsy

Hypoglossal nerve palsy causes atrophy of the ipsilateral tongue and deviation of the tongue when protruded towards the side of the lesion. This occurs due to the overaction of the functioning genioglossus muscle on the unaffected side of the tongue.

  • Hypoglossal nerve palsy
    Left hypoglossal nerve palsy 4

To complete the examination…

Explain to the patient that the examination is now finished.

Thank the patient for their time.

Dispose of PPE appropriately and wash your hands.

Summarise your findings.

References

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Uterine Fibroids – Causes, Symptoms, Diagnosis, Treatment

Uterine Fibroids or leiomyomata are the most common benign tumor affecting women. Fibroids originate from uterine smooth muscle cells (myometrium) whose growth is primarily dependent on the levels of circulating estrogen. Fibroids can either present as an asymptomatic incidental finding on imaging, or symptomatically. Common symptoms include abnormal uterine bleeding, pelvic pain, disruption of surrounding pelvic structures(bowel and bladder), and back pain. Uterine fibroids typically are seen in three significant locations: subserosal (outside the uterus), intramural (inside the myometrium), and submucosal (Inside the uterine cavity). They can further be broken down to pedunculated or not. Fibroids are classically diagnosed by physical exam and ultrasound imaging, which carries a high sensitivity for this pathology. Fibroids continue to be the leading indication for hysterectomy.

Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bladder causing a frequent need to urinate. They may also cause pain during sex or lower back pain.[rx][rx] A woman can have one uterine fibroid or many. Occasionally, fibroids may make it difficult to become pregnant, although this is uncommon.[rx]

Types of Uterine Fibroids

Schematic drawing of various types of uterine fibroids: a=subserosal fibroids, b=intramural fibroids, c=submucosal fibroid, d=pedunculated submucosal fibroid, e=cervical fibroid, f=fibroid of the broad ligament

Growth and location are the main factors that determine if a fibroid leads to symptoms and problems.[rx] A small lesion can be symptomatic if located within the uterine cavity while a large lesion on the outside of the uterus may go unnoticed. Different locations are classified as follows:

  • Intramural fibroids  – are located within the muscular wall of the uterus. Unless they are large, they may be asymptomatic. Intramural fibroids begin as small nodules in the muscular wall of the uterus. With time, intramural fibroids may expand inwards, causing distortion and elongation of the uterine cavity.
  • Subserosal fibroids  – are located on the surface of the uterus. They can also grow outward from the surface and remain attached by a small piece of tissue and then are called pedunculated fibroids.[rx]
  • Submucosal fibroids – are most common type, located in the muscle beneath the endometrium of the uterus and distort the uterine cavity; even small lesions in this location may lead to bleeding and infertility. A pedunculated lesion within the cavity is termed an intracavitary fibroid and can be passed through the cervix.
  • Cervical fibroids – are located in the wall of the cervix (neck of the uterus). Rarely, fibroids are found in the supporting structures (round ligament, broad ligament, or uterosacral ligament) of the uterus that also contain smooth muscle tissue.

Fibroids may be single or multiple. Most fibroids start in the muscular wall of the uterus. With further growth, some lesions may develop towards the outside of the uterus or towards the internal cavity. Secondary changes that may develop within fibroids are hemorrhage, necrosis, calcification, and cystic changes. They tend to calcify after menopause.[rx]

If the uterus contains too many to count, it is referred to as diffuse uterine leiomyomatosis.

Uterine Fibroids

Extrauterine fibroids of uterine origin, metastatic fibroids

Fibroids of uterine origin located in other parts of the body, sometimes also called parasitic myomas have been historically extremely rare, but are now diagnosed with increasing frequency. They may be related or identical to metastasizing leiomyoma.

They are in most cases still hormone dependent but may cause life-threatening complications when they appear in distant organs. Some sources suggest that a substantial share of the cases may be late complications of surgeries such as myomectomy or hysterectomy. Particularly laparoscopic myomectomy using a morcellator has been associated with an increased risk of this complication.[rx][rx][rx]

There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can be dangerous depending on their location.[rx]

  • In leiomyoma with vascular invasion – an ordinary-appearing fibroid invades into a vessel but there is no risk of recurrence.
  • In intravenous leiomyomatosis – leiomyomata grow in veins with uterine fibroids as their source. Involvement of the heart can be fatal.
  • In benign metastasizing leiomyoma – leiomyomata grow in more distant sites such as the lungs and lymph nodes. The source is not entirely clear. Pulmonary involvement can be fatal.
  • In disseminated intraperitoneal leiomyomatosis – leiomyomata grow diffusely on the peritoneal and omental surfaces, with uterine fibroids as their source. This can simulate a malignant tumor but behaves benignly.

Mullerian anomalies can be either clinically asymptomatic and missed in routine gynecological examinations or manifest with infertility and amenorrhea. These pathologies represent unique challenges for establishing reproductive health. The American fertility association has classified this anomaly in seven categories :

  • Class I: Hypoplasia/uterine hypoplasia. (Mayer Rokitansky Kuster Hauser syndrome)
  • Class II: Unicornuate uterus
  • Class III: Uterus didelphys.
  • Class IV: Bicornuate uterus
  • Class V: Septate uterus
  • Class VI: Arcuate uterus
  • Class VII: T-shaped uterus resulting from the exposure to Diethylstilbestrol in fetal life

Mayer Rokitansky Kuster Hauser syndrome has a prevalence of 1 in 4000 to 5000 births and is one of the most frequent Mullerian abnormalities. It characteristically presents with uterine and vaginal agenesis or hypoplasia and can be accompanied by renal and bone abnormalities. Patients usually arrive at care due to primary amenorrhea with normal secondary sexual characteristics. Treatment of vaginal aplasia consists of the creation of a neovagina surgically or by dilation. Depression, anxiety, and female identity issues often occur in these patients, thus seeking counseling and peer support groups are recommended activities before and during treatment. Alternatives for having children include adoption and gestational surrogacy; this merits discussion during the consult.

Causes of Uterine Fibroids

The exact pathophysiology behind the development of uterine fibroids is unclear. Research suggests that the starting event for fibroid development begins with a single uterine smooth muscle cell(myometrium), which is then followed by deviations from the normal signaling pathways of cellular division. Fibroids are considered to be estrogen-dependent tumors, and there is evidence showing that leiomyomas overexpress certain estrogen and progesterone receptors when compared to normal surrounding myometrium.

Fibroids are a result of the inappropriate growth of uterine smooth muscle tissue or myometrium. Their growth is dependent on estrogen and progesterone levels. The underlying pathophysiology is uncertain.

  • Genetic changes – Many fibroids contain changes in genes that differ from those in normal uterine muscle cells.
    Hormones – Estrogen and progesterone, two hormones that stimulate development of the uterine lining during each menstrual cycle in preparation for pregnancy, appear to promote the growth of fibroids. Fibroids contain more estrogen and progesterone receptors than normal uterine muscle cells do. Fibroids tend to shrink after menopause due to a decrease in hormone production.
  • Other growth factors – Substances that help the body maintain tissues, such as insulin-like growth factor, may affect fibroid growth.
  • Extracellular matrix (ECM) – ECM is the material that makes cells stick together, like mortar between bricks. ECM is increased in fibroids and makes them fibrous. ECM also stores growth factors and causes biologic changes in the cells themselves.
  • Fibroids can grow
    • In the muscle wall of the uterus (myometrial)
    • Just under the surface of the uterine lining (submucosal)
    • Just under the outside lining of the uterus (subserosal)
    • On a long stalk on the outside the uterus or inside the uterus (pedunculated)

Fibroids are more common in the following groups of women

  • Black women: Fibroids are two to three times more common in black women – but the exact reason is not known.
  • Women who have never been pregnant.
  • Women whose mother or sister has had fibroids.
  • Women who are very overweight. But it’s not clear whether the extra weight itself is the cause.

Fibroids are less common in these women

  • Women who have had several children.
  • Women who have used birth control pills for several years.

It’s not clear whether there’s a link between your diet and the development of fibroids.

Symptoms of Uterine Fibroids

Many women who have fibroids don’t have any symptoms. In those that do, symptoms can be influenced by the location, size and number of fibroids.

In women who have symptoms, the most common signs and symptoms of uterine fibroids include

  • Heavy menstrual bleeding
  • Menstrual periods lasting more than a week
  • Pelvic pressure or pain
  • Heavy bleeding (which can be heavy enough to cause anemia) or painful periods
  • Feeling of fullness in the pelvic area (lower stomach area)
  • Enlargement of the lower abdomen
  • Frequent urination
  • Pain during sex
  • Bleeding between periods
  • Heavy bleeding during your period, sometimes with blood clots
  • Periods that may last longer than normal
  • Needing to urinate more often
  • Pelvic cramping or pain with periods
  • Feeling fullness or pressure in your lower belly
  • Pain during intercourse
  • Complications during pregnancy and labor, including a six-time greater risk of cesarean section
  • Reproductive problems, such as infertility, which is very rare
  • Frequent urination
  • Difficulty emptying the bladder
  • Constipation
  • Backache or leg pains

Rarely, a fibroid can cause acute pain when it outgrows its blood supply, and begins to die.

Fibroids are generally classified by their location. Intramural fibroids grow within the muscular uterine wall. Submucosal fibroids bulge into the uterine cavity. Subserosal fibroids project to the outside of the uterus.

Uterine Fibroids

Diagnosis of Uterine Fibroids

History and Physical
  • History and physical exam include a thorough menstrual history to determine the timing, quantity, and any potential aggravating factors for the abnormal bleeding. Common presenting symptoms include metrorrhagia, menorrhagia, or a combination of the two. Less common presenting symptoms include dyspareunia, pelvic pain, bowel problems, urinary symptoms, or signs and symptoms related to anemia. Most of the less frequent symptoms are a reflection of the mass effect produced by leiomyomas on surrounding structures. Patients may also be completely asymptomatic with an incidental finding of fibroids on imaging.
  • A speculum exam with a bimanual exam should be performed to rule out any vaginal or cervical pathology, as well as assess the size, and shape of the female reproductive organs. A large asymmetric uterus felt upon the exam is indicative of fibroids. Finally, consider evaluating for conjunctival pallor and thyroid pathology to identify potential secondary symptoms or causes of abnormal bleeding.
Laboratory studies
  • The initial evaluation should include a beta-human chorionic gonadotropin test to rule out pregnancy, CBC, TSH, and a prolactin level to evaluate for the non-structural causes in the differential. Include an endometrial biopsy for women over 35.
  • The International Federation of Gynecology and Obstetrics (FIGO) has developed a classification system that allows for the determination of the extent of invasion into the endometrial cavity. The FIGO scale ranges from 0 to 8, with the lower number indicating closer proximity to the endometrium.
  • If bleeding is the predominant symptom and there is a concern for anemia or other sequelae of recurrent blood loss, a complete blood count (CBC) is indicated. Further evaluation of blood work should include a thyroid-stimulating hormone level to rule out thyroid disease as the cause of abnormal bleeding if the index of suspicion is low for leiomyomata as the etiology .
Radiologic studies
  • Transvaginal ultrasound  is the gold standard for imaging uterine fibroids. It has a sensitivity of around 90 to 99% for the detection of uterine fibroids. Ultrasound can improve with the use of saline-infused sonography, which helps increase the sensitivity for the detection of subserosal and intramural fibromas. Fibroid appearance is as a firm, well-circumscribed, hypoechoic mass. On ultrasound, tend to have a variable amount of shadowing, and calcifications or necrosis may distort the echogenicity.
  • Ultrasound – Ultrasounds use sound waves to take a picture of your uterus. A technician will place a device either in your vagina or on your abdomen to get the images. Then your doctor can see if you have fibroids and where and how large they are.
  • Lab tests – Your doctor may want you to have blood tests to help figure out why you have fibroids. Your complete blood count (CBC) can help them decide whether you have anemia (low levels of red blood cells) or other bleeding disorders.
  • Magnetic resonance imaging (MRI) – If your doctor needs more information after you have an ultrasound, you may also have an MRI. MRIs show more detailed images of fibroids and can help doctors decide the best treatment. Your doctor may also suggest an MRI if you have a large uterus or are close to menopause.
  • Hysterosonography – In this test, a technician pushes saline into your uterine cavity to make it larger. This helps them see fibroids that are growing into your uterus (submucosal fibroids) and the lining of your uterus. This is useful if you’re trying to get pregnant or have heavy periods.
  • Hysterosalpingography – If your doctor needs to see if your fallopian tubes are blocked, you might have a hysterosalpingography. Your doctor uses dye to highlight your uterus and fallopian tubes on an X-ray to help see these areas better.
  • Hysteroscopyis where the physician uses a hysteroscope to visualize the inside of the uterus. This imaging modality allows for better visualization of fibroids inside the uterine cavity. This method allows for the direct removal of intrauterine growths during the procedure.
  • Electric Magnetic Resonance Imaging MRIhas the benefit of providing a better picture of the number, size, vascular supply, and boundaries of the fibroids as they relate to the pelvis. Nevertheless, it is unnecessary for a routine diagnosis when fibroids are suspected. It has not been shown to differentiate leiomyosarcoma from leiomyoma.
  • Hysterosalpingography – is a special X-ray test. It may detect abnormal changes in the size and shape of the uterus and fallopian tubes.
  • Sonohysterography is a test in which fluid is put into the uterus through the cervix. Ultrasonography is then used to show the inside of the uterus. The fluid provides a clear picture of the uterine lining.
  • Laparoscopy uses a slender device (the laparoscope) to help your health care professional see the inside of the abdomen. It is inserted through a small cut just below or through the navel. Fibroids on the outside of the uterus can be seen with the laparoscope.

Treatment of Uterine Fibroids

While deciding on treatment options for uterine fibroids, the patient’s age, presenting symptoms, and desire for fertility preservation all merit consideration. The locations and size of the fibroids will both determine the available treatment options. Management options can be broken down into three categories starting at surveillance with progression to medical management or surgical therapy with increasing severity of symptoms.

Surveillance – This is the preferred method in women with asymptomatic fibroids. The current recommendations do not require serial imaging when following these patients.  Most fibroids do not require treatment unless they are causing symptoms. After menopause, fibroids shrink, and it is unusual for them to cause problems.

Symptomatic uterine fibroids can be treated by
  • medication to control symptoms (i.e., symptomatic management)
  • medication aimed at shrinking tumors
  • ultrasound fibroid destruction
  • myomectomy or radiofrequency ablation
  • hysterectomy
  • uterine artery embolization

In those who have symptoms, uterine artery embolization and surgical options have similar outcomes with respect to satisfaction.[rx]

Medical Management

Primarily revolves around decreasing the severity of bleeding and pain symptoms.

  • Gonadotropin-releasing hormone (GnRH) agonists. Medications called GnRH agonists treat fibroids by blocking the production of estrogen and progesterone, putting you into a temporary menopause-like state. As a result, menstruation stops, fibroids shrink and anemia often improves. GnRH agonists include leuprolide (Lupron, Eligard, others), goserelin (Zoladex) and triptorelin (Trelstar, Triptodur Kit). Many women have significant hot flashes while using GnRH agonists. GnRH agonists typically are used for no more than three to six months because symptoms return when the medication is stopped and long-term use can cause loss of bone. Your doctor may prescribe a GnRH agonist to shrink the size of your fibroids before a planned surgery or to help transition you to menopause.
  • Progestin-releasing intrauterine device (IUD). A progestin-releasing IUD can relieve heavy bleeding caused by fibroids. A progestin-releasing IUD provides symptom relief only and doesn’t shrink fibroids or make them disappear. It also prevents pregnancy.
  • Tranexamic acid (Lysteda, Cyklokapron). This nonhormonal medication is taken to ease heavy menstrual periods. It’s taken only on heavy bleeding days. Tranexamic acid improves blood clotting and is used to reduce heavy menstrual bleeding and to minimize postoperative blood loss. Tranexamic acid is a derivative of the amino acid, lysine.  This medication is a reversible inhibitor of lysine receptor sites on plasminogen that, when bound, prevent fibrin degradation and functionally stabilize clot formation .
  • Selective estrogen receptor modulators –  bind to estrogen receptors to mimic or block estrogen activity, and have differential effects across tissue types (e.g., bone, brain, liver). Tamoxifen was introduced to block estrogen action in the treatment of breast cancer, but has estrogen–like effects on the uterus. Raloxifene has estrogen-like effects on bone, but anti-estrogen effects in the breast and uterus. It is used to treat osteoporosis and prevent breast cancer, and reduce fibroid size.
  • Hormonal contraceptives This treatment group includes oral contraceptive pills (OCP) and the levonorgestrel intrauterine device(IUD). OCPs are common options in the management of abnormal uterine bleeding related to symptomatic fibroids. However, there is only limited data showing their effectiveness in uterine fibroids, and larger randomized controlled trials are necessary. The levonorgestrel IUD is currently the recommended hormonal therapy for symptomatic fibroids due to the lack of systemic effects and low side effect profile. Caution should is necessary when treating fibroids that distort the intrauterine cavity as they can lead to a higher rate of expulsion.
  • GnRH Agonist (leuprolide) This method works by acting on the pituitary gland to decrease gonadal hormone production, thus decreasing the hormone-stimulated growth of the fibroid. A study by Friedman et al. showed a decrease in uterine size by 45% at 24 weeks of treatment on a GnRH agonist with a return to pretreatment size 24 weeks after cessation. Long-term therapy with a GnRH agonist has also been shown to result in statistically significant bone loss. Because of this and its relatively short-term effect, the American College of Obstetricians and Gynecologists (ACOG) has recommended that it’s use be limited to 6 months or less. Leuprolide is most effective when used as a pre-surgical therapy for symptomatic fibroids.
  • Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Anti-inflammatories have been shown to decrease prostaglandin levels, which are elevated in women with heavy menstrual bleeding and are responsible for the painful cramping experienced in menstruation. They have not been shown to decrease the size of the fibroids.
  • Levonorgestrel intrauterine devices –  are effective in limiting menstrual blood flow and improving other symptoms. Side effects are typically few as the levonorgestrel (a progestin) is released in low concentration locally.[rx] While most levongestrel-IUD studies concentrated on treatment of women without fibroids a few reported good results specifically for women with fibroids including a substantial regression of fibroids.[rx][rx]
  • Cabergoline – in a moderate and well-tolerated dose has been shown in two studies to shrink fibroids effectively. The mechanism of action responsible for how cabergoline shrinks fibroids is unclear.[rx]
  • Ulipristal acetate – is a synthetic selective progesterone receptor modulator (SPRM) that has tentative evidence to support its use for presurgical treatment of fibroids with low side-effects.[rx] Long-term UPA-treated fibroids have shown volume reduction of about 70%.[rx] In some cases UPA alone is used to relieve symptoms without surgery.[rx]
  • Danazol – is an effective treatment to shrink fibroids and control symptoms. Its use is limited by unpleasant side effects. Mechanism of action is thought to be antiestrogenic effects. Recent experience indicates that safety and side effect profile can be improved by more cautious dosing.[rx]
  • Progesterone antagonists – such as mifepristone have been tested, there is evidence that it relieves some symptoms and improves quality of life but because of adverse histological changes that have been observed in several trials it can not be currently recommended outside of research setting.[rx][rx] Fibroid growth has recurred after antiprogestin treatment was stopped.[rx]
  • Aromatase inhibitors – have been used experimentally to reduce fibroids. The effect is believed to be due partially by lowering systemic estrogen levels and partially by inhibiting locally overexpressed aromatase in fibroids.[rx] However, fibroid growth has recurred after treatment was stopped.[rx] Experience from experimental aromatase inhibitor treatment of endometriosis indicates that aromatase inhibitors might be particularly useful in combination with a progestogenic ovulation inhibitor.

Other potential medical therapies include aromatase inhibitors, and selective estrogen receptor modulators (SERM), such as raloxifene or tamoxifen. There is little evidence supporting the use of these medications in the treatment for symptomatic uterine fibroids. Tranexamic acid has been approved for the treatment of abnormal and heavy uterine bleeding but has not been approved or shown to decrease the disease burden in uterine fibroids.

Surgical Therapy

  • Endometrial AblationIt offers an alternative to surgery in patients whose primary complaint is heavy or abnormal bleeding. There is a larger risk of a failed procedure with submucosal fibroids because they cause disruption of the uterine cavity and can prevent proper cauterization of the entire endometrium.
  • Uterine Artery Embolization – A minimally invasive approach for those who wish to preserve fertility. This technique works by decreasing the total blood supply to the uterus, thereby decreasing the flow to the fibroids and minimizing bleeding symptoms. The procedure has been shown effective in controlling menorrhagia. However, according to De La Cruz et al., only limited studies show the effects on fertility preservation with this technique. 
  • Myomectomy An invasive surgical option for those who desire fertility preservation. There is no large randomized controlled trial showing that myomectomy can improve fertility for patients. Furthermore, the outcome is highly dependent on the location and size of the fibroid. Nevertheless, it can be an effective treatment option in those wishing to avoid hysterectomy.
  • Hysterectomy – Hysterectomy was the classical method of treating fibroids. Although it is now recommended only as last option, fibroids are still the leading cause of hysterectomies in the US.
  • Endometrial ablation – Endometrial ablation can be used if the fibroids are only within the uterus and not intramural and relatively small. High failure and recurrence rates are expected in the presence of larger or intramural fibroids.
There are three types of myomectomy
  • In a hysteroscopic myomectomy (also called transcervical resection) – the fibroid can be removed by either the use of a resectoscope, an endoscopic instrument inserted through the vagina and cervix that can use high-frequency electrical energy to cut tissue, or a similar device.
  • A laparoscopic – myomectomy is done through a small incision near the navel. The physician uses a laparoscope and surgical instruments to remove the fibroids. Studies have suggested that laparoscopic myomectomy leads to lower morbidity rates and faster recovery than does laparotomic myomectomy.[53]
  • A laparotomic – myomectomy (also known as an open or abdominal myomectomy) is the most invasive surgical procedure to remove fibroids. The physician makes an incision in the abdominal wall and removes the fibroids from the uterus. Laparoscopic myomectomy has less pain and shorter time in hospital than open surgery.[rx]

Other procedures

Radiofrequency ablation is a minimally invasive treatments for fibroids.[rx] In this technique the fibroid is shrunk by inserting a needle-like device into the fibroid through the abdomen and heating it with radio-frequency (RF) electrical energy to cause necrosis of cells. The treatment is a potential option for women who have fibroids, have completed child-bearing and want to avoid a hysterectomy.

  • MRI guided focused ultrasound surgeryThis treatment option utilizes MRI and ultrasound waves to focus on the fibroid, resulting in cauterization. As a relatively new treatment, there is not enough clinical evidence to support its long term effectiveness at this time.
  • HysterectomyRemains the definitive treatment for fibroids.
  • Myolysis – A needle is inserted into the fibroids, usually guided by laparoscopy, and electric current or freezing is used to destroy the fibroids.
  • Uterine Fibroid Embolization (UFE), or Uterine Artery Embolization (UAE) – A thin tube is thread into the blood vessels that supply blood to the fibroid. Then, tiny plastic or gel particles are injected into the blood vessels. This blocks the blood supply to the fibroid, causing it to shrink. UFE can be an outpatient or inpatient procedure. Complications, including early menopause, are uncommon but can occur. Studies suggest fibroids are not likely to grow back after UFE, but more long-term research is needed. Not all fibroids can be treated with UFE. The best candidates for UFE are women who:
    • Have fibroids that are causing heavy bleeding
    • Have fibroids that are causing pain or pressing on the bladder or rectum
    • Don’t want to have a hysterectomy
    • Don’t want to have children in the future

Noninvasive procedure

MRI-guided focused ultrasound surgery (FUS) is:

  • A noninvasive treatment option – for uterine fibroids that preserves your uterus, requires no incision and is done on an outpatient basis.
  • Performed while you’re inside an MRI scanner – equipped with a high-energy ultrasound transducer for treatment. The images give your doctor the precise location of the uterine fibroids. When the location of the fibroid is targeted, the ultrasound transducer focuses sound waves (sonications) into the fibroid to heat and destroy small areas of fibroid tissue.
  • Newer technology – so researchers are learning more about the long-term safety and effectiveness. But so far data collected show that FUS for uterine fibroids is safe and effective.

Minimally invasive procedures

Certain procedures can destroy uterine fibroids without actually removing them through surgery. They include:

  • Uterine artery embolization – Small particles (embolic agents) are injected into the arteries supplying the uterus, cutting off blood flow to fibroids, causing them to shrink and die. This technique can be effective in shrinking fibroids and relieving the symptoms they cause. Complications may occur if the blood supply to your ovaries or other organs is compromised. However, research shows that complications are similar to surgical fibroid treatments and the risk of transfusion is substantially reduced.
  • Radiofrequency ablation – In this procedure, radiofrequency energy destroys uterine fibroids and shrinks the blood vessels that feed them. This can be done during a laparoscopic or transcervical procedure. A similar procedure called cryomyolysis freezes the fibroids. With laparoscopic radiofrequency ablation, also called Lap-RFA, your doctor makes two small incisions in the abdomen to insert a slim viewing instrument (laparoscope) with a camera at the tip. Using the laparoscopic camera and a laparoscopic ultrasound tool, your doctor locates fibroids to be treated. After locating a fibroid, your doctor uses a specialized device to deploy several small needles into the fibroid. The needles heat up the fibroid tissue, destroying it. The destroyed fibroid immediately changes consistency, for instance from being hard like a golf ball to being soft like a marshmallow. During the next three to 12 months, the fibroid continues to shrink, improving symptoms. Because there’s no cutting of uterine tissue, doctors consider Lap-RFA a less invasive alternative to hysterectomy and myomectomy. Most women who have the procedure get back to regular activities after 5 to 7 days of recovery. The transcervical — or through the cervix — approach to radiofrequency ablation also uses ultrasound guidance to locate fibroids.
  • Laparoscopic or robotic myomectomy – In a myomectomy, your surgeon removes the fibroids, leaving the uterus in place. If the fibroids are few in number, you and your doctor may opt for a laparoscopic or robotic procedure, which uses slender instruments inserted through small incisions in your abdomen to remove the fibroids from your uterus. Larger fibroids can be removed through smaller incisions by breaking them into pieces (morcellation), which can be done inside a surgical bag, or by extending one incision to remove the fibroids.
  • Hysteroscopic myomectomy – This procedure may be an option if the fibroids are contained inside the uterus (submucosal). Your surgeon accesses and removes fibroids using instruments inserted through your vagina and cervix into your uterus.
  • Endometrial ablation – This treatment, performed with a specialized instrument inserted into your uterus, uses heat, microwave energy, hot water or electric current to destroy the lining of your uterus, either ending menstruation or reducing your menstrual flow. Typically, endometrial ablation is effective in stopping abnormal bleeding. Submucosal fibroids can be removed at the time of hysteroscopy for endometrial ablation, but this doesn’t affect fibroids outside the interior lining of the uterus. Women aren’t likely to get pregnant following endometrial ablation, but birth control is needed to prevent a pregnancy from developing in a fallopian tube (ectopic pregnancy).
  • Abdominal myomectomy – If you have multiple fibroids, very large fibroids or very deep fibroids, your doctor may use an open abdominal surgical procedure to remove the fibroids. Many women who are told that hysterectomy is their only option can have an abdominal myomectomy instead. However, scarring after surgery can affect future fertility.
  • Hysterectomy – This surgery — the removal of the uterus — remains the only proven permanent solution for uterine fibroids. But hysterectomy is major surgery. Hysterectomy ends your ability to bear children. If you also elect to have your ovaries removed, the surgery brings on menopause and the question of whether you’ll take hormone replacement therapy. Most women with uterine fibroids may be able to choose to keep their ovaries.

Morcellation during fibroid removal

  • Morcellation — a process of breaking fibroids into smaller pieces — may increase the risk of spreading cancer if a previously undiagnosed cancerous mass undergoes morcellation during myomectomy. There are several ways to reduce that risk, such as evaluating risk factors before surgery, morcellating the fibroid in a bag or expanding an incision to avoid morcellation.
  • All myomectomies – carry the risk of cutting into an undiagnosed cancer, but younger, premenopausal women generally have a lower risk of undiagnosed cancer than do older women.

Also, complications during open surgery are more common than the chance of spreading an undiagnosed cancer in a fibroid during a minimally invasive procedure. If your doctor is planning to use morcellation, discuss your individual risks before treatment.

The Food and Drug Administration (FDA) advises against the use of a device to morcellate the tissue (power morcellator) for most women having fibroids removed through myomectomy or hysterectomy. In particular, the FDA recommends that women who are approaching menopause or who have reached menopause avoid power morcellation. Older women in or entering menopause may have a higher cancer risk, and women who are no longer concerned about preserving their fertility have additional treatment options for fibroids.

What if I become pregnant and have fibroids?

Women who have fibroids are more likely to have problems during pregnancy and delivery. This doesn’t mean there will be problems. Most women with fibroids have normal pregnancies. The most common problems seen in women with fibroids are:

  • Cesarean section – The risk of needing a c-section is six times greater for women with fibroids.
  • Baby is breech – The baby is not positioned well for vaginal delivery.
  • Labor fails to progress
  • Placental abruption – The placenta breaks away from the wall of the uterus before delivery. When this happens, the fetus does not get enough oxygen.
  • Preterm delivery

Talk to your obstetrician if you have fibroids and become pregnant. All obstetricians have experience dealing with fibroids and pregnancy. Most women who have fibroids and become pregnant do not need to see an OB who deals with high-risk pregnancies.

Possible Complications

Complications of fibroids include

  • Severe pain or very heavy bleeding that needs emergency surgery.
  • Twisting of the fibroid – This can cause blocked blood vessels that feed the tumor. You may need surgery if this happens.
  • Anemia (not having enough red blood cells) from heavy bleeding.
  • Urinary tract infections – If the fibroid presses on the bladder, it can be hard to empty your bladder completely.
  • Infertility, in rare cases.

If you are pregnant, there’s a small risk that fibroids may cause complications

  • You may deliver your baby early because there is not enough room in your womb.
  • If the fibroid blocks the birth canal or puts the baby in a dangerous position, you may need to have a cesarean section (C-section).
  • You may have heavy bleeding right after giving birth.

References

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Treatment of Benign Prostatic Hyperplasia (BPH)

Treatment of Benign Prostatic Hyperplasia (BPH)/Benign prostatic hyperplasia (BPH) is among the commonest urological abnormality affecting the aging male. The cause of the increase in prostatic volume is multifactorial, but current research has implicated hormonal aberrations. Clinical assessment of the patient is integral to determining the optimal treatment strategy. Exclusion of prostatic cancer and complications of BPH are critical prior to the commencement of conservative and non-invasive strategies. Recently, the introduction of pharmaceutical agents has changed the landscape of management of BPH. Alpha-blockers, 5-alpha reductase inhibitors and now phosphodiesterase-5 inhibitors provide significant symptomatic improvement for BPH, particularly when used in combination. Invasive surgical therapies remain the gold standard for refractory and complicated BPH disease.

Treatment of Benign Prostatic Hyperplasia (BPH)

MEDICAL THERAPY FOR BPH – MONOTHERAPY AGENTS

Medical therapy is now first-line treatment for most men with symptomatic BPH. They are non-invasive, reversible, cause minimal side effects, and significantly improve symptoms (75, 130). With these recommendations, the rates of prescriptions for the medical management for BPH have increased drastically over the past decade (131-132). This increased interest has further lead to the development of safer, more efficacious agents.

Alpha-Blockers

There are 3 main components to clinically significant BPH: static, dynamic and detrusor muscle components as outlined above. The dynamic component is associated with an increase in smooth muscle tone of the prostate. These smooth muscle cells contract under the influence of noradrenergic sympathetic nerves, thereby constricting the urethra. Prostatic tissue contains high levels of both alpha1 and alpha2 adrenoceptors – 98% of the alpha1 adrenoceptors are associated with stromal elements of the prostate. Thus alpha1-receptor blockers relax smooth muscle, resulting in relief of bladder outlet obstruction that enhances urine flow. Different subtypes of alpha1 receptors have been identified, with alpha1A predominating. Two alpha1A-adrenoceptors generated by genetic polymorphism have been identified with different ethnic distributions but similar pharmacologic properties.

Prazosin

Prazosin (titrated up to 5mg day) has been shown to significantly increase flow rates by 36-59% compared to placebo 6-28% but 17% of men discontinued the drug due to side effects such as dizziness (21%), headache (14%), syncope (3.4%) and retrograde ejaculation (13%).

Alfuzosin

Alfuzosin (5 mg bid or10 mg daily) has shown symptom score reduction of 31-65% (compared to placebo 18-39%) and flow rate increases of 22-54% (compared to placebo 10-30%). Hence the results were similar to those of prazosin but with only 3-7% discontinuations due to dizziness (3-7%), headache (1-6%) and syncope (<1 %).

Terazosin

Terazosin (2-10mg) had a symptom score reduction of 40-70% (compared to placebo 16-58%) and improved flow rates 19-40% (placebo 5-46%). Between 9-15 % of men discontinued the drug, related to dizziness (10-20%), headache (1-7%), asthenia (7-10%), syncope (0.5-1.0%) and postural hypotension (3-9%). Thus terazosin was effective and superior to placebo in reducing symptoms and increasing the peak urinary flow rate. The effect of terazosin on the peak urinary flow rate was apparent in studies as soon as 8 weeks of therapy. Most importantly, the effect of terazosin on symptoms and peak urinary flow rate was independent of the baseline prostate size for the range of prostate volumes reported.

Doxazosin

Doxazosin (4-12mg/day) is a selective alpha1-adrenoceptor antagonist and produced a significant increase in maximum urinary flow rate (2.3 to 3.6 ml. per sec) at doses of 4 mg, 8 mg, and 12 mg, and an average flow rate compared with placebo. The increase in maximum flow rate was significantly greater than a placebo within 1 week of initiating therapy and the drug significantly decreased patient-assessed total, obstructive, and irritative BPH symptoms. Blood pressure was significantly lower with all doxazosin doses compared with placebo. Adverse events, primarily mild to moderate in severity, were reported in 48% of patients on doxazosin compared to 35% on placebo, with only 11% discontinuing treatment (a similar number to placebo). The main side effects were dizziness (15-24%), headache (12%) and hypotension (5-8%) and abnormal ejaculation (0.4%).

Tamsulosin

Tamsulosin (0.4 mg once daily dose) is a selective alpha-blocker for the alpha1A subtype which predominates in the human prostate, having 12 times more affinity for the receptors in the prostate than in the aorta thereby reducing side effects mediated through blood vessels receptors. Symptom scores were reduced by 20-50% (placebo 18-30%), flow rates improved 20-45% (placebo 5-15%) but only 3-7% of men discontinued drug because of dizziness (3-20%), headache (3-20%), syncope (0.3%) and retrograde ejaculation (5-10%). The rate of retrograde ejaculation was much higher than alfuzosin but the blood pressure-lowering side effects are less with tamsulosin. There are different formulations including extended-release with lower pharmacological peaks and troughs which may offer fewer side effects.

Silodosin

Silodosin (8mg daily) is similar to tamsulosin being a selective blocker for the alpha1A receptor subtype. Symptoms scores were reduced by 40-50% (placebo 20-30%), flow rates improved by 17-30% (placebo 5-14%). Despite these favorable urinary outcomes, a significant proportion of patients experienced ejaculatory dysfunction (13-23%). These rates are higher compared to tamsulosin, however, discontinuation rates secondary to ejaculatory dysfunction remain at 1-2%. Typical side effects include thirst (10%), loose stools (9%) and dizziness (5%).

Table 12Commonly used alpha-blockers

Group Drug
Nonselective alpha-blockers
  • Phenoxybenzamine
  • Nicergoline
  • Thymoxamine
Selective alpha1 blockers
  • Prazosin
  • Alfuzosin
Super-selective alpha1A blockers
  • Tamsulosin
  • Silodosin
Long-acting alpha1 blockers
  • Terazosin
  • Doxazosin

5-alpha reductase inhibitors

The enzyme 5-alpha reductase is crucial in the amplification of androgen action in the prostate by modulating the conversion of testosterone to DHT. Within the prostate, 90% of testosterone is converted to DHT (72, 150). There are 2 isoforms of the enzyme 5-alpha reductase which are encoded by separate genes (151). Type 1 isoenzyme is expressed highly in the skin, liver, hair follicles and sebaceous glands, and prostate whereas type 2 is responsible for male virilization of the male fetus, and in adulthood resides in the prostate, genital skin, facial and scalp follicles (152-153). Inhibitors of these enzymes potentially decrease serum and intra-prostatic DHT levels, thus reducing prostatic tissue growth.

Finasteride

Finasteride was the first of these to be trialed in humans and shown to decrease DHT levels. It acts predominantly on the type 2 isoenzyme of 5-alpha reductase and has until recently been the only available 5-alpha reductase inhibitor. There is some evidence that patients on finasteride experience fewer serious complications associated with the progression of BPH compared with those prescribed an alpha-blocker, such as acute urinary retention or undergoing BPH-related surgery, but more prospective data are needed. Dutasteride is also available and blocks both isoenzymes of 5-alpha reductase. Dutasteride shows a 60-fold greater inhibition of the type 1 isoenzyme than finasteride and is also active against the type 2 isoform. Finasteride reduces serum DHT levels by 65-70% and prostatic levels by 85-90%, although the intraprostatic levels of testosterone are reciprocally elevated as the testosterone is not being converted to DHT.

Dutasteride

Dutasteride unlike finasteride blocks both the type I and Type II 5-alpha reductase isomers. In terms of monotherapy, a one year randomized, double-blinded comparison of finasteride and dutasteride in men with BPH (EPICS: Enlarged Prostate International Comparator Study) found a trend for dutasteride improvement over finasteride in IPSS (International Prostate Symptom Score) that did not reach statistical significance (abstract). Another non-randomized comparative trial with 240 patients, published only in abstract form, showed a small improvement in AUASI and Qmax for dutasteride. However, dutasteride and finasteride have never been compared in long-term therapy, either as monotherapy or in combination with an alpha-blocker. These medications appear to exert continued effects beyond 1 year so comparison after only 1 year is likely to be premature.

The tolerability of 5-alpha reductase inhibitors in most studies has been excellent with the most relevant adverse effects being related to sexual function. They include reduced libido, erectile dysfunction, and, less frequently, abnormal ejaculation. Specifically for dutasteride in the Combat study, in the monotherapy arm of 1623 patients the side effect were: erectile dysfunction (6.0%) ; retrograde ejaculation (0.6%); altered (decreased) libido (2.8%); ejaculation failure (0.5%); semen volume decreased (0.3%); loss of libido (1.3%); breast enlargement (1.8%); nipple pain (0.6%); breast tenderness (1.0%) and dizziness (0.7%).

Phosphodiesterase 5 Inhibitors

Phosphodiesterase 5 (PDE5) inhibitors (e.g. sildenafil, tadalafil and vardenafil) have been used predominantly to treat erectile dysfunction in men. However, recent data suggests they also have efficacy in treating LUTS secondary to BPH. Specifically, the cyclic nucleotide monophosphate cyclic GMP represents an important mediator in the control of the lower urinary tract outflow region (bladder, urethra). PDE5 inhibitors exert effects by several mechanisms including: calcium-dependent relaxation of endothelial smooth muscle, alteration of the spinal micturition reflex pathways and increased blood flow to the lower urinary tract. PDE inhibitors are regarded as efficacious, have a rapid onset of action and favourable effect-to-side-effect ratio (171).

Anticholinergic Medications

High-level evidence suggests that for selected patients with bladder outlet obstruction due to BPH and concomitant detrusor overactivity, combination therapy with an alpha-receptor antagonist and anticholinergic can be helpful (176). Such agents help particularly with the irritative urinary symptoms of frequency and urgency. Caution is recommended, however, when considering these agents in men with an elevated residual urine volume or a history of spontaneous urinary retention (164).

Botulinum Toxin A Injection

Injection of botulinum toxin A into the prostate is a novel treatment for LUTS secondary to BPH. First reported in 2003 (177), trans-perineal injection of 100 units of botulinum toxin into each lobe of the prostate under trans-rectal guidance is required. In this randomized controlled trial, thirty patients demonstrated significant improvement in IPSS (65% decrease) and serum PSA (51% decrease) compared to controls, who had injections of saline without botulinum toxin A, at a median follow-up of 20 months. Subsequent long term follow-up of 77 patients up to 30 months has shown similar results – significant reduction in IPSS (approximately 50% lower), significant improvement in maximum flow rate (approximately 70% higher), and significant reduction in serum PSA values (approximately 50% lower). Importantly, no adverse events were noted (178).

WATCH AND WAIT/LIFESTYLE CHANGE

Many men who present with LUTS are often seeking a full assessment of their prostatic health rather than immediate treatment of symptoms that may not be exceptionally bothersome. People with mild symptoms may wish to pursue lifestyle changes as a way of improving their quality of life but with the option of review if such measures fail or symptoms worsen. Furthermore, when an adequate history is taken, hidden agendas such as fear of prostate cancer may even be revealed and fears allayed.

Often drinking habits may be responsible for symptoms such as nocturia, where considerable fluid volumes are consumed in the evening. Reducing fluid intake may diminish nocturia and evening urgency. Furthermore, caffeine and alcohol acting as diuretics can further exacerbate LUTS. Simple shifts in daily fluid intake may fulfil patient expectations and result in satisfactory outcomes. Voiding diaries are useful for making patients aware of drinking habits and may be the catalyst for initiating and monitoring changes. Bladder retraining (by using timed voiding, strengthening pelvic floor exercises and monitoring oral intake) is also an option in some individuals, once a voiding diary has been examined.

PHYTOTHERAPY FOR BPH

Phytotherapy, or the use of plant extracts, is becoming widely used in the management of many medical conditions including BPH. Often these agents are promoted to aid “prostatic health” and a significant proportion of men try them. Factors also contributing to their widespread use include the perception that they are supposedly ”natural” products; the presumption of their safety (although this is not adequately proven); their alleged potential to assist in avoiding surgery, and even the unproven claim that they may prevent prostate cancer. The widespread availability of these products (without prescription) in vitamin shops, supermarkets, pharmacies and over the internet has contributed to their usage and reflects the demand for these phytotherapeutic agents. The mechanisms of action are poorly understood but have been proposed to be (1) anti-inflammatory, (2) inhibitors of 5-alpha reductase, and more recently (3) through alteration in growth factors (110).

Table 11Phytotherapy used in the treatment of benign prostatic hyperplasia

Phytotherapeutic plant extract Proposed Mechanism of action
Saw palmetto- fruit
(Serenoa repens)
Antiandrogenic, Anti-inflammatory
African plum- bark
(Pygeum africanum)
Antiandrogenic, potential growth factor manipulation, anti-inflammation actions
Pumpkin- seed
(Cucurbita pepo)
Phytosterols are thought to be amongst the active compounds
Cernilton- pollen
(Secale cereal, Rye)
Inhibition of alpha adrenergic receptors
South African star grass- root
(Hypoxis rooperi)
Antiandrogenic, alteration in detrusor function
Stinging nettle- root Steroid hormone manipulation reducing prostate growth
Opuntia- flower
(Cactus)
Unknown
Pinus- flower
(Pine)
Unknown

Saw Palmetto Berry (Serenoa repens)

Extracts from the berries of the American dwarf palm (saw palmetto) are the most popular and widely available plant extracts used to treat symptomatic BPH today (115-116). At least eight possible mechanisms of action for saw palmetto have been advocated including anti-androgenic properties, anti-inflammatory properties, induction of apoptosis to name a few (114). Several studies have found that saw palmetto suppresses growth and induces apoptosis of prostate epithelial cells by inhibition of various signal transduction pathways (117). However, it is most commonly believed that saw palmetto works as a naturally occurring 5-alpha reductase inhibitor, blocking the conversion of testosterone to DHT, as demonstrated in several in vitro studies (112, 118-121). Thus, saw palmetto may be expected to reduce prostate size. While demonstrated in animal models (122), this is not the case in several trials using saw palmetto in men with BPH (123-124). The only trial to show in vivo effects of saw palmetto involved needle biopsies of the prostate gland, before and after treatment with saw palmetto or placebo. Although the mechanism is unclear, there was a significant increase in prostatic epithelial contraction in the saw palmetto group (125).

African plum tree (Pygeum africanum)

Extracts come from the bark of the African plum tree. It is hypothesized, based on in vitro observation, that it acts on the prostate through inhibition of fibroblast growth factors, has anti-estrogenic effects and inhibits chemotactic leukotrienes. No strong clinical data exists of its efficacy although trials are in progress.

Pumpkin Seed (Cucurbita pepo)

Dried or fresh seeds have been taken to relieve symptoms. Phytosterols are thought to be amongst the active compounds. Side effects have not been reported but the evidence is lacking with no current clinical trials.

Rye Pollen (Secale cereale)

This is prepared from rye grass pollen extract. In a systematic review summarizing evidence from randomised and clinically controlled trials (108), rye pollen was found to be well tolerated but only achieved modest improvement in symptom outcomes and did not significantly improve objective measures such as peak and mean urinary flow rates. Again, several mechanisms of action have been proposed including an improvement in detrusor activity, a reduction in prostatic urethral resistance, inhibition of 5-alpha reductase activity and an influence on androgen metabolism in the prostate.

Other extracts

South African Star Grass (Hypoxis rooperi), Opuntia (Cactus flower), stinging nettle and Pinus (Pine flower) have also been studied and used, however the data numbers are small and the types of trials do not allow conclusions to be drawn at this stage (110).

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What Is Central Nervous System? – What You Need To Know

What Is Central Nervous System?/The central nervous system (CNS) embryology is a broad subject. This article serves as a summary of CNS organogenesis as well as a review the framework of embryology, the embryogenesis of the brain and spinal cord, various tests that can be performed in utero to test for CNS anomalies, and problems that may be encountered during embryogenesis, with particular attention to the CNS.

The CNS system involves 3 germinal layers: ectoderm, mesoderm, and endoderm.

  • The ectoderm is the key initiating player in the embryogenesis of the CNS. The ectoderm is further sub-specialized as the (1) surface ectoderm, which differentiates into the epidermis, nails, and hair. The ectoderm is also sub-specialized to form the (2) neural ectoderm, which gives rise to the neural tube and neural crest, which subsequently give rise to the brain, spinal cord, and peripheral nerves.
  • The endoderm gives rise to the lining of the gastrointestinal and respiratory systems. It also gives rise to abdominal organs such as the liver, pancreas, and bladder.
  • The mesoderm is differentiated into 3 parts:
  • Paraxial mesoderm – This part of the mesoderm contains mostly somites which give rise to the axial skeleton, dermis, and muscle.
  • Intermediate mesoderm This part of the mesoderm gives rise to the gonads, kidneys, and urogenital structures.
  • Lateral plate mesoderm – is further classified into parietal mesoderm and visceral mesoderm, which give rise to the limb skeleton and muscular wall of the gut tube, respectively.

Embryological Transformations

Because these changes do not occur at once, embryology is a complicated subject. The following timing of embryological developments, with particular attention to the CNS, offers a greater understanding of the process.

  • Weeks 1 to 3 – Zygote formation, blastocyst, and gastrulation occur
  • Mid-fourth week – Embryo is linear and uniform; notochord formation occurs
  • Late-fourth week – Many forms of differential growth occur; upper limb buds always develop before the lower limb bud
  • Fifth week – Limb buds more pronounced
  • The sixth week – Can begin to see eyes and auricular hillocks, which will develop into the external ears
  • The seventh week – Formation of eyes, ears, and fingers
  • Late eighth week – Formation of all organ systems
  • Nine to 12 weeks (11 to 14 gestational age) – Embryo has a large head, and small body and this is the time where the body grows in an attempt to catch up with the limbs. The genitalia can be recognized during this period giving a chance for parents to find out the gender of the embryo.
  • Thirteen to 16 weeks (15 to 18 gestational age) – Coordinated limb developments and ossification of skull occur; Ovaries differentiate and contain primordial ovarian follicles that contain oogonia; the eyes face anteriorly, and ears are in place.
  • Seventeen to 20 weeks (18 to 22 gestational ages) – Eyebrows and head hair visible at 20 weeks
  • Twenty-one to 25 weeks (23 to 27 gestational age) – Type II pneumocytes to secrete surfactant. It is after this stage when babies are considered viable.
  • Twenty-six to 29 weeks (28 to 31 gestational age) – Eyelids open; the quantity of white fat increases. The CNS has matured and can control breathing as well as temperature function. Additionally, the bone marrow takes over (from the yolk sac) as the major site of erythropoiesis.
  • Thirty to 34 weeks (32 to 36 gestational age) – Maturation and growth of organs occur

Thirty-five to 38 weeks (37 to 40 gestational age): Baby now has a firm grasp with hands. Testes may have descended in males.

Development of Central Nervous System

Embryogenesis: Weeks 2 to 8

Beginning with the trilaminar germ disc, which refers to the epiblast and hypoblast, the epiblast cells undergo an epithelial-mesenchymal transition that replaces the hypoblast. They also proliferate in the middle layer to form the mesoderm where it will remain mesenchymal to form connective tissue. The primitive streak then starts to appear superiorly from the thickened region of ectoderm. It grows caudal to cranial and induces the notochord formation. The ectoderm then invaginates as cells migrate to form the primitive node and primitive pit where the notochordal process is formed.

  • The primitive pit – is a depression at the center of the primitive node, which is an opening in the notochordal canal.
  • Neurulation – refers to the folding of the neural plate. The neural plate folds, via induction from the notochord, into the neural tube, which then becomes the neuroectoderm, which finally forms the CNS, namely the brain and spinal cord; the brain from cranial two-thirds of the segment and spinal cord from caudal one-third of the segment)
  • Neural Crest cells – form dorsal root ganglia and connective tissue in the head and neck.
  • Notochord:
  • Defines longitudinal axis
  • Forms parts of the intervertebral discs, and not the spinal cord or spine
  • The notochordal process formed on top of the primitive node
  • Elongation of the notochordal process occurs caudally and goes upward to the cranial end

The CNS is derived from the neuroectoderm: notochord induces the formation of the neural plate (thickening of the ectodermal layer), which further differentiates to form neural folds with a neural groove in between, leading to the formation of the neural tube (via neurulation).

Spinal Cord

The spinal cord is formed from the neural plate, now contains 3 layers:

  • Ventricular layer that lines the central canal
  • Mantle layer – that contains neuronal bodies, which will eventually form the gray matter
  • Marginal layer – that contains axons, and will eventually form the white matter

While this article summarizes the embryological changes that occur within the CNS, the peripheral nervous system (PNS) is formed from neuroepithelial cells. These cells travel from the pia mater to the ventricular layer of the spinal cord, where they differentiate and migrate to form glioblasts (for example, support cells, Schwann cells), neurons, and ependymal cells. As this information is often tested on boards, that myelin sheath, a sheath composed of support cells, wraps around axons and insulate neurons to increase the speed of neuronal conduction.

  • Myelination of peripheral axons occurs via the neurolemma, which comes from Schwann cells (which come from neural crest cells).
  • Myelination of CNS axons occurs via oligodendrocytes, which are neuroepithelium derivatives.

Three membranous layers cover the whole CNS:

  • Dura mater  derived from surrounding mesenchyme and is tough and durable.
  • Arachnoid mater  derived from neural crest; forms as a single layer with Pia mater.
  • Pia mater  derived from neural crest; intimately covers the CNS.

Brain

During brain formation, there are 3 primary brain vesicles that differentiate into 5 secondary brain vesicles. See image.

  • Prosencephalon, which becomes the forebrain  This later develops into the cerebral hemispheres which contain structures underneath such as epithalamus, thalamus, and hypothalamus. This section of the brain is responsible for consciousness, sensorimotor transformation, and sensory integration.
  • Mesencephalon, which becomes the midbrain – This part of the brain undergoes little structure reorganization compared to the spinal cord and other brain vesicles.
  • Rhombencephalon, which becomes the hindbrain – This part can be further divided into 3 segments:
  • Metencephalon – The dorsal growth of the cerebellum (integrates sensory information to fine-tune output)
  • Caudal myelencephalon – Similar to the structure of the spinal cord with “closed” central canal of Medulla
  • Rostral myelencephalon – “Open part” of medulla; cerebrospinal fluid (CNF) is produced via choroid plexus and leaks into the subarachnoid space.

Finally, the hypophysis gives rise to the pituitary gland, which has 2 origins. The posterior pituitary is an outgrowth of the hypothalamus, and, therefore, has a direct connection. On the other hand, the anterior pituitary is an ectodermal growth from the mouth. It depends on a dense capillary network and communicates with the brain via the vascular system.

Testing of Central Nervous System

  • Non-invasive testing can be performed at 10 weeks of gestation. This tests for cell-free DNA in plasma of pregnant women and helps identify certain anomalies or diseases.
  • Amniocentesis, which is usually performed between 14 and 20 weeks, is the sampling of the amniotic fluid to screen for fetal anomalies. This is a diagnostic test.
  • First-trimester testing looks for risk of trisomy 21, trisomy 18, trisomy 13, and other neural tube defects.
  • Alpha-fetoprotein (AFP) is a hormone that is elevated in amniotic fluid in anomalies of the CNS and ventral abdominal wall. It is decreased when the fetus has trisomy 21, trisomy 18, or other chromosomal defects.
  • Anatomy sonogram can be performed throughout pregnancy, but particularly between weeks 16 to 22 to estimate the fetal weight and gestational age using measurements from:
  • Head circumference
  • Biparietal diameter
  • Femur length (from epiphysis to epiphysis)
  • Abdominal circumference

Although beyond the scope of this article, there is also a Quad-screen test which can be performed in the second trimester. The components of this screening test include AFP, hCG, Estriol, and Inhibin-A.

Pathophysiology of Central Nervous System

Embryogenesis can be complicated and result in mild or extreme defects (pathophysiological changes).

  • Teratogenesis – is defined as any external factor that can influence the growth of the embryo. Embryos are highly susceptible and critical between weeks 3 and 8 because that is when organ systems develop.
  • Dysraphism – is the failure of fusion between symmetric halves of an anatomical structure. These include, and are not limited to, spina bifida malformations.
  • Spina bifida occulta – occurs when the vertebral column fails to fuse, but other layers develop normally. It is the least severe form of dysraphism and usually affects the lumbosacral region (S1 to S2 most commonly). It can be associated with moles, angioma, lipoma, and abnormal hair growth in the area of abnormality.
  • Spina bifida aperta – occurs when there is an incomplete fusion of skin with or without a cyst. The spinal cord is still covered by the arachnoid mater, thus preserving subarachnoid space and preventing leakage of the CSF.
  • Spina bifida cystica – is the most severe form of dysraphism. Patients may develop urinary or fecal incontinence. 80% of these lesions occur in the lumbosacral region.

Dysraphism in the cranium causes malformations analogous to spina bifida:

  • Encephalocele Protrusion of the brain into the subarachnoid space. It can be associated with Chiari III malformation during part of the cerebellum protrudes, and the spinal cord gets twisted. This is commonly associated with cleft lip and palate.
  • Anencephaly – is where the cerebral cortex and thalamic structures are generally absent, but the cerebellum, brainstem, and spinal cord are present (but may be deformed). This can occur due to the failure of notochord signaling which is necessary for median hinge point formation or induction of neural crest cell maturation.
  • Holoprosencephaly  Failure of features to form along the midline of the face. Features include single central incisor, cyclopia, or unpaired cerebral hemisphere.
  • Craniorachischisis totalis is when the entire neural plate fails to fold, and CNS is open to the amniotic cavity. These are often associated with still-born fetuses.

References

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Kidney Transplant – Causes, Indications, Treatment

Kidney Transplant provides superior outcomes to dialysis as a treatment for end-stage kidney disease. Therefore, it is essential that kidney transplantation be part of an integrated treatment and management plan for chronic kidney disease (CKD). Developing an effective national program of transplantation is challenging because of the requirement for kidney donors and the need for a multidisciplinary team to provide expert care for both donors and recipients.

Kidney transplantation is the treatment of choice in patients with end-stage renal disease or severe chronic kidney disease as it improves the quality of life and has better survival advantages compared to dialysis. Various factors merit consideration to match the donor kidney with the recipient, as the donor kidney act as an alloantigen. In general, when transplanting tissue or cells from a genetically different donor to the graft recipient, the alloantigen of the donor induces an immune response in the recipient against the graft. This response can destroy the graft if not controlled. The whole process is called allograft rejection.

Allograft rejection is inflammation with specific pathologic changes in the allograft, due to the recipient’s immune system recognizing the non-self antigen in the allograft, with or without dysfunction of the allograft.

kidney transplant

Types of Kidney Transplant

Both innate and adaptive immune systems play a significant role in rejection, But the T lymphocytes are the principal cells that recognize the allograft. There are other costimulatory molecules, and cytokines also play a major role in this reaction. Depending on the histopathology and immunological characteristics, the renal transplant rejections can be classified broadly under the following categories :

  • Hyperacute rejection – Happens minutes after transplant, and it is related to the preformed antibody or ABO incompatibility; this is rarely seen now due to the very sensitive cross-match tests performed before the transplant.
  • Acute rejection – This can happen any time after transplant, usually within days to weeks after transplant. It classifies into the following:
  • Antibody-mediated rejection- ABMR – which usually demonstrates evidence of circulating donor-specific alloantibodies and immunological evidence of antibody-mediated injuries to the kidney. Like inflammation of glomeruli (Glomerulitis) or peritubular capillary (peritubular capillaritis).
  • Acute T-cell mediated rejection- TCMR: which characterized by lymphocytic infiltration of the tubules, interstitium, and sometimes the arterial intima.
  • Chronic rejection – It usually develops more than three months post-transplant. It can either be chronic antibody-mediated rejection or chronic T cells mediated rejection.

A mixture of acute rejection superimposed on chronic rejection.

  • The Banff classification, originally founded in 1991 and later updated in 2007, 2009, 2013, and 2017 established specific criteria for the diagnosis of kidney allograft rejection. Based on the 2017 revised Banff criteria, CAAMR and CATMR are diagnosed and classified as follows:

I) CAAMR (all criteria must be present):

1. Histological evidence of chronic tissue injury (one or more of the following)

  • Transplant glomerulopathy without evidence of thrombotic microangiopathy or glomerulonephritis
  • Severe multilayering of the glomerular basement membrane on electron microscopy
  • New-onset arterial intimal fibrosis

2.Evidence of antibody interaction with vascular endothelium (one or more of the following)

  • Linear C4d deposition of peritubular capillaries
  • Moderate or severe microvascular inflammation in the absence of glomerulonephritis
  • Increased gene expression of gene transcripts strongly suggests antibody-mediated rejection

3. Positive DSA Antibodies to HLA and non-HLA antigens.

II) CATMR is classified as follows (after ruling out other causes of IFTA)

  • Grade IA – More than 25% interstitial inflammation of the cortex with “moderate tubulitis” in 1 or more tubules, excluding severely atrophic tubules.
  • Grade IB – Greater than 25% interstitial inflammation of the cortex with “severe tubulitis” in 1 or more tubules, excluding severely atrophic tubules
  • Grade II – Chronic allograft arteriopathy indicated by neointima formation, intimal arterial fibrosis, and mononuclear infiltration

Causes of Kidney Transplant

Certain factors correlate with an increased risk of rejection of the renal allograft after the transplantation. These factors are:

  • Congenital, familial and metabolic disorders – These are conditions you are born with, inherit or that affect your metabolic system.
  • Diabetes – This autoimmune disorder affects the kidneys, pancreas and other organs.
  • Glomerular diseases – These are diseases that affect the glomeruli, which strain fluid in the kidneys.
  • Hypertensive nephrosclerosis – This means there is damage to the kidneys caused by high blood pressure.
  • Malignant hypertension – This is an extremely high blood pressure that damages the organs.
  • Polycystic kidney disease – This disease causes numerous cysts or growths on the kidneys.
  • Renovascular and other vascular diseases – These diseases cause blockages or narrowing in the renal arteries or veins.
  • Tubular and interstitial diseases – These diseases affect the portions of the kidney outside the glomerulus, a cluster of blood vessels that filter waste products from the blood.
  • Temporary lack of kidney function – Your new kidney may not start working immediately and you may need dialysis until it resumes normal kidney function.
  • Organ rejection – Your body may reject the donor organ and you may need medication to help your body accept the new kidney.
  • Kidney failure – Your new kidney may fail after a number of years and you may need to have a second transplant or go back on dialysis.
  • Cancer – Immunosuppressant medication taken after transplant may leave you more vulnerable to disease.
  • Diabetes – Medications taken after a transplant can cause diabetes.
  • Heart attack or stroke – A transplant puts you at a higher risk than a healthy person who hasn’t had a transplant, especially if you have high blood pressure, high cholesterol or diabetes.

Potential side effects of a kidney transplant may include:

  • Narrowing of the artery leading to the kidney—also called renal artery stenosis
  • Blood clots
  • Infection
  • Bleeding
  • Weight gain
  • High blood pressure
  • Prior sensitization – high panel reactive antibodies
  • Type of transplant: Deceased donor has a higher rejection than a living transplant
  • Advanced age of the donor
  • Prolonged cold ischemia time
  • HLA mismatch
  • Positive B cell crossmatch
  • ABO incompatibility
  • Recipient’s age: Younger recipients have more rejection than older ones
  • Recipient’s race: African American race greater than White race
  • Delayed Graft function
  • Therapy non-compliance
  • Previous episodes of rejections
  • Inadequate immunosuppression

kidney transplant

Pathophysiology

Renal transplant rejection, as stated earlier, is an immunological response that leads to inflammation with specific pathological changes in the allograft, due to the recipient’s immune system recognizing the non-self (foreign) antigen in the allograft. There are different mechanisms postulated depending on the type of rejection, as follows:

  • Hyperacute rejection – It is related to preexisting circulating antibodies in the recipient’s blood against the donor antigen (usually ABO blood group or HLA antigen), which is present at the time of transplantation. These antibodies attack and destroy the transplanted organ as soon as or within a few hours after allograft is revascularized.
  • Acute T cell-mediated rejection – in which the recipient’s lymphocytes become activated by recognition of foreign [non-self] donor antigens in the transplanted organ by antigen-presenting cells (APC) through direct, semi-direct or indirect pathways, which leads to activation and infiltration of the T cells and damage to the allograft.
  • ABMR – It is related to antibodies against foreign [non-selfx] donor antigens, mainly HLA antigen, which leads to damage to the allograft through activation of the complement-dependent pathway as well as independent mechanisms recruiting NK cells, polymorphonuclear cells, platelets and macrophages to attack the allograft. These antibodies can be either preexisting at a low level before the transplant or synthesized de novo post-transplant.
  • Chronic rejection – it is related to both immune and nonimmune mediated factors. The primary risk factor for chronic rejection is non-compliance with immunosuppressive medication. It can be either chronic antibody-mediated rejection, which is mainly related to the presence of donor HLA-antigens donor Specific Antibody (DSA) or Chronic cellular rejection, which is uncommon.

Histopathology of Kidney Transplant

The standard way to detect rejection is a renal allograft biopsy, which serves to accurately grade the severity of rejection, differentiate between different types, and guide the treatment.

There are two major classifications for the histopathological diagnosis of renal allograft biopsy: the Banff classification system and the Cooperative Clinical Trials in Transplantation (CCTT). Later, both were incorporated into the Banff 97 classification, to standardize the histopathological diagnosis of renal allograft biopsy. Subsequently, Banff has had updates at regular intervals; the last one was in 2017.

When performing a kidney biopsy, it should have adequate tissue to give a definitive interpretation. Adequate core biopsy must contain ten glomeruli and two arteries and section thickness 3 to 4 microns (marginal if 7 to 10 glomeruli and one artery; unsatisfactory if less than seven glomeruli or no arteries).

The histological characteristics of each type of rejection are as follows:

  • Hyperacute rejection – The transplanted kidney turns mottled, dusky, and black as soon as it revascularized. Severe endothelial injury, PMN infiltration, whispered thrombosis, ischemic tissue necrosis will appear on biopsy.
  • ABMR – Histological features of ABMR include: arteriolar fibrinoid necrosis, fibrin thrombi in glomerular capillaries, glomerulitis, and peritubular Capillaritis, interstitial hemorrhage. Also, the presence of peritubular Capillary linear staining for C4d, which is a degradation product of the complement pathway that binds covalently to the endothelium, is highly suggestive of ABMR.
  • Acute T Cell-Mediated Rejection – Characterized by diffuse lymphocytic infiltration in the tubule, interstitium of the kidney, and in severe cases, vessels of the allograft
  • Chronic rejection lesions – like interstitial fibrosis, tubular atrophy, vascular fibrous intimal thickening, glomerular basement membrane double contouring (transplant glomerulopathy), arteriolar hyalinosis, hyaline arteriolar thickening

Banff system uses scores to assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies. It focuses mostly, but not exclusively, on the diagnostic features seen in rejection. According to the scoring of the various lesions described above, the staging is as below.

  • Category 1 – Normal biopsy or nonspecific changes
  • Category 2 – Antibody-mediated rejection – AMR: depending on the features of lesion further divided into acute AMR, chronic AMR active chronic AMR
  • Category 3 – Suspicious (borderline) for acute T cell-mediated rejection – TCMR.
  • Category 4 – TCMR. Depending on the score of chronic lesions, it further divides into acute TCMR, chronic TCMR, acute, chronic TCMR
  • Category 5 – Interstitial fibrosis and tubular atrophy – IFTA
  • Category 6 – Other changes not considered to be the result of acute or chronic rejection

Indications of Kidney Transplant

The indication for kidney transplantation is end-stage renal disease (ESRD), regardless of the primary cause.

  • This is defined as a glomerular filtration rate below 15 ml/min/1.73 m2. Common diseases leading to ESRD include renovascular disease, infection, diabetes mellitus, and autoimmune conditions such as chronic glomerulonephritis and lupus; genetic causes include polycystic kidney disease, and a number of inborn errors of metabolism. The commonest ’cause’ is idiopathic (ie unknown).
  • Diabetes is the most common known cause of kidney transplantation, accounting for approximately 25% of those in the United States. The majority of renal transplant recipients are on dialysis (peritoneal dialysis or hemodialysis) at the time of transplantation.
  • However, individuals with chronic kidney disease who have a living donor available may undergo pre-emptive transplantation before dialysis is needed. If a patient is put on the waiting list for a deceased donor transplant early enough, this may also occur pre-dialysis.

Advantages

  • No longer need dialysis as long as kidney functions adequately
  • Blood pressure is often easier to manage, but may still require medication
  • Long-term follow-up care is less time-consuming than dialysis
  • Fluid and dietary restrictions are usually no longer necessary
  • May return to work
  • Improved quality of life with expected increase in lifespan
  • More cost-effective than dialysis
  • Having a transplant means that you do not have to dialyse.
  • You might find you have more energy, making you feel better able to cope with everyday life, including work or studies.
  • Your sex life and fertility will probably improve (if it has been affected by CKD).
  • If you have Type 1 diabetes and have a kidney and pancreas transplant you should no longer need to take insulin or tablets to control your blood sugar.
  • You will not need to travel to the hospital for dialysis. However, you will need to come to the hospital for regular clinic appointments for up to six months after your transplant. After this time you will need to come to the clinic around three to four times a year depending on your needs.
  • You will have a less restrictive diet than if you are on dialysis, although you will need to follow a low fat diet after a transplant.
  • You do not need space at home to store equipment.
  • You will be able to restart any sport or exercise after the transplant, although if you play contact sports please discuss this with your kidney doctor or nurse first. You must be a healthy weight for the operation so exercise is important while you are waiting for a transplant.

Contraindications of Kidney Transplant

Contraindications include both cardiac and pulmonary insufficiency, as well as hepatic disease and some cancers. Concurrent tobacco use and morbid obesity are also among the indicators putting a patient at a higher risk for surgical complications.

  • Kidney transplant requirements vary from program to program and country to country. Many programs place limits on age (e.g. the person must be under a certain age to enter the waiting list) and require that one must be in good health (aside from the kidney disease).
  • Significant cardiovascular disease, incurable terminal infectious diseases and cancer are often transplanted exclusion criteria. In addition, candidates are typically screened to determine if they will be compliant with their medications, which is essential for survival of the transplant. People with mental illness and/or significant on-going substance abuse issues may be excluded.
  • HIV was at one point considered to be a complete contraindication to transplantation. There was fear that immunosuppressing someone with a depleted immune system would result in the progression of the disease. However, some research seems to suggest that immunosuppressive drugs and antiretrovirals may work synergistically to help both HIV viral loads/CD4 cell counts and prevent active rejection.

Disadvantages

  • Risks involved from general anesthesia as with any major operation
  • Addition of immunosuppressive medication (and possible side effects) to your current medicines
  • Need for continued care by a kidney specialist. Your kidney function and response to the medications must be medically managed for a healthy, long-term outcome.
  • Transplantation is a treatment not a cure for the underlying cause of your kidney failure.

kidney transplant

Diagnosis of Kidney Transplant

Evaluation

The approach for elevated serum creatinine in a renal transplant recipient would be the same as evaluating for AKI with added workup for the rejection.

The specific workup for evaluating allograft dysfunction should include the following:

  • Blood type testing – A test to determine what type of blood—O, A, B, or AB—you have, and whether your blood is compatible with the potential donor’s blood. Type O is the most common blood type and is considered a universal donor, meaning someone who has this type of blood can donate to any other blood type. Type AB is considered a universal recipient and can receive blood from people of any blood type. Between the different types of blood, there are some that can and cannot give and receive one another. This test will determine blood type compatibility with your donor.
  • Serum crossmatching – A test involving the mixing of your blood with that of the kidney donor to determine whether your body’s cells will attack the donor’s cells. If this happens, it means you have antibodies against this donor’s cells, and the crossmatch is considered “positive,” an indication that your body would reject a kidney from this donor. If your body does not produce antibodies against the donor’s cells, the crossmatch is “negative,” meaning your body will likely accept the donor organ and cells. For a kidney transplant, you will need a negative crossmatch in order to proceed.
  • HLA (human leukocyte antigen) testing – A blood test that determines which antigens you (and the potential donor) have inherited. Antigens are proteins found on the cells and they are what trigger the body to produce antibodies, which fight off bacteria, viruses, and anything perceived as foreign to the body. While there are many different types of antigens, there are six that have been identified as particularly important for successful kidney transplant. This test will help determine whether your HLA is likely to fight against (reject) your donor’s HLA.
  • Mental health evaluation. Psychological and social issues involved in organ transplantation, such as stress, financial issues, and support by family and/or significant others are assessed. These issues can greatly affect the outcome of a transplant. The same kind of evaluation is done for a living donor.
  • Blood tests. Blood tests are done to help find a good donor match, to check your priority on the donor list, and to help the chances that the donor organ will not be rejected.
  • Diagnostic tests. Diagnostic tests may be done to check your kidneys as well as your overall health status. These tests may include X-rays, ultrasound, kidney biopsy, and dental exams. Women may get a Pap test, gynecology evaluation, and a mammogram.
  • Rule out prerenal causes – Check orthostatic vital sign, blood pressure, and volume status
  • Rule out post-renal – causes mainly obstructive uropathy in older adults by bladder scan, renal US
  • CBC – Look for anemia and thrombocytopenia to rule out TMA
  • Serum Creatinine – This blood test measures kidney function. It is checked each day while you are in hospital.
  • Renal Scan – This test monitors blood flow to the kidney and kidney function.
  • Renal Ultrasound – This test checks the kidney for any blockages or fluid collections around the kidney.
  • Kidney Biopsy – This test is used to check for rejection.
  • Electrolyte abnormality – related to CKD, AKI
  • UA and urine culture – It is essential to rule out infection as a cause of AKI
  • Check for proteinuria – Either UPCR or 24-hour urine collection as nephrotic range proteinuria correlates with the presence of extensive transplant glomerulopathy
  • Check BK Virus, CMV PCR – in clinically indicated patients
  • Testing for donor-specific antibodies
  • Transplant renal ultrasound with doppler for renal arterial and venous indices
  • Many transplant centers use testing for donor-derived free DNA testing. This test can be positive even before the actual rise in serum creatinine, suggesting possible rejection.

Differential Diagnosis

While dealing with renal allograft dysfunction, equal weight should be given to find out the possible etiologies other than the rejection.

The following are the most common reasons for allograft dysfunctions other than the allograft rejection.

A.  Immediate Post Transplant (less than one week):

  • Postischemic acute tubular necrosis or Ischemia-reperfusion injury.
  • Volume depletion leading to pre-renal AKI

3. Surgical complications:

  • Fluid collection – urinoma, perinephric hematoma or lymphocele
  • Vascular thrombosis – arterial and venous
  • Multiple renal arteries from the donor’s kidney – infarction of the part of the allograft or necrosis of the ureter leading to urinary obstruction or urinary leak.
  • Aeroembolism
  • Calcium oxalate crystals deposits in renal allograft

B. Early (1 week to 3 months) and Late Post Transplant (over three months)

  • Volume depletion
  • Acute tubular necrosis
  • Calcineurin inhibitor nephrotoxicity – manifesting as acute azotemia as well as chronic progressive renal disease.
  • Urinary obstruction
  • Infections  – Bacterial pyelonephritis andViral infections – BK ( polyomavirus) and CMV
  • Acute and chronic interstitial nephritis

Recurrent primary glomerular diseases

  • FSGS
  • Primary membranous nephropathy
  • Diabetic nephropathy
  • Ig A nephropathy
  • C3 GN
  • De novo glomerular disease

Thrombotic microangiopathy

  • In patients with a prior history of TTP, HUS, antiphospholipid antibody syndrome
  • Associated with calcineurin inhibitor nephrotoxicity

Transplant renal artery stenosis

Post-transplant lymphoproliferative disease 

Preparation

You have to meet certain criteria to be approved for a kidney transplant. You cannot have an active infection, cancer or severe circulatory problems involving your heart, brain or major blood vessels. You must be willing to take medications for the rest of your life to prevent your body from rejecting the new kidney.

You will need a thorough medical evaluation. This includes:

  • A physical examination
  • A chest X-ray
  • An electrocardiogram (EKG)
  • Blood tests to check for:
  • Anemia
  • Viral illnesses such as HIV, hepatitis, herpes simplex virus and cytomegalovirus
  • Blood samples to check:
  • Your blood type and tissue type to determine if a donor is a good match.
  • Possible additional tests:
  • Cardiac tests
  • Screenings for certain types of cancer

If you smoke or have problems with substance abuse, you must complete a treatment program before you receive your new kidney.

While you prepare for your kidney transplant, you will meet regularly with a transplant team at the medical center where you will have your surgery. These professionals can offer you a wide range of support services during the pre-transplant period.

The transplant team usually includes:

  • A doctor who specializes in kidney problems (a nephrologist)
  • A transplant surgeon
  • Nurses
  • A social worker

If your kidney transplant will come from a living donor, you usually will be able to schedule the time of your transplant surgery. In most cases, your pre-transplant waiting period will be only a few weeks. During this time, your donor will have medical tests. These will ensure that he or she is strong enough to undergo surgery. Additional tests will confirm that the donor’s kidneys are functioning normally.

If you do not have a living kidney donor, your name will be placed on a waitlist for a kidney from a dead donor. This donor must be a good match for you. The average waiting time for a kidney from a dead donor is two to three years. While you are on the waiting list, the transplant team will evaluate your health periodically. You must have medical insurance that will cover the cost of a transplant or be able to pay for it yourself.

What happens during a kidney transplant?

A kidney transplant requires a stay in a hospital. Procedures may vary depending on your condition and your healthcare provider’s practices.

Generally, a kidney transplant follows this process:

  • You will remove your clothing and put on a hospital gown.
  • An intravenous (IV) line will be started in your arm or hand. More catheters may be put in your neck and wrist to monitor the status of your heart and blood pressure, and to take blood samples. Other sites for catheters include under the collarbone area and the groin blood vessels.
  • If there is too much hair at the surgical site, it may be shaved off.
  • A urinary catheter will be inserted into your bladder.
  • You will be positioned on the operating table, lying on your back.
  • Kidney transplant surgery will be done while you are asleep under general anesthesia. A tube will be inserted through your mouth into your lungs. The tube will be attached to a ventilator that will breathe for you during the procedure.
  • The anesthesiologist will closely watch your heart rate, blood pressure, breathing, and blood oxygen level during the surgery.
  • The skin over the surgical site will be cleansed with an antiseptic solution.
  • The surgeon will make a long incision into the lower abdomen on one side. The surgeon will visually inspect the donor kidney before implanting it.
  • The donor kidney will be placed into the belly. A left donor kidney will be implanted on your right side; a right donor kidney will be implanted on your left side. This allows the ureter to be accessed easily for connection to your bladder.
  • The renal artery and vein of the donor kidney will be sewn to the external iliac artery and vein.
  • After the artery and vein are attached, the blood flow through these vessels will be checked for bleeding at the suture lines.
  • The donor ureter (the tube that drains urine from the kidney) will be connected to your bladder.
  • The incision will be closed with stitches or surgical staples.
  • A drain may be placed in the incision site to reduce swelling.
  • A sterile bandage or dressing will be applied.

Talk with your healthcare provider about what you will go through during your kidney transplant.

kidney transplant

Treatment of Kidney Transplant

The treatment plan determination uses multiple factors, including the type of rejection, the severity of the histological lesion, the chronicity score, and the recipient comorbidity. So what will be discussed is a general guideline, but tailoring medical treatment of individual characteristics is needed.

1. Hyperacute rejection

No effective therapy usually leads to early allograft nephrectomy, and so prevention is the key by assuring through the following

  • i) ABO-compatibility between donor and recipient. Sometimes, it is advisable to address ABO incompatibility under specific criteria, and careful pre-transplant preparation of recipient with the removal of anti-ABO antibodies by plasmapheresis is an option, IVIG with or without rituximab
  • ii) Pre-transplant cross-match [complement cell cytotoxicity test]: Recipient serum is added to donor lymphocytes. If the test is positive (which means the recipient has an antibody that reacts with the donor HLA antigens on lymphocyte), one should not proceed with transplant unless these antibodies are removable pre-transplant.

2. Antibody-Mediated Rejection

The treatment of acute antibody-mediated rejection also depends on the level of the antibody levels. Higher antibody levels need plasma exchange for the removal of the antibodies. The following are the different modalities used for AMR:

  • i) Plasma Exchange: 3 to 5 sessions daily on every other day is used for antibody removal followed by IVIG and rituximab
  • ii) IVIG: IV immunoglobulin (100 to 200 mg/kg) is used followed by the last session of plasma exchange when used in combination with plasmapheresis or higher dose 2g/kg after the final session of plasmapheresis.
  • iii) Rituximab: Anti CD20 cell antibody rituximab (375 mg/m^2) is used in combination with IVIG followed by plasma exchange
  • iv) Bortezomib: Plasma cell inhibitor bortezomib (1.3 mg/m^2) is also used in combination with plasma exchange and IVIG
  • v) Splenectomy: Splenectomy is very rarely an option, but there are anecdotal reports of successful treatment of refractory rejections
  • vi) Optimize the dose and the level of the maintenance immunosuppressive drugs.

3. T Cell-Mediated rejection

They receive treatment with the following agents based on the severity of the lesion.

  • i) Methyl Prednisone IV (250 to 1000 mg daily) targeting T cells, B cells, and macrophages; given for 3 to 5 days
  • ii) rATG – Rabit anti-thymocyte globulin IV (1 to 1.5 mg/kg) targeting T cell receptors. The duration varies among different transplant centers, but in general, it is for 7 to 14 doses based on the response and Cd3 level.
  • iii) Optimize the dose and the level of the maintenance immunosuppressive drugs.

4.  Chronic rejection

Since the antibody-mediated rejection mechanism is a major cause of chronic rejection, the same therapy as ABMR has been used, but generally, these measures are ineffective when Scr is over 3 mg/dl and/or heavy proteinuria.

Anti-Rejection Medications

Anti-rejection medications, also known as immunosuppressive agents, help to prevent and treat rejection. They are necessary for the “lifetime” of the transplant. If these medications are stopped, rejection may occur and the kidney transplant will fail.

Below is a list of medications that might be used after a kidney transplant. A combination of these drugs will be prescribed dependent on the specific transplant needs.

Anti-inflammatory Medication

Prednisone is taken orally or intravenously. Most side effects of prednisone are related to drug dosage levels. Prednisone is used at low dosages to minimize side effects. The possible side effects of prednisone are:

  • Changes in physical appearance such as puffiness of the face and weight gain.
  • Irritation to the stomach lining.
  • Increased risk of bruising and decreased rate of healing.
  • Increased sugar level in the blood (steroid-induced diabetes).
  • Unexplained mood changes. This may mean depression, irritability, or high spirits.
  • General muscle weakness or pain in knees or joints.
  • Formation of cataracts. A clouding of the lens of the eye occurs infrequently with long-term use of prednisone.

Anti-proliferative Medications

Azathioprine (Imuran®) is taken orally or intravenously. The most common side effects associated with azathioprine are:

  • Thinning of hair
  • Irritation of the liver
  • Decreased white blood cell count

Mycophenolate mofetil Although most centers still use treatments based on steroids and ciclosporin, tacrolimus and mycophenolate mofetil have emerged as effective and well-tolerated options for inducing and maintaining immunosuppression.  Mycophenolate mofetil (CellCept) is taken orally. The most common side effects of mycophenolate mofetil are:

  • Abdominal aches and/or diarrhea
  • Decreased white blood cell count
  • Decreased red blood cell count

Mycophenolate sodium – is taken orally. It provides the same active ingredient as mycophenolate mofetil and generally has the same side effect profile. It is enterically coated to potentially reduce abdominal aches and diarrhea.
Sirolimus (Rapamune) is taken orally. The most common side effects of sirolimus are:

  • Decreased platelet count
  • Decreased white blood cell count
  • Decreased red blood cell count
  • Elevated cholesterol and triglycerides

Cytokine Inhibitors

Cyclosporine (Neoral, Gengraf) is taken orally. The most common side effects of cyclosporine therapy are:

  • Kidney dysfunction
  • Tremors
  • Irritation of the liver
  • Excessive body hair growth
  • High blood pressure
  • Swollen/bleeding gums
  • High potassium in the blood
  • Increased sugar level in the blood (drug-induced diabetes)

Tacrolimus

(Prograf) is taken orally. The most common side effects of tacrolimus therapy are:

  • Kidney dysfunction
  • High blood pressure
  • High potassium in the blood
  • Increased sugar level in the blood (drug-induced diabetes)
  • Tremors
  • Headaches
  • Insomnia

Antilymphocyte Medications

Antithymocyte globulin (Thymoglobulin®) is given intravenously. Thymoglobulin can cause:

  • Decreased white blood cell and platelet counts
  • Sweating
  • Itching
  • Rash
  • Fever

Muromonab-CD3 (OKT3)

It is given intravenously and can cause

  • Chills
  • Fever
  • Diarrhea
  • Headache
  • Shortness of breath

Anti-interleukin 2 receptor antibodies

Another major advance in the area of induction immunosuppression is the development of the anti-interleukin 2 receptor antibodies (basiliximab and daclizumab). These drugs have produced impressive reductions in the rates of early rejection in adult and paediatric transplants  Once again, cost issues have restricted the use of these promising drugs.

Anti-interleukin-2 Receptor Antibody (Zenapax or Simulect) These two drugs are given intravenously. These medications rarely cause side effects but can include:

  • Chills
  • Headache
  • Allergic reaction

Alemtuzumab (Campath)

  • Fever
  • Chills
  • Rash
  • Shortness of breath
  • Decreased white blood cell counts

Sirolimus

Sirolimus is another immunosuppressant that has entered the clinical arena in the United States and, more recently, in Europe. Impressive reductions in the rates of early rejection and hypertension with sirolimus compared with alternative agents need to be balanced against adverse changes in lipid profiles and a lack of data on long term outcome.

Ciclosporin

Almost 20 years after ciclosporin’s introduction, clinicians are still learning how to use this drug. Recent studies have shown that it is better to adjust the dose of ciclosporin according to blood levels two hours after treatment (C2 monitoring) than trough levels. Preliminary data show that this new technique produces reductions in rejection rates and side effects. The advantage of this technique needs to be compared with the claims of alternative immunosuppressive agents.

CNI Minimization

  • Minimization refers to lowering target blood trough levels of CNIs, with or without another immunosuppressive agent. A systematic review and meta-analysis showed that CNI minimization was associated with a relatively low risk of AR and overall improved allograft function. The timing of CNI minimization was also studied. CNI minimization during the first six months post-transplant reduced the incidence of rejection compared to reducing CNI doses in the second 6 months post-transplant. No head to head trials, however, were conducted to compare early and late minimization directly.
  • Combining low dose CNI with mycophenolic acid (MPA) preparations also reduced the risk of AR with no difference in mortality. Pairing CNI minimization with a mammalian target of rapamycin (mTOR) inhibitor (such as sirolimus or everolimus) did not increase the risk of biopsy-proven AR. It led to an improvement in kidney function in some studies. It is worth noting. However, that full dose CNI plus mTOR inhibitor therapy increases the risk of nephrotoxicity.

CNI Conversion

  • Conversion refers to switching CNI to another maintenance drug. Converting from CNI to an mTOR inhibitor showed improvement in kidney function, which was more observed with the conversion from Cyclosporine compared to Tacrolimus. Conversion to an mTOR inhibitor was also associated with a lower risk of cytomegalovirus (CMV) infection.
  • Conversion to Sirolimus showed better outcomes in patients with GFR exceeding 40 ml/min with less proteinuria, suggesting that conversion should occur before significant parenchymal damage. Grimbert et al. suggested that early conversion to mTOR inhibitors within one year was associated with increased production of dnDSA, which increased the risk of antibody-mediated rejection.

CNI Withdrawal

  • Withdrawal refers to tapering CNIs until completely discontinued. CNI withdrawal with either MPA or mTOR inhibitor-based regimens was associated with an increased risk of rejection. Early withdrawal (<6 months post-transplant) was associated with an increased risk of graft loss, with insufficient evidence for both rejection and a decrease in renal function. Late withdrawal with the continuation of MPA preparations was associated with an overall greater risk of rejection. CNI withdrawal from Azathioprine based regimens was also associated with increased rejection.

CNI Avoidance

  • Avoidance refers to CNI free regimens planned from the start. Initial trials to avoid CNIs while using Daclizumab or anti-thymocyte globulin were associated with an increased risk of AR, which required reintroduction of CNIs in some patients. Sirolimus based immunosuppression regimens were also compared to CNI based regimens. Comparing Sirolimus to Tacrolimus in MPA based regimens showed an increased risk of graft loss. Sirolimus, however, was associated with improved kidney function and reduced risk of CMV infection.

Belatacept

  • A novel fusion protein that inhibits T cell activation, was also compared to CNI based regimens. Vincenti et al. randomized patients into three groups; a Cyclosporine, an intensive Belatacept, and a less intensive Belatacept based regimen. Patients were followed for seven years.
  • Patients on Belatacept based regimens showed a 43% reduction in risk of graft loss and death, compared to cyclosporine. Kidney function improved in both belatacept based regimens, while it declined with cyclosporine.

Who is on my transplant team?

A successful transplant involves working closely with your transplant team. Members of the team include:

  • You—you are an important part of your transplant team.
  • Your family members – this may include your spouse, parents, children, or any other family member you would like to involve.
  • Transplant surgeon – the doctor who places the kidney in your body.
  • Nephrologist – a doctor who specializes in kidney health and may work closely with a nurse practitioner or a physician’s assistant.
  • Transplant coordinator – a specially trained nurse who will be your point of contact, arrange your appointments, and teach you what to do before and after the transplant.
  • Pharmacist – a person who tells you about all your medicines, fills your prescriptions and helps you avoid unsafe medicine combinations and side effects.
  • Social worker – a person trained to help you solve problems in your daily life and coordinate care needs after your transplant.
  • Dietitian – an expert in food and nutrition who teaches you about the foods you should eat and avoid, and how to plan healthy meals.

Your transplant team will be able to provide the support and encouragement you need throughout the transplant process.

What happens after a kidney transplant?

In the hospital

  • After the surgery, you will be taken to the recovery room. Once your blood pressure, pulse, and breathing are stable and you are alert, you may be taken to the intensive care unit (ICU) for close monitoring. In time, you will be moved out of the ICU to a regular nursing unit as you recover and you are closer to going home. Kidney transplant usually calls for several days in the hospital.
  • A kidney from a living donor may start to make urine right away. Urine production in a cadaver kidney may take longer. You may need to continue dialysis until urine output is normal.
  • You will have a catheter in your bladder to drain your urine. The amount of urine will be measured to check how the new kidney is working.
  • You will get IV fluids until you are able to eat and drink enough on your own.
  • Your team will closely watch how your antirejection medicines are working to make sure you are getting the best dose and the best combination of medicines.
  • Blood samples will be taken often to check the status of the new kidney, as well as other body functions, such as the liver, lungs, and blood system.
  • You will slowly move from liquids to more solid foods as tolerated. Your fluids may be limited until the new kidney is working fully.
  • Usually, by the day after the procedure, you may start moving around. You should get out of bed and move around several times a day.
  • Take a pain reliever for soreness as advised by your healthcare provider. Avoid aspirin or certain other pain medicines that may increase the chance of bleeding. Be sure to take only recommended medicines.
    Nurses, pharmacists, dietitians, physical therapists, and other members of the transplant team will teach you how to take care of yourself once you are discharged from the hospital including care for your incisions.
  • You will be ready to go home when your vital signs are stable, the new kidney is working, and you do not need constant hospital care.

At home

  • Once you are home, it is important to keep the surgical area clean and dry. Your healthcare provider will give you specific bathing instructions. Generally, the incision should not be submerged in water until the skin heals as this increases the risk for infection. The stitches or surgical staples will be removed during a follow-up office visit.
  • You should not drive until your healthcare provider tells you it’s OK. Plan to have someone drive you home from the hospital and to your follow-up appointments.
  • Avoid any activity or position that causes pressure to be placed on the new kidney. Other activity restrictions may apply.
  • Check your blood pressure and weight at home every day. Increases in these may mean your kidneys are not filtering fluid properly. You need to be seen by your transplant team promptly.

Tell your healthcare provider if you have

  • Fever, which may be a sign of rejection or infection
  • Redness, swelling, or bleeding or another drainage from the incision site
  • Increase in pain around the incision site, which may be a sign of rejection or infection

Fever and tenderness over the kidney are some of the most common symptoms of rejection. A rise in your blood creatinine level (blood test to measure kidney function) and/or blood pressure may also suggest rejection.

When to Call the Transplant Team

You should call the Transplant Team if you experience any of these symptoms, or any time anything about your health changes, even if it is not related to your transplant:

  • The temperature of 100°F or greater
  • Blood pressure greater than 170/100 for two readings in a row
  • Weight gain of more than three pounds in a day or five to seven pounds in a week
  • Cough, shortness of breath, sore throat, chills
  • Nausea, vomiting or stomach pain
  • Diarrhea
  • Decreased appetite
  • Blood in the urine or bowel movements, painful urination
  • Increased pain, redness, or pus-like drainage at the incision
  • Pain, tenderness or swelling in the area of the new kidney
  • Feeling unusually tired
  • Persistent headache or flu-like symptoms
  • Any unexplained rash, sores, or bruising
  • Swelling of the hands, feet or ankles
  • Inability to take medications for any reason
  • Anything that concerns you about your health

LifeStyle After Kidney Transplant

The following lifestyle advice is usually recommended to help you stay healthy after a kidney transplant.

Stop smoking

If you smoke, it’s strongly recommended that you stop as soon as possible because smoking can reduce the life of your new kidney and can increase your risk of developing some types of cancer.

The NHS Smokefree website can provide support and advice to help you stop, and your GP can also recommend and prescribe treatments that can help. Read more about stopping smoking.

Diet

Most people are able to enjoy a much more varied diet after a kidney transplant, although you may be advised to avoid some foods after the operation until the kidney is working properly. During the early stages after a transplant, while you’re on higher doses of immunosuppressant medication (see below), you should avoid eating foods that carry a high risk of food poisoning, including:

  • unpasteurized cheese, milk or yogurt
  • foods containing raw eggs (such as mayonnaise)
  • undercooked or raw meats, fish and shellfish

Once your kidney is working properly and the best immunosuppressant dose for you has been identified, you’ll usually be advised to follow a generally healthy diet, as this can reduce your risk of complications such as diabetes.

A healthy diet should include:

  • at least 5 portions of fruit and veg a day
  • plenty of potatoes, bread, rice, pasta and other starchy foods; ideally you should choose wholegrain varieties
  • some milk and dairy foods
  • some meat, fish, eggs, beans and pulses, and other non-dairy sources of protein

Avoid food that contains high levels of salt, as salt can cause high blood pressure, which can be dangerous for people with a kidney transplant. See facts about salt for more information and advice.

Exercise and weight loss

Once you’ve started to recover from the effects of surgery, you should try to do regular physical activity.

Adults should do at least 150 minutes (2 hours and 30 minutes) of moderate-intensity exercise every week. This includes any activity that increases your heart and breathing rate – it may make you sweat, but you are still able to hold a normal conversation.

Examples include:

  • fast walking
  • riding a bike on level ground or with few hills
  • swimming
  • tennis

Choose physical activities that you enjoy, as you’re more likely to continue doing them. It’s unrealistic to meet these exercise targets immediately if you have not exercised much in the past. You should aim to start gradually and then build on it. If you’re overweight or obese, you should try to achieve a healthy weight. This can be safely done through a combination of eating a healthy, calorie-controlled diet and regular exercise. Aim for a body mass index (BMI) of 18.5 to 25.

Alcohol, drugs and medications

Regularly drinking alcohol above the maximum recommended limits can raise your blood pressure, which can be dangerous for people with a kidney transplant. To keep your risk of alcohol-related harm low, the NHS recommends:

  • not regularly drinking more than 14 units of alcohol a week
  • spread your drinking over 3 days or more if you drink as much as 14 units a week
  • it’s a good idea to have several alcohol-free days each week

Read more about alcohol units and get tips on cutting down your alcohol consumption. Alcohol is also high in calories, so you’ll gain weight if you drink regularly. Being overweight will also increase your blood pressure. Read more about the calories in alcohol.

You should also avoid taking any illegal drugs after a kidney transplant, as they can damage your kidneys, cause a sudden rise in blood pressure, and react unpredictably with your immunosuppressant medications. Finally, always check with your care team before taking any medication, including over-the-counter medicines and herbal remedies such as St John’s wort. Some medications could be potentially harmful if you have had a kidney transplant and are taking immunosuppressant medication.

Immunosuppressants and infection

If you have a kidney transplant, you’ll usually need to take immunosuppressant medications for the rest of your life to prevent your body’s immune system from attacking the new kidney. Widely used immunosuppressants include tacrolimus, ciclosporin, azathioprine, mycophenolate, prednisolone and sirolimus.

However, taking immunosuppressive medications on a long-term basis will weaken your immune system and make you more vulnerable to infections, so you’ll need to take extra precautions against infection:

  • avoid contact with people you know currently have infections, such as chickenpox or flu
  • practice good personal hygiene – wash your hands regularly with soap and hot water, particularly after going to the toilet and before preparing food and eating meals
  • if you cut or graze your skin, clean the area thoroughly with warm water, dry it, then cover it with a sterile dressing
  • Make sure your vaccinations are up to date, although you won’t be able to have any vaccines that contain live viruses, such as measles, mumps, and rubella (MMR) vaccine.

When to get medical advice

If you think you may have an infection, contact your GP or transplant center for advice. Prompt treatment may be required to prevent serious complications from developing.

Symptoms of the infection can include:

  • a high temperature of 38C or above
  • feeling hot and shivery
  • headache
  • aching muscles
  • diarrhea
  • vomiting

Complications of kidney transplant

Although rates of serious complications have fallen sharply in the last few decades, kidney transplants – like any other type of surgery – are not risk-free.The risks of a kidney transplant include:

  • risks related to the procedure itself
  • risks related to the use of immunosuppressant medications (which reduce the activity of your immune system)
  • risks related to something going wrong with the transplanted kidney

Most complications occur in the first few months after a transplant, but can develop after many years. Some of the main short-term and long-term complications of a kidney transplant are outlined below.

Short-term complications

Infection

  • Minor infections, such as urinary tract infections (UTIs), colds and flu, are common after kidney transplants.
  • Potentially more serious infections, such as pneumonia and cytomegalovirus (CMV), can occur and may require hospital treatment.

Blood clots

  • Blood clots can develop in the arteries that have been connected to the donated kidney. This is estimated to occur in around 1 in 100 kidney transplants.
  • In some cases, it may be possible to dissolve the blood clots using medication, but it’s often necessary to remove the donated kidney if the blood supply is blocked.

Narrowing of an artery

  • Narrowing of the artery connected to the donated kidney, known as arterial stenosis, can sometimes occur after a kidney transplant. In some cases, it can develop months, or even years, after the transplant.
  • Arterial stenosis can cause a rise in blood pressure. The artery often needs to be stretched to widen it, and a small metal tube called a stent may be placed inside the affected artery to stop it narrowing again.

Blocked ureter

  • The ureter (the tube that carries urine from the kidney to the bladder) can become blocked after a kidney transplant. It can be blocked soon after the transplant – by blood clots, for example. It can also be blocked months or years later, usually due to scar tissue.
  • It may be possible to unblock the ureter by draining it with a small tube called a catheter. Sometimes surgery may be required to unblock the ureter.

Urine leakage

  • Occasionally, urine may leak from where the ureter joins the bladder after surgery. This usually occurs during the first month after the procedure. The fluid may build up in the tummy or leak through the surgical incision.
  • If you develop a urine leak, you’ll usually need to have further surgery to repair it.

Acute rejection

  • Acute rejection means the immune system suddenly begins to attack the donated kidney because it recognises it as foreign tissue.
  • Despite the use of immunosuppressants, acute rejection is a common complication in the first year after a transplant, affecting up to 1 in 3 people.
  • In many cases, acute rejection does not cause noticeable symptoms and is only detected by a blood test. If it does occur, it can often be successfully treated with a short course of more powerful immunosuppressants.

Long-term complications

Immunosuppressant side effects

Immunosuppressants prevent your body’s immune system from attacking the new kidney, which would cause the transplanted kidney to be rejected. A combination of 2 or 3 different immunosuppressants is usually taken long term.

These can cause a wide range of side effects, including:

  • an increased risk of infections
  • an increased risk of diabetes
  • high blood pressure
  • weight gain
  • abdominal pain
  • diarrhea
  • extra hair growth or hair loss
  • swollen gums
  • bruising or bleeding more easily
  • thinning of the bones
  • acne
  • mood swings
  • an increased risk of certain types of cancer, particularly skin cancer

The doctor in charge of your care will be trying to find the right dose that is high enough to “dampen” the immune system to stop rejection, but low enough that you experience very few or no side effects.

Finding the optimal dose to achieve both goals is often a difficult balancing act. It may take several months to find the most effective dose that causes the least amount of side effects.

Diabetes

Diabetes is a common complication of having a kidney transplant.   Diabetes is a lifelong condition that causes a person’s blood sugar level to become too high. Some people develop it after a kidney transplant because, as they no longer feel unwell, they eat more and gain too much weight. Some types of immunosuppressants can also make you more likely to develop diabetes.

Symptoms of diabetes include:

  • feeling very thirsty
  • going to the toilet to urinate a lot, especially at night
  • tiredness

Diabetes can often be controlled using a combination of lifestyle changes, such as alterations to your diet, and medication.

High blood pressure

High blood pressure is also a common long-term complication of a kidney transplant.

  • Many people who need a kidney transplant already have an increased risk of developing high blood pressure, and taking immunosuppressants can make the condition worse.
  • High blood pressure doesn’t usually cause any noticeable symptoms, but it can increase your risk of developing other serious conditions, such as heart disease, heart attacks and strokes.
  • Because of the risk of high blood pressure, you’ll have your blood pressure checked at your follow-up appointments. You can also check your own blood pressure at home with a simple device available from most pharmacies. Read more about testing your blood pressure.

Cancer

The long-term use of immunosuppressants also increases your risk of developing some types of cancer, particularly types known to be caused by viruses (as you will be more vulnerable to the effects of infection).

These include:

  • Most types of skin cancer – including melanoma and non-melanoma
  • Kaposi’s sarcoma – a type of cancer that can affect both skin and internal organs
  • Lymphoma – a cancer of the lymphatic system

You can reduce your risk of skin cancer by avoiding exposure to the sun during the hottest part of the day and by applying sun cream to your lips and all exposed areas of your skin every day.

Transplant Costs

The costs of a kidney transplant include the transplant evaluation, testing, surgery, follow-up care, and medication.
These costs are variable and depend on the patient’s recovery and time spent in the hospital.  Other costs associated with transplantation include:

  • Extensive lab tests
  • Anesthesia
  • Fees for transplant surgeons and operating room personnel
  • Organ recovery
  • Lodging and food for family members while the patient is hospitalized
  • Physical therapy and rehabilitation
  • Anti-rejection drugs and other medications (monthly estimated cost is approximately $3,000 immediately following transplant)

According to the United Network for Organ Sharing (UNOS), the first-year billed charges for a kidney transplant are usually more than $262,000.

References

kidney transplant

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Bone Marrow Transplant – Indications, Contraindications

Bone Marrow Transplant (hematopoietic stem cell transplant) (HPSCT) involves the administration of healthy hematopoietic stem cells in patients with dysfunctional or depleted bone marrow. This helps to augment bone marrow function and allows, depending on the disease being treated, to either destroy tumor cells with malignancy or to generate functional cells that can replace the dysfunctional ones in cases like immune deficiency syndromes, hemoglobinopathies, and other diseases.

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous (the patient’s own stem cells are used), allogeneic (the stem cells come from a donor), or syngeneic (from an identical twin).[rx][rx] It is most often performed for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia.[rx] In these cases, the recipient’s immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease are major complications of allogeneic HSCT.[rx]

Types of Bone Marrow Transplant

There are two major types of bone marrow transplants. The type used will depend on the reason you need a transplant.

Autologous Transplants

  • Autologous transplants involve the use of a person’s own stem cells. They typically involve harvesting your cells before beginning a damaging therapy to cells like chemotherapy or radiation. After the treatment is done, your own cells are returned to your body.
  • Stem cells are removed from you before you receive high-dose chemotherapy or radiation treatment. The stem cells are stored in a freezer. After high-dose chemotherapy or radiation treatments, your stems cells are put back in your body to make normal blood cells. This is called a rescue transplant.
  • This type of transplant isn’t always available. It can only be used if you have healthy bone marrow. However, it reduces the risk of some serious complications, including GVHD.

Allogeneic Transplants

  • The term allo means other. Stem cells are removed from another person, called a donor. Most times, the donor’s genes must at least partly match your genes. Special tests are done to see if a donor is a good match for you. A brother or sister is most likely to be a good match. Sometimes parents, children, and other relatives are good matches. Donors who are not related to you, yet still match, may be found through national bone marrow registries.
  • Allogeneic transplants are necessary if you have a condition that has damaged your bone marrow cells. However, they have a higher risk of certain complications, such as GVHD. You’ll also probably need to be put onmedications to suppress your immune system so that your body doesn’t attack the new cellsThis can leave you susceptible to illness.
    • Related donor transplant — Typically patients begin by trying to identify a relative to be their donor. Siblings are most likely to be a close match (based on HLA typing).
    • Matched unrelated donor transplant — If you don’t have a relative available who is a match, doctors can search international donor registries for an unrelated donor.
    • Haploidentical transplant — If you have not been able to find a closely matched donor, you may be able to receive stem cells from a donor who is a half-match for you. This option broadens the pool of potential donors. Haploidentical, or half-matched, transplants rely on advances in drug therapies to prevent graft-versus-host disease.
    • Cord blood transplant — Stem cells from donated cord blood don’t need to match you as closely. The immune cells in cord blood are not yet trained to fight foreign invaders, like bacteria, so they’re less likely to interact adversely with your tissues. Normally, a unit of cord blood doesn’t have enough stem cells for a transplant in an adult. But doctors can combine units of cord blood and also greatly expand the number of cells per unit using specialized techniques in the lab.

Umbilical cord blood transplant

  • This is a type of allogeneic transplant. Stem cells are removed from a newborn baby’s umbilical cord right after birth. The stem cells are frozen and stored until they are needed for a transplant. Umbilical cord blood cells are very immature so there is less of a need for perfect matching. Due to the smaller number of stem cells, blood counts take much longer to recover.

Syngeneic (identical twin transplant)

  • Stem cells are donated by an identical twin, which is an ideal donor because of the matching genetic identity between donor and recipient.

Parent-child transplant and haplotype mismatched transplant

  • Cells from a parent, child, brother, or sister are not always a perfect match for a patient’s HLA type, but they are a 50% match. Doctors are using these types of transplants more often, to expand the use of transplantation as an effective cancer treatment.

Before the transplant, chemotherapy, radiation, or both may be given. This may be done in two ways

  • Ablative (myeloablative) treatment  – High-dose chemotherapy, radiation, or both are given to kill any cancer cells. This also kills all healthy bone marrow that remains and allows new stem cells to grow in the bone marrow.
  • Reduced-intensity treatment also called a mini transplant – Lower doses of chemotherapy and radiation are given before a transplant. This allows older people, and those with other health problems to have a transplant.

Pre Procedure of Bone Marrow Transplant

  • Major Histocompatibility Complex (MHC) – The group of genes on the short arm of chromosome 6 (p6) that encodes human leukocyte antigens (HLA) which are considered being highly polymorphic leading to a large difference in the resultant expressed proteins on human cells. They are divided into MHC I and MHC II
  • Human Leukocyte Antigens (HLA) These are the proteins expressed on the cellular surface and play an important role in alloimmunity. HLA can be divided into (HLA-A, B, and C) which are encoded by class I MHC and are expressed on all cell types and present peptides derived from the cytoplasm and are recognized by CD8+ T cells. The other HLA type is classified as (HLA- DP, DQ, and DR) which are encoded by MHC II and can be found on antigen-presenting cells (APCs) and this class is recognized by CD4+ T cells.
  • Syngeneic Bone Marrow Transplantation The donor and the recipient are identical twins. The advantages include no graft versus host disease (GVHD) and no graft failure. However, only a tiny number of transplant patients will have the ability to have an identical twin for transplantation.
  • Autologous Bone Marrow Transplantation – The bone marrow products are collected from the patient and are reinfused after purification methods. The advantages include no GVHD. The disadvantage is that the bone marrow products may contain abnormal cells that can cause relapse in the case of malignancy hence; theoretically, this method cannot be used in all cases of abnormal bone marrow diseases.
  • Allogenic Transplantation The donor is an HLA matched family member, unrelated matched donor or mismatched family donors (haploidentical).
  • Engraftment The process of which infused transplanted hematopoietic stem cells produce mature progeny in the peripheral circulation
  • Preparative Regimen – This is a regimen that comprises high-dose chemotherapy and/or total body irradiation (TBI) which are administered to the recipient prior to stem cell infusion to eliminate the largest number of malignant cells and to allow for immunosuppression in the recipient so that engraftment can occur.

Indications of Bone Marrow Transplant

Indications for stem cell transplantation are as follows:

Malignant (cancerous)

  • Acute myeloid leukemia (AML)
  • Chronic myeloid leukemia (CML)
  • Acute lymphoblastic leukemia (ALL)
  • Hodgkin lymphoma (HL) (relapsed, refractory)
  • Non-Hodgkin lymphoma (NHL) (relapsed, refractory)
  • Neuroblastoma
  • Ewing sarcoma
  • Multiple myeloma
  • Myelodysplastic syndromes
  • Gliomas, other solid tumors

Non-malignant (non-cancerous)

  • Thalassemia
  • Sickle cell anemia
  • Aplastic anemia
  • Fanconi anemia
  • Malignant infantile osteopetrosis
  • Mucopolysaccharidosis
  • Pyruvate kinase deficiency
  • Immune deficiency syndromes
  • Autoimmune diseases[rx]

Malignant Disease

  • Multiple MyelomaAutologous stem cell transplant accounts for most hematopoietic stem cell transplants according to CIBMTR in 2016 in the United States. Studies have shown increased overall survival and progression-free survival in patients younger than 65 years old when consolidation therapy with melphalan is initiated followed by autologous stem cell transplantation and lenalidomide maintenance therapy. The study showed a favorable outcome of high-dose melphalan plus stem-cell transplantation when compared with consolidation therapy with melphalan, prednisone, lenalidomide (MPR). It also showed a better outcome in patients who received maintenance therapy with lenalidomide.
  • Hodgkin and Non-Hodgkin Lymphoma  – Studies have shown that chemotherapy followed by autologous stem cell transplantation in cases of recurrent lymphomas (HL and NHL) that do not respond to initial conventional chemotherapy have better outcomes. A randomized controlled trial by Schmitz N et al. showed a better 3-year outcome of high-dose chemotherapy with autologous stem cell transplant compared to aggressive conventional chemotherapy in relapsed chemosensitive Hodgkin lymphoma. However, the overall survival was not significantly different between the two groups. The number of hematopoietic stem cell transplant recipients comes second after multiple myeloma according to CIBMTR.
  • Acute Myeloid Leukemia Allogenic stem cell transplant has shown to improve outcomes in patients with AML who fail primary induction therapy and do not achieve a complete response and may prolong overall survival. The study recommended that early HLA typing for patients with AML can help if they fail induction therapy and are considered for bone marrow transplant.
  • Acute Lymphocytic Leukemia Allogenic stem cell transplant is indicated in refractory and resistant cases when induction therapy fails for the second time in inducing remission. Some studies suggest an increased benefit of allogeneic hematopoietic stem cell transplant in patients with high risk ALL including patients with Philadelphia chromosome and those with t(4, 11).
  • Myelodysplastic Syndrome Allogenic stem cell transplant is considered being curative in cases of disease progression and is only indicated in intermediate- or high-risk patients with MDS.
  • Chronic Myeloid Leukemia/Chronic Lymphocytic LeukemiaRecipients with these two diseases come at the bottom of the list of patients who received allogeneic stem cell transplant in 2016. Hematopoietic stem cell transplantation has shown high cure rates but with available treatments like tyrosine kinase inhibitors and high success rates with the low adverse risk profile, HSCT is reserved for patients with the refractory disease to first-line agents in CML.
  • Myelofibrosis, Essential Thrombocytosis, and Polycythemia Vera Allogenic stem cell transplant has shown to improve outcomes in patients with myelofibrosis and those who had a diagnosis of myelofibrosis that was preceded by essential thrombocytosis and polycythemia vera.
  • Solid TumorsAutologous stem cell transplant is considered the standard of care in patients with germ cell tumors (testicular tumors) that are refractory to chemotherapy (after the third recurrence with chemotherapy). HSCT has also been studied in medulloblastoma, metastatic breast cancer, and other solid tumors.

Non-Malignant Diseases

  • Aplastic Anemia Systematic and retrospective studies have suggested an improved outcome with hematopoietic stem cell transplant in acquired aplastic anemia when compared with conventional immunosuppressive therapy. Allogenic stem cell transplant has shown better outcomes when it was collected from bone marrow compared to peripheral blood in a study that involved 1886 patients with acquired aplastic anemia. Patients with aplastic anemia need a preparative regimen given they still can develop immune rejection to the graft.
  • Severe Combined Immune Deficiency Syndrome (SCID) – Large retrospective studies have shown increased overall survival in infants with SCID when they received the transplant early at birth before the onset of infections.
  • Thalassemia – Allogenic stems transplant from a matched sibling donor is considered an option to treat Thalassemia and has shown 15-year survival reaching 80%. However, recent retrospective data showed similar overall survival compared with conventional treatment that consists of multiple transfusions in the case of thalassemia.
  • Sickle Cell Anemia – Allogenic stem cell transplant is recommended for the treatment of sickle cell disease.
  • Other Nonmalignant Diseases  – Stem cell transplant has been used in the treatment of chronic granulomatous disease, leukocyte adhesion deficiency, Chediak-Higashi syndrome, Kostman syndrome, Fanconi anemia, Blackfan-Diamond anemia, and enzymatic disorders. Moreover, the role of stem cell transplant is being explored in autoimmune diseases including systemic sclerosis, systemic lupus erythematosus, and has already shown promising results in cases like relapsing-remitting multiple sclerosis.

Bone marrow transplants can benefit people with a variety of both cancerous (malignant) and noncancerous (benign) diseases, including:

  • Acute leukemia
  • Adrenoleukodystrophy
  • Aplastic anemia
  • Bone marrow failure syndromes
  • Chronic leukemia
  • Hemoglobinopathies
  • Hodgkin’s lymphoma
  • Immune deficiencies
  • Inborn errors of metabolism
  • Multiple myeloma
  • Myelodysplastic syndromes
  • Neuroblastoma
  • Non-Hodgkin’s lymphoma
  • Plasma cell disorders
  • POEMS syndrome
  • Primary amyloidosis

In which diseases and at which stages bone marrow transplant is employed?

Acute myeloblastic leukemia

  • In acute myeloblastic leukemias that develop after myelodysplastic syndrome.
  • In patients with acute myeloblastic leukemia without any t(8;21), t(15;17), (Inv 16) abnormality.
  • In patients who do not respond to remission induction therapy.
  • In patients with Flt-3positive acute myeloblastic leukemia.

Acute lymphoblastic leukemia

  • In patients with unfavorable cytogenetic findings such as Philadelphia chromosome, 11q23 positive.
  • In patients with leukocyte counts in excess of 30-50 thousand microliters.
  • In patients with the central nervous system or testicle involvement.
  • In patients who do not respond to initial remission induction therapy.

Myelodysplastic syndrome

  • In patients with blast rate >5%.
  • In patients with Intermediate 1, Intermediate 2 or a higher risk score.
  • In patients with cytopenia in more than one sequence

Non-Hodgkin’s lymphomas

  • 1. In diffuse large cell lymphomas:
  • Upon first relapse (recurrence of the disease after the treatment)
  • Upon the first remission in patients with high, high intermediate risk.
  • 2. Mantle cell lymphoma; after initial treatment
  • 3. Follicular lymphoma;
  • Patients who do not respond sufficiently to initial treatment.
  • Patients with first remission shorter than > 12 months
  • Patients with a 2nd relapse (disease recurring).
  • Patients experiencing conversion into diffuse large B cell lymphoma.
  • Hodgkin’s lymphoma
  • Patients who fail to start remission with initial treatment.
  • Patients who respond to initial treatment, but later experience a relapse.
  • Multiple myeloma
  • Subsequent to initial treatment (after reduction of protein M with 2-4 courses of chemotherapy).

What are bone marrow transplantation suitability criteria?

  • Criteria for Autologous Stem Cell Transplant (Multiple Myeloma, Hodgkin’s and Non-Hodgkin’s Lymphoma etc.):
  • Heart ejection fraction > 50%,
  • Liver function tests should not exceed twice the normal limits,
  • Lung function tests: DLCO > 60 %,
  • Good patient performance.

Criteria for Myeloablative Allogeneic Stem Cell Transplant

  • Age < 55,
  • HLA matching sibling (6 out of 6 or 5 out of 6 markers),
  • Heart ejection fraction > 50%,
  • Normal liver function tests,
  • Lung function tests; DLCO > 60%.

Criteria for Non-Myeloablative (Reduced Dose Regime) Allogeneic Stem Cell Transplant

  • Age < 65,
  • HLA matching sibling or relative.

What are bone marrow diseases?

  • Acute Myeloblastic Leukemia
  • Acute Lymphoblastic Leukemia
  • Non-Hodgkin’s Lymphoma
  • Hodgkin’s Lymphoma
  • Multiple Myeloma
  • Myelodysplastic Syndrome
  • Chronic Myelocytic Leukemia
  • Chronic Lymphocytic Leukemia
  • Aplastic Anemia
  • Paroxysmal Nocturnal Hemoglobinuria
  • Primary Amyloidosis
  • Solid Cancers: Testicle cancer, ovarian cancer
  • Hereditary Diseases: Hemoglobinopathies

Contraindications of Bone Marrow Transplant

There are no absolute contraindications for hematopoietic stem cell transplant.

Rules for bone marrow transplant

These rules have been prepared as a guide for patients and their relatives.

  • Stick to the physician’s prescription in using all medications.
  • Make sure to come for regular check-ups. Please, arrive on an empty stomach and without having used any medication.
  • Chemotherapy will inhibit the optimum functioning of the immune system for about a year. This is why it is very important to give extra care and attention to personal hygiene, nutrition, use of protective masks, accepting visitors, handshakes, and sexual relations throughout the entire year.
  • Instructions for daily life after bone marrow transplant
  • Your home should be especially clean following the transplant. Allocate a separate room for the patient. Remove dust magnet such as thick carpets and curtains from this room. Do not clean and air the patient’s room which he/she is still inside. If the room/home lacks central heating, make sure to light and clean the fire stove when the patient is outside the room. Adjust the room temperature carefully.
  • The patient’s room must be away from any type of construction activity.
  • All house plants and any kind of pet including cats, dogs, fish, and birds must be removed from the house for a year due to the risk of infection.
  • Make sure to keep the rest of the house equally clean and tidy.
  • Pay attention to land hygiene, take a wash at least two times a day, allocate a separate towel for the patient, and prevent its use by anyone else. Wash and iron the towel after each use. Take showers instead of baths, and use only moisturizing soaps.
  • Use a paper towel for hand and face hygiene.
  • Do not have guests for the first 100 days. Reduce the number of guests as much as possible in the subsequent period. Refrain from close contact including kissing, handshaking, and cuddling.
  • Change the patient’s bed linen at least twice a week, frequently air the mattress.
  • Do not use feather and wool-stuffed pillows.
  • Make sure to wash all new clothes before use. Do not use corduroy or plush textiles.
  • Make sure that the patient uses two masks whilst traveling or outdoors.
  • Patients should not swim for a year (sea or pool) and should not use saunas.
  • Prevent direct contact with sunlight for one year. Walks should be taken in the afternoon.
  • Women should not get epilation for one year. Depilatory creams may be used if the physician approves.
  • Give extra care to hygiene when getting the patient’s haircut.
  • Brush teeth with a soft brush 3 times a day, try not to get gums bleeding.
  • Do not use deodorants, perfumes, makeup, or hair dye for a year.
  • Do not smoke or consume alcohol, steer clear of smoky, dusty, and dirty environments.
  • Do not come in contact with people who have cold, flu, or infection.
  • Immediately seek medical attention in case of bleeding, bruising, and swelling.
  • Dress according to climate, avoid getting ill.
  • Menstruation irregularities may develop in women following the transplant. Seek medical attention from the gynecology department in accordance with the physicians’ recommendations.
  • Treatment will cause a loss in a sense of thirst, hunger, and taste for the first three months after the transplant. This is why patients have to drink three liters of water per day for a year. Drinking less can result in serious electrolyte disorder thus increasing the risk of getting sick. Liquid intake may also be supported by drinking milk, diluted yogurt, tea, fruit juice, or soup. Chew sugar-free chewing gum for building an appetite or suck on sweets for a sense of taste. Drink homemade lemonade 30 minutes before meals, if feeling nauseous.
  • Do not drink spring water from unknown sources. Only drink bottled water.
  • Use only pasteurized milk and cheese.
  • Milk taken outside should be boiled for 15 minutes.
  • Take single-use pasteurized and homemade yogurt.
  • Thoroughly rinse all fruit and vegetables, leave them in water with vinegar for 30 minutes, and peel all skin before consuming.
  • Eat seasonal fruit and vegetables. Avoid consuming processed foods and drinks with additives.
  • Thoroughly cook all food. Strictly avoid eating salami, sausage, bacon, cured meat, spices, raw onions and garlic, tomato paste, animal fat, innards, legumes, pickles, creams, kebabs, pizzas, burgers and any sort of fast foods.
  • Thoroughly cook all meats and eggs, make sure eggs are not cracked.
  • Do not crack nuts with your teeth, use nutcrackers.
  • Refrain from eating strawberries as they grow too close to the soil.
  • Do not eat frozen, stale, or canned food. Food should be consumed in 24 hours.
  • Store food in airtight containers.
  • Use latex gloves to prepare food.
  • Use mask whilst preparing food for the patient.
  • Pay attention to expiration dates for all products and foods.
  • Do not discuss distressing issues with the patient. Keep patient’s spirit high

Equipment

Special equipment exists for the collection, preservation, and administration of stem cell products. An interprofessional team approach is a mainstay of ensuring the high-quality collection and infusion of stem cell products.

The group of specialists involved in the care of patients going through a transplant is often referred to as the transplant team. All individuals work together to give the best chance for a successful transplant. The team consists of the following:

  • Healthcare providers – Healthcare providers who specialize in oncology, hematology, immunology, and bone marrow transplantation.
  • Bone marrow transplant nurse coordinator – A nurse who organizes all aspects of care provided before and after the transplant. The nurse coordinator will provide patient education, and coordinates the diagnostic testing and follow-up care.
  • Social workers – Professionals who will help your family deal with many issues that may arise, including lodging and transportation, finances, and legal issues.
  • Dietitians – Professionals who will help you meet your nutritional needs before and after the transplant. They will work closely with you and your family.
  • Physical therapists – Professionals will help you become strong and independent with movement and endurance after the transplantation.
  • Pastoral care – Chaplains who provide spiritual care and support.
  • Other team members – Several other team members will evaluate you before transplantation and will give follow-up care as needed. These include, but are not limited to, the following:
    • Pharmacists
    • Respiratory therapists
    • Lab technicians
    • Infectious disease specialists
    • Dermatologists
    • Gastroenterologists
    • Psychologists

An extensive evaluation is completed by the bone marrow transplant team. The decision for you to undergo a bone marrow transplant will be based on many factors, including the following:

  • Your age, overall health, and medical history
  • Extent of the disease
  • Availability of a donor
  • Your tolerance for specific medicines, procedures, or therapies
  • Expectations for the course of the disease
  • Expectations for the course of the transplant
  • Your opinion or preference

Preparation

Preparation includes:

  • Preparative regimen
  • Collection of hematopoietic stem cells
  • Instant infusion or cryopreservation followed by infusion

Technique

Mechanism of Action

The mechanism of action of stem cell transplant against malignancy in leukemia is based on the effect of the graft and donor immunity against malignant cells in recipients. These findings were demonstrated in a study that involved over 2000 patients with different leukemia. These patients received stem cell transplantation and showed that the lowest rate of relapses was in patients who received non-T-cell-depleted bone marrow cells and in those who developed GVHD compared to patients who received T-cell-depleted stem cells, those who did not develop GVHD, and patients who received syngeneic grafts. These findings support the notion that donor cellular immunity plays a central role in the engraftment’s efficacy against tumor cells.

The mechanism of action in autoimmune diseases is believed to be secondary to the increase in T-cell regulatory function which promotes immune tolerance. However, more studies are still needed to determine the exact pathophysiology.

In hemoglobinopathies, the transplanted stem cells produce functional cells after engraftment that replaces the diseased cells.

HLA Typing and Administration

HLA typing is an important step to determine the best donor suitable for stem cell collection. In theory, matched, related donors are the best candidates, followed by matched unrelated donors, cord blood, and then haploidentical donors. HLA typing is analyzed at either an intermediate-resolution level, which entails the detection of a small number of matched alleles between the donor serum and the recipient, or at a high-resolution level to determine the specific number of polymorphic alleles at a higher level. PCR and next-generation sequencing are used for HLA typing, and the results are reported as a score correlating with a match of two alleles for a specific HLA type. Different institutions use a different number of HLA subtypes for eligibility of donors but according to studies that showed matching for HLA-A, B, C, and DRB1 at a high-resolution level were associated with improved survival and outcomes. Recommendations about donor HLA assessment and matching have been proposed by the Blood and Marrow Transplant Clinical Trials Network (BM CTN).

The process may vary depending on the source of the stem cell site collection, whether it is bone marrow, peripheral blood, or cord blood. Moreover, there is a slight difference based on whether it is autologous, allogeneic, or syngeneic. For example, the procedure consists of initial mobilization of stem cells, in which peripheral blood stem cells are collected given the low number and the need for high levels of progeny cells, and then this is followed by a preparative regimen and finally, infusion.

Mobilization and collection involved the use of medication to increase the number of stem cells in the peripheral blood given that there are not enough stem cells in the peripheral blood. The agents used include granulocyte colony-stimulating factors (G-CSF) or chemokine receptor 4 (CXCR4) blockers like plerixafor. G-CSF is believed to enhance neutrophils to release serine proteases which lead to a break of vascular adhesion molecules and the release of hematopoietic stem cells from the bone marrow. Plerixafor blocks the binding of stromal cell-derived factor-1-alpha (SDF-1) to (CXCR4) which leads to the mobilization of stem cells to the peripheral blood. CD34+ is considered the marker for progenitor hematopoietic stem cells in the peripheral blood, and usually, a dose of 2 to 10 x 10/kg CD34+ cells/kg is needed for proper engraftment. Chemotherapy can be used in some instances for mobilization of hematopoietic stem cells; this process is termed chemoembolization.

The usual site of bone marrow collection is the anterior or posterior iliac crest. The procedure can be performed under local or general anesthesia. Complications include pain, fever, and serious iatrogenic complications can occur in less than 1% of cases. Multiple aspirations are done with each aspirate containing 15 mL. The goal is to collect up to 1 to 1.5 L of bone marrow product from the aspirations. The dose of nucleated cells from bone marrow should range between 2 to 4 x 10 cells/kg as studies showed that overall survival and long-term engraftment is strongly influenced by cell dose in allogeneic hematopoietic stem cell transplantation.

The preparative regimen consists of administration of chemotherapy with or without total body irradiation for the eradication of malignant cells and induction of immune tolerance for the transfused cells to engraft properly. This process is not only limited to patients with malignancies but also extends to cases like aplastic anemia and hemoglobinopathies given that these patients have an intact immune system that could cause graft failure if there is no conditioning.

The preparative regimen is divided into myeloablative conditioning and reduced-intensity conditioning. The preparative regimen depends on the disease being treated, existing comorbidities, and the source of the harvested hematopoietic stem cells. The preparative regimen consists of chemotherapy, total body irradiation, or both. There are different combination regimens used in the preparative period, and the choice of the regimen depends on the disease being treated, existing comorbidities, and previous exposure to radiation.

In the special case of SCID, there is no need for a preparative regimen in patients receiving from HLA-matched siblings given that there are no abnormal cells that are needed to be eliminated and because immunosuppression caused by SCID can prevent graft rejection. Reduced-intensity conditioning is preferred in patients with prior radiotherapy, older age, the presence of comorbidities, and history of extensive chemotherapy before BMT. The advantages of using reduced-intensity conditioning include less need for transfusion due to the transient post-transplant pancytopenia and less damage to the liver in cases of chemotherapy and lung due to radiation. However, the relapse rates are higher, but these regimens are more tolerated with a better safety profile in a specific patient population. Most of the chemotherapies used in preparative regimens consist of either potent immunosuppressive agents (high doses of cyclophosphamide 60 mg/kg IV), alkylating agents especially busulfan 130 mg/m2 IV, nucleoside analogs (fludarabine 40 mg/m2) and other agents like melphalan, antithymocyte globulin, rituximab, gemcitabine, and many others. Total body irradiation (TBI) is performed using fractionated doses because it has shown less pulmonary toxicity when compared with one dose regimen. The administration of the preparative regimen should immediately precede the bone marrow transplantation, and as a general rule, the effect of the regimen should produce bone marrow suppression within 1 to 3 weeks of administration.

Reinfusion of either fresh or cryopreserved stem cells can occur in an ambulatory setting and takes up to 2 hours. Before the infusion begins, quality measures are performed to ensure the number of CD34+ cells is sufficient.

Rehabilitation after stem cell transplant

The process of stem cell transplant doesn’t end when you go home. You’ll feel tired, and some people have physical or mental health problems in the rehabilitation period. You might still be taking a lot of medicines. These ongoing needs must now be managed at home, so caregiver and friend/family support is very important.

Transplant patients are followed closely during rehab. You might need daily or weekly exams along with things like blood tests, and maybe other tests, too. During early rehab, you also might need blood and platelet transfusions, antibiotics, or other treatments. At first you’ll need to see your transplant team often, maybe even every day, but you’ll progress to less frequent visits if things are going well. It can take 6 to 12 months, or even longer, for blood counts to get close to normal and your immune system to work well. During this time, your team will still be closely watching you.

Some problems might show up as much as a year or more after the stem cells were infused. They can include:

  • Graft-versus-host disease (in allogeneic transplants)
  • Infections
  • Lung problems, such as pneumonia or inflammation that makes it hard to breathe
  • Kidney, liver, or heart problems
  • Low thyroid function
  • Overwhelming tiredness (fatigue)
  • Limited ability to exercise
  • Slowed growth and development (in children)
  • Cataracts
  • Reproductive or sexual problems, like infertility, early menopause, pain or discomfort during sex, or loss of interest in sex
  • New cancers caused by the transplant

Other problems can also come up, such as:

  • Memory loss, trouble concentrating
  • Emotional distress, depression, body image changes, anxiety
  • Social isolation
  • Changes in relationships
  • Changes in how you view the meaning of life
  • Feeling indebted to others
  • Job and insurance concerns

What complications and side effects may happen following BMT?

Complications may vary, depending on the following:

  • Type of marrow transplant
  • Type of disease requiring a transplant
  • Preparative regimen
  • Age and overall health of the recipient
  • The variance of tissue matching between donor and recipient
  • Presence of severe complications

The following are complications that may happen with a bone marrow transplant. However, each individual may experience symptoms differently. These complications may also happen alone, or in combination:

  • Infections – Infections are likely in the patient with severe bone marrow suppression. Bacterial infections are the most common. Viral and fungal infections can be life-threatening. Any infection can cause an extended hospital stay, prevent or delay engraftment, and/or cause permanent organ damage. Antibiotics, antifungal medicines, and antiviral medicines are often given to try to prevent serious infection in the immunosuppressed patient
  • Low platelets and low red blood cells – Thrombocytopenia (low platelets) and anemia (low red blood cells), as a result of nonfunctioning bone marrow, can be dangerous and even life-threatening. Low platelets can cause dangerous bleeding in the lungs, gastrointestinal (GI) tract, and brain.
  • Pain – Pain-related to mouth sores and gastrointestinal (GI) irritation is common. High doses of chemotherapy and radiation can cause severe mucositis (inflammation of the mouth and GI tract).
  • Fluid overload – Fluid overload is a complication that can lead to pneumonia, liver damage, and high blood pressure. The main reason for fluid overload is because the kidneys cannot keep up with a large amount of fluid being given in the form of intravenous (IV) medicines, nutrition, and blood products. The kidneys may also be damaged from disease, infection, chemotherapy, radiation, or antibiotics.
  • Respiratory distress – Respiratory status is an important function that may be compromised during transplant. Infection, inflammation of the airway, fluid overload, graft-versus-host disease, and bleeding are all potentially life-threatening complications that may happen in the lungs and pulmonary system.
  • Organ damage – The liver and heart are important organs that may be damaged during the transplantation process. Temporary or permanent damage to the liver and heart may be caused by infection, graft-versus-host disease, high doses of chemotherapy and radiation, or fluid overload.
  • Graft failure – Failure of the graft (transplant) taking hold in the marrow is a potential complication. Graft failure may happen as a result of infection, recurrent disease, or if the stem cell count of the donated marrow was insufficient to cause engraftment.
  • Graft-versus-host disease – Graft-versus-host disease (GVHD) can be a serious and life-threatening complication of a bone marrow transplant. GVHD occurs when the donor’s immune system reacts against the recipient’s tissue. As opposed to an organ transplant where the patient’s immune system will attempt to reject only the transplanted organ, in GVHD the new or transplanted immune system can attack the entire patient and all of his or her organs. This is because the new cells do not recognize the tissues and organs of the recipient’s body as the self. Over time and with the help of medicines to suppress the new immune system, it will begin to accept its new body and stop attacking it. The most common sites for GVHD are the GI tract, liver, skin, and lungs.

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Below is a glossary of common terms used when discussing the bone marrow transplant (BMT) process.

Acyclovir: A drug used specifically against and for the prevention of herpes virus; given IV or orally.
Allogeneic Transplant: A transplant between 2 individuals who are not genetically identical.
Alopecia: Hair loss
Amphotericin: A drug used specifically against fungal infections: given IV.
ANC: Absolute Neutrophil Count represents the total number of white cells that are capable of fighting bacterial infections.
Anemia: A condition in which blood has a low number of red blood cells. Signs and symptoms of anemia may include: fatigue, weakness, pale color, headaches, dizziness, low blood pressure and elevated heart rate.
Antibodies: Protein substances in the blood stream that react against bacteria, viruses and other materials harmful to the body.
Antibiotics: Drugs used to fight infections.
Antigen: A chemical (sometimes a protein) recognized by the body’s immune system as being foreign.
Aplastic anemia: A disease where the bone marrow does not produce an adequate number of red cells, white cells and platelets.
ATG: Anti-thymocyte globulin is an antibody made in horses or rabbits against T-cells and used to increase the likelihood of engraftment in bone marrow transplant recipients or to treat graft vs. host disease.
Autologous transplant: A transplant in which the donor and recipient are the same person.
Bactrim/Septra: A medication taken IV/orally to prevent gastrointestinal infections as well as a type of lung infection called pneumocystis.
Betadine: Brown soap that effectively kills germs when applied to the skin.
Biopsy: The removal of a small piece of tissue from the body for purposes of diagnosis (i.e., bone marrow, skin, liver, lung).
Blood type: Blood cells contain factors that are not the same in all people. Before a transfusion can occur, blood samples from the donor and recipient are classified as type A, B, AB, or 0. Another test called “cross match” ensures the compatibility of the blood between donor and recipient.
BMTU: Bone Marrow Transplant Unit
Bone marrow: A spongy material found in the center of the bones that contains stem cells that manufacture blood cells. The 3 major types of blood cells that bone marrow stem cells produce are red blood cells (RBC), white blood cells (WBC) and platelets. Each has an important function. See red blood cell, white blood cell and platelets.
Bone Marrow Transplant (BMT): A procedure in which bone marrow stem cells are collected from one individual (the donor) and given to another (the recipient). The stem cells can be collected either directly from the bone marrow or from the blood by a procedure called leukapheresis. Sometimes the patient serves as his or her own bone marrow stem cell donor.
Busulfan: A chemotherapy drug that is given prior to bone marrow transplantation.
Cancer: Diseases that are characterized by the uncontrolled and abnormal growth of cells. Examples: leukemia, lymphoma, and neuroblastoma.
CBC: The Complete Blood Count includes the level of hemoglobin and number of red and white blood cells and platelets in the blood.
CD34: A unique marker that is found on the surface of bone marrow stem cells. Special chemicals called monoclonal antibodies can be used to identify the CD34 positive stem cells in the bone marrow or blood. CD34 positive stem cells can be purified and T cell depleted for transplantation from donors who are mismatched (haplocompatible) with the recipient.
Central line or catheter: A central line or central venous catheter is a soft flexible tube that is placed under the skin and then directed into a large vessel leading into the heart. The catheter allows fluids, medications, nutrition and blood products to be given without sticking the patient with a needle. Blood can also be drawn through the catheter for laboratory tests. The catheter may have either one or two tubes or lumen.
Chemotherapy: Drugs primarily used to destroy cancer cells but also used in bone marrow transplant patients without cancer in order to ensure successful engraftment. These drugs have side effects that affect other normal cells in the body. Another name commonly used is “chemo.”
Chimerism: The state in which donor cells have durably engrafted in the recipient. Full donor chimerism implies that 100% of bone marrow and blood cells are of donor origin, while mixed or partial chimerism means that recipient cells are also present.
Clotrimazole: Anti-fungal agent. See Mycostatin.
Conditioning regimen: Term used for those chemotherapy drugs and sometimes radiation that collectively prepare the body for transplant. The conditioning regimen usually takes 6-8 days to complete.
Culture: A laboratory procedure in which samples of blood, urine or other body fluid are used to determine the presence of an infection.
Donor: The family member (parent, brother or sister) or unrelated volunteer who donates his/her bone marrow stem cells. Sometimes the patient serves as his or her own donor. On the day of transplant, the donor either goes to the operating room and under general anesthesia has multiple bone marrow aspirations (bone marrow harvest) to remove a portion of bone marrow, or undergoes a procedure called leukapheresis to collect bone marrow stem cells from the blood.
EKG: Electrocardiogram – a machine that records electrical measurements of the heart’s impulses.
Engraftment: The successful growth of donor bone marrow stem cells in the recipient.
Erythrocytes: Red blood cells.
Fludarabine: An immunosuppressive chemotherapy drug that is given prior to transplant in order to prevent rejection of the donor cells by the recipient’s immune system.
Gastrointestinal (GI): Pertains to the digestive tract which includes the mouth, throat, esophagus, stomach, small and large intestine and rectum.
G-CSF Granulocyte Colony Stimulating Factor. A drug that is found naturally in the body and that stimulates the production of granulocytes (neutrophils) by the bone marrow. GCSF is also used to increase the number of stem cells circulating in the blood.
Graft vs. Host Disease
(GVHD):
A reaction between the transplanted T lymphocytes of the donor (graft) and the tissues/organs of the patient (host). The T- cells of the donor graft can attack the recipient’s tissues. The skin, GI tract, liver and other organs can be affected.
Granulocyte: A type of white blood cell that helps fight infections.
Haplocompatible: When the donor and recipient share half of their HLA antigens. All parents are haplocompatible with their children since children inherit half of their HLA antigens from their mother and half from their father.
Hematocrit: A measure of red blood cell volume. A normal hematocrit (Hct) is between 36-48. A low Hct (for example <20) may result in the need for a red blood cell transfusion.
Hematology: The branch of medicine that studies and treats diseases of the blood and blood forming organs. A hematologist is a physician that specializes in this area of practice.
Hematopoietic Referring to the tissue that produces the components in the blood including red cells, white cells and platelets, that is, bone marrow. Another term for a bone marrow transplant (BMT) is “hematopoietic stem cell transplant (HSCT)”
Hemoglobin: A measure of red blood cell volume.
Hemoglobinopathy: A disorder of the bone marrow cells that produce erythrocytes (red blood cells). Two hemoglobinopathies for which a bone marrow transplant is commonly done are thalassemia major and sickle cell disease.
Hemorrhage: Refers to a large amount of blood loss over a short period of time.
HEPA filter: A High Efficiency Particulate Aerosol filter found in each of the transplant rooms which prevents harmful germs from entering the room via the air system.
Histocompatibility: The degree of tissue similarity between the donor and recipient that will determine how easily the donor cells will be accepted and/or the likelihood and severity of GVHD.
Histocompatibility (HLA) typing: Blood tests of the tissue typing system. The HLA and MLC determine the likeness between potential donor – recipient pairs.
HLA: Human Leukocyte Antigen. See histocompatibility typing.
Hyperalimentation: Intravenous administration of nutrients needed by the body. It is also called total parenteral nutrition (TPN). The nutrients in the form of fluid are given through the central line.
Immune system: The body’s system of defenses against disease. The immune system is primarily composed of white blood cells and antibodies.
Immunology: A branch of medicine which studies the body’s natural defense mechanisms against disease. An immunologist is a physician that specializes in this area of practice.
Immunosuppressed: The state where the body has a reduced ability to adequately fight infections.
Infection: Invasion of any part of the body by germs. Bacteria, viruses, and fungi are the major germs that infect transplant recipients.
Informed consent: The process whereby a patient/parent/legal guardian is given information about a specific surgery or treatment (i.e., bone marrow transplant). All potential risks and benefits must be understood prior to the signing of a consent form. It is a legal document that gives the physician permission to perform the procedure.
Intralipid: Usually given in conjunction with hyperalimentation. This IV solution contains fat and provides the body with needed nutrients.
Intravenous (IV): The administration of fluids/medications directly into a vein.
Isolation: Procedures (for example, handwashing) in the transplant rooms that minimize the exposure of transplant patients to infection.
IV pump: The machine that delivers fluids and medications intravenously.
Jugular: Refers to the veins in the neck in which catheters may be placed for leukapheresis procedures.
Kostmann’s syndrome: An inherited disorder of neutrophils in which affected children present with severe infections and very low to absent neutrophil counts; also called severe congenital neutropenia.
Leukapheresis A procedure that is used to collect bone marrow stem cells from the blood (see PBSC). Typically, the donor of the PBSC is treated prior to the procedure with several days of GCSF injections to mobilize the bone marrow stem cells into the circulating blood. The blood is then passed through a machine that collects that part of the blood containing the stem cells. The remaining blood is returned to the donor.
Leukemia: A cancer of the bone marrow that is characterized by the abnormal growth of white blood cells.
Leukocyte: A type of white blood cell.
LFT’s: Liver function tests are measurements from blood samples that reveal how well the liver is working.
Lymphocytes: A type of white blood cell that is especially important in fighting viral and bacterial infections as well as in rejecting transplants.
Lymphoma: Cancer of the lymph nodes.
Metastatic: Refers to cancers in which there has been spreading to distant parts of the body from the original or primary site of the tumor.
MLC: Mixed Lymphocyte Culture. Sometimes used in histocompatibility typing in which donor and recipient cells are mixed together in a test tube to determine their compatibility with each other.
Myeloablation: The process of conditioning or preparing a patient for a bone marrow transplant in which the bone marrow stem cells are destroyed or ablated. Generally, the conditioning regimen contains very high doses of chemotherapy and often total body irradiation.
Neuroblastoma: A type of cancer that involves the adrenal gland or nervous system.
Neutrophil: A type of white blood cell that plays a major role in fighting bacterial and fungal infections.
Non-myeloablative: The conditioning regimen prior to transplant in which limited amounts of chemotherapy are administered in order to prevent rejection of the donor bone marrow stem cells without destroying the recipient’s bone marrow.
Nystatin: A medication specifically used to fight a fungal or yeast infection.
Oncology: The study and treatment of cancer. An oncologist is a physician who specializes in this area of practice.
PBSC (peripheral blood stem cells): Peripheral Blood Stem Cells. These are bone marrow stem cells that are circulating in the blood and can be collected by leukapheresis. To increase the number of PBSC donors receive GCSF for several days prior to the leukapheresis.
Pharmacokinetics: The measurement of how a drug is taken up and eliminated by the body. The pharmacokinetics of busulfan is measured in a child who is going to receive this drug as part of his or her conditioning regimen in order to determine the optimal dose for that child.
Phenytoin (Dilantin): A drug used to help prevent seizures. Patients are put on this while they are receiving Busulfan, a chemotherapy that can cause seizures.
PICU: Pediatric Intensive Care Unit.
Platelets: A type of blood cell that is necessary to stop bleeding and allow injured areas to form clots. A normal platelet count is 140,000-300,000. A platelet transfusion may be needed with platelet counts <15,000 or to help stop bleeding.
Quinton catheter: A type of temporary central venous catheter that is inserted into a large vein in the neck and used for leukapheresis. A similar type of central venous catheter for leukapheresis is a Vascath. Both catheters are usually removed after the leukaphersis is complete.
Rad: A unit of measurement in the administration of radiation.
Radiation Therapist: A physician who specializes in the use of radiation in the treatment of diseases.
Radiation Therapy: Treatment using high energy radiation. (See total body irradiation).
Red Blood Cells (RBC): Cells found in the blood responsible for carrying oxygen to tissues in the body.
Severe Combined Immunodeficiency Disease (SCID): A group of inherited diseases characterized by severely abnormal lymphocytes and the inability to make antibodies. Children with SCID are susceptible to infections from bacteria, viruses, and fungi which are ultimately fatal without a bone marrow stem cell transplant.
Stem cells: The youngest bone marrow cell from which other bone marrow cells are formed.
Syngeneic Transplant: A transplant between identical twins.
Total Body Irradiation (TBI): Treatment using radiation to kill cancer cells and/or prepare the body for transplant by destroying diseased cells and suppressing the recipient’s immune system’s ability to reject the donor cells.
Transfusion: A procedure that supplies the body with a specific types of blood cells (red blood cells or platelets) that are low in number.
Umbilical cord blood: The blood that is collected from the placenta after the umbilical cord is separated from a newborn baby. This blood contains large numbers of bone marrow stem cells and can be used as a source of donor cells from a sibling or unrelated donor for a bone marrow transplant.
Vascath: A temporary central venous catheter that is used for leukapheresis procedures. It is usually inserted into a large vein in the neck or the groin and removed once the procedure is over.
Veno-occlusive disease (VOD): A severe complication following a bone marrow transplant in which there is progressive liver failure. VOD may be mild and resolve without any treatment or may be severe and often fatal.
Venous: Referring to veins in the body that carry blood from all of the organs and tissues back to the heart. Central lines and leukapheresis catheters are venous catheters, i.e., they are placed in large veins.
White blood cells (WBC): Cells found in the blood and tissues that aid in fighting infections and making antibodies for the immune system’s attack against disease. There are several types of white blood cells including neutrophils and lymphocytes. The normal WBC is 5,000-10,000
Xenogeneic transplant: A transplant between two different species, for example, bone marrow from a baboon transplanted into a human.
Yeast: A germ that can infect recipients of bone marrow transplants. One kind of yeast or fungus is Candida. Fluconozole is an antibiotic that is given during the transplant period to reduce the risk of fungal infections. Yeast or fungal infections are very dangerous and when yeast is cultured or a yeast infection is suspected a very powerful antibiotic, amphoteracin is usually administered.
Zoster: A viral infection that may occur post bone marrow transplant in a patient who has previously had chicken pox. Zoster or shingles is the reactivation of the chicken pox virus (varicella).

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References

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Total Knee Replacement (TKR) Techniques

Total Knee Replacement(TKR) is a viable treatment for symptomatic osteoarthritis of the knee refractory to conservative measures. In those with end-stage degenerative changes compromising the articular cartilage affecting multiple compartments of the knee, the literature has yet to identify a potentially viable alternative option for the regeneration of cartilage.  Thus, TKA has demonstrated reproducible, long-term, successful results in such patients concerning outcomes of decreased pain and improved overall quality of life.

Recent estimates project that by the year 2030 there will be 3.48 million TKAs performed annually.  Although it is an extremely common and increasingly routine surgery, attention to detail is critical during the procedure to ensure that a well-balanced and functional TKA is performed to mitigate the risks of implanting components that might otherwise be subject to increased wear and early failure. Even with appropriate technique, new technologic advances, and a better understanding of knee kinematics, approximately 1 out of 5 people that undergo a TKA will remain unsatisfied. There are numerous TKA designs and different levels of constraint that may be necessary for particular cases. Unicompartmental arthroplasty, cruciate-retaining, and posterior stabilizing implants are typically used as potential index procedure options. However, in patients with significant varus/valgus instability, those undergoing revision surgery including component revisions, patients with the pre-existing poor bone quality, or in the setting of appreciable osseous defects, more constrained prosthetic components are given consideration.  These include, but are not limited to semi-constrained, hinged, or distal femoral replacement options.

Anatomy and Physiology of Total Knee Replacement

The knee is made up of 3 separate compartments

  • Medial tibiofemoral joint
  • Lateral tibiofemoral joint
  • Patellofemoral joint

The knee is typically described as a hinged joint; however, there are more complex and subtle motion and dynamic considerations.  Physiologically, the knee also undergoes axial rotation and femoral “rollback” in deeper degrees of flexion. Additionally, terminal rotatory motion, known as the “screw home mechanism,” occurs as the tibia externally rotates when the knee goes into terminal extension. The lateral tibial plateau is convex and sits more proximal than the medial tibial plateau which is concave. The medial femoral condyle is larger than the lateral side. 60% of the force through the knee joint occurs on the medial tibial plateau. Thus, the medial tibial plateau is of more dense bone, and this is also why the more common wear pattern seen in osteoarthritis occurs on the medial side.

Numerous ligaments act on the knee to provide stability of the joint including:

  • An anterior cruciate ligament (ACL) – Important for axial rotation as well as preventing anterior translation of the tibia on the femur
  • A posterior cruciate ligament (PCL) – Important for preventing posterior translation of the tibia on the femur, as well as allowing for femoral rollback.
  • Lateral collateral ligament (LCL) – Varus restraint, and is typically attenuated in significant varus deformity
  • Medial collateral ligament (MCL) – Valgus restraint, and is typically attenuated in significant valgus deformity
  •  Posterolateral corner (PLC) – The primary stabilizer of external tibial rotation

Mechanical Alignment

  • The distal femur is in approximately 9 degrees of anatomic valgus relative to the joint line while the proximal tibia in 3 degrees of anatomic varus relative to the joint line.
  • The typical patellar Q angle is between 13 degrees and 19 degrees, with an increased Q angle increases the risk of patellar maltracking and dislocation.

Indications of Total Knee Replacement

The most common underlying diagnosis and indication for TKA are end-stage, degenerative osteoarthritis of the knee, with approximately 94- 97% of knee replacements performed for primary or post-traumatic osteoarthritis. These patients must have degenerative changes with pain and limitation of function in the knee that has failed conservative and non-operative measures. Other underlying diagnoses that may be treatable with a knee replacement include rheumatoid arthritis, peri-articular fractures, or malignancy. However, patients with malignancy may commonly require mega prostheses.

TKA is an elective procedure that is, in most cases, reserved for patients experiencing chronic, debilitating symptoms that continue to persist despite the exhaustion of all conservative and nonoperative treatment modalities.

Clinical symptoms of osteoarthritis include

  • Knee pain
  • Pain with activity and improving with rest
  • The pain gradually worsens over time
  • Decreased ambulatory capacity

Clinical evaluation includes

  • Full knee exam including a range of motion and ligamentous testing
  • Knee radiographs include standing anteroposterior, lateral, 45-degree posteroanterior, and skyline view of the patella

Radiographic evidence of osteoarthritis include

  • Joint space narrowing
  • Subchondral sclerosis
  • Subchondral cysts
  • Osteophyte formation

Conservative treatment includes

  • Non-steroidal anti-inflammatory medication
  • Weight loss
  • Activity modification
  • Bracing
  • Physical therapy
  • Viscosupplementation
  • Intra-articular steroid injection
  • Decreased ambulatory capacity

Clinical evaluation includes

  • Full knee exam including a range of motion and ligamentous testing
  • Knee radiographs include standing anteroposterior, lateral, 45-degree posteroanterior, and skyline view of the patella

Radiographic evidence of osteoarthritis include

  • Joint space narrowing
  • Subchondral sclerosis
  • Subchondral cysts
  • Osteophyte formation

Contraindications of Total Knee Replacement

There are few absolute contraindications for TKA including an active infection in the joint, and remote infection, or bacteremia. Relative contraindications include a significant vascular disease that may lead to poor wound healing and increased risk for infection. There is currently discussion and controversy in the literature as to risk stratification and increased complications associated with obesity. Patients with a BMI greater than 30 have an increased risk of infection and medical complications compared to non-obese patients. This risk further increases for those with a BMI  greater than 40. Patients with BMI over 40 were found to have a statistically significant increase in superficial infection, deep infection, operative time, deep vein thrombosis (DVT), length of stay, renal insufficiency, reoperation, and wound dehiscence.

TKA is contraindicated in the following clinical scenarios

  • Local knee infection or sepsis
  • Remote (extra-articular), active, ongoing infection or bacteremia
  • Severe cases of vascular dysfunction

Absolute

  • Active or latent (less than 1 year) knee sepsis
  • Presence of active infection elsewhere in body
  • Extensor mechanism dysfunction
  • Medically unstable patient

Relative

  • Neuropathic joint
  • Poor overlying skin condition
  • Morbid obesity
  • Noncompliance due to major psychiatric disorder, alcohol, or drug abuse
  • Insufficient bone stock for reconstruction
  • Poor patient motivation or unrealistic expectation
  • Severe peripheral vascular disease

Equipment

Each implant company has a specific system with trays that come with the necessary tools and trial components. Basic equipment that will be used in all cases and will improve the efficiency and safety of the case include:

  • Standard operating table
  • De Mayo leg holder, paint roller, or other equivalent patient positioning instrumentation
  • Tourniquet

    • Overall use remains debated in the literature
    • Use and duration is surgeon-specific
  • Retractors
  • Osteotomes
  • Sagittal saw
  • Mallet
  • Lamina spreaders
  • Cement-specific equipment

    • Cement mixer system
    • Pressurizing gun
  • Pulse lavage irrigation
  • Suction
  • Bovie electrocautery

In revision cases, may also require other equipment including

  • Currettes
  • Reamers
  • Cones
  • Sleeves
  • Stemmed options including offset adjusting capabilities
  • Bone grafting options

Implant Types

Implant types have continued to evolve since the 1950s.  Insall et al. initially described in the 1970s the different models of knee prostheses. He placed them into two categories; condylar replacements that spared ligaments, and hinged-type components that sacrificed the ligaments. Four models were described, with increasing complexity in each model:

  • Unicondylar
  • Duocondylar
  • Geometric
  • Guepar

In modern arthroplasty, most implants are a derivative of these models that were initially described. From least complex to most complex they include unicompartmental, cruciate retaining, posterior stabilizing, constrained non-hinged, constrained hinged prosthetic components.

Cruciate Retaining (CR)

The ACL is sacrificed, overall feasibility mandates a competent and functional PCL.

Can be used in those with mild varus/valgus deformity. Should be avoided in those with inflammatory arthritis due to increased risk for short-term or delayed rupture of PCL.

Benefits

  • fewer patellar complications (theoretical)
  • Increased quadriceps strength (controversial, depends in part on surgical exposure utilized)
  • Improved stair climbing
  • Preserved PCL proprioception (theoretical)
  • Lower shear forces on the tibial component
  • Improved femoral bone stock preservation
  • Preserves near-normal knee kinematics
  • Avoids cam-post jump complication that exists in posterior stabilized prosthetic components

Disadvantages

  • Risk of postoperative PCL degeneration or rupture that can lead to flexion instability
  • Tight PCL can lead to increased wear on polyethylene and dysfunctional TKA kinematics

Posterior Stabilizing (PS)

Can be used in those with absent PCL, inflammatory arthritis, and may be beneficial in those with a previous patellectomy as it can add some anteroposterior stability that is absent due to the weak extensor mechanism. PS femoral prosthetic component contains a box in the femoral component with a post on the polyethylene liner that substitutes for the resected PCL.

Benefits

  • Can theoretically be easier to achieve ligamentous balance in the knee without having to worry about accounting for the physiologic effects of the intact PCL
  • Greater deformity correction compared to cruciate-retaining implants
  • Theoretically improved knee range of motion
  • Decreased polyethylene wear due to congruent articular surfaces

Disadvantages

  • Cam-post jump of the post over the femoral box, typically due to mid-late flexion instability
  • Polyethylene wear on post can lead to osteolysis
  • Patellar clunk that may occur due to a soft tissue nodule and is present when going from flexion into extension
  • The increased theoretical risk of technical error which can involve elevating the joint line

Overall, multiple studies have not demonstrated a significant difference in function, satisfaction or implant survival between cruciate-retaining and posterior stabilizing implants.

Constrained Non-Hinged

Varus-valgus constrained design is used in cases where there is LCL or MCL deficiency, moderate bone loss, or flexion gap laxity. This implant has a large tibial post with a deep femoral box.

Benefits

  • Allows for coronal stability in severe coronal bone deformities

Disadvantages

  • Increased femoral bone loss and is a poor option in younger patients unless necessary.
  • Increased risk of aseptic loosening due to increased constraint
  • Increased polyethylene wear and increased risk of cam fracture

Constrained Hinge

Rotating hinge prostheses are used in complex revision arthroplasty cases with significant bone loss, ligamentous laxity, or in oncologic cases. Femoral and tibial components link with an axle and the tibial bearing can rotate around the tibial platform. This rotation allows for a lower constraint and therefore a decreased risk of aseptic loosening. Early implants were uniplanar without allowing rotation and had a high rate of aseptic loosening.

Advantages

  • Very versatile and has application for many salvage cases

Disadvantages

  • Significant bone resection needed for implant
  • Although lower with a rotating hinge, still at risk for aseptic loosening due to increased constraint

Personnel

Total joint arthroplasty has transitioned from a fee for service to a bundled payment to incentivize quality of care over the quantity of cases. In 2015, the Center for Medicare and Medicaid Services (CMS) announced the Comprehensive Care for Joint Replacement Model (CJR). Bozic et al. in 2014 demonstrated that 70% of the total cost was post-discharge and they have created CJR in hopes of stimulating a reduction in cost and complications.  This effort has led to the development of standardized protocols and an interprofessional approach for patients undergoing knee replacement. At our institution, personnel integral to the success of a knee replacement include:

  • Primary care physician
  • Joint class instructor
  • Pre-operative intra-operative and post-anesthesia nurses
  • Scrub technician, circulating RN
  • Implant representative
  • Physician assistant/first assistant
  • Resident physician
  • Orthopedic surgeon
  • Case manager
  • Inpatient occupational and physical therapist 
  • Outpatient physical therapist
  • Home health nurse

Preparation

Non-Operative Management

Numerous non-operative treatments are employed in the pre-surgical management of knee arthroplasty. Treatments include both pharmacologic and non-pharmacologic options. Multiple studies have investigated these different treatment options, and guidelines have been put in place by the American Academy of Orthopaedic Surgeons in the 2013 evidence-based guidelines, 2nd edition.

The AAOS recommends with strong evidence for low-impact aerobic exercises, neuromuscular education, and strengthening. They also recommend strongly for the use of NSAIDs and tramadol.

The AAOS recommends moderate weight loss in patients with a BMI greater than 25.

The AAOS recommends strongly against acupuncture, glucosamine/chondroitin, viscosupplementation.

The AAOS recommends moderate against lateral wedge insoles.

The AAOS cannot recommend for or against manual therapy (i.e., chiropractic, joint manipulation), physical agents including electrotherapeutic modalities, biologic injections, corticosteroid injections, valgus directing force brace, acetaminophen, opioids, or pain patches.

Pre-operative Evaluation

A review of the literature did not demonstrate a uniform protocol as to what pre-operative evaluation is necessary before knee replacement. A thorough history and physical exam are necessary. Co-morbidities, smoking status, alcohol consumption, and mental status should all undergo evaluation. The patient risk for the development of thromboembolic events should be a consideration. However, typically, most patients will undergo an evaluation and pre-operative clearance by their primary care provider and potentially cardiologist if significant cardiac co-morbidities are present. Other subspecialty pre-operative evaluations may be necessary depending on patients’ other co-morbidities (i.e., rheumatology, nephrology, neurology). Bernstein et al.  developed a protocol that assessed patients for 19 different risk factors. Identifying these risk factors allowed for pre-operative intervention and these patients were found to have a statistically significant shorter length of stay, and lower average total direct variable cost. No difference was noted in the patients’ 90-day readmission rate.

Pre-operative Surgical Planning

It is essential to assess for previous surgical incisions, patients limb-lengths, limb deformity, the range of motion, ligamentous stability and gait. Patients neurovascular status should also be considered, Ankle-brachial index may be a prudent screening, and if less than 0.9, avascular consultation should be obtained. Patients with pre-existing peripheral vascular disease should also have their PAD assessed.

Plain radiography typically provides sufficient detail, and further studies are typically not necessary. Weight-bearing AP, lateral and sunrise views should be routinely performed. AP hip to ankle x-rays allow for the evaluation of extra-articular deformities and allow for assessment of the mechanical axis. Radiographic markers can be placed during imaging to allow for the use of templating software to assess for estimated implant sizing and positioning. A lateral patellar shift of more than 3mm was an independent risk factor for patellar maltracking. Images should be interpreted to assess for the Insall-Salvati ratio, a pre-existing slope of the tibial plateau, and coronal alignment. Custom implants are made based on CT or MRI sequences, and these studies should be performed when a custom implant is desired. Custom implants can be particularly helpful in patients with significant deformity where intramedullary or extra-medullary guides will not work, as well as in patients with pre-existing hardware.

Laboratory testing

Basic pre-operative labs should be performed such as CBC, BMP, HbA1c in diabetic patients. A goal of HbA1c of less than 7.0 is desirable; however, studies have shown that an HbA1c under 8.0 is acceptable to avoid excessive delay and complications in knee replacement. Many centers also perform a pre-operative urinalysis and nasal swabs/decolonization in potential MRSA carriers.  Other considerations include checking a total lymphocyte count (TLC) and serum albumin as these are markers of potential underlying malnutrition that may increase the risk of wound complications following the elective TKA procedure.

Technique

Surgical Technique

Patients are typically placed supine on the operative table; a general or spinal anesthetic is administered. A systematic review performed by Johnson et al. found no statistically significant differences between the two including mortality, surgical duration, or nerve palsy. Typically a standard midline incision with a medial parapatellar arthrotomy is used. However, other approaches include the lateral parapatellar approach, midvastus, and subcastes approach. More extensile approaches include the quadriceps snip, V-Y turndown, and tibial tubercle osteotomy. It is essential during the approach to maintain thick skin flaps and to respect the blood flow that comes from medial to lateral. Maintaining a small cuff is necessary during the arthrotomy to allow for adequate repair at the conclusion of the procedure. The medial soft tissues at the proximal tibia are skeletonized off of the bone, and a soft tissue release is performed medially. The same procedure is performed on the lateral side. However, most cases involve varus deformities, and a more extensive medial release is the choice. The infrapatellar fat pad can either be partially or completely excised. The medial and lateral meniscus, as well as ACL, will require excision. The PCL should also be sacrificed if a posterior stabilizing implant is desired. It is not necessary to resurface the patella in all cases. However, in patients with significant anterior knee pain or patellofemoral arthritis, it should be. It is worth noting that the revision rate and incidence of anterior knee pain are higher in those that do not undergo resurfacing. But those with resurfacing have a higher chance of complications such as tendon injury or fracture. Overall the patient satisfaction rates are equal between the two treatments.

The sequence of steps during knee arthroplasty will be dependent on the technique selected by the operative surgeon. These techniques include:

 Measured Resection

  • Traditionally was associated with cruciate-retaining implants, however, can also be used for PS implants as well.
  • Most surgeons desire a neutral mechanical axis, and the femur is cut in 5 to 7 degrees of valgus with approximately 9 to 10mm of bony resection distally. The tibia is cut perpendicularly to the tibial axis. Typically an intramedullary guide is utilized on the femur, and an extramedullary guide is utilized on the tibia. The anatomic slope of the tibial plateau is restored if CR implant is to be used. Should be a neutral tibial plateau cut if PS implant is being used due to risk for CAM jump phenomenon with an increased tibial slope.
  • Anatomic landmarks are used to reference a neutral femoral implant rotation.

    1. Transepicondylar axis(TEA): Connects lateral condyle prominence to sulcus of the medial epicondyle. Implants placed parallel to this will provide a rectangular flexion gap and result in improved patellofemoral tracking, femorotibial kinematics, and coronal stability.
    2. Whiteside line(AP axis of femur): Starts at the center of the trochlear sulcus and ends posteriorly at the midpoint of intercondylar notch and typically is perpendicular to TEA.
    3. Posterior Condylar axis (PCA): Goes based upon a line connecting posterior condyles, in most cases externally rotating the posterior condylar axis by 3 degrees will create a line parallel to the TEA. This, however, can be very deceiving in patients with a valgus knee and hypoplastic lateral femoral condyle and can lead to malrotation of the implant.
  • Osteophytes should be removed before any bone cuts.
  • The pitfall of the technique is that it is difficult to perform soft-tissue releases after performing bony cuts. Ligament releases after bony cuts can affect the flexion/extension gaps and lead to poor balancing. Changing ligament tension in extension will affect the flexion gap and vice versa.
  • There is an increased incidence of femoral condylar liftoff in this technique compared to gap balancing

Gap Balancing

  • Traditionally associated with PS implants, but can be used for CR as well.
  • Before any bony cuts or soft tissue release, the removal of all osteophytes is necessary; this is particularly important in gap balancing because removing osteophytes after balancing will change the ligamentous tension and will affect flexion/extension gaps.
  • Typically a proximal tibial cut is performed then lamina spreaders are placed on medial and lateral sides to assess tension on both sides in extension. Structures are released until a neutral alignment, and symmetric extension gap is achieved.
  • The same steps are then performed with the knee at 90 degrees of flexion. A rectangular flexion gap equal to the extension gap is desired, the posterior femoral condyle cuts are then performed.
  • Joint line elevation is a potential pitfall of this technique and can lead to abnormal contact forces on the patellofemoral joint as well as mid-flexion instability.

Hybrid Technique

  • The hybrid technique is a blend of the two techniques described above.

Patellar maltracking is one of the most common complications encountered in knee arthroplasty. Iatrogenic causes of the complication can be avoided by:

  • Lateralizing femoral and tibial implants
  • Avoiding internal rotation of the femoral and tibial prosthesis
  • Avoiding overstuffing or under-sizing patellar component
  • Medializing patellar component

A uniform strategy for wound closure does not exist, and many studies have found different materials to be superior. Typically a heavy ethibond suture or barbed suture is used for arthrotomy closure. Followed by absorbable suture or barbed suture is used for the deep and superficial dermis. Skin closure can be with either a running non-braided absorbable suture with either derma bond/steri-strips or staples. Silver lined dressings can be used and should be maintained for several days without being removed until drainage has stopped. For complex revisions or in high-risk patients, incisional wound vacs or negative pressure dressings are also an option.

Complications

  • Periprosthetic Fracture 

Periprosthetic fractures can occur in the distal femur, proximal tibia, or patella. They are most commonly located in the supracondylar region of the distal femur. The most common classification system used for periprosthetic fractures of the distal femur is the Lewis and Rorabeck classification. In this classification system, type-I is non-displaced with a stable component; type-II has more than 5mm of displacement or greater than 5 degrees of angulation with a stable component, and type-III has a loose component. There are several additional classification systems; All of which fail to classify intra-operative periprosthetic fractures.  The anatomic location is typically used to describe these fractures. Risk factors that may predispose patients to periprosthetic fractures include:

  • Anterior notching of the femur
  • Osteoporosis, osteolysis
  • Implant loosening
  • Rheumatoid arthritis
  • Neurologic disorder
  • Corticosteroid use
  • Increased age
  • Female sex

Treatment options can include open reduction internal fixation, knee immobilizer, revision arthroplasty if components are loose, or distal femoral replacement, if there is not adequate bone stock or significant comminution, is present.

Prosthetic Joint infection

  • Occurs in 1 to 2% of primary knee replacements
  • Most common pathogens:

    • Staphylococcus aureus
    • Staphylococcus epidermidis
  • Acute infection

    • Within 6 weeks of surgery
  • Chronic infection

    • After 6 weeks of surgery
  • Laboratory evaluation

    • CBC
    • ESR
    • CRP
    • IL-6
    • Synovial analysis

      • WBC count

        • 27800 is the cutoff in the first 6 weeks after surgery
        • Following 6 weeks, WBC count of 1100 is suggestive of infection
      • Culture
      • Gram stain
      • Alpha-defensin
  • Imaging:

    • Can demonstrate periosteal reaction, implant loosening, or osteolysis.
    • The bone scan is useful if other tests are equivocal. Its sensitivity is 99%%, however, has very poor specificity (30 to 40%)
  • Treatment:

    • IV antibiotics for 12 weeks
    • In acute infections, a polyethylene liner exchange in addition to synovectomy and irrigation and debridement can be attempted.

      • 50 to 55% success rate
    • In chronic infections or those that have failed other treatments a two-stage revision is recommended and is the gold standard in the United States. In Europe, a one stage revision is routinely performed.
    • Two-stage revision involves the placement of an antibiotic spacer for approximately 2 to 3 months.

      • These spacers typically have 3 grams of vancomycin and 4 grams of tobramycin per 40-gram bag of cement used.
      • Spacers can be either static or articulating.
      • With two stage revision, repeat frozen section should be performed before reimplantation.

        • Persistence of infection is demonstrated by greater than 5 PMN per hpf in 5 hpf at x400 magnification

Other Complication

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Causes of Total Knee Arthroplasty

Causes of Total Knee Arthroplasty/Total Knee Arthroplasty (TKA) is one of the most cost-effective and consistently successful surgeries performed in orthopedics. Patient-reported outcomes are shown to improve dramatically with respect to pain relief, functional restoration, and improved quality of life. TKA provides reliable outcomes for patients’ suffering from end-stage, tri-compartmental, degenerative osteoarthritis (OA). While OA affects millions of Americans, the knee is the most commonly affected joint plagued by this progressive condition which is hallmarked by a gradual degeneration and loss of articular cartilage. The most common clinical diagnosis associated with TKA is primary OA, but other potential underlying diagnoses include inflammatory arthritis, fracture (post-traumatic OA and/or deformity), dysplasia, and malignancy.

Types of Total Knee Arthroplasty

There are 2 main types of surgery:

  • Total knee replacement – both sides of your knee joint are replaced
  • Partial (half) knee replacement – only 1 side of your joint is replaced in a smaller operation with a shorter hospital stay and recovery period.

Anatomy and Physiology

The knee is a synovial hinge joint with minimal rotational motion. It is comprised of the distal femur, proximal tibia, and the patella. There are 3 separate articulations and compartments: medial femorotibial, lateral femorotibial, and patellofemoral. The stability of the knee joint is provided by the congruity of the joint as well as by the collateral ligaments. The capsule surrounds the entire joint and extends proximally into the suprapatellar pouch. Articular cartilage covers the femoral condyles, tibial plateaus, trochlear groove, and patellar facets. Menisci are interposed in the medial and lateral compartments between the femur and tibia which act to protect the articular cartilage and support the knee.

The mechanical axis of the femur, defined by a line drawn from the center of the femoral head to the center of the knee, is 3 degrees valgus to the vertical axis. The anatomic axis of the femur, defined by a line bisecting the femoral shaft, is 6 degrees valgus to the mechanical axis of the femur and 9 degrees valgus to the vertical axis. The proximal tibia is oriented to 3 degrees of varus. The varus position of the proximal tibia, along with the offset of the hip center of rotation, results in the weight-bearing surface of the tibia is parallel to the ground. The sagittal alignment of the proximal tibia is sloped posteriorly approximately 5 to 7 degrees. The asymmetry of the natural bony anatomy maintains the alignment of the joint and ligamentous tension. The knee is comprised of 2 separate joints: the tibiofemoral and patellofemoral joints.

Patellofemoral Joint

The patellofemoral joint (PFJ) functions to increase the lever arm of the extensor mechanism. The patella transmits the tensile forces generated by the quadriceps tendon to the patellar tendon. The maximum contact force between the patella and femoral trochlea occurs at 45 degrees of knee flexion, and joint reaction forces reach 7-times body weight in the position of deep squatting.

The quadriceps muscles provide dynamic stability of the PFJ, and passive anatomic restraints include the following:

  • Medial patellofemoral ligament: Primary passive restraint against lateral translation at 20 degrees of flexion
  • Medial patellomeniscal ligament: Contributes 10% to 15% of the total restraining force
  • Lateral retinaculum: Provides 10% of the total restraining force

Tibiofemoral Articulation

The tibiofemoral articulation transmits body weight from the femur to the tibia and generates joint reaction forces of 3 and 4-times body weight during walking and climbing, respectively. Motion occurs in the sagittal plane from 10 degrees of hyperextension to about 140 to 150 degrees of hyperflexion. Extremes of flexion are often limited secondary to direct contact between the posterior thigh and calf. The tibiofemoral contact point and femoral center of rotation move posteriorly with increasing degrees of flexion in order to optimize knee flexion prior to impingement. Normal gait only requires a range of motion (ROM) from 0 to 75 degrees.

Knee stability in the coronal plane is provided by the lateral collateral ligament (LCL), which resists varus stresses, and the medial collateral ligament, which resists valgus stress forces. In addition, the anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) provide resistance to anteriorly directed and posteriorly directed forces at the knee, respectively.  Resistance to external rotatory forces is provided by the posterolateral corner structures (PLC).

Indications of Total Knee Arthroplasty

Once considered a procedure reserved for the elderly, low-demand patient population, primary TKA is offered more frequently and provides consistent positive outcomes in younger cohorts of patients.  In general, the most common underlying diagnosis associated with performing TKAs across all patient age groups is primary, end-stage, tri-compartmental osteoarthritis.

TKA is an elective procedure that is, in most cases, reserved for patients experiencing chronic, debilitating symptoms that continue to persist despite the exhaustion of all conservative and nonoperative treatment modalities.

Clinical symptoms of osteoarthritis include

  • Knee pain
  • Pain with activity and improving with rest
  • The pain gradually worsens over time
  • Decreased ambulatory capacity

Clinical evaluation includes

  • Full knee exam including a range of motion and ligamentous testing
  • Knee radiographs include standing anteroposterior, lateral, 45-degree posteroanterior, and skyline view of the patella

Radiographic evidence of osteoarthritis include

  • Joint space narrowing
  • Subchondral sclerosis
  • Subchondral cysts
  • Osteophyte formation

Conservative treatment includes

  • Non-steroidal anti-inflammatory medication
  • Weight loss
  • Activity modification
  • Bracing
  • Physical therapy
  • Viscosupplementation
  • Intra-articular steroid injection
  • Decreased ambulatory capacity

Clinical evaluation includes

  • Full knee exam including range of motion and ligamentous testing
  • Knee radiographs include standing anteroposterior, lateral, 45-degree posteroanterior, and skyline view of the patella

Radiographic evidence of osteoarthritis include

  • Joint space narrowing
  • Subchondral sclerosis
  • Subchondral cysts
  • Osteophyte formation

Contraindications of Total Knee Arthroplasty

TKA is contraindicated in the following clinical scenarios

  • Local knee infection or sepsis
  • Remote (extra-articular), active, ongoing infection or bacteremia
  • Severe cases of vascular dysfunction

Absolute

  • Active or latent (less than 1 year) knee sepsis
  • Presence of active infection elsewhere in body
  • Extensor mechanism dysfunction
  • Medically unstable patient

Relative

  • Neuropathic joint
  • Poor overlying skin condition
  • Morbid obesity
  • Noncompliance due to major psychiatric disorder, alcohol, or drug abuse
  • Insufficient bone stock for reconstruction
  • Poor patient motivation or unrealistic expectation
  • Severe peripheral vascular disease

Equipment of Total Knee Arthroplasty

TKA prosthesis designs have been evolving since the 1950s, beginning with Walldius’ design of the first hinged-knee replacement. In the early 1970s, the total condylar prosthesis (TCP) was the first TKA prosthesis designed to resurface all 3 compartments of the knee. The TCP was a posterior-stabilized design. The 4 main categories of TKA prosthesis designs are listed below in the order of increasing levels of constraint by design.

A TKA system will consist of instrumentation that helps the surgeon prepare the ends of the femur, tibia, and patella to receive an implant.  The instrumentation will be specific to the brand and type of implant being used with each company and model having specific intricacies.

In general, the instrumentation will consist of:

  • Intramedullary femoral guide to help establish the distal femoral alignment
  • The distal femoral cutting guide
  • Femoral sizing guide
  • The 4-in-1 femoral cutting guide
  • The extramedullary or intramedullary tibial guide
  • The proximal tibial cutting guide
  • Patella sizing guide
  • Femoral component trial
  • Tibial baseplate trial
  • Patellar button trial
  • Trial plastic bearing

The final implants will come in individual sterile packages and will consist of

  • Femoral component, typically made of cobalt-chrome
  • The tibial component, typically made of cobalt-chrome or titanium
  • Tibial polyethylene bearing, made of an ultra-high molecular weight (UHMW) polyethylene
  • Patellar button, made of UHMW polyethylene

Personnel

  • Anesthesia team
  • Operating room nurse
  • Surgical technician
  • Surgical assistant

Cruciate-Retaining

The cruciate-retaining TKA prosthesis depends on an intact PCL to provide stability inflection. Thus, its use is contraindicated in patients with pre-existing or intra-operatively recognized PCL insufficiency.  Caution is given to any patient presenting with at least moderate instability in any plane of motion, especially PLC instability patients.  PLC instability predisposes the native PCL in a cruciate-retaining TKA to abnormally high stresses and forces, ultimately leading to early failure and TKA instability requiring revision.  Cruciate-retaining TKA is contraindicated in patients suffering from inflammatory arthritic conditions given the increased risk of early PCL attenuation (e.g. Rheumatoid Arthritis).

Proposed advantages of the cruciate-retaining TKA design include:

  • Avoidance of tibial post-cam impingement and dislocation
  • Retaining more normal anatomy theoretically resembles normal knee kinematics
  • Preserved bone stock (less distal femur resected compared to PS TKA prosthesis)
  • Native PCL proprioception

Proposed disadvantages of the cruciate-retaining TKA design include:

  • A tight PCL can lead to early/accelerated polyethylene wear
  • Loose/ruptured PCL results in flexion instability and possible subluxation/dislocation

Multiple meta-analyses have demonstrated satisfactory survivorship and similar outcomes comparing the cruciate-retaining and posterior-stabilized TKA prosthesis designs.

Posterior-Stabilized

The posterior-stabilized TKA design is slightly more constrained and requires the surgeon to sacrifice the PCL. The femoral component contains a cam that is designed to engage the tibial polyethylene post as the knee flexes.

Proposed advantages of the posterior-stabilized TKA design include:

  • Facilitates overall balancing of the knee in the setting of an absent PCL
  • Theoretically, better knee flexion
  • Lower ranges of axial rotation and condylar translation

Proposed disadvantages of the posterior-stabilized TKA design include:

  • Cam jump that can result secondary to a loose flexion gap, or in knee hyperextension
  • Patellar clunk syndrome
  • Tibial post wear and/or fracture

Constrained Nonhinged Design

The constrained nonhinged prosthesis employs a larger tibial post and deeper femoral box, yielding more stability and constraint (within 2 to 3 degrees) in both varus-valgus and internal-external rotatory planes. Indications include collateral ligament attenuation or deficiency, flexion gap laxity, and moderate bone loss in the setting of neuropathic arthropathy. Downsides to this design include not only increased risk of earlier aseptic loosening secondary to the increased inter-component constraint, but also the requirement of more femoral bone resection to accommodate the components.

Constrained Hinged Design

The constrained hinged design is comprised of linked femoral and tibial components. Rotating hinge options allow the tibial bearing to rotate around a yoke that theoretically mitigates the risk of aseptic loosening at the expense of increasing levels of prosthetic constraint. Indications include global ligamentous deficiencies, resections in the setting of tumors, and massive bone loss in the setting of a neuropathic joint.

Other Component Considerations

Modularity and mobile-bearing designs are other noteworthy additional prosthetic design considerations.

Mobile bearing designs allow polyethylene rotation on the tibial baseplate. Although this design concept remains controversial in terms of its generation of reproducibly superior patient-reported outcome measures, advocates cite its utilization and relative indications in younger patient populations secondary to improved wear rates.  However, one notable disadvantage includes the potential for bearing spin-out, which is seen especially in the setting of a loose flexion gap.

All-polyethylene tibial base plates contrast the conventional metal tray with polyethylene inserts (i.e. tibial component modularity) that allow surgeons more flexibility for intra-operative adjustments for fine-tuning TKA stability. A surgeon is able to upsize or downsize the polyethylene after the final tibial implant fixation has been achieved between the metal implant and cement (or bone) interfaces. This allows for a final check and balance step which many TKA surgeons appreciate. In contrast, advocates for the all-polyethylene base plates cite significant cost savings and decreased rates of osteolysis when comparing TKA cohorts, especially in the elderly TKA patient populations.

Preparation

  • Full medical and drug history before surgery
  • Appropriate pre-surgical workup, clearance, and optimization
  • Pre-operative radiographs of the affected knee
  • Pre-operative templating of the affected knee to estimate the component size
  • Primary TKA system of choice
  • Have various final implant sizes ready and available in the hospital
  • Have increasing prosthesis constraint options ready and available in the hospital
  • Have revision total knee replacement system of choice ready and available if needed
  • +/- antibiotic cement, surgeon preference

Nonoperative Treatment Modalities

According to the 2011 American Academy of Orthopaedic Surgeons (AAOS), Evidence-Based Clinical Guidelines for the treatment of symptomatic hip or knee osteoarthritis, strong or moderately strong recommendations for nonoperative treatment modalities include weight loss, physical activity, physical therapy programs, and NSAIDs and/or tramadol. Other modalities that were not supported by moderate or strong evidence but are often considered reasonable alternative treatment options include but are not limited to acupuncture, chondroitin supplementation, hyaluronic acid injections, corticosteroid injections, lateral wedge insoles, and offloading braces.

  • tibial component: high-density polyethylene spacer
  • femoral component: metallic component, surfaces contoured similarly to the femoral condyles and trochlea
  • patellar component: high-density polyethylene; may be metal-backed

Most designs use polymethylmethacrylate (PMMA) cement for fixation. Cementless designs are available, where fixation is achieved initially by friction, then by ingrowth of bone into the prosthesis.

There are many designs in use, but broadly speaking, TKA is characterized by the degree of constraint, polyethylene spacer fixation, and posterior cruciate ligament (PCL) retention or removal.

  • unconstrained prostheses – most widely used; the patient’s supporting soft tissues help maintain stability
  • semi-constrained implants – more stable, decreased range of motion; closely conforming tibial and femoral components
  • constrained implants – hinged mechanism; most stable, but most limited range of motion, meaning more mechanical stress and susceptibility to wear, fatigue, and loosening; usually used in:
    • revision arthroplasty
    • elderly patients with highly unstable ligaments
    • combination with tumor resection
  • fixed bearing: the tibial spacer is fixed in a metal tibial tray
  • mobile bearing: a mobile polyethylene insert glides along the surface of the metallic tibial component

The PCL, an important knee stabilizer, can be:

  • retained; this is usually the case with unconstrained prostheses
  • removed
  • removed and substituted for by a PCL-substituting mechanism in the prosthesis

The decision whether to retain or remove the PCL depends mostly on the surgeon’s preference and experience.

The most cost-effective and commonest method of follow-up. Baseline radiographs should be obtained immediately post-operation.

Normal appearance on routine views:

  • AP
    • mechanical axis corrected to 0 degrees, results in femoral component placed 5-9 degrees valgus to long axis of femur
    • tibial component: aligned perpendicular to long axis of tibia
    • polyethylene (radiolucent) spacer in tibiofemoral joint space: equal width medially and laterally; NB: beam angle, patient positioning or post-op flexion contracture may distort this
  • lateral
    • femoral component: perpendicular to long femoral axis, unless surgeon has chosen to flex component by up to 3 degrees
    • tibial component: perpendicular to long tibial axis or posteriorly inclined by up to 5 degrees
    • patella: anterior and articular sides parallel to each other. Oblique patella on true lateral view suspicious for subluxation, patella Alta for patellar tendon rupture, and significant patella baja for quadriceps tendon rupture
  • skyline Merchant view
    • for assessing patellofemoral alignment: patellar component should be centered above femoral component trochlea

True axial imaging allows assessing for the rotational alignment of the femoral component. To this end, two lines are drawn, which should be parallel:

  • transepycondylar line, or axis: drawn between the sulcus of medial epicondyle and peak of the lateral epicondyle
  • a second line is drawn across the posterior margins of the femoral component
  • if the lines diverge medially, the component is externally rotated: can cause an increased medial flexion gap and result in flexion instability
  • if they diverge laterally, the component is internally rotated: early or delayed patellofemoral complications may ensue, especially if internal rotation exceeds 5 degrees

Preoperative Evaluation: Clinical Examination

A thorough history and physical examination are required before performing a TKA in any patient. Patients should be asked about any and all previous interventions and treatments. Prior joint replacements, arthroscopic procedures, or other surgeries around the knee should be considered. Old surgical scars can affect the planned surgical approach. In addition, patients with a history of prior injuries or procedures can present with mechanical axis deformities, retained hardware, or knee instability in any plane. A multitude of factors can impact the TKA prosthesis of choice that is most appropriate for the patient.

We recommend each patient pursuing elective TKA surgery first receive a comprehensive medical evaluation with any appropriate medical optimization tests performed before the TKA procedure. A surgeon must consider the relevant risks and potential benefits of performing TKA on a case-by-case basis.

Physical examination includes evaluation of the overall mechanical axis of the limb. It is critical to ensure hip pathology is either ruled out or at least considered before performing any surgery around the knee. The vascular status of the limb should also be assessed by observing the skin for any chronic venous stasis changes, cellulitis, or even wounds/ulcerations that may be present on the extremity. Distally, the pulses should be symmetric and palpable. Consideration should be given for a vascular surgeon consultation in the preoperative setting in any patient presenting with peripheral vascular disease (PVD). The surgeon should also be aware of the possibility of PVD presenting as knee pain out of proportion in the setting of relatively benign radiographs.

The preoperative range of motion should be noted at the knee and adjacent joints (hip, ankle). The soft tissues should be examined for evidence of gross atrophy, overall symmetry, and ligamentous stability in all planes at the knee joint. It is essential to document the presence of any laxity in the varus/valgus plane and the ability to correct the deformity. These parameters help prepare the surgeon for soft tissue releases that may be required to facilitate mechanical axis correction, as well as plan for additional bone resection that may be needed in the setting of significant contractures.

Preoperative Evaluation: Radiographs

Preoperative radiographs, including a weight-bearing anteroposterior (AP) view, are evaluated for overall mechanical alignment, the presence of deformity, and bone loss. The tibiofemoral angle can help estimate the magnitude of coronal deformity. The femoral resection angle is calculated as the difference between the mechanical and anatomic axis of the femur. The lateral view of the knee is essential for appreciating the native posterior slope of the proximal tibia as well as the presence of posterior osteophytes on the femoral condyles.

The patellofemoral radiographic view is not necessary for TKA templating but allows the surgeon to evaluate the magnitude of patellofemoral arthritis and deformity. In cases of advanced patellofemoral deformity, osteophyte removal may be needed prior to attempting to evert the patella during the procedure. In addition, a surgeon can plan for a possible lateral release to improve patellar tracking.

Technique

The goal of TKA is the same regardless of surgeon, implant, or technique. The variability in the procedure lies in the technique.  Some of the variations in the operative technique for TKA are listed below.

  • General anesthesia versus regional anesthesia
  • Tourniquet versus tourniquet-less surgery
  • Standard versus patient-specific instrumentation
  • Standard versus patient-specific implants
  • Traditional versus robotic-assisted TKA
  • Traditional versus navigation-assisted TKA
  • Traditional versus sensor-assisted TKA
  • Measured resection versus gap balancing
  • Cruciate-retaining implant versus cruciate stabilized the implant
  • Resurfaced versus non-resurfaced patella
  • Cement versus cement-less (press fit) TKA

Surgical Approaches

The most common approaches for the standard primary TKA procedure include the medial parapatellar, midvastus, and subcastes approach.  The medial parapatellar approach is commonly utilized and entails proximal dissection through a medial cuff of the quadriceps tendon to facilitate superior tissue quality closure at the conclusion of the procedure. Distally, a meticulous, continuous medial subperiosteal dissection sleeve is performed while maintaining intimacy with the proximal tibial bone. The extent of dissection is often dictated by the anticipated amount of deformity to be corrected. In general, this medial release is aggressive in cases of severe varus deformity, and most minimal in cases of moderate to advanced valgus knee deformity. The medial meniscus is also resected with this sleeve of soft tissue.

Alternatives to the standard medial parapatellar arthrotomy include the midvastus and subvastus approaches. The midvastus approach spares the quadriceps tendon. Instead, the vastus medialis obliquus (VMO) muscle belly is dissected along a trajectory directed toward the superomedial aspect of the proximal pole of the patella.

The subvastus approach also spares the quadriceps tendon and lifts the muscle belly of the VMO off the intermuscular septum. The subvastus approach preserves the vascularity of the patella and is cautioned as it can limit exposure in particularly challenging cases or in particularly obese patients.

Procedural Steps

Depending on surgeon preference, the specific order of bone resections and soft tissue releases will vary. However, a general overview of a preferred method is the goal of this technical summary of the TKA procedure.

Once the arthrotomy is complete, the patella is everted, and the knee is flexed with additional soft tissue releases required prior to achieving knee dislocation.  If the surgeon elects to proceed with the femur first, an intramedullary (IM) drill is utilized in order to gain access to the femoral canal for the utilization of a distal femoral IM jig. The angle set on the guide is based on the patient-specific preoperative evaluation (AP Xray), generally yielding 5 or 7 degrees of valgus. Although system-specific, most surgeons prefer resecting 9 to 10 mm of the distal femur.

Next, the proximal tibia is cut utilizing an IM or extramedullary (EM) guide with the goal of cutting the bone perpendicular (or within 2 to 3 degrees of varus for surgeons aiming for an “anatomic” TKA procedure) to the tibial axis. We prefer an IM guide and a perpendicular tibial cut. The rotation is set referencing the medial one-third of the tibial tubercle (proximally) and a point slightly medial to the center of the ankle joint (distally). This alignment is also referenced with the second ray of the foot and the tibial crest.

Once the tibial cut is performed, the extension gap can be assessed. A spacer block is then inserted with the knee in full extension, and the overall balance of the knee is assessed using an alignment rod to facilitate and verify overall varus-valgus and tibial slope parameters achieved.

Next, the flexion gap is attained after utilizing an AP sizing guide that is positioned with respect to the bony landmarks on the femur (usually Whiteside’s line or the native transepicondylar axis [TEA]). Depending on the anterior or posterior referencing style of the operating surgeon, the flexion gap is set and adjusted as needed utilizing the system-specific incremental sizing adjustments available with respect to the cutting guides. Prior to making the bony cuts, the flexion gap should be visualized, and soft tissue balancing appreciated. A spacer block can facilitate this assessment. The surgeon should ensure a rectangular flexion gap will be the ultimate result after the bone resections. After satisfactory check and balancing steps are verified, the anterior, posterior, anterior chamfer and posterior chamfer cuts are made. Care is taken to protect the collateral soft tissue structures (LCL, MCL) with retractors.

Next, the intercondylar notch cut is made perpendicular to the TEA. The attention is again turned back to the proximal tibia to finish preparation, sizing, and rotational alignment. One must be cautious to avoid internal rotation and/or component overhang which can lead to inferior TKA results. The femoral and tibial trial implants are impacted, and a provisional spacer trial is inserted. The knee is reduced and assessed for stability from 0 degrees of extension through mid-flexion stability.

If planning to resurface the patella, the resection is recommended after first appreciating the native anatomy and size of the entire patellofemoral joint. Inferior TKA outcomes can result from either over-resection, which can compromise implant-bone stock and lead to patella fracture, or under-resection, which can lead to chronic postoperative pain secondary to an overstuffed PFJ.

Finally, the stability parameters are again verified, and patellar tracking is appreciated and must pass intraoperative tracking tests. Most surgeons either use a natural range of motion tracking test to ensure the TKA passes the “no thumb” test, or a towel clip technique can be used.

Patellar maltracking, most commonly occurring laterally, can most often be corrected with a standard lateral release. In more severe cases or in scenarios consistent with component malalignment, consideration should be given to the correction of component position(s).

Wound Closure

The most recent literature remains controversial with respect to the ideal position of the knee and suture material utilized during the TKA closure. Attention to detail is required and a methodical closure is unanimously advocated. A preferred method includes closure with uni- or bi-directional barbed suture for the arthrotomy, deep fascial, and deep dermal/subcutaneous layers. Staples or monocryl can be used for the skin. A sterile dressing is then applied and left in place without being changed for the first 7 days. In addition, a minimal website/ace soft wrap dressing is applied to the knee for, at most, 24 hours to facilitate the appropriate balance between wound healing and postoperative movement of the knee.

Other Considerations

Topical tranexamic acid (TXA) is the preferred application while waiting for the cement to fully harden and prior to dropping the tourniquet. In addition, other controversial technical modalities in TKA include the use of a tourniquet, cementing the patella, femoral, and/or tibial components, as well as incorporating a betadine soak to the wound as part of the copious saline irrigation that is applied prior to closure of the arthrotomy and surgical wound. Preferred techniques include the use of a tourniquet, cementing all components, and saline-only copious pulsatile irrigation prior to arthrotomy closure.

Post-operative Rehabilitation

The length of postoperative hospitalization is 5 days on average depending on the health status of the patient and the amount of support available outside the hospital setting.[rx] Protected weight bearing on crutches or a walker is required until specified by the surgeon[rx] because of weakness in the quadriceps muscle[rx] In the immediate post-operative period, up to 39% of knee replacement patients experience inadequate pain control.[rx]

To increase the likelihood of a good outcome after surgery, multiple weeks of physical therapy is necessary. In these weeks, the therapist will help the patient return to normal activities, as well as prevent blood clots, improve circulation, increase range of motion, and eventually strengthen the surrounding muscles through specific exercises. Whether techniques such as neuromuscular electrical stimulation are effective at promoting gains in knee muscle strength after surgery are unclear.[rx] Often a range of motion (to the limits of the prosthesis) is recovered over the first two weeks (the earlier the better). Over time, patients are able to increase the amount of weight-bearing on the operated leg, and eventually are able to tolerate full weight-bearing with the guidance of the physical therapist.[rx] After about ten months, the patient should be able to return to normal daily activities, although the operated leg may be significantly weaker than the non-operated leg.[rx]

For post-operative knee replacement patients, immobility is a factor precipitated by pain and other complications. Mobility is known as an important aspect of human biology that has many beneficial effects on the body system.[rx] It is well documented in the literature that physical immobility affects every body system and contributes to functional complications of prolonged illness.[rx] In most medical-surgical hospital units that perform knee replacements, ambulation is a key aspect of nursing care that is promoted to patients. Early ambulation can decrease the risk of complications associated with immobilization such as pressure ulcers, deep vein thrombosis (DVT), impaired pulmonary function, and loss of functional mobility.[rx] Nurses’ promotion and execution of early ambulation on patients has found that it greatly reduces the complications listed above, as well as decreases length of stay and costs associated with further hospitalization.[rx] Nurses may also work with teams such as physical therapy and occupational therapy to accomplish ambulation goals and reduce complications.[rx]

Continuous passive motion (CPM) is a postoperative therapy approach that uses a machine to move the knee continuously through a specific range of motion, with the goal of preventing joint stiffness and improving recovery.[rx][rx] There is no evidence that CPM therapy leads to a clinically significant improvement in range of motion, pain, knee function, or quality of life.[rx] CPM is inexpensive, convenient, and assists patients in therapeutic compliance. However, CPM should be used in conjunction with traditional physical therapy.[rx] In unusual cases where the person has a problem that prevents standard mobilization treatment, then CPM may be useful.[rx]

Cryotherapy, also known as ‘cold therapy’ is sometimes recommended after surgery for pain relief and to limit swelling of the knee. Cryotherapy involves the application of ice bags or cooled water to the skin of the knee joint. However, the evidence that cryotherapy reduces pain and swelling is very weak and the benefits after total knee replacement surgery have been shown to be very small.[rx]

Some physicians and patients may consider having ultrasonography for deep venous thrombosis after knee replacement.[rx] However, this kind of screening should be done only when indicated because to perform it routinely would be unnecessary health care.[rx] If a medical condition exists that could cause deep vein thrombosis, a physician can choose to treat patients with cryotherapy and intermittent pneumatic compression as a preventive measure.

Neither gabapentin nor pregabalin has been found to be useful for pain following a knee replacement.[rx] A Cochrane review concluded that early multidisciplinary rehabilitation programs may produce better results at the rate of activity and participation.[rx]

Complications

TKA complications result in inferior outcomes and patient-reported satisfaction scores. Although TKA remains a reliable and reproducibly successful surgery in patients suffering from debilitating advanced degenerative arthritic knees, reports still cite that up to 1 in 5 patients who have undergone primary TKA remain dissatisfied with the outcome.

Periprosthetic Fracture

TKA periprosthetic fractures (PPFs) are further characterized by location and residual stability of the implants. Distal femur PPFs occur at a 1% to 2% rate, and risk factors include compromised patient bone quality, increased constrained TKA components, and while controversial, anterior femoral notching is a potential risk factor for postoperative fracture.

Tibial PPFs occur at a 0.5% to 1% rate, and risk factors include a prior tibial tubercle osteotomy, component malposition and/or loosening, as well as utilization of long-stemmed components. Patellar PPFs occur less frequently in unresurfaced TKA cases, and incidence rates range from 0.2% up rates as high as 15% or 20%. Risk factors for fracture include osteonecrosis, technical errors in asymmetric or over-resection, and implant-related associations including the following:

  • Central, single peg implants
  • Uncemented fixation
  • Metal-backed components

Aseptic Loosening

TKA aseptic loosening occurs secondary to a macrophage-induced inflammatory response resulting in eventual bone loss and TKA component loosening. Patients often present with pain that is increased during weight-bearing activity and/or recurrent effusions. Patients may have minimal pain at rest or with range of motion. Serial imaging and infectious labs are required to appropriately work up these conditions which eventually are treated with revision surgery if symptoms persist and the patient is considered a reasonable surgical candidate. The steps in aseptic loosening include: particulate debris formation, macrophage-induced osteolysis, micromotion of the components, and dissemination of particulate debris.

Wound Complications

The TKA postoperative wound complication spectrum ranges from superficial surgical infections (SSIs) such as cellulitis, superficial dehiscence and/or delayed wound healing to deep infections resulting in full-thickness necrosis resulting in returns to the operating room for irrigation, debridement (incision and drainage), and rotational flap coverage.

Periprosthetic Joint Infection

The incidence of prosthetic total knee infection (TKA PJI) following primary TKA is approximately 1% to 2% as reported in the literature.  Risk factors include patient-specific lifestyle factors (morbid obesity, smoking, intravenous [IV] drug use and abuse, alcohol abuse, and poor oral hygiene) and patients with a past medical history consisting of uncontrolled diabetes, chronic renal and/or liver disease, malnutrition, and HIV (CD4 counts less than 400). PJI is the most common reason for revision surgery.

The most common offending bacterial organisms in the acute setting include Staphylococcus aureusStaphylococcus epidermidis, and in chronic TKA PJI cases, coagulase-negative staphylococcus bacteria.  Treatment in the acute setting (less than 3 weeks after index surgery) can be limited to incision and drainage, polyethylene exchange, and retention of components. In addition, IV antibiotics are utilized for up to 4 to 6 weeks duration. Outcomes vary and are often influenced by multiple intraoperative, patient-related factors, and offending bacterial organism, but studies site a 55% successful outcome rate.

More aggressive treatments, especially in the setting of presentation beyond the acute (3 to 4-week time point) include a 1 or 2-stage revision TKA procedure with interval antibiotic spacer placement. The surgeon must ensure and document evidence of infection eradication.

Other Complications and Considerations

Other potential complications after TKA are beyond the scope of this review but include:

  • TKA instability – can occur in the coronal or sagittal plane(s).  Also, consideration is given for patellar maltracking or other PFJ issues (for example, overstuffing the joint) in the postoperative setting when patients complain of persistent anterior knee pain
  • Extensor mechanism disruption or rupture
  • Patellar clunk syndrome – Often occurs 12 months after TKA and is associated with popping, catching during knee extension. It is caused by nodule formation on the posterior quad tendon near its insertion on the patella. Patellar clunk syndrome is associated with posterior stabilized knee design. The cause of scar tissue formation is unknown but the pain results from tissue entrapment in the intercondylar notch. Treatment is surgical, either arthroscopic or open debridement/synovectomy. Conservative measures are often unsuccessful. physical therapy may help with quad strengthening after surgery but is not curative. Recurrence after surgical treatment is rare. More aggressive intervention such as revision TKA is often not warranted in the absence of component malposition.
  • Peroneal nerve palsy – One of the most common complications after TKA to correct the valgus deformity. During soft tissue balancing of a valgus knee, the iliotibial band preferentially affects the extension space more than flexion space and inserts on Gerdy’s tubercle. The popliteus is preferentially affected flexion space more than extension space.
  • Stiffness
  • Vascular injury and bleeding
  • Metal hypersensitivity
  • Heterotopic ossification
  • Infection, superficial and deep
  • Blood clot
  • Pulmonary embolism
  • Fracture
  • Dislocation
  • Instability
  • Osteolysis resulting in component loosening
  • Pain
  • Stiffness
  • Vascular injury
  • Nerve injury

Commonly Required and Suggested Home Preparations

Deep bending and squatting can lead to knee injuries during the recovery period. A patient can minimize these risks by making advanced arrangements and preparing his or her home. For example:

  • Arrange for a spouse, friend or other caregiver to provide meals and help around the house.
  • Arrange for transportation, as most patients cannot drive for the first 4 to 6 weeks after surgery.
  • Stock up on pre-made meals and toiletry items to avoid having to run errands post-surgery.
  • If possible, arrange to spend sleeping and waking hours on the same floor in order to avoid stairs.
  • If possible, adjust the bed height (not too high or too low) to help ease the transition in and out of bed.
  • Take away or move anything that might be tripped over, such as area rugs or electrical cords.
  • Make sure all stairs have sturdy railings.
  • Install small rails or grab bars near toilets and in showers.
  • Install a modified toilet seat; a higher seat will put less stress on the knees and make it easier to sit down and get up.
  • Put a small stool in shower to avoid standing on a slippery surface.
  • Have a comfortable, supportive chair with an ottoman to keep leg elevated for intervals.
  • Have cold packs on hand to help alleviate swelling.
  • Consider practicing using walkers, canes and other assistive devices ahead of time to ensure proficiency using them.

References

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Total Hip Arthroplasty – Indications, Contraindication

Total Hip Arthroplasty (THA) is one of the most cost-effective and consistently successful surgeries performed in orthopedics.  THA provides reliable outcomes for patients’ suffering from end-stage degenerative hip osteoarthritis (OA), specifically pain relief, functional restoration, and overall improved quality of life. Other underlying diagnoses include hip osteonecrosis (ON), congenital hip disorders, and inflammatory arthritis[rx][rx][rx]

Total hip arthroplasty, or surgical replacement of the hip joint with an artificial prosthesis, is a reconstructive procedure that has improved the management of those diseases of the hip joint that have responded poorly to conventional medical therapy.

Anatomy of Total Hip Arthroplasty

The hip is a ball-and-socket type diarthrodial joint. Hip joint stability is achieved via a dynamic interplay from osseous and soft tissue anatomic components. Osseous components include the proximal femur (head, neck, trochanters), and the acetabulum, which is formed from 3 separate ossification centers (the ilium, ischium, and pubic bones). The native acetabulum is oriented in 15 to 20 degrees of anteversion and 40 degrees of abduction. The femoral neck is oriented in 15 to 20 degrees of anteversion and is angled 125 degrees with respect to its diaphysis[rx].

Soft tissue structures involved in hip joint stability include the labrum and joint capsule. The iliofemoral ligament (IFL) is the strongest of the 3 divisions of capsular ligaments. The IFL functions to restrict extension and external rotation of the hip. The other 2 components are the ischiofemoral and pubofemoral ligaments. The acetabular labrum is anchored at the periphery of the outer rim and functions to maintain negative joint pressure and deepen the hip socket[rx].

Types and Approaches of Total Hip Arthroplasty

There are several different surgical approaches described in the literature

Posterior 

The posterior (Moore or Southern) approach accesses the joint and capsule through the back, taking piriformis muscle and the short external rotators of the femur. This approach gives excellent access to the acetabulum and femur and preserves the hip abductors and thus minimizes the risk of abductor dysfunction postoperatively. It has the advantage of becoming a more extensile approach if needed. Critics cite a higher dislocation rate, although repair of the capsule, piriformis, and the short external rotators along with the use of modern large diameter head balls reduces this risk. Limited evidence suggests that the posterior approach may cause less nerve damage.[rx]

Posterolateral

This is the most common approach for primary and revision THA cases. This dissection does not utilize a true inner nervous plane. The intermuscular interval involves blunt dissection of the gluteus maximus fibers and sharp incision of the fascia lata distally. The deep dissection involves meticulous dissection of the short external rotators and capsule. Care is taken to protect these structures as they are later repaired back to the proximal femur via trans-osseous tunnels.

Anterior 

The DA approach is becoming increasingly popular among THA surgeons. The inner nervous interval is between the tensor fascia lata (TFL) and sartorius on the superficial end, and the gluteus medius and rectus femoris (RF) on the deep side. DA THA advocates cite the theoretical decreased hip dislocation rates in the postoperative period and the avoidance of the hip abduction musculature.

Anterolateral

Compared to the other approaches, the anterolateral (AL) approach is the least commonly used approach secondary to its violation of the hip abductor mechanism. The interval exploited includes that of the TFL and gluteus medius musculature; this may lead to a postoperative limp at the tradeoff of a theoretically decreased dislocation rate.

Lateral 

The lateral approach is also commonly used for hip replacement. The approach requires elevation of the hip abductors (gluteus medius and gluteus minimus) to access the joint. The abductors may be lifted up by osteotomy of the greater trochanter and reapplying it afterward using wires (as per Charnley) or may be divided at their tendinous portion, or through the functional tendon (as per Hardinge) and repaired using sutures. Although this approach has a lower dislocation risk than the posterior approach, critics note that occasionally the abductor’s muscles do not heal back on, leading to pain and weakness which is often very difficult to treat.

Minimally invasive approaches

The dual incision approach and other minimally invasive surgery seek to reduce soft tissue damage by reducing the size of the incision. However, component positioning accuracy and visualization of the bone structures can be significantly impaired as the approaches get smaller. This can result in unintended fractures and soft tissue injury. The majority of current orthopedic surgeons use a “minimally invasive” approach compared to traditional approaches which were quite large comparatively.

Indications of Total Hip Arthroplasty

The most common indication for THA includes end-stage, symptomatic hip OA. In addition, hip ON, congenital hip disorders including hip dysplasia, and inflammatory arthritic conditions are not uncommon reasons for performing THA. Hip ON, on average, presents in the younger patient population (35 to 50 years of age) and accounts for approximately 10% of annual THAs [rx].

Total hip replacement is most commonly used to treat joint failure caused by osteoarthritis. Other indications include

  • Rheumatoid arthritis
  • Avascular necrosis
  • Traumatic arthritis
  • Protrusio acetabuli
  • Certain hip fractures
  • Benign and malignant bone tumors
  • Arthritis associated with Paget’s disease
  • Ankylosing spondylitis and juvenile rheumatoid arthritis.
  • The aims of the procedure are pain relief and improvement in hip function.
  • Hip replacement is usually considered only after other therapies, such as physical therapy and pain medications, have recently failed.