Category Archive Dr. Harun Ar Rashid

Pain – Causes, Symptoms, Diagnosis, Treatment

Pain is an unpleasant signal to us that something hurts.  It is a complex experience-and differs greatly from individual to individual, even between those with similar injuries and/or illnesses.  Pain can be very light, almost unnoticeable, or explosive.  Some people experience pain as pricking, tingling, stinging, burning, shooting, aching, or electricity.  Pain warns us that something is not quite right in our body and can cause us to take certain actions and avoid others.  Pain also can significantly impact our quality of life—by adversely affecting our physical and emotional well-being; upsetting relationships with family, coworkers, and friends; and limiting our mobility and participation in daily activities.

Hundreds of pain syndromes or disorders make up the spectrum of pain.  For example, there is the pain of childbirth, the pain of a heart attack, the pain of a headache or backache, and the pain that sometimes follows amputation of a limb.  There also is pain that accompanies cancer and the pain that follows severe trauma, such as head and spinal cord injuries.

Pain is often a debilitating symptom of many diseases and is considered a disease itself when it persists beyond recovery from an injury or illness.  Pain often goes away on its own or with treatment, but it can persist and develop into long-term chronic pain. Millions of Americans have pain every day.  Chronic pain is one of the most common reasons adults in the U.S. seek medical care, affecting 50 million people.

Committee on Advancing Pain Research, Care, and Education; Institute of Medicine of the National Academies. (2011). Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, D.C. The National Academies Press.

A Pain Primer What Do We Know About Pain?

Pain can be classified as acute or chronic, and the two kinds differ greatly.

  • Acute pain usually results from a specific injury, disease, and/or inflammation. It generally comes on suddenly, for example, after physical trauma or surgery, and can be accompanied by anxiety or emotional distress.  Normally, acute pain is a protective response to tissue damage resulting from injury, disease, overuse, or environmental stressors.  The cause of acute pain usually can be diagnosed and treated.  The pain is self-limiting, meaning it is confined to a given period of time and severity.  Acute pain, however, can become chronic.
  • Chronic pain is a medical disease that can be made worse by environmental and psychological factors.  Chronic pain persists over a long period and can be challenging to manage.  People with chronic pain often suffer from more than one painful condition.  They also have an increased risk for developing problems with physical functioning, cognition, and emotional reactions.  There may be common mechanisms that put some people at higher risk for developing multiple pain disorders.  It is not known whether these disorders share a common cause.

Anatomy of Pain


To sense pain, thousands of specialized sensory nerve cells or neurons—called nociceptors— throughout the body trigger a series of responses to a noxious (painful) stimulus.  The stimulus triggers an electrical impulse that travels through nerves from the site of the injury or diseased area to the spinal cord and up to the brain.  Nociceptors in the head and face relay pain signal directly to the brain stem, where pain pathways converge.

Brain Regions

One brain region that receives pain signals is the thalamus.  The thalamus is a relay station that distributes sensory signals to many other brain regions, including those in the cortex—which process the nociceptive (reacting to or causing pain) information from the body and generates the complex experience of pain.  This has multiple components including the: 1) sensory-discriminative aspect which helps us localize where on our body an injury has occurred, 2) affective-motivational aspect which conveys just how unpleasant the experience is, and 3) cognitive-evaluative aspect which involves thoughtful planning on how to avoid the pain.

Brain Systems

Many of the characteristics of pain have been associated with specific brain systems, although much remains to be learned.  Additionally, researchers have found that many of the brain systems involved with the experience of pain overlap with the experience of basic emotions.  Consequently, when people experience undesirable emotions (e.g., fear, anxiety, anger), the same brain systems responsible for these emotions also amplify the experience of pain.

Fortunately, there also are systems in the brain that help to dampen or decrease pain.  For example, there are descending signals from the brain that are sent back down the spinal cord that can inhibit (block or interfere with) the intensity of incoming nociceptive signals and reduce the pain experience.  One way these descending signals result in pain reduction is by releasing molecules (such as endogenous or self-produced opioids) into the spinal cord that can prevent pain signals from being relayed to the brain from the nerves outside of the brain and spinal cord (peripheral nervous system).

Neurochemistry of Pain


Our ability to perceive pain involves intricate connections among many different brain regions.  The nervous system uses a set of chemicals, called neurotransmitters, to communicate between neurons within and across these stations in the pain pathway.  These chemicals are released by neurons in tiny packets (vesicles) into space between two cells.  When they reach their target, they bind to special proteins on the surface of the cells called receptors.  The transmitter then activates the receptor, which functions much like a gate. The gate will either close to block (inhibitory receptor) the signal or open to send (excitatory receptor) the signal along to the next station.  This is known as the gate control theory of pain.

There are many neurotransmitters in the human body and they play a role in normal function as well as in disease.  In the case of nociception and pain, they act in various combinations at all levels of the nervous system to transmit and modify signals generated by noxious stimuli.

  • Glutamate.  Glutamate plays a major role in nervous system function and in pain pathophysiology.  It heightens the process called central sensitization (see below) and contributes to making pain persist.  Much attention has been given to developing molecules/drugs that block certain receptors for glutamate because of their potential in reducing pain.
  • GABA.   GABA (or gamma-aminobutyric acid) generally decreases or blocks the activity of neurons.  Most of what is known of its role in pain is related to its function in inhibiting spinal cord neurons from transmitting signals and therefore dampening pain.  Chemicals that are similar to GABA have been explored as possible analgesics, but because GABA is so widespread in the nervous system it is difficult to make a GABA-like drug without affecting other nervous system functions.
  • Norepinephrine and Serotonin.  Norepinephrine and serotonin dampen the incoming signals from painful stimuli from the site of the injury or inflammation.  Drugs that modulate the activity of these transmitters, such as some antidepressants, are effective in treating some chronic pain conditions, likely by enhancing the availability of the transmitters through a recycling and reuse process.  Serotonin receptors also are present on the nerves that supply the surface of the brain involved in migraines, and their modulation by a class of drugs called “triptans” is effective in acutely treating migraines.
  • Opioids.  Opioids are involved in pain control, as well as pleasure and addiction.  Their receptors are found throughout the body and can be activated by endogenous opioid peptides (two or more amino acids that work together to interfere with pain signals) that are released by neurons in the brain. Enkephalins, dynorphins, and endorphins are some of the body’s own natural pain killers.  Endorphins may be familiar with their role in the feeling of well-being during exercise.  Opioid receptors also can be activated by morphine, which mimics the effect of our endogenous opioids.  Morphine is naturally produced by the body and like similar synthetic opioids, is a very potent, but potentially addictive pain killer that is widely used for severe acute and chronic pain management.  However, there is limited research suggesting that the long-term use of opioids for chronic pain is an effective pain management tool.  In addition, research suggests that opioid-induced hyperalgesia (an enhanced pain response) can occur with frequent and/or long-term use of opioids, which can result in a person becoming more sensitive to pain.

Central Sensitization

Central sensitization refers to changes in the nervous system that are associated with the development and maintenance of chronic pain.  When this occurs, the nervous system goes through a process called wind-up and is in a continued state of high reactivity.  This persistent state of reactivity lowers the threshold for a sensation to evoke a pain response and subsequently maintains pain even after the initial injury might have healed.  People who experience allodynia and/or hyperalgesia may have a heightened sensitivity to pain and touch.  Allodyniaoccurs when someone experiences pain as a result of stimuli that aren’t normally painful.  Hyperalgesiaoccurs when a stimulus is more painful than it should be.

Genetics of Pain

Differences in our genes highlight how differently we experience pain. Scientists believe that genetic variations can determine our risk for developing chronic pain, how sensitive we are to painful stimuli, whether certain therapies will reduce our pain, and how we experience acute and/or chronic pain. Many genes contribute to pain perception, and mutations in one or more pain-related genes account for some of the variability of pain experiences. Some people born insensate to pain—meaning they cannot feel pain—have a mutation in part of a gene that plays a role in the electrical activity of nociceptors and other types of neurons. A different mutation in that same gene can cause a severe and disabling pain condition. Scientists have identified many genes involved in pain by screening large numbers of people with pain conditions for shared gene mutations. While genes play a role in determining our sensitivity to pain, they only account for a portion of this variability. Ultimately, our individual sensitivity to pain is governed by a complex interaction of genes, cognitions, mood, our environment, and early life experiences.

Inflammation and Pain

The link between the nervous and immune systems also is important. Cytokines, a group of proteins found in the nervous system, are also part of the immune system—the body’s shield for fighting off disease and responding to injury. Cytokines can trigger pain by promoting inflammation, even in the absence of injury or damage. After a trauma, cytokine levels rise in the brain and spinal cord and at the site of the injury. Improvements in our understanding of the precise role of cytokines in producing pain may lead to new classes of drugs that can block the action of these substances to produce analgesia.

Neural Circuits and Chronic Pain

The pain that we perceive when we have an injury or infection alerts us to the potential for tissue damage. Sometimes this protective pain persists after the healing occurs or may even appear when there was no apparent cause. This persistent pain is linked to changes in our nervous system, which respond to internal and external change by reorganizing and adapting throughout life. This phenomenon is known as neuronal plasticity, a process that allows us to learn, remember, and recover from brain injury. Following an injury or disease process, the nervous system sometimes undergoes a structural and functional reorganization that is not a healthy form of plasticity. Long-term, inappropriate, or inadequate changes in both the peripheral and central nervous system can make us hypersensitive to pain and can make it persist after injuries have healed. For example, sensory neurons in the peripheral nervous system, which normally detect noxious/painful stimuli, may alter the electrical or molecular signals they send to the spinal cord. This in turn triggers genes to alter production of receptors and chemical transmitters in spinal cord neurons, setting up a chronic pain state. Increased activity of neurons in the spinal cord, in turn, enhances pain signaling pathways to the brain stem and in the brain. This central sensitization is difficult to reverse and makes pain persist beyond its protective role.

How is Pain Diagnosed?

There is no way to objectively measure pain.  Only the person experiencing pain can describe how much pain he/she is feeling.  After learning about a patient’s pain history and other medical concerns, a healthcare provider may conduct physical exams, clinical assessments, and order diagnostic tests and imaging to assess pain intensity and diagnose or rule out any conditions.

Healthcare providers have many approaches and technologies to help identify the cause of a patient’s pain.  Primarily these include:

  • musculoskeletal and neurological examination in which the physician tests movement, reflexes, sensation, balance, and coordination.
  • Laboratory tests (e.g., blood, urine, cerebrospinal fluid) can help the physician diagnose infection, cancer, nutritional problems, endocrine abnormalities, and other conditions that may cause pain.
  • Electrodiagnostic procedures including electromyography (EMG)nerve conduction studiesevoked potential (EP) studies, and quantitative sensory testing measure the electrical activity of muscles and nerves.  They help physicians evaluate muscle symptoms that may result from a disease or an injury to the body’s nerves or muscles.  EMG tests muscle activity and identifies which muscles or nerves are affected by weakness or pain.  Nerve conduction studies (usually performed along with an EMG) record how nerves are functioning.  EP studies measure electrical activity in the brain in response to sight, sound, or touch stimulation.  Quantitative sensory testing can establish thresholds for sensory perception which can then be compared to normal values.  These tests are used to detect abnormalities in sensory function and nerve disorders.
  • Imaging, especially magnetic resonance imaging or MRI, provides a look inside the body’s structures and tissues, such as the brain and spinal cord.  MRI uses magnetic fields and radio waves to differentiate between healthy and diseased tissue.  Ultrasound imaging uses high-frequency sound waves to obtain images inside the body.
  • Nerve blocks not only can treat but also can help to diagnose the cause of pain.  A person’s response to a nerve block may the help provider to determine what is causing the pain or where it is coming from, since pain signals can spread throughout the body.
  • Psychological assessments often are performed when assessing chronic pain.  There is a high prevalence of depression, anxiety, and emotional distress associated with chronic pain (and vice versa), and often the diagnoses can be hard to separate.  A provider may ask a patient to complete psychological questionnaires or ask how the person is feeling emotionally.
  • X-rays produce pictures of the body’s structures, such as bones and joints.  Bone scans can help diagnose and track infection, fractures, or other bone disorders.

How is Pain Treated?

The goal of pain management is to improve function—enabling individuals to work, attend school, and participate in daily activities.  The many treatment options will vary depending on the type of pain, its duration, and patient access.

The best way to prevent, assess, and treat people who experience chronic pain is the biopsychosocial treatment model.  This model allows patients, healthcare providers, and caregivers to view pain as a dynamic interaction among and within the biological, psychological, and social factors unique to that individual.  It provides the best foundation for tailoring the most comprehensive pain management program for each person.
Interdisciplinary treatment—which involves team members from different healthcare specialties working collaboratively to set goals, make decisions, and share resources and responsibilities—is based on the biopsychological model that is important when assisting chronic pain sufferers.

For the most part, the medications, procedures, interventions, and therapies listed below have been shown in clinical trials to help relieve or manage pain associated with a specific condition(s), but none have been proven fully effective in relieving all types of pain.  Discuss with your healthcare provider which treatment, or combination of treatments, will be most effective for you and your pain condition. It is important to remember that, while not all pain is curable, all pain can be treated.  Common treatments include:

Acupuncture involves the application of needles to precise points on the body to relieve pain.  It is part of a category of healing called traditional Chinese medicine.  Evidence of the effectiveness of acupuncture for pain relief is conflicting and clinical studies to investigate its benefits are ongoing.

Analgesic refers to the class of drugs that includes most “painkillers.”  This includes classes of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and naproxen, as well as acetaminophen and opioids (which have a narcotic effect and can induce sedation and pain relief).  Nonprescription or over-the-counter pain relievers are generally used for mild to moderate pain.  Prescription opioid pain relievers, sold through a pharmacy under the direction of a physician, are used for moderate to severe acute pain and are usually prescribed for short periods of time.

Anticonvulsants are used to treat seizure disorders because they dampen abnormally fast electrical impulses.  They also are prescribed by physicians to treat various pain conditions, particularly neuropathic pain

Antidepressants are often used to treat chronic pain and are particularly used to help manage musculoskeletal pain, neuropathic pain, and headache-related pain.

Anti-inflammatory diets (nutrition) are another approach to chronic pain management.  Research suggests that some people with chronic pain can benefit from eating anti-inflammatory foods to help reduce their level of pain with limited negative side effects.  

Beta-blockers are medications that inhibit one arm of the sympathetic nervous system and adrenal “fight or flight” hormones.  Propranolol and timolol are used to prevent migraine headaches.

Biofeedback is used to treat many common pain problems, most notably headache and back pain.  Biofeedback enables individuals to learn how to change physiological activity for the purpose of improving health and performance.  The biofeedback machine provides rapid and accurate feedback that helps people become aware of, follow, and gain control over certain bodily functions, including muscle tension, heart rate, breath rate, and skin temperature.  Feedback in conjunction with changes in thinking, emotions, and behavior leads to physiological changes that can be sustained over time without continued use of the biofeedback machine.  Biofeedback is often used in combination with other treatment methods, generally without side effects.

Botox (botulinum toxin) is a Food and Drug Administration (FDA)-approved treatment for chronic migraines—those that last for or occur for 15 or more days a month.  Botox is injected around pain fibers that are involved in headaches.  Botox enters the nerve endings and blocks the release of chemicals involved in pain transmission.

Calcitonin gene-related peptide (CGRP) monoclonal antibodies are a class of FDA-approved medications to help prevent frequent migraines.  Some of the new medications include Aimovig, Ajovy, and Emgality.

Chiropractic care may ease back pain, neck pain, headaches, and musculoskeletal conditions.  It involves “hands-on” therapy designed to adjust the relationship between the body’s structure (mainly the spine) and its functioning.  Chiropractic spinal manipulation includes the adjustment and manipulation of the joints and adjacent tissues.  Such care also may involve therapeutic and rehabilitative exercises.  A review of numerous clinical trials to assess the effectiveness of spinal manipulations concludes that there is only low-quality evidence of their benefit for acute and sub-acute low back pain.  For chronic back pain, however, there is evidence of small to moderate treatment relief.

Cognitive-behavioral therapy is a well-established treatment for pain that involves helping an individual improve coping skills—pacing day-to-day activities, addressing negative thoughts and emotions that can amplify pain, and learning relaxation methods to help prepare for and cope with pain and changes in the nervous system.  It is used for chronic pain, postoperative pain, cancer pain, and transitions from acute to chronic pain.

Counseling can give an individual pain sufferer much-needed support, whether it comes from family, group, or individual counseling.  Support groups can provide an important supplement to drug or surgical treatment.  Psychological treatment also can help people learn how to better handle physiological changes produced by pain.

Electrical stimulation, including implanted electric nerve stimulation, and deep brain or spinal cord stimulation, is the modern-day version of age-old practices in which the nerves or muscles are stimulated by heat or massage.  The following techniques require specialized equipment and trained personnel:

  • TENS (transcutaneous electrical stimulation) uses tiny electrical pulses, delivered through the skin to nerve fibers, to cause changes in muscles, such as numbness or contractions.  This in turn produces temporary pain relief.  TENS can activate subsets of peripheral nerve fibers that can block pain transmission at the spinal cord level.
  • Peripheral nerve stimulation uses electrodes placed surgically or percutaneously (injected through the skin) on a peripheral nerve.  The individual is then able to send an electrical current as needed to the affected nerve, using a controllable electrical generator.
  • Spinal cord stimulation uses electrodes surgically or percutaneously inserted between the spine’s protective covering (the dura) and the spinal column.  The individual can send a pulse of electricity to the spinal cord using an implanted electrical pulse generator that resembles a cardiac pacemaker.
  • Deep brain stimulation is considered a more extreme treatment and involves surgical stimulation of the brain, usually the thalamus or motor cortex.  It treats chronic pain in cases that do not respond or have stopped responding to less invasive or conservative treatments.
  • Exercise also may be part of the pain treatment regime for most people with pain.  A physician or physical therapist can recommend an appropriate routine.  Participation in some form of exercise, physical activity, and stretching may help individuals with pain better manage their symptoms, handle daily activities, and maintain flexibility and muscle strength.  Exercise, sleep, and relaxation can all help reduce stress, thereby helping to alleviate pain.  Supervised exercise has been proven to help many people with low back pain.

Hypnosis, in general, is used to control physical function or response—that is, the amount of pain an individual can withstand.  How hypnosis works is not fully understood, and there is limited research suggesting its effectiveness.  Some believe that hypnosis enables individuals to improve their ability to concentrate and/or relax.

Injections are sometimes used to deliver pain relief medication locally.

  • Facet injections target the facet joints (small stabilizing joints in the spine between and behind vertebrae).   A person may get pain relief from the local anesthetic and may notice longer lasting relief starting two to five days after injection.
  • Steroid injections work by decreasing inflammation and reducing the activity of the immune system.  Injecting steroids into one or two local areas allows doctors to directly deliver a high dose of medication.
  • A sacroiliac joint injection is used to diagnose the source of a person’s pain, as well as to provide therapeutic pain relief associated with sacroiliac joint dysfunction.  The injection provides pain relief by reducing inflammation within the joint.
  • Trigger point injections involve injecting a small amount of local anesthetic, sometimes with a steroid medication, directly into a painful trigger point (a specific site on the muscles that causes pain when pressed during an exam).

Low-power lasers have been used by some healthcare providers as a treatment for pain.  This low-intensity light therapy (not thermal) triggers biochemical changes within cells and may have an effect on pain, inflammation, and tissue repair, but this method is considered controversial.

Marijuana (cannabis) continues to remain highly controversial as a medical treatment to manage pain.  Scientific studies are underway to test the safety and usefulness of cannabis for treating different medical conditions.  Although marijuana has not been approved for any medical use at the federal level, several states and the District of Columbia permit the use of medical marijuana as a treatment.

  • Marinol is an FDA-approved medication with the active ingredient dronabinol, a synthetic form of tetrahydrocannabinol (THC) used to treat chemotherapy-induced nausea and vomiting.  Initial research has found that Marinol was no more effective than placebo for post-surgical and nerve-related pain, and only slightly more effective than placebo for chronic non-cancer pain.

Muscle relaxants are used to relax and reduce tension in muscles.  Muscle relaxants are not a class of drugs, which means that they do not all have the same chemical structure or work the same way in the brain.  The term “muscle relaxers” describes a group of drugs that act as central nervous system depressants and have sedative properties for musculoskeletal pain.

  • Anxiolytics include medications in the class of benzodiazepines, used to decrease central nervous system activity.  These drugs can act as muscle relaxants and are sometimes used to manage anxiety.

Nerve blocks use drugs, chemical agents, or surgical techniques to interrupt the relay of pain messages between specific areas of the body and the brain.  Nerve blocks may involve local anesthesia, regional anesthesia or analgesia, or surgery, and are routinely used for traditional dental procedures.  Nerve blocks also can be used to prevent or even diagnose pain and may involve the injection of local anesthetics to numb the nerve and/or steroids to reduce inflammation.

A local nerve block may use one of several local anesthetics such as lidocaine or bupivacaine.  Peripheral nerve blocks involve targeting a nerve or group of nerves that affect a part of the body.  Nerve blocks also may take the form of what is commonly called an epidural, in which a drug is administered into the space between the dura and the spinal column.  This procedure is best known for its use during childbirth.  However, it is also used to treat acute or chronic leg or arm pain due to an irritated spinal nerve root.

  • Neurolytic blocks employ injection of chemical agents such as alcohol, phenol, or glycerol, or the use of radiofrequency energy, to kill nerves responsible for transmitting nociceptive signals.  Neurolytic blocks are most often used to treat cancer pain or pain in the cranial nerves.
  • Sympathectomy, also called sympathetic blockade, typically involves injecting local anesthetic next to the sympathetic nervous system (involved with regulating heart rate, breathing, blood pressure, and response to stressful or dangerous situations).  The procedure is often performed to treat neuropathic pain of a limb (e.g., complex regional pain syndrome) as well as vascular disease pain and other conditions.
  • Surgical blocks are performed on cranial, peripheral, or sympathetic nerves.  They are most often used to relieve cancer pain and extreme facial pain, such as that experienced with trigeminal neuralgia.  There are several types of surgical nerve blocks and they are not without problems and complications.  Nerve blocks can cause muscle paralysis and, in many cases, result in partial numbness.  For that reason, the procedure should be reserved for a select group of individuals and should only be performed by skilled surgeons.  Types of surgical nerve blocks include:
  • Spinal dorsal rhizotomy, in which the surgeon cuts the root or rootlets of one or more of the nerves radiating from the spinal cord.  Other rhizotomy procedures include cranial rhizotomy and trigeminal rhizotomy, performed as a treatment for extreme facial or cancer pain.

Physical therapy and rehabilitation may help to decrease pain and improve mobility.  by increasing function, controlling pain, and aiding recovery.  Individuals may engage in a number of physical therapy treatments simultaneously.  A few of the most common forms (in addition to exercise, electrical stimulation, and ultrasound) are:

  • Traction sometimes is used to decrease pain and improve mobility in the spine.
  • Joint mobilization can occur when a physical therapist passively moves the joints of the body in specific directions to help decrease pain and improve mobility.
  • Heat and ice are often used in physical therapy.  Heat can increase circulation to the injured tissues, relax the muscles, and provide pain relief.  Ice typically is used to help decrease pain and control inflammation.
  • Kinesiology taping uses a flexible tape to support body parts and muscles to reduce bruising/swelling and provide pain relief.

Placebos are defined as substances without any therapeutic effect that is typically used as a controlling factor in clinical studies to determine the effectiveness of medical treatment.  Placebos are inactive substances, such as sugar pills, or harmless procedures such as saline injections, and may be prescribed more for the psychological benefit to the patient than for any physiological effect.  Placebos, however, do offer some individuals pain relief.  Although placebos have no direct effect on the underlying causes of pain, evidence from clinical studies suggests that many conditions such as migraine headache, back pain, post-surgical pain, rheumatoid arthritis, angina, and depression sometimes respond well to them.  This is known as the placebo response, which is defined as the observable or measurable change that can occur after the administration of a placebo.  One significant component responsible for the effect of placebo is the degree to which people expect the treatment to work.  Placebos work in part by stimulating the brain’s own analgesics.

Relaxation and mindfulness are ways for people to respond to the physical sensation of pain, which can have a major impact on how the body’s nervous system creates and perceives pain.  An individual’s automatic reactions to pain, often unconsciously, can amplify the pain-generating activity of the nervous system.  Relaxation strategies (e.g., imagery, progressive muscle relaxation, autogenic relaxation) and mindfulness techniques (e.g., exercises that help the individual observe physical, cognitive, and emotional reactions and make skillful choices to relieve pain) are evidence-based practices to help shift the nervous system back toward a normal non-pain state.

R.I.C.E.Rest, Ice, Compression, and Elevation—are four components prescribed by many orthopedists, coaches, trainers, nurses, and other professionals for temporary muscle or joint injuries, such as sprains or strains.

Radiofrequency ablation (RFA) uses an electrical current produced by a radio wave to heat up a small area of nerve tissue, thereby decreasing pain signals from that specific area. The degree of pain relief can vary depending on the cause and location of the pain.  Some individuals can experience pain relief for up to 6-12 months.

Serotonergic agonists—the triptans (including sumatriptan, naratriptan, and zolmitriptan)—are used specifically for acute migraine headaches because they block pain pathways in the brain.  Taken as pills, shots, or nasal sprays, they can relieve many symptoms of migraine.

Surgery may be recommended for some people with pain that significantly impacts their daily functioning.  Surgery may be considered when less invasive treatments have not been helpful.  However, surgical procedures are not always successful and may not be appropriate for all people.

Topical pain creams/gels are sprayed on or rubbed into the skin over painful muscles or joints.  Although they are all designed to relieve pain, they have different ingredients.  Topical pain creams and gels (e.g., compounded pain creams to treat specific pain) are sometimes prescribed by a physician, while others can be bought over the counter.  There is limited evidence about the effectiveness of such creams.  Below are the most common ingredients in products available without a prescription.

  • Capsaicin (pronounced cap-SAY-sin) is a chemical found in chili peppers and is also a primary ingredient in prescription or over-the-counter pain-relieving creams as a treatment for several pain conditions, including shingles.  This topical cream may be helpful for deep pain.  It works by reducing the amount of substance P—a compound thought to be involved in the synaptic transmission of pain and other nerve impulses—that is found in nerve endings and interferes with the transmission of pain signals to the brain.  Individuals can become desensitized to the compound, however, perhaps because of long-term capsaicin-induced damage to nerve tissue.  Some people cannot tolerate the burning sensation they experience when using capsaicin cream.
  • Counterirritants include ingredients such as menthol, methylsalycylate (oil of evergreen), and camphor.  They are called counterirritants because they create a burning or cooling sensation that distracts the person from the pain.
  • Salicylates are the same ingredients that give aspirin its pain-relieving quality and are found in some creams.  When absorbed into the skin, they may help with pain, particularly in joints close to the skin, such as fingers, knees, and elbows.

Sex/Gender and Pain

According to the Institute of Medicine’s (IOM) 2011 report: Relieving Pain in America (, women often report a higher prevalence of chronic pain than men and are at a greater risk for many pain conditions.  Women also are likely to have more pain from certain diseases, such as cancer.  In addition, some chronic pain disorders occur only in women while others occur predominantly in women.  These include chronic fatigue syndrome, endometriosis, fibromyalgia, interstitial cystitis, vulvodynia, and temporomandibular disorders.

The IOM report notes three theories that might explain the gender differences in pain experience:

  • A gender-role theory that assumes that it is more socially acceptable for women to report pain;
  • An exposure theory that suggests that women are exposed to more pain risk factors; and
  • A vulnerability theory proposing that women are more vulnerable to developing certain types of pain, such as musculoskeletal pain.

Of these, the vulnerability theory is best supported by scientific evidence.

Race/Ethnicity and Pain

According to the 2011 IOM report, cultural perspectives and identification in a specific racial or ethnic group can influence a patient’s report of pain. Initial research also indicates that healthcare providers’ expectations of a person’s pain can be influenced by race or ethnicity. People of different races/ethnicities often experience different rates of clinically painful conditions. Some research has shown that African Americans, Asians, and Hispanics demonstrate lower pain tolerance compared to Caucasians. Stereotypes also have resulted in the undertreatment of racial/ethnic minorities. Some studies suggest that there are such disparities in pain management for a variety of conditions and treatment settings. They indicate that African Americans and Hispanics are more likely to have their pain undertreated than Caucasians.

Pain in the Older Population and Children

According to the 2011 IOM report, the likelihood of experiencing pain and the type of care one receives differs for children and the very old, compared to young and middle-aged adults.

Older people

Pain is the number one medical complaint of older Americans.  Research suggests that more severe pain and pain that interferes with activities increases with age.  Evidence also shows that older people are more vulnerable to severe or persistent pain and that the inability to tolerate severe pain also increases with age.  Some of the most common causes of pain in older adults include joint pain, post-surgical pain, chronic disease, and conditions associated with aging.

Pain management in the older population differs from that in younger people.  For example, older people are much more likely to experience medication-related side effects than younger people.


Pain in children also requires special attention.  Identifying the problem and getting a proper diagnosis can be particularly difficult because young children often are not able to describe the degree of pain that they are experiencing.  Also, a child’s pain is often undertreated for various reasons, one being there are few evidence-based recommendations regarding medication-prescribing practices for children and adolescents.  Although treating pain in children poses challenges to physicians and parents alike, children should never be undertreated.  Specific tools and questionnaires for measuring pain in children have been developed that, when combined with feedback from parents, can help physicians select the most effective treatments.



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Esophageal Achalasia – Causes, Symptoms, Treatment

Esophageal Achalasia/Achalasia is a rare neurodegenerative motor smooth muscle motility disorder of the esophagus resulting in deranged oesophageal peristalsis and loss of lower oesophageal sphincter function that makes it difficult for food and liquid to pass into your stomach. Achalasia occurs when nerves in the tube connecting your mouth and stomach (esophagus) become damaged. As a result, the esophagus loses the ability to squeeze food down, and the muscular valve between the esophagus and stomach (lower esophageal sphincter) doesn’t fully relax — making it difficult for food to pass into your stomach.

Achalasia is a rare disorder that makes it difficult for food and liquid to pass from the swallowing tube connecting your mouth and stomach (esophagus) into your stomach.

Synonyms of Achalasia

  • Cardiospasm
  • Dyssynergia esophagus
  • Esophageal peristalsis
  • Megaesophagus
  • Esophageal achalasia;
  • Swallowing problems for liquids and solids;
  • lower esophageal sphincter spasm

Types of Achalasia

  • Achalasia Type 1 (Classic Achalasia)
    • No contractility or peristalsis
    • The lower esophageal sphincter fails to relax (all Achalasia types)
    • Responds to Laparoscopic Heller Myotomy
  • Achalasia Type 2 (with esophageal compression)
    • No normal peristalsis (but some pressurizations)
    • The lower esophageal sphincter fails to relax (all Achalasia types)
    • Responds to all treatment options
  • Achalasia Type 3 (Spastic Achalasia)
    • No normal peristalsis
    • Spastic contractions in distal esophagus (>20% of swallows)
    • The lower esophageal sphincter fails to relax (all Achalasia types)
    • Responds poorly to treatment

Causes of Esophageal Achalasia

Dysphagia could be during the oropharyngeal or pharyngeal phases of swallowing.

A. Oropharyngeal dysphagia

It is a delay in the transit of liquid or solid bolus during the oropharyngeal phase of swallowing. It could be due to three main subgroups – (1) neurological, (2) muscular, or (3) anatomical.

  • Neurological causes include cerebrovascular accidents (post-stroke dysphagia), brainstem infarctions with cranial nerve involvement. Other causes include basal ganglia lesions as in Parkinson’s disease. Also, head and neck injuries and surgery, multiple sclerosis, central nervous tumor, botulism, amyotrophic lateral sclerosis, supranuclear palsy, and degenerative cervical spine disease.
  • Muscular causes include polymyositis, muscular dystrophy, and myasthenia gravis (a lesion at the neuromuscular junction).
  • Anatomical causes include Zenker diverticulum, enlarged thyroid, esophageal web, tumors, abscess, external compression by an aortic aneurysm (known as dysphagia aortic). Also, cervical discectomy and fusion may be associated with postoperative dysphagia.

B. Esophageal dysphagia- could be due to mechanical obstruction, or motility disorders. 

  • Mechanical obstruction causes include Schatzki ring, esophageal stricture, esophageal carcinoma, eosinophilic esophagitis.
  • Motility disorder causes include esophageal spasm, achalasia, ineffective esophageal motility, and scleroderma.

Mechanical obstruction is associated with dysphagia only to solid food, while the motility disorder causes are usually associated with solid and liquid dysphagia. The dysphagia may be intermittent (e.g., Schatzki ring, esophageal spasm) or permanent (as in esophageal stricture, carcinoma, achalasia, scleroderma, ineffective esophageal motility).

C. Rheumatological disorders

  • Sjogren syndrome (occurs in one-third of patients and caused by both xerostomia and abnormal esophageal motility, mainly of the proximal esophagus.
  • Systemic lupus erythematosus
  • Mixed connective tissue disease
  • Rheumatoid arthritis.
  • Systemic sclerosis (as part of the CREST syndrome)

D. Medications

Several drugs may contribute to the severity of dysphagia. The mechanisms by which these drugs may cause dysphagia include xerostomia and changes in esophageal motility. Also, the dysphagia may be secondary to the development of drug-induced esophagitis or the development of gastroesophageal reflux disease. Examples of these drugs are:

  • Antipsychotic (e.g., olanzapine, clozapine)
  • Tricyclic antidepressant
  • Potassium supplements
  • NSAIDs
  • Bisphosphonates
  • Calcium channel blockers
  • Nitrates
  • Theophylline
  • Alcohol
  • Medications with immunosuppressant effects (e.g., cyclosporin) can predispose to infective esophagitis and dysphagia
  • Opioids

It is important to note here that narcotic sedatives such as opioids can lead to compromise of airway due to central effects and could increase the risk of aspiration in patients with dysphagia. The use of opiates, even in low disease, in patients with psychiatric disorders or Parkinson’s disease, can develop hypercontractile or hypertensive esophageal consequences mimicking type III achalasia.


  • Diffuse esophageal spasm.
  • Esophageal cancer.
  • Eosinophilic esophagitis
  • Hiatal hernia.
  • Parkinson disease.
  • Zenker diverticulum.
  • Multiple sclerosis.
  • Paterson-Kelly syndrome.
  • Dysphagia lusoria is a type of dysphagia that develops in childhood, due to compression of the esophagus by vascular abnormality. Usually, there is an aberrant right subclavian artery arising from the left side of the aortic arch, or a double aortic arch, or other rare anomalies.
  • Benign strictures.
  • Esophageal webs and rings
  • Esophageal reflux

Symptoms of Esophageal Achalasia

Achalasia symptoms generally appear gradually and worsen over time. Signs and symptoms may include:

  • Inability to swallow (dysphagia), which may feel like food or drink is stuck in your throat
  • Regurgitating food or saliva
  • Heartburn
  • Belching
  • Chest pain that comes and goes
  • Coughing at night
  • Pneumonia (from aspiration of food into the lungs)
  • Weight loss
  • Vomiting
  • Trouble swallowing (dysphagia). This is the most common early symptom.
  • Regurgitation of undigested food.
  • Chest pain that comes and goes; pain can be severe.
  • Cough at night
  • Weight loss/malnutrition from difficulty eating. This is a late symptom.
  • Hiccups, difficulty belching (less common symptoms)

Diagnosis of Esophageal Achalasia

Achalasia can be overlooked or misdiagnosed because it has symptoms similar to other digestive disorders. To test for achalasia, your doctor is likely to recommend:

  • Endoscopy – Approximately 2% to 4% of patients with suspected achalasia have pseudoachalasia from infiltrating malignancy or stricture. Potential risk factors for malignancy-associated pseudoachalasia include older age at the time of diagnosis, shorter duration of symptoms, and more weight loss (12 vs 5 kg) on presentation. Patients with 2 or more of these risk factors on presentation should undergo a careful investigation to rule out malignancy.,
  • Barium esophagram – A barium esophagram is a noninvasive radiologic study that can assist with initial diagnosis or response to treatment with graded PD. A barium swallow evaluates the morphology of the esophagus and classically shows a dilated or tortuous esophagus with a narrowed LES and “bird’s beak” appearance.
  • Manometry – HRM is the gold standard test for the diagnosis of achalasia. Conventional manometry tracings in patients with achalasia show the absence of esophageal peristalsis and incomplete LES relaxation with residual pressures of over 10 mm Hg. HRM with esophageal pressure topography is more sensitive and specific than conventional manometry and is able to classify achalasia into 3 distinct subtypes, which can have treatment implications. Type II achalasia has the best response to treatment, followed by type I achalasia, whereas type III achalasia is the most difficult to treat.,
  • Esophageal manometry. This test measures the rhythmic muscle contractions in your esophagus when you swallow, the coordination and force exerted by the esophagus muscles, and how well your lower esophageal sphincter relaxes or opens during a swallow. This test is the most helpful when determining which type of motility problem you might have.
  • X-rays of your upper digestive system (esophagram). X-rays are taken after you drink a chalky liquid that coats and fills the inside lining of your digestive tract. The coating allows your doctor to see a silhouette of your esophagus, stomach, and upper intestine. You may also be asked to swallow a barium pill that can help to show a blockage of the esophagus.
  • Upper endoscopy. Your doctor inserts a thin, flexible tube equipped with a light and camera (endoscope) down your throat, to examine the inside of your esophagus and stomach. Endoscopy can be used to define a partial blockage of the esophagus if your symptoms or results of a barium study indicate that possibility. Endoscopy can also be used to collect a sample of tissue (biopsy) to be tested for complications of reflux such as Barrett’s esophagus.

Treatment of Esophageal Achalasia

Achalasia treatment focuses on relaxing or stretching open the lower esophageal sphincter so that food and liquid can move more easily through your digestive tract.

Specific treatment depends on your age, health condition and the severity of the achalasia.

Nonsurgical treatment

Nonsurgical options include:

  • The management plan. may include (i) elimination of certain food consistencies from the diet. (ii) adjustment of meal bolus seizes and (iii) use of techniques such as chin-tuck, head-turn, and supraglottic maneuvers to help in minimizing/preventing aspiration. Also, strengthening and coordinating muscles involved in swallowing. Gastroscopy tubes may be indicated in patients who fail to respond to the above-stated measures.
  • Pneumatic dilation. A balloon is inserted by endoscopy into the center of the esophageal sphincter and inflated to enlarge the opening. This outpatient procedure may need to be repeated if the esophageal sphincter doesn’t stay open. Nearly one-third of people treated with balloon dilation need repeat treatment within five years. This procedure requires sedation.
  • Botox (botulinum toxin type A). This muscle relaxant can be injected directly into the esophageal sphincter with an endoscopic needle. The injections may need to be repeated, and repeat injections may make it more difficult to perform surgery later if needed. Botox is generally recommended only for people who aren’t good candidates for pneumatic dilation or surgery due to age or overall health. Botox injections typically do not last more than six months. A strong improvement from the injection of Botox may help confirm a diagnosis of achalasia.
  • BT injection. for achalasia is an effective short-term therapy. BT injection into the LES locally inhibits the release of acetylcholine, causing relaxation of the smooth muscle, which allows for easier passage of food bolus into the gastric body.
  • Balloon dilation. In this non-surgical procedure, you’ll be put under light sedation while a specifically designed balloon is inserted through the LES and then inflated. The procedure relaxes the muscle sphincter, which allows food to enter your stomach. Balloon dilation is usually the first treatment option in people in whom surgery fails. You may have to undergo several dilation treatments to relieve your symptoms, and every few years to maintain relief.
  • Stretching the esophagus (pneumatic dilation). The doctor inserts a balloon in the valve between the esophagus and stomach and blows it up to stretch the tight muscles. You might need this procedure several times before it helps.


  • Muscle relaxants – such as nitroglycerin (Nitrostat) or nifedipine (Procardia) before eating. These medications have limited treatment effects and severe side effects. Medications are generally considered only if you’re not a candidate for pneumatic dilation or surgery, and Botox hasn’t helped. This type of therapy is rarely indicated.
  • Sublingual nifedipine – significantly improves outcomes in 75% of people with mild or moderate disease. It was classically considered that surgical myotomy provided greater benefit than either botulinum toxin or dilation in those who fail medical management.[rx] However, a recent randomized controlled trial found pneumatic dilation to be non-inferior to laparoscopic Heller myotomy.[rx]
  • Pharmacotherapy-nitrates, calcium-channel blockers – (e.g., nifedipine 10 to 20 mg sublingual 15 to 30 minutes before meals). It acts by lowering the lower esophageal sphincter resting pressure. Nitrates, calcium channel blockers, and phosphodiesterase-5 inhibitors to reduce the lower esophageal sphincter (LES) pressure.
  • Calcium channel blockers  – inhibit the entry of calcium into the cells blocking smooth muscle contraction, leading to a decrease in LES pressure. Hypotension, pedal edema, headache, the rapid development of tolerance, and incomplete symptom improvement are limiting factors to its use. Nitrates increase nitric oxide concentrations in smooth muscles, causing an increase in cyclic adenosine monophosphate levels, which leads to smooth muscle relaxation. These treatments are less effective, provide only short-term relief of symptoms, and are primarily reserved for patients who are waiting for or who refused more definitive therapy, such as pneumatic dilatation or surgery.
  • Scopolamine – also known as hyoscine Devil’s Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is formally used as a medication for treating motion and sickness, achalasia, and postoperative nausea and vomiting. It is also sometimes used before surgery to decrease saliva.[rx] When used by injection, effects begin after about 20 minutes and last for up to 8 hours.[rx] It may also be used orally and as a transdermal patch.[rx]


Surgical options for treating achalasia include:

  • Peroral endoscopic myotomy (POEM) – is an effective minimally invasive alternative to laparoscopic Heller myotomy to treat achalasia at limited centers. Dissection of the circular fibers of the LES is achieved endoscopically, leading to relaxation of the LES; however, the risk of gastroesophageal reflux is high because it does not include an antireflux procedure. Esophagectomy is the last resort.
  • Heller myotomy. The surgeon cuts the muscle at the lower end of the esophageal sphincter to allow food to pass more easily into the stomach. The procedure can be done noninvasively (laparoscopic Heller myotomy). Some people who have a Heller myotomy may later develop gastroesophageal reflux disease (GERD). To avoid future problems with GERD, a procedure known as fundoplication might be performed at the same time as a Heller myotomy. In fundoplication, the surgeon wraps the top of your stomach around the lower esophagus to create an anti-reflux valve, preventing acid from coming back (GERD) into the esophagus. Fundoplication is usually done with a minimally invasive (laparoscopic) procedure.
  • Peroral endoscopic myotomy (POEM). In the POEM procedure, the surgeon uses an endoscope inserted through your mouth and down your throat to create an incision in the inside lining of your esophagus. Then, as in a Heller myotomy, the surgeon cuts the muscle at the lower end of the esophageal sphincter. POEM may also be combined with or followed by later fundoplication to help prevent GERD. Some patients who have a POEM and develop GERD after the procedure are treated with daily oral medication.



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X-Linked Agammaglobulinemia – Symptoms, Treatment

X-Linked Agammaglobulinemia /Agammaglobulinemia is a rare form of primary immune deficiency autosomal recessive inheritance disorders characterized by the absence of circulating B cells and low serum levels of all immunoglobulin classes or complete absence of B lymphocytes and complete lack of immunoglobulins. In the presence of normal T cell counts and function that are related to antibody deficiency (hypogammaglobulinemia) and is manifested in a variety of immune deficiency disorders in which the immune system is compromised. Immunoglobulins are produced by plasma cells, which themselves are the result of the development and differentiation of B cells. Any factor that impedes the development of the B cell lineage and/or the function of mature B cells may result in levels of serum immunoglobulins that are reduced (ie, hypogammaglobulinemia) or nearly absent (ie, agammaglobulinemia). Primary agammaglobulinemia is most commonly inherited as an X-linked trait, but autosomal-recessive (AR) forms also exist. This group of immune deficiencies may be the consequence of an inherited condition, an impaired immune system from a known or unknown cause, relation to autoimmune diseases, or a malignancy.

Immunoglobulin deficiencies may be referred to by many different names, as there are several variables within the separate but related immune disorders; and there are also many subgroups. Antibody deficiency, immunoglobulin deficiency, and gamma globulin deficiency are all synonyms for hypogammaglobulinemia.

Bruton agammaglobulinemia or X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency disorder characterized by the absence of mature B cells, resulting in severe antibody deficiency and recurrent infections.  It can manifest in an infant as soon as the protective effect of maternal immunoglobulins wanes at around three-six months of age.

Synonyms of Agammaglobulinemia

  • hypogammaglobulinemia
  • autosomal recessive agammaglobulinemia
  • X-linked agammaglobulinemia with growth hormone deficiency
  • X-linked agammaglobulinemia (XLA)
  • Bruton’s agammaglobulinemia;
  • X-linked agammaglobulinemia;
  • Immunosuppression – agammaglobulinemia;
  • Immunodepressed – agammaglobulinemia;
  • Immunosuppressed – agammaglobulinemia

Causes of X-Linked Agammaglobulinemia

X- linked agammaglobulinemia is caused by a mutation in the Bruton tyrosine kinase (BTK) gene, located on the long arm of the X-chromosome. BTK is a member of the Tec family and encodes for cytoplasmic non-receptor tyrosine kinases, which are signal transduction molecules. BTK is critical in the maturation of pre-B cells to mature B cells, a process that occurs in the bone marrow. The disease has been associated with 544 mutations that include mainly missense mutations, insertions, deletions, and splice-site mutations.

Autosomal recessive agammaglobulinemia has been reported to be caused by genes that affect B cell development. Up to 15% are presumed to be autosomal recessive. The genetic cause of ARAG is much more complex as it involves other genes, mapped to loci on different chromosomes, 22q11.21 (IGLL1), 14q32.33 (IGHM), and 9q34.13 (LCRR8).

Beyond the primary hypogammaglobulinemia, a secondary immunodeficiency may be caused by drugs or other viral infections that affect the function of both T and B lymphocytes. Those drugs include steroids, azathioprine, cyclosporin, cyclophosphamide, leflunomide, methotrexate, mycophenolate, rapamycin, and tacrolimus. One such example of a viral infection that causes immunodeficiency, HIV (AIDS), mainly affects CD4+T cells, which in turn hampers cellular immune responses, resulting in opportunistic infections and cancers.

It has been reported that 85% of patients with chronic lymphocytic leukemia (CLL) were found to have developed hypogammaglobulinemia along the disease course. Its incidence rate increases with the duration and advancing stages of the disease. It is, therefore, more important to monitor patients for the development of any antibody deficiencies.

Congenital rubella infections also have a profound effect on immune system development. Defects observed may be transient, and can include complete immune paralysis, and other immunoglobulin abnormalities.

  • Autosomal recessive agammaglobulinemia (ARA)
  • Common variable immunodeficiency disease (CVID)
  • Transient hypogammaglobulinemia of infancy (THI)
  • X-linked hyper IgM syndrome (Hyper-IgM)
  • X-linked lymphoproliferative disease (X-LPD)
  • Severe combined immunodeficiency disease (SCID)
  • Acrodermatitis
  • Ataxia telangiectasis
  • Common variable immunodeficiency
  • Growth hormone deficiency
  • Lymphoproliferative disorder
  • Pediatric atopic dermatitis
  • Pediatric severe combined immunodeficiency
  • T cell disorders
  • The dermatologic manifestation of vitamin A deficiency
  • Transient hypogammaglobulinemia of infancy

Symptoms of X-Linked Agammaglobulinemia

The major symptoms of agammaglobulinemia are serial bacterial infections resulting from failures in specific immune responses because of defects in B-lymphocytes. These lymphocytes govern the production of antibodies. Males with X-linked primary agammaglobulinemia usually begin to show signs of such infections only late in the first year of life, after the IgG antibodies from the mother have been depleted.

Infections by almost any of the enterovirus family and the poliomyelitis virus can result in unusually severe illness in children with agammaglobulinemia. Echovirus infection can cause a group of symptoms that closely resembles dermatomyositis. These symptoms may include muscle weakness, often in the hip and shoulder areas, and difficulty swallowing. Areas of patchy, reddish skin may appear around the eyes, knuckles and elbows and occasionally on the knees and ankles. (For more information on this disorder, choose “dermatomyositis” as your search term in the Rare Disease Database.)

Infections caused by mycoplasma bacteria can lead to severe arthritis including joint swelling and pain, in children with primary agammaglobulinemia. Hemophilus influenza is the most common mucous-producing infection (pyogenic) that occurs in people with X-linked agammaglobulinemia. Children may also have repeated infections with pneumococci, streptococci, and staphylococci bacteria, and infrequently pseudomonas infections.

Males with X-linked form of agammaglobulinemia have very low levels of IgA, IgG, and IgM antibodies circulating in their blood. Specialized white blood cells (neutrophils) are impaired in their ability to destroy bacteria, viruses, or other invading organisms (microbes). This occurs because neutrophils require antibodies from the immune system to begin to destroy invading bacteria (opsonization). The levels of circulating neutrophils in children with agammaglobulinemia may be persistently low, or may wax and wane (cyclic, transient neutropenia) in people with these disorders. The number of B-lymphocytes in children with X-linked agammaglobulinemia is less than one one-hundredth of the normal number.

Only about 10 persons in 5 or 6 families have been diagnosed with X-linked agammaglobulinemia with growth hormone deficiency. The boys in these families have reduced or undetectable numbers of B-lymphocytes. Clinicians and geneticists speculate that a second mutation in the BTK gene, very close to the mutation in this gene that causes XLA, is responsible for the combination of agammaglobulinemia and very short stature.

Autosomal recessive agammaglobulinemia has been reported to be due to genes that affect B cell development.

Symptoms include frequent episodes of:

  • Bronchitis (airway infection)
  • Chronic diarrhea
  • Conjunctivitis (eye infection)
  • Otitis media (middle ear infection)
  • Pneumonia (lung infection)
  • Sinusitis (sinus infection)
  • Skin infections
  • Upper respiratory tract infections
  • Bronchiectasis (a disease in which the small air sacs in the lungs become damaged and enlarged)
  • Asthma without a known cause

Diagnosis of X-Linked Agammaglobulinemia

B cells undergo maturation, differentiation, and storage in tonsils, adenoids, intestinal Peyer’s patches, and lymph nodes. Due to mutations in B cells, these structures remain underdeveloped. However, lymph nodes can appear normal due to T cell hypertrophy.

History and Physical

Family history of immunodeficiency consistent with X-linked inheritance

To establish the extent of disease and needs of an individual diagnosed with X-linked agammaglobulinemia (XLA), the following evaluations are recommended:

  • A complete blood count with differential
  • Chemistries that include renal and liver function tests, total protein, albumin, and CRP
  • Quantitative serum immunoglobulins and titers to vaccine antigens as baseline measurements prior to initiation of gammaglobulin substitution therapy
  • Baseline chest and sinus x-rays
  • If the patient is able to cooperate, base line pulmonary function tests
  • Consultation with a clinical geneticist and/or genetic counselor

A typical diagnostic test sequence would evaluate serum levels of IgG, IgM, and IgA, the number of CD19-positive or CD20-positive B cells in circulation, humoral vaccine responses, BTK protein expression in peripheral monocytes, and Btk gene sequencing.

The physical evaluation may reveal signs of recurrent and chronic sinopulmonary infections, which include postnasal discharge, tympanic membrane perforation, digital clubbing, and bronchiectasis. One of the greatest clinical clues in the diagnosis of XLA is absent or atrophied tonsils and lymph nodes. Some patients may also show signs of growth failure.

Test results consistent with a diagnosis of XLA in a male patient with a history of recurrent bacterial infections would include finding:

  • Serum levels of IgG, IgM, and IgA that are more than two standard deviations below age-matched controls
  • Absence of mature B lymphocytes in the peripheral circulation (i.e., fewer than 1-2%)
  • Little or no increase in antibody titers 3-4 weeks after protein- or polysaccharide antigen vaccines (e.g., immunizing against pneumococcal pneumonia or diphtheria-tetanus)
  • Low or absent BTK protein or mRNA expression levels
  • Detection of disease-causing mutations in the Btk gene

During the early stages of life – passively transferred maternal IgG provides protection against various infections. From 6 to 12 months of age, these antibodies start depleting, causing children with XLA to present with recurrent sino-pulmonary infections such as otitis media, sinusitis, bronchitis, and pneumonia. More than 50% of children with X-linked agammaglobulinemia have had serious infections within their first two years of life.

Pyogenic encapsulated bacteria – such as Streptococcus pneumonia and Haemophilus influenzae, are the most commonly isolated pathogens in patients with XLA. Other commonly encountered infectious organisms include Staphylococcus aureus, Pseudomonas, and Mycoplasma species. Less commonly, some patients can acquire opportunistic infections from the Pneumocystis jirovecii and other fungi.

Patients with XLA – are also at higher risk of developing bloodborne bacterial infections. About 3% to 4% of patients with XLA have been reported to develop bacterial meningitis, caused predominantly by Streptococcus pneumoniae and Haemophilus influenza type B. Other less commonly reported causative bacteria were Pseudomonas, Neisseria meningitides, Staphylococcus aureus, Escherichia coli, and Listeria monocytogenes. Septic arthritis and osteomyelitis are other common associations reported among patients with XLA.

Patients with XLA – have frequent gastrointestinal infections, and Giardia lamblia is a frequently isolated pathogen from the stool samples of these patients; it can sometimes be difficult to eradicate. Persistent infection can result in chronic diarrhea and malabsorption. Another unusual pathogen, Campylobacter jejuni, is known for causing gastrointestinal manifestations, bacteremia, and skin lesions.

Laboratory findings

  • Marked reduction in all classes of serum immunoglobulins []
    • The serum IgG concentration is typically <200 mg/dL (2 g/L). Most but not all individuals with XLA do have some measurable serum IgG, usually between 100 and 200 mg/dL, and ~10% of individuals have serum concentration of IgG >200 mg/dL.
    • The serum concentrations of IgM and IgA are typically <20 mg/dL. Particular attention should be given to serum IgM concentration. Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration is almost always associated with immunodeficiency.
  • Markedly reduced numbers of B lymphocytes (CD 19+ cells) in the peripheral circulation (<1%) []
  • Antibody titers to vaccine antigens. Individuals with XLA fail to make antibodies to vaccine antigens like tetanus, H influenzae, or S pneumoniae.
  • Severe neutropenia in ~10%-25% of individuals at the time of diagnosis, usually in association with pseudomonas or staphylococcal sepsis [
  • Male proband. The diagnosis of XLA is established in a male proband with suggestive clinical and laboratory findings and identification of a hemizygous pathogenic variant in BTK by molecular genetic testing
Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
  • Single-gene testing. Sequence analysis of BTK is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
    Note: (1) Because approximately 3%-5% of individuals with a BTK pathogenic variant have large deletions that include all or part of BTK and the closely linked gene TIMM8A (also called DDP) resulting in XLA and deafness-dystonia-optic neuropathy syndrome (DDON; also called Mohr-Tranebjærg syndrome) [Richter et al 2001, Sedivá et al 2007], additional testing with chromosomal microarray analysis (CMA) may be warranted. (2) For individuals with clinical features of XLA and DDON, consider CMA testing first.
  • A multigene panel that includes BTK and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes BTK) fails to confirm a diagnosis in an individual with features of XLA. Such testing may also provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

Imaging Test

X-linked agammaglobulinemia (XLA) is an inborn error of immune function that can cause life-threatening infections and chronic lung disease such as bronchiectasis. Delays in diagnosis are detrimental to the prognosis and quality of life of patients.

The diagnosis relies on clinical suspicion by history, especially family history, and physical examination followed by laboratory and genetic tests.

Initial laboratory tests include:

  • Complete blood count with differentials
  • Quantitative serum immunoglobulin levels (IgG, IgA, and IgM)
  • Serum specific antibody titers response to immunization such as against tetanus or diphtheria

In patients with XLA, serum levels of all immunoglobulins are either low or nearly undetectable, and there will be an absent antibody response to vaccinations. If initial test results are positive, the diagnosis of XLA can be further aided by lymphocyte phenotyping using flow cytometry. The test will document an absent or reduced B-cell count and normal T-cell count. Definitive diagnosis can be made by detecting BTK gene mutation, using the Western blot technique.

Newborn screening tests have been developed for the diagnosis of XLA & other B cell defects. According to studies, immunoglobulin kappa-deleting recombination excision circles (KRECs assay), are a useful screening tool for early B cell maturation defects. Polymerase chain reactions are performed on dried blood spots to detect KRECs. KRECs are normally formed during allelic exclusion in the process of B cell maturation in normal individuals. An absence of KRECs indicates defects in B cell maturation, as in cases of XLA.

These patients have repeated sinopulmonary infections, and a variety of screening methods are used to diagnose and monitor the patient’s condition such as FEV1 (forced expiratory volume at 1 sec), FEV (forced vital capacity), and TLCO (transfer factor for carbon monoxide), as well as basic exercise tests. Imaging techniques employed include MRI and HRCT (high-resolution computerized tomography). Other tests involve sampling cultures of induced sputum and blood gas analysis. Since there is no local or national guideline for screening or treatment, the process lacks standardization, which creates a lot of variation in treatment methodologies.

In pediatric patients, clinical and laboratory tests are typically done with less frequency and are more complicated when compared to adults. For instance, infants may require sedation or general anesthetic for imaging. And lung function testing tends to be less reliable in children under 6 years.

Due to the high risk for pulmonary infectious and non-infectious complications, these patients are often treated with broad-spectrum antibiotics before a definitive diagnosis has been made. In these situations, fiberoptic bronchoscopy (FOB) and bronchoalveolar lavage (BAL) can provide a definitive diagnosis. In addition, audiological evaluation, including audiometry, acoustic immittance assessment, and auditory brainstem-evoked response, should be an integral part of the clinical care/management of these patients.

As mentioned earlier, a variant of XLA is associated with a growth hormone deficiency; however, no current guidelines are available regarding routine monitoring of growth hormone levels in patients with XLA.

Treatment of X-Linked Agammaglobulinemia

There is no curative treatment for XLA. However, management is by preventing, reducing, and treating infections.

The optimal management of patients with XLA includes

  • Regular immunoglobulin replacement therapy, using intravenous or subcutaneous infusions
  • Therapeutic and prophylactic use of antibiotics to treat and prevent bacterial infections
  • Careful monitoring to manage reactions arising from immunoglobulin infusions, complications of infections, or the emergence of clinical disease (e.g., autoimmune, inflammatory, malignant)
  • Support (nutritional, social, psychological, and educational)
  • Counseling about the importance of receiving all available immunizations except for those containing live bacteria or viruses, e.g., polio (OPV, oral polio vaccine), measles/mumps/rubella (MMR), chickenpox (Varivax), BCG, yellow fever, and rotavirus (Rota-Teq)

Intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) therapy requires several considerations:

  • A dose of 400 to 800 mg/kg every 3 to 4 weeks has been established to maintain an IgG trough greater than 5g/L. Dose adjustments may be necessary for XLA patients with bronchiectasis and/or refractory infections such as meningoencephalitis.
  • Both IVIG and SCIG – are appropriate first-line therapies. IVIG may be preferred if a larger infusion volume due to a higher dose requirement is needed. SCIG has been reported to have a lower incidence of adverse reactions and allows for a more stable IgG trough following injection.
  • Most adverse reactions are transient and pose no serious threat to the patient. These include immediate effects such as headache, fever, myalgia, hypo/hypertension, nausea, and chest pain. Reactions that resemble anaphylaxis are associated with higher transfusion rates and occur during the infusion. Although IgA deficiency is associated with a risk of anaphylaxis during IVIG infusion, antibodies against IgA are unlikely in XLA patients due to agammaglobulinemia. Reactions may temporarily require cessation of the infusion until symptomatically managed with agents such as NSAIDs (for flushing, pain, and headache), diphenhydramine (for pruritus, rashes, and flushing), ondansetron (for nausea or vomiting), or muscle relaxants (for muscular spasm).
  • Delayed reactions are of greater concern, though less common, and include thromboembolism due to hyperviscosity, renal failure secondary to osmotic injury associated with sucrose-containing preparations, pseudo hyponatremia, autoimmune hemolytic anemia, aseptic meningitis, and neutropenia.

The primary precautionary measure against infections for these patients is hygiene-focused, such as handwashing and avoidance of respiratory droplets. If possible, these patients should avoid the ingestion of untreated drinking water.

Replacement of IV immunoglobulins (IVIG) – has altered the outcome & quality of life in patients with X-linked agammaglobulinemia. Being the cornerstone of treatment, immunoglobulins are replaced every 3-4 weeks intravenously or every 1-2 weeks subcutaneously. Patients might require a loading dose (e.g., 1 dose of 1 g/kg body weight or divided into separate doses), followed by maintenance therapy (400 to 600 mg/kg/month). These doses and intervals are adjusted to maintain serum trough level at least above 500 mg/dl and may vary on a case-by-case basis. For instance, patients with chronic refractory sinusitis or chronic lung disease may require higher trough levels (>800 mg/dl).

Though IVIG – is the main treatment option for these patients, it has its drawbacks such as;

  • It protects against most of pathogens, but protection against uncommon pathogens is limited if the donor pool has not been exposed to them.
  • During treatment, only IgG is replaced while the rest of the immunoglobulins are not; these include IgA, and IgM, which have their unique functions, particularly protecting mucosal surfaces.
  • Replacement IVIG therapy is very costly and not sustainable – especially in areas with limited resources.

Subcutaneous administration of IgG – is an alternative to IVIG in case of difficult IV access or adverse reaction to IVIG. Just as safe as IVIG, with fewer systemic adverse effects, and smaller fluctuations in serum concentrations, the ability to self-administer IgG at home brings added convenience to this method. Overall this method will improve the patient’s quality of life. In very rare cases with subcutaneous IgG, local side effects like swelling, erythema, and tenderness may occur. These side effects tend to resolve within 24 hours.

Hematopoietic stem cell transplantation (HSCT) – is an alternate treatment for these patients. It is a tedious procedure with difficulty in matching suitable donors, making this treatment less popular. Additionally, there are heightened risks of allogeneic HSCT, including rejection and graft-versus-host disease. Often people in developing countries opt for HSCT because of lack of resources and high costs, making IVIG less suitable.

A potential therapy for XLA – is stem cell gene therapy, which has the potential to cure XLA. However, this technology is still in its developing stages and is associated with severe complications because of the random integration of the vector into chromosomes; this can lead to an increased risk of cancer, and in some cases, even death. While adenovirus vectors have been under investigation as a method to repair the BTK gene, the long-term success of this treatment is still unknown.

In addition to IVIG – these patients will require aggressive antibiotic therapy for any suspected or documented infections. The prolonged use of antibiotic therapy may be indicated in some patients for ongoing pulmonary infections or chronic sinusitis. As prophylactic therapy, many antibiotics options exist, but with little reliable data available, the effectiveness of a specific regimen for patients with XLA is lacking. It is typically initiated with amoxicillin, trimethoprim-sulfamethoxazole, or azithromycin. If these are deemed non-effective, others such as amoxicillin-clavulanate or clarithromycin may be used. Some practitioners opt between full therapeutic doses or half-doses, some rotate preventative antibiotics every 1 to 6 months, and others stick with one agent.

Antibiotics – are prescribed for people with agammaglobulinemia when bacterial infections occur. Some patients are treated with antibiotics as a preventive measure (prophylactically). All people who are immunodeficient should be protected as much as possible from exposure to infectious diseases.

Corticosteroids – or any drug that depresses the immune system (immunosuppressant drugs) should be avoided as much as possible, as well as physical activities such as rough contact sports that risk damage to the spleen. In people with immunodeficiency with elevated IgM, there is a tendency to bleed excessively associated with abnormally low levels of circulating platelets in the blood (thrombocytopenia). This may complicate any surgical procedure.

Muscle injections  – of immunoglobulin (Imig) were common before IVIg was prevalent, but are less effective and much more painful; hence, IMIg is now uncommon. Subcutaneous treatment (SCIg) was recently approved by the U.S. Food and Drug Administration (FDA), which is recommended in cases of severe adverse reactions to the IVIg treatment.

Genetic counseling – is recommended for people with agammaglobulinemias and their families. Another treatment is symptomatic and supportive. The goal of the regimen is to ensure coverage over the following organisms: Enterococcus faecalis, Staphylococcus species, Streptococcus species, Streptococcus pneumonia, and also some gram-negative bacteria like Escherichia coli, Hemophilus influenzae, Proteus mirabilis, and Neisseria gonorrhoeae.

Patients that develop bronchiectasis may benefit from bronchopulmonary hygiene, regular macrolide, and inhaled corticosteroids. The need for short- and long-acting inhaled B2 agonists, in bronchiectasis, is debatable.

Other considerations

It is not recommended and dangerous for XLA patients to receive live attenuated vaccines such as live polio, or measles, mumps, rubella (MMR vaccine).[3] Special emphasis is given to avoiding the oral live attenuated SABIN-type polio vaccine that has been reported to cause polio to XLA patients. Furthermore, it is not known if active vaccines in general have any beneficial effect on XLA patients as they lack the normal ability to maintain immune memory.

XLA patients are specifically susceptible to viruses of the Enterovirus family, and mostly to: poliovirus, cox sackieviruscoxsackie virus (hand, foot, and mouth disease), and Echoviruses. These may cause severe central nervous system conditions as chronic encephalitis, meningitis, and death. An experimental anti-viral agent, pleconaril, is active against picornaviruses. XLA patients, however, are apparently immune to the Epstein-Barr virus (EBV), as they lack mature B cells (and so HLA co-receptors) needed for the viral infection.[rx] Patients with XLA are also more likely to have a history of septic arthritis.[rx]

It is not known if XLA patients are able to generate an allergic reaction, as they lack functional IgE antibodies. There is no special hazard for XLA patients in dealing with pets or outdoor activities.[rx] Unlike in other primary immunodeficiencies XLA patients are at no greater risk for developing autoimmune illnesses.

Agammaglobulinemia (XLA) is similar to the primary immunodeficiency disorder Hypogammaglobulinemia (CVID), and their clinical conditions and treatment are almost identical. However, while XLA is a congenital disorder, with known genetic causes, CVID may occur in adulthood and its causes are not yet understood. In addition, to X-linked agammaglobulinemia, a couple of autosomal recessive agammaglobulinemia gene mutations have been described including mutations in IGHM,[rx] IGLL1, CD79A/B,  BLNK [rx], and deletion of the terminal 14q32.33 chromosome.[rx]

XLA was also historically mistaken as Severe Combined Immunodeficiency (SCID), a much more severe immune deficiency (“Bubble boys”). A strain of laboratory mouse, XID, is used to study XLA. These mice have a mutated version of the mouse Btk gene and exhibit a similar, yet milder, immune deficiency as in XLA



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Hughes Syndrome – Causes, Symptoms, Treatment

Hughes Syndrome/Antiphospholipid syndrome (APS) is a systemic autoimmune, hypercoagulable, thrombo inflammatory, and thrombosis and/or pregnancy complications syndrome caused by the persistent presence of antiphospholipid antibodies (APL) in plasma of patients with vascular thrombosis and/or pregnancy morbidity along with persistent anti-phospholipid antibodies (APLA), including lupus anticoagulant (LA), anti-β2-glycoprotein I (anti-β2GPI) and/or anti-cardiolipin (ACL) antibodies. Signs and symptoms vary, but may include blood clots, miscarriage, rash, chronic headaches, dementia, and seizures.[rx] These antibodies are often referred to by different terms, including anticardiolipin antibody, lupus anticoagulant, and antiphospholipid antibody. APS can be primary or secondary, and also can be referred to by the name Hughes syndrome or “sticky blood”.

Antiphospholipid syndrome is an acquired autoimmune disorder characterized by recurrent arterial or venous thrombosis and/or pregnancy losses, in the presence of persistently elevated levels of anticardiolipin antibodies and/or evidence of circulating lupus anticoagulant (these abnormalities are detected by blood tests). Antiphospholipid syndrome can be primary or secondary.

Other Names

  • Familial antiphospholipid syndrome;
  • Antiphospholipid antibody syndrome;
  • Lupus anticoagulant, familial;
  • APS;
  • Hughes syndrome
  • antiphospholipid antibody syndrome
  • APLS
  • lupus anticoagulant syndrome
  • primary antiphospholipid syndrome
  • secondary antiphospholipid syndrome
  • catastrophic antiphospholipid syndrome
  • Categories: Blood Diseases
  • Subtypes: Catastrophic antiphospholipid syndrome

Causes of Hughes Syndrome

Antiphospholipid syndrome (APS) is caused by the body’s immune system producing abnormal antibodies called antiphospholipid antibodies. Antiphospholipid syndrome is an autoimmune disorder of unknown cause. Autoimmune disorders are caused when the body’s natural defenses (antibodies, lymphocytes, etc.) against invading organisms attack perfectly healthy tissue. Researchers believe that multiple factors including genetic and environmental factors play a role in the development of APS. In rare cases, APS has run in families suggesting that a genetic predisposition to developing the disorder may exist.This increases the risk of blood clots developing in the blood vessels, which can lead to serious health problems, such as:

  • deep vein thrombosis (DVT)
  • strokes
  • heart attacks

It’s not clear why these abnormal antibodies are produced, or why many people have antiphospholipid antibodies but don’t develop blood clots. A combination of genetic and environmental factors is thought to be responsible.

Antiphospholipid antibodies

Antibodies are proteins produced by the immune system to help fight off infection and illness. They’re part of the body’s defense system and are produced to help protect against “foreign invaders”, such as bacteria and viruses. Antibodies signal the immune system to release chemicals to kill these bacteria and viruses, and to prevent infection from spreading. In APS, the immune system produces abnormal antibodies that rather than attacking bacteria and viruses, mistakenly attack proteins found on the outside of cells in the blood and blood vessels.

It’s not known how this causes the blood to clot more easily. But most experts believe that keeping your blood at the correct consistency (not too runny and not too sticky) is a delicate balancing act that relies on different types of proteins and fats working together. This balance may be disrupted by the abnormal antibodies in people with APS.

Genetic factors

Research into the genetics around APS is still at an early stage, but it seems the genes you inherit from your parents may play a role in the development of abnormal antiphospholipid antibodies. APS isn’t passed down directly from parents to children in the same way as other conditions, such as hemophilia and sickle cell anemia.

But having a family member with antiphospholipid antibodies increases the chance of your immune system also producing them. Studies have shown that some people with APS have a faulty gene that plays a role in other autoimmune conditions, such as lupus. This may explain why some people develop APS alongside another immune system condition.

Environmental factors

It’s thought that one or more environmental triggers may be needed to trigger APS in some people.Environmental factors that may be responsible include:

  • viral infections, such as the cytomegalovirus (CMV) or parvovirus B19
  • bacterial infections, such as E. coli (a bacteria often associated with food poisoning) or leptospirosis (an infection usually spread by certain animals)
  • certain medications, such as anti-epileptic medicine or the oral contraceptive pill

Another theory is that many people with abnormal antiphospholipid antibodies only go on to develop APS if they have a higher risk of developing blood clots.

For example, if they:

  • eat an unhealthy diet, leading to high cholesterol levels in the blood
  • don’t do enough exercise
  • take the contraceptive pill or hormone replacement therapy (HRT)
  • smoke
  • are obese

But this doesn’t explain why some children and adults who don’t have any of these risk factors still develop APS.

Symptoms of Hughes Syndrome

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO). The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Signs and symptoms of the antiphospholipid syndrome can include:

  • Blood clots in your legs (DVT). Signs of a DVT include pain, swelling and redness. These clots can travel to your lungs (pulmonary embolism).
  • Repeated miscarriages or stillbirths. Other complications of pregnancy include dangerously high blood pressure (preeclampsia) and premature delivery.
  • Stroke. A stroke can occur in a young person who has antiphospholipid syndrome but no known risk factors for cardiovascular diseases.
  • Transient ischemic attack (TIA). Similar to a stroke, a TIA usually lasts only a few minutes and causes no permanent damage.
  • Rash. Some people develop a red rash with a lacy, net-like pattern.
  • Neurological symptoms. Chronic headaches, including migraines; dementia, and seizures are possible when a blood clot blocks blood flow to parts of your brain.
  • Cardiovascular disease. Antiphospholipid syndrome can damage heart valves.
  • Bleeding. Some people have a decrease in blood cells needed for clotting. This can cause episodes of bleeding, particularly from your nose and gums. You can also bleed into your skin, which will appear as patches of small red spots.
  • Stroke. A clot in your brain can cause sudden numbness, weakness, or paralysis of your face, arm, or leg. You may have difficulty speaking or understanding speech, visual disturbances, and a severe headache.
  • Pulmonary embolism. If a clot lodges in your lung, you may experience sudden shortness of breath, chest pain, and coughing up blood-streaked mucus.
  • Deep vein thrombosis (DVT). Signs and symptoms of DVTs include swelling, redness, or pain in a leg or arm.
  • sudden pain, warmth, and swelling in one leg or arm
  • shortness of breath
  • chest pain
  • coughing up blood-streaked mucus
  • numbness, paralysis, or weakness in your face or limbs
  • slurred speech
  • problems with your vision.
Medical Terms Other Names
Learn More:
Percent of people who have these symptoms is not available through HPO
Arterial thrombosis
Blood clot in artery
Autoimmune thrombocytopenia 0001973 
Autosomal dominant inheritance 0000006 
Blurred vision 0000622 
Central retinal artery occlusion 0025342 
Inflammation of iris
Corneal inflammation
Lupus anticoagulant 0025343 
Retinal detachment
Detached retina
Retinal vasculitis 0025188 
Scleritis 0100532 
Venous thrombosis
Blood clot in vein
Visual loss
Loss of vision

more  ]

Vitritis 0011531 

To classify as antiphospholipid syndrome a patient must have at least one of the two following clinical manifestations in addition to the presence of certain laboratory abnormalities.

  1. Venous or arterial thrombosis: this may involve the cerebral vascular system, coronary arteries, pulmonary emboli or thromboses, hepatic or renal veins, ocular veins or arteries
  2. Recurring miscarriages or premature births: patients may have pre-eclampsia in pregnancy and babies may be unexpectedly small
Skin disorders in antiphospholipid syndrome

Livedo reticularis affects up to 80% of people with antiphospholipid antibodies. Other features include:

  • Splinter haemorrhage (one or more red or black streaks on a nail)
  • Leg ulcers, both arterial and venous ulcers
  • Superficial thrombophlebitis
  • Blue toe syndrome
  • Vasculitis involving medium-sized and small vessels
Neurological defects in antiphospholipid syndrome
  • Migraine headaches
  • Seizures
  • Stroke
  • Multi-infarct dementia
Cardiac abnormalities in antiphospholipid syndrome
  • Heart murmur
  • Cardiac valve vegetations
Eye disorders in antiphospholipid syndrome
  • Blindness
Blood abnormalities in antiphospholipid syndrome
  • Thrombocytopenia (low platelet count)
  • Hemolytic anemia (low red cell count due to the destruction of the cells by antibodies)

The catastrophic antiphospholipid syndrome refers to the blockage of blood vessels in multiple organs, which may occur over days or weeks. The condition is serious and often lethal.

Diagnosis of Hughes Syndrome

History and Physical

The clinical features vary significantly and can be as mild as asymptomatic APLA positivity, or as severe as catastrophic APLS. Arterial and venous thrombosis and pregnancy-related complications are the hallmarks of the disease. However, several other organ systems may be involved (non-criteria manifestations).

Specific blood tests

To diagnose APS, the blood needs to be tested for the abnormal antiphospholipid antibodies that increase the risk of blood clots.

This requires a blood test specifically designed to look for these antibodies. A diagnosis of APS can only be made after 2 abnormal blood test results, with at least a 12-week gap between them. This is because harmless antiphospholipid antibodies can sometimes develop in the body for short periods of time.  Usually, this is the result of an infection or a side effect of medication, such as antibiotics. If antiphospholipid antibodies are identified during the first blood test, another test will be needed at a later date to confirm whether the abnormal antibodies are still present.

Vascular Thrombosis

APLS can cause arterial and/or venous thrombosis involving any organ system. APLS related thrombotic events can occur without preceding risk of thrombosis. They can be recurrent and can involve vessels unusual for other-cause-thrombosis (such as upper extremity thrombosis, Budd-Chiari syndrome, and sagittal sinus thrombosis). Venous thrombosis involving the deep veins of lower extremities is the most common venous involvement and may lead to pulmonary embolism resulting in pulmonary hypertension. Any other site may be involved in venous thrombosis, including pelvic, renal, mesenteric, hepatic, portal, axillary, ocular, sagittal, and inferior vena cava.

Arterial thrombosis may involve any sized arteries (aorta to small capillaries). The most common arterial manifestation of APLS is transient ischemic events (TIAs) or ischemic stroke, and the occurrence of TIA or ischemic stroke in young patients without other risk factors for atherosclerosis shall raise suspicion for APLS. Other sites for arterial thrombosis may include retinal, brachial, coronary, mesenteric, and peripheral arteries. The occurrence of arterial thrombosis carries a poor prognostic value, given the high risk of recurrence in these cases.

Pregnancy Morbidity

Pregnancy loss in patients with APLS is common, especially in the second or third trimester. While genetic and chromosomal defects are the most common cause of early (less than 10-week gestation) pregnancy loss, they may also occur in patients with APLS. Tripple positivity (lupus anticoagulant, anticardiolipin and anti-beta-2-glycoprotein-I antibodies), previous pregnancy loss, history of thrombosis, and SLE are risk factors for adverse pregnancy-related outcomes and pregnancy losses in APLS. Besides pregnancy losses, other pregnancy-related complications in APLS include pre-eclampsia, fetal distress, premature birth, intrauterine growth retardation, placental insufficiency, abruptio placentae, and HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelet count).

Cutaneous Involvement

Several cutaneous manifestations have been reported, although all are non-specific for APLS. Livedo reticularis is the most common cutaneous manifestation seen in APLS. However, it can also be seen in the healthy population and in other disorders such as SLE, other connective tissue diseases, vasculitides, sepsis, multiple cholesterol emboli, and Sneddon syndrome. Skin ulcerations, especially in lower extremities ranging from small ulcers to large ulcers resembling pyoderma gangrenosum, have been reported in APLS. Other cutaneous manifestations include nail-fold infarcts, digital gangrene, superficial thrombophlebitis, and necrotizing purpura.

Valvular Involvement

Cardiac valve involvement is very common in APLS, with some studies noting a prevalence as high as 80%.  Mitral and aortic valves are most commonly involved with thickening, nodules, and vegetations evident on echocardiography. This may lead to regurgitation and/or stenosis.

  • Hematological Involvement – Thrombocytopenia has been seen in more than 15% of APLS cases. Severe thrombocytopenia leading to hemorrhage is rare. Positive Coomb test is frequently seen in APLS, although hemolytic anemia is rare.
  • Neurological Involvement – The most common neurological complication of APLS includes TIAs and ischemic stroke, which may be recurrent, leading to cognitive dysfunction, seizures, and multi-infarct dementia. Blindness secondary to the retinal artery or vein occlusion can occur. Sudden deafness secondary to sensorineural hearing loss has been reported.
  • Pulmonary Involvement – Pulmonary artery thromboembolism from deep vein thrombosis is common and may lead to pulmonary hypertension. Diffuse pulmonary hemorrhage resulting from pulmonary capillaritis has been reported.
  • Renal Involvement – Hypertension, proteinuria, and renal failure secondary to thrombotic microangiopathy is the classic renal manifestation of APLS, although this is not specific to APLS. Other renal manifestations reported include renal artery thrombosis leading to refractory hypertension, fibrous intimal hyperplasia with organized thrombi with or without recanalization, and focal cortical atrophy.
  • Catastrophic Anti-Phospholipid Syndrome (CAPS) – CAPS is a rare but life-threatening complication of APLS, with less than 1% of patients with APLS developing CAPS. Mortality is very high (48%), especially in patients with SLE and those with cardiac, pulmonary, renal, and splenic involvement. It is characterized by thrombosis in multiple organs over a short period of time (a few days). Small and medium-sized arteries are most frequently involved. Clinical presentation varies depending on the organ involved and may include peripheral thrombosis (deep vein, femoral artery or radial artery), pulmonary (acute respiratory distress syndrome, pulmonary embolism, pulmonary hemorrhage), renal (thrombotic microangiopathy, renal failure), cutaneous (livedo reticularis, digital ischemia, gangrene, skin ulcerations), cerebral (ischemic stroke, encephalopathy), cardiac (valve lesions, myocardial infarction, heart failure), hematological (thrombocytopenia), and gastrointestinal (bowel infarction) involvement.

Preliminary criteria for the classification of CAPS were published in 2013.  The four criteria are:

  • Involvement of three or more organs/systems/tissues
  • Manifestations developing simultaneously or within less than one week
  • Histopathological confirmation of small vessel occlusion in at least one organ/tissue
  • Laboratory confirmation of the presence of APLA

Definite CAPS can be classified by the presence of all four criteria, while probable CAPS can be classified if 3 criteria are present and the fourth is incompletely fulfilled.


In addition to clinical criteria, the diagnosis of APLS requires the presence of lupus anticoagulant or moderate-high titers of IgG or IgM anticardiolipin or anti-beta-2-glycoprotein I antibodies. The criteria also require a repeat APLA test to be positive 12 weeks after the initial positive test to exclude clinically unimportant or transient antibody. If that duration is less than 12 weeks, or the gap between two separate clinical manifestations and positive laboratory tests is more than 5 years, the diagnosis of APLS is questionable. 

Lupus Anticoagulant Test

Lupus anticoagulant test is the strongest predictor for adverse pregnancy-related events. It is more specific but less sensitive than anticardiolipin antibodies in predicting thrombosis. A positive lupus anticoagulant test is seen in 20% of patients with anticardiolipin antibodies, and anticardiolipin antibodies are seen in 80% of patients with a positive lupus anticoagulant test.  A false-positive syphilis test does not fulfill the criteria for a diagnosis of APLS, but one should always check APLA in patients with previous thrombotic or adverse pregnancy-related events. The presence of a lupus anticoagulant indicates the presence of a coagulation inhibitor of phospholipid-dependent coagulation reactions. It does not react directly with coagulation factors and is not associated with bleeding complications. False-positive and false-negative results can be seen in patients on heparin or warfarin.

It is a four-step test:

  • Prolonged phospholipid-dependent coagulation screening test (activated partial thromboplastin time or dilute Russell viper venom time)
  • Inability to correct the prolonged screening test despite mixing the patient’s plasma with normal platelet-poor plasma. This indicates the presence of an inhibitor
  • Correction or improvement in the prolonged screening test after the addition of excess phospholipid. This indicates phospholipid dependency
  • Exclusion of other inhibitors.

Anticardiolipin and Anti-beta-2-glycoprotein I Antibodies

Anticardiolipin antibodies and anti-beta-2-glycoprotein I antibodies are assessed by enzyme liked immunosorbent assay (ELISA), and common assays include tests for IgG and IgM isotypes. IgG antibodies correlate better with clinical manifestations than IgM or IgA. Titers more than 40 GPL units are associated with thrombotic events, while lower titers have a less proven association with thrombotic events.

Other Laboratory Findings

  • aCL antibodies
  • Anti-beta-2 glycoprotein I antibodies
  • Activated partial thromboplastin time (aPTT)
  • LA tests such as dilute Russell viper venom time (DRVVT)
  • Syphilis (false-positive serology)
  • Complete blood cell count (thrombocytopenia, Coombs-positive haemolytic anaemia)

Blood tests that are used to detect the presence of autoantibodies include:

  • Lupus anticoagulant testing (e.g., dilute Russell viper venom test or DRVVT and hexagonal phase phospholipid neutralization test)
  • Cardiolipin antibodies
  • Beta2 glycoprotein I (β2GP1) antibodies
  • Partial thromboplastin time (PTT)
  • Prothrombin time (PT)
  • Complete blood count (CBC), to evaluate blood cells and platelets
  • A variety of additional tests to evaluate other causes of a person’s symptoms, such as 1:1 Mix study (dilute PTT) to screen for lupus anticoagulant in the blood

Thrombocytopenia or anemia can be seen in APLS frequently. Renal failure and proteinuria may indicate renal involvement with thrombotic microangiopathy. Erythrocyte sedimentation rate may be high during the acute thrombotic event. However, markers of inflammation are usually normal otherwise. Patients with SLE may have positive serologies specific for SLE, such as ANA, anti-Ds-DNA, Anti-smith, etc. Hypocomplementemia is not usually seen in APLS, and when present with renal involvement, it indicates lupus nephritis. Notably, positive ANA and even anti-Ds-DNA is frequently seen in primary APLS without associated SLE, and the presence of these antibodies alone does not imply a diagnosis of SLE in patients without any clinical features of SLE. It may also be important to test a patient with multiple thrombotic events or pregnancy losses for other hypercoagulable states (hyperhomocysteinemia, Factor V Leiden and prothrombin mutations, deficiency of protein C, protein S, or antithrombin III) when indicated.

Classification Criteria

The initial classification criteria, known as the Sapporo criteria, was published in 1999, which was updated in 2016. The revised Sapporo classification criteria for APLS require at least one laboratory and one clinical criterion to be met. One of the following clinical findings should be confirmed to diagnose antiphospholipid antibody syndrome.

Vascular Thrombosis

  • One or more events of arterial, venous, or small-vessel thrombosis of any organ. Thrombosis must be objectively confirmed with appropriate imaging or histopathology. For histopathology, thrombosis shall be present without significant vessel wall inflammation.
  • Superficial venous thrombosis shall not be included as a criterion.
  • A thrombotic episode in the past can be included as a criterion as long as it was appropriately confirmed by appropriate diagnostic means, and there was no other cause of thrombosis.

Pregnancy Morbidity 

  • One or more unexplained fetal deaths of the morphologically normal fetus (normal fetal morphology confirmed by ultrasound or direct examination) at or beyond 10 weeks of gestation.
  • One or more premature births of morphologically normal neonates before the 34th week of gestation. Prematurity must be secondary to eclampsia, severe preeclampsia, or placental insufficiency.
  • Three or more consecutive spontaneous abortions before the 10th week of gestation after ruling out any anatomic or hormonal abnormalities in the mother and parental chromosomal causes.

Laboratory Criteria

One of the following laboratory findings should be confirmed to diagnose antiphospholipid antibody syndrome.

  • Detection of lupus anticoagulant in plasma on two or more occasions, 12 or more weeks apart.
  • Detection of IgG or IgM anticardiolipin antibodies in serum or plasma in moderate to high titers (more than 40 GPL or more than 99th percentile) measured by standard ELISA on two or more occasions, twelve or more weeks apart.
  • Detection of IgG or IgM anti-beta-2-glycoprotein I antibody in serum or plasma in moderate to high titers (more than 99th percentile) measured by standard ELISA, on two or more occasions, 12 or more weeks apart.

Anticardiolipin antibodies

  • Anti-cardiolipin antibodies can be detected using an enzyme-linked immunosorbent assay (ELISA) immunological test, which screens for the presence of β2glycoprotein 1 dependent anticardiolipin antibodies (ACA). A low platelet count and positivity for antibodies against β2-glycoprotein 1 or phosphatidylserine may also be observed in a positive diagnosis.
  • Classification with APS requires evidence of both one or more specific, documented clinical events (either a vascular thrombosis and/or adverse obstetric event) and the confirmed presence of a repeated aPL. The Sapporo APS classification criteria (1998, published in 1999) were replaced by the Sydney criteria in 2006.[rx] Based on the most recent criteria, classification with APS requires one clinical and one laboratory manifestation:


  • A documented episode of arterial, venous, or small vessel thrombosis — other than superficial venous thrombosis — in any tissue or organ by objective validated criteria with no significant evidence of inflammation in the vessel wall
  • 1 or more unexplained deaths of a morphologically normal fetus (documented by ultrasound or direct examination of the fetus) at or beyond the 10th week of gestation and/or 3 or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded or at least 1 premature birth of a morphologically normal neonate before the 34th week of gestation due to eclampsia or severe pre-eclampsia according to standard definitions, or recognized features of placental insufficiency


  • Anti-cardiolipin IgG and/or IgM measured by standardized, non-cofactor dependent ELISA on 2 or more occasions, not less than 12 weeks apart; medium or high titer (i.e., > 40 GPL or MPL,[rx] or > the 99th percentile)
  • Anti-β2 glycoprotein I IgG and/or IgM measured by standardized ELISA on 2 or more occasions, not less than 12 weeks apart; medium or high titer (> the 99th percentile)
  • Lupus anticoagulant detected on 2 occasions not less than 12 weeks apart according to the guidelines of the International Society of Thrombosis and Hemostasis.
  • There are 3 distinct APS disease entities: primary (the absence of any comorbidity), secondary (when there is a pre-existing autoimmune condition, most frequently systemic lupus erythematosus, SLE), and catastrophic (when there is simultaneous multi-organ failure with small vessel occlusion).

According to a 2016 consensus statement,[rx] it is advisable to classify APS into one of the following categories for research purposes:

  • I: more than one laboratory criterion present in any combination;
  • IIa: lupus anticoagulant present alone
  • IIb: anti-cardiolipin IgG and/or IgM present alone in medium or high titers
  • IIc: anti-β2 glycoprotein I IgG and/or IgM present alone in a titer greater than 99th percentile

The International Consensus Statement is commonly used for Catastrophic APS diagnosis.[rx] Based on this statement, a Definite CAPS diagnosis requires:

  • a) Vascular thrombosis in three or more organs or tissues and
  • b) Development of manifestations simultaneously or in less than a week and
  • c) Evidence of small vessel thrombosis in at least one organ or tissue and
  • d) Laboratory confirmation of the presence of aPL.

VDRL, which detects antibodies against syphilis, may have a false-positive result in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive), although the more specific test for syphilis, FTA-Abs, that use recombinant antigens will not have a false-positive result

Treatment of Hughes Syndrome

APS is characterized by recurrent thrombotic events that have not been properly managed. Thus anti-thrombotic medication is necessary for long-term management to reduce thrombotic risk or pregnancy morbidity. Choosing the type of pharmacological treatment and the intensity and duration of anticoagulation depends on the clinical type, comorbidities, severity of the APS, and the risk of bleeding. Change of life habits that are known to increase the risk of thrombotic events has to be stressed in addition to avoiding estrogens and cigarette smoking. When present, the active control of elevated serum LDL-cholesterol and triglycerides, arterial hypertension, and blood sugar, is recommended.

Patients with APS may be evaluated in an outpatient setting. In-patient evaluation is required if the patient presents with a significant clinical event. Patients with CAPS require intense observation and treatment, often in the intensive care unit.

Venous thromboembolism

  • Venous thromboembolism is the most common initial clinical manifestation in APS and occurs in 32% of patients who meet consensus conference diagnostic criteria ().
  • Initial treatment consists of unfractionated or low molecular-weight heparin for at least 5 days overlapped with warfarin therapy ().
  • The use of warfarin with an international normalized ratio (INR) of 2.0- 3.0 reduces the risk of recurrent venous thrombosis by 80% to 90% irrespective of the presence of aPL (). For long-term treatment of venous thromboembolism, retrospective case series have suggested that high-intensity warfarin (INR 3.0) is more effective than either aspirin or warfarin administered with an INR < 3.0 (, ).
  • Some studies have found that high-intensity warfarin is better than moderate-intensity warfarin for the prevention of recurrent thrombosis. However, a significant excess of minor bleeding was evident in patients who were given high-intensity warfarin ().

Arterial thromboembolism

  • Arterial events in APS most commonly involve the cerebral circulation with stroke being the initial clinical manifestation in 13% and a transient ischemic attack in 7% of patients. () The association between APS and another arterial thrombosis, including myocardial infarction, is less certain.
  • Warfarin and aspirin appear to be equivalent for the prevention of thromboembolic complications in patients with a first ischemic stroke and aPL. Patients with a first ischemic stroke and a single positive antiphospholipid antibody test result who do not have another indication for anticoagulation may be treated with aspirin (325 mg/d) or moderate-intensity warfarin (INR, 1.4 – 2.8) (). Aspirin is likely to be preferred because of its ease of use and lack of need for laboratory monitoring.
  • It is known that aPL may persist in the serum of APS patients for long periods of time, but thrombotic events occur only occasionally. It has been suggested that aPL (‘first hit’) raises the thrombophilic threshold (i.e., induces a prothrombotic/proinflammatory phenotype in endothelial cells), but that clotting only takes place in the presence of a ‘second hit’ or triggering event (i.e., an infection, a surgical procedure, use of estrogens, prolonged immobilization, etc.) ().
  • In general, treatment regimens for APS must be individualized based on the patient’s current clinical status, presence of co-morbidities, and history of thrombotic events. Asymptomatic individuals in whom blood test findings are positive do not require specific treatment in addition to avoidance of known risk factors.

Prophylactic therapy

  • Eliminate other risk factors such as oral contraceptives, smoking, hypertension, hyperhomocysteinemia, or hyperlipidemia.
  • Low-dose aspirin is usually used. Clopidogrel may be useful in patients allergic to aspirin.
  • In patients with SLE, consider HQC, which may have intrinsic antithrombotic properties.
  • Consider the use of statins, especially in patients with hyperlipidemia.

Initial therapies

  • Corticosteroids, such as prednisone – Prednisone is used to treat conditions such as arthritis, blood disorders, breathing problems, severe allergies, skin diseases, cancer, eye problems, and immune system disorders. Prednisone belongs to a class of drugs known as corticosteroids.
  • Hydroxychloroquine – Hydroxychloroquine (HCQ) is an important disease-modifying agent for the treatment of systemic autoimmune diseases, particularly SLE. In animal models of APS, treatment with HCQ leads to smaller thrombi and less durable persistence.[] HCQ may also mediate a reduction of aPL-β2GPI complex binding to phospholipid bilayers and human monocytes.[]
  • Low molecular weight heparin – Several LMWH products are now available for clinical use. Dosing requirements are individualized for each product (). The advantages of LMWH over unfractionated heparin are reviewed separately.
  • Unfractionated heparin – Unfractionated heparin is preferred to LMWH in certain circumstances. The major potential advantage of unfractionated heparin over LMWH is in the setting of hemorrhage (a rare complication of the APS). Unfractionated heparin can be reversed quickly with protamine while LMWH is not completely reversible with this approach. The major condition in which hemorrhage is due to APS is when antibodies to prothrombin are present.
  • Warfarin – Following stabilization of the patient, warfarin is begun. Warfarin is the standard of care for the chronic management of patients with APS who are not pregnant. INR should be maintained between 2.0 and 3.0 (). However, aPL may create problems in monitoring the INR. A monotonous diet with only slight variations in the amount of vitamin K intake, intensification of monitoring when a different medication has to be used, and above all, patient education on the importance of close monitoring are crucial for the APS management to succeed.
  • Statins – Statins, which function as 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been widely used for primary and secondary cardiovascular disease prevention due to their cholesterol-lowering, anti-inflammatory, and anti-thrombotic effects.[] Fluvastatin-treated APS mice have significantly smaller thrombi, decreased inflammatory molecules (intercellular cell adhesion molecule [ICAM]-1), and reduced leukocyte adhesion to endothelial cells compared with controls.[]
  • Vitamin K antagonists – Vitamin K antagonists such as warfarin have historically been the primary treatment for thrombotic APS. Their efficacy in preventing recurrent thrombosis has been supported by multiple studies. One systemic review suggested that anticoagulation with moderate-intensity warfarin (INR between 2.0 and 3.0) reduced the risk of recurrent venous thrombosis by 80% to 90%.[]
  • Aspirin. Aspirin is of minimal or no benefit for the prevention of thrombotic APS manifestations in patients who have experienced previous events according to retrospective series (). However, some studies suggest that aspirin (81 mg/day) reduces the risk of thrombosis in aPL- positive patients (). In addition to its antiplatelet effects, low-dose aspirin (ASA) (50 to 100 mg) enhances leukocyte-derived interleukin-3 production, which stimulates normal trophoblast growth and hormone expression ().
  • Clopidogrel – It has anecdotally been reported to be helpful in patients with APS and may be useful in those allergic to aspirin. Its use is not advised for the treatment of APS ().
  • Heparin – The initial approach to thrombosis in APS is identical to that of many other thromboses. For acute thrombotic events, the first therapy is heparin. Low molecular weight heparin (LMWH) has replaced unfractionated heparin as the standard of care for most thrombotic events.
  • Full dose LMWH (1mg/Kg twice daily) is usually given simultaneously with warfarin and is overlapped with warfarin for a minimum of four to five days until the International Normalized Ratio (INR) has been within the therapeutic range (2.0 to 3.0) for two consecutive days ().

Some characteristics of heparin

  • The antithrombotic effects include potentiating the anti-thrombin effects of antithrombin and other endogenous antithrombin effectors, increasing the levels of factor Xa inhibitor, and inhibiting platelet aggregation.
  • Heparin may also bind to aPLs and render them inactive ().
  • Heparin may also block tissue factor-mediated placental bed immunopathology (, ).

GPIIbIIIa inhibitors

  • Platelet glycoproteins/IIa and IIb/IIIa – aPL-enhanced thrombosis in vivo can be abrogated by infusions of a GPIIb/IIIa antagonist monoclonal antibody. Recently, it has been reported that heterozygosity for platelet glycoproteins/IIa and IIb/IIIa increase arterial thrombosis in patients with APS (). These data indicate that GPIIb/IIIa antagonists or platelet membrane glycoprotein IIb/IIIa receptor inhibitors may prove to be useful in the treatment of an acute thrombotic event, particularly an arterial event, in patients with APS. In addition, the combination of GPIIb/IIIa antagonists and an ADP receptor antagonist, e.g., ticlopidine, is an attractive therapeutic strategy. It provides fast and continuous platelet inhibition since pre-stimulation of platelets by agonists leads to the exposure of phosphatidylserine on the outer membrane of the cell. As a result, it produces an anti-β2GPI/β2GPI complex on the exposed phosphatidylserine before interacting with a specific platelet receptor to potentiate activation ().
  • B cell-directed therapy – Anecdotal reports have reported a beneficial effect of Rituximab on APLA titers. A recent open-label pilot study of Rituximab in primary APS reported that Rituximab had some efficacy in controlling non-criteria manifestations such as thrombocytopenia, hemolytic anemia, and skin ulcers though it did not substantially change the APLA profile.
  • Hydroxychloroquine (HCQ) – HCQ inhibits the aPL-induced expression of platelet GPIIb/IIIa receptor (platelet activation) dose-dependently and also reverses the binding of aPL–β2GPI complexes to phospholipid bilayers (). In SLE patients, those receiving HCQ experienced fewer thrombotic events and results from the Baltimore Lupus Cohort showed a decreased risk of arterial thrombosis (). HCQ could be used in patients with APS and thrombosis as a second-line agent together with anticoagulation therapy. We still do not have a study result for a consistent recommendation for HCQ in APS although, in SLE, it is known to reduce the thrombotic risk, including during pregnancy.
  • Rituximab (RTX) – RTX has been shown to be a good treatment for life-threatening CAPS in a few patients and case reports suggest it may be successful in patients with aPL, autoimmune-mediated thrombocytopenia, and hemolytic anemia. Statute. demonstrated normalization of ACL antibody titer after autologous hematopoietic stem-cell transplantation in patients with APS secondary to SLE (). Recently, an uncontrolled and nonrandomized pilot study suggested that the safety of rituximab in aPL-positive patients with non-criteria manifestations of APS is consistent with the safety profile of rituximab. Despite causing no substantial change in aPL profiles, rituximab may be effective in controlling some but not all non-criteria manifestations of APS ().
  • Eculizumab – Complement activation plays an important role in APS pathogenesis. For example, murine studies have shown that complement activation is required for aPL-mediated fetal loss.[] In these models, complement inhibition prevents fetal growth restriction and can also reduce aPL-mediated thrombus formation.[,] Eculizumab is a humanized monoclonal antibody currently approved for the treatment of atypical hemolytic uremic syndrome and paroxysmal nocturnal hematuria.[]
  • Defibrotide – is a mixture of oligonucleotides derived from the controlled depolymerization of porcine intestinal mucosal DNA with antithrombotic, anti-ischemic, and anti-inflammatory activities. It binds to the vascular endothelium, modulates platelet activity, promotes fibrinolysis, decreases thrombin generation and activity, and reduces circulating levels of plasminogen activator inhibitor type 1 (PAI-1).[] It may also act
  • Coenzyme Q10 (CoQ10) – plays an important role in the electron transport chain of the mitochondrial membrane, while adequate CoQ10 levels protect cells from protein oxidation and lipid peroxidation. Supplementation of CoQ10 has been trialed in patients with coronary artery disease, where it decreases the production of proinflammatory cytokines.[]


  • Though there aren’t any exercises that can help specifically with the condition, regular exercise keeps you fit, keeps your heart healthy, and helps prevent blood clots.
  • Yoga, walking, swimming, and Tai Chi are good low-impact types of exercise that can help you physically and mentally. Tai Chi also helps with any problems you have with your balance.
  • Speak to a member of your healthcare team before you make any changes to your regular exercise routine.


You should aim to routinely stick to a healthy, balanced diet, containing a good mix of carbohydrates, proteins, fruit, vegetables and low-fat dairy products.

It’s important to make sure your diet has food containing vitamin K in it. Vitamin K affects your blood’s ability to clot and can affect how warfarin works. Too little vitamin K in your diet can increase your INR levels, while too much decreases them. Vitamin K is mostly found in leafy green vegetables, such as:

  • spinach
  • kale
  • broccoli
  • asparagus
  • lettuce.
  • chickpeas
  • liver
  • egg yolks
  • wholegrain cereals
  • mature cheese and blue cheese
  • avocado
  • olive oil.

While it’s important to make sure you have these vegetables in your diet, you need to balance the amount you eat each day. Too much could increase your risk of clotting and affect your INR levels, but too little is unhealthy. Speak to your doctor about the amount of vitamin K in your diet and how it could affect your warfarin dose. Some herbs and spices also affect your blood flow and the time it takes to clot.

The anticoagulant effect of warfarin can also be affected by:

  • cranberry juice
  • grapefruit juice
  • pomegranate juice
  • garlic
  • Dong Quai
  • danshen (red sage)
  • devil’s claw
  • Korean ginseng
  • green tea.

A member of your healthcare team should be able to advise you on a good healthy diet that won’t interfere with your treatment. Increasing the amount of essential fatty acids in your diet, particularly omega-3 fatty acids, could help reduce the risk of clots. These are found in oily fish. However, there are no clinical trials to support this. If you’re trying for a baby, it may be best to avoid fish liver oil supplements, as they contain large amounts of vitamin A, which can be harmful.

Complementary and alternative treatments

At present, there are no complementary medicines that have been shown to help with APS. Besides vitamin K, supplements such as vitamin C, vitamin E, coenzyme Q10, and the remedies devil’s claw and St John’s wort can also alter the body’s reaction to warfarin. Speak to your doctor, pharmacist, or healthcare team before trying any new treatment.

Current treatment of thrombosis

Treatments in APS are directed at modulating the final event or second hit. Treatments that modulate the early effects of aPL on target cells – that is monocytes or endothelial cells (first hit) – would be more beneficial and potentially less harmful than current treatments.

The current antithrombotic approach to aPL-positive patients may be replaced by an immunomodulatory approach in the future as our understanding of the mechanisms of aPL-mediated thrombosis improves. Understanding the molecular mechanisms triggered by aPL and identifying biomarkers released as a consequence of cell activation may help us design new ways to treat clinical manifestations in APS.

The main target recognized by aPL binds to endothelial cells and monocytes through its fifth domain. aPL/anti-β2GPI antibodies then bind to the domain I of β2GPI, and upon clustering and formation of complexes, they trigger cell activation ().

Therefore, blocking the binding of aPL or inhibiting the binding of β2GPI to target cells may be the most specific approach to ameliorate their pathogenic effects without interrupting any important physiologic mechanisms. Recently, Ioannou et al. demonstrated that the soluble recombinant domain I of β2GPI abrogates, in a dose-dependent fashion, the in vitro and in vivo effects of anti-β2GPI antibodies. This underscores the possibility of utilizing decoy peptides that are part of β2GPI to abrogate the binding of pathogenic aPL to target cells in the treatment of patients with APS. Nevertheless, human studies are needed to establish the safety and efficacy of such treatment (, ).



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Mitochondrial Disease – Causes, Symptoms, Treatment,

Mitochondrial diseases are caused by defects in mitochondria, which are energy factories found inside almost all the cells in the body.  Mitochondrial diseases that cause prominent muscular problems are called mitochondrial myopathies (Myo means muscle and pathos means disease), while mitochondrial diseases that cause both prominent muscular and neurological problems are called mitochondrial encephalomyopathies (encephalon refers to the brain).

A typical human cell relies on hundreds of mitochondria to meet its energy needs.  The symptoms of mitochondrial disease vary because a person can have a unique mixture of healthy and defective mitochondria, with a unique distribution in the body.  In most cases, mitochondrial disease is a multisystem disorder affecting more than one type of cell, tissue, or organ.

Because muscle and nerve cells have especially high energy needs, muscular and neurological problems are common features of mitochondrial disease.  Other frequent complications include impaired vision, cardiac arrhythmia (abnormal heartbeat), diabetes, and stunted growth.  Usually, a person with mitochondrial disease has two or more of these conditions, some of which occur together so regularly that they are grouped into syndromes.

What causes mitochondrial myopathies?

Mitochondrial diseases are caused by genetic mutations.  Genes provide the instructions for making proteins, and the genes involved in mitochondrial disease normally make proteins that work inside mitochondria.  Within each mitochondrion, these proteins make up part of an assembly line that uses fuel molecules (sugars and fats) derived from food combined with oxygen to manufacture the energy molecule adenosine triphosphate or ATP.

Proteins at the beginning of the assembly line import sugars and fats into the mitochondrion and then break them down to provide energy.  Proteins toward the end of the line—organized into five groups called complexes I, II, III, IV, and V—harness that energy to make ATP.  This highly efficient part of the ATP manufacturing process requires oxygen, and is called the respiratory chain.  Some mitochondrial diseases are named for the part of the respiratory chain that is affected, such as complex I deficiency.

A cell filled with defective mitochondria becomes deprived of ATP and can accumulate a backlog of unused fuel molecules and destructive forms of oxygen called free radicals or reactive oxygen species.  These are the targets of antioxidant compounds (found in many foods and nutritional supplements) that appear to offer general defenses against aging and disease.

In such cases, excess fuel molecules are used to make ATP by inefficient means, which can generate potentially harmful byproducts such as lactic acid.  (This also occurs when a cell has an inadequate oxygen supply, which can happen to muscle cells during strenuous exercise.)  The buildup of lactic acid in the blood—called lactic acidosis—is associated with muscle fatigue, and might damage muscle and nerve tissue.

Muscle and nerve cells use the ATP derived from mitochondria as their main source of energy.  The combined effects of energy deprivation and toxin accumulation in these cells can lead to many muscular and neurological symptoms.

What are the symptoms of mitochondrial myopathy?


The main symptoms of mitochondrial myopathy are muscle fatigue, weakness, and exercise intolerance.  The severity of any of these symptoms varies greatly from one person to the next, even in the same family.

In some individuals, weakness is most prominent in muscles that control movements of the eyes and eyelids.  Two common consequences are the gradual paralysis of eye movements, called progressive external ophthalmoplegia (PEO), and drooping of the upper eyelids, called ptosis.  Often, people automatically compensate for PEO by moving their head to look in different directions, and might not notice any visual problems.  Ptosis can impair vision and cause a listless expression, but can be corrected by surgery.

Mitochondrial myopathies also can cause weakness and wasting in other muscles of the face and neck, which can lead to difficulty with swallowing and, more rarely, slurred speech.  People with mitochondrial myopathies also may experience muscle weakness in their arms and legs.

Exercise intolerance, also called exertional fatigue, refers to unusual feelings of exhaustion brought on by physical exertion.  The degree of exercise intolerance varies greatly among individuals.  Some people might have trouble only with athletic activities like jogging, while others might experience problems with everyday activities such as walking to the mailbox or lifting a milk carton.

Sometimes, mitochondrial disease is associated with muscle cramps.  In rare instances it can lead to muscle breakdown and pain after exercise.  This breakdown causes leakage of a protein called myoglobin from the muscles into the urine (myoglobinuria).  Cramps or myoglobinuria usually occur when someone with exercise intolerance “overdoes it,” and can happen during the overexertion or several hours afterward.

While overexertion should be avoided, moderate exercise appears to help people with mitochondrial myopathy maintain strength.


Mitochondrial encephalomyopathy typically includes some of the symptoms of myopathy plus one or more neurological symptoms.  Again, these symptoms vary greatly among individuals in both type and severity.

In addition to affecting eye muscles, mitochondrial encephalomyopathy can affect the eye itself and parts of the brain involved in vision.  For instance, vision loss, due to optic atrophy (shrinkage of the optic nerve) or retinopathy (degeneration of some of the cells that line the back of the eye), is a common symptom of mitochondrial encephalomyopathy.

Sensorineural hearing loss is a common symptom of mitochondrial diseases.  It is caused by damage to the inner ear (the cochlea) or to the auditory nerve, which connects the inner ear to the brain.  Sensorineural hearing loss is permanent but it can be managed through alternative forms of communication, hearing aids, or cochlear implants.  Hearing aids amplify sounds before they reach the inner ear.  Cochlear implants bypass damaged parts of the inner ear and stimulate the auditory nerve.

Mitochondrial diseases can cause ataxia, which refers to trouble with balance and coordination.  People with ataxia are prone to falls, and may need to use supportive aids such as railings, a walker, or a wheelchair.  Physical and occupational therapy also may help.

Other common symptoms of mitochondrial encephalomyopathy include migraine headaches and seizures.  There are many effective medications for treating and helping to prevent migraines and seizures, including anticonvulsants and other drugs developed to treat epilepsy.

Special issues in mitochondrial disease

Respiratory care

Mitochondrial diseases can affect the muscles or parts of the brain that support breathing.  A person with mild respiratory problems might require occasional respiratory support, such as pressurized air.  Someone with more severe problems might require permanent support from a ventilator.  People should watch for signs of respiratory problems (such as shortness of breath or morning headaches) and have regular checkups with a respiratory specialist.

Cardiac care

Some mitochondrial diseases can cause cardiomyopathy (heart muscle weakness) or arrhythmia (irregular heart beat).  Although dangerous, cardiac arrhythmia is treatable with a pacemaker, which stimulates a normal heartbeat.  People with mitochondrial disorders may need to have regular examinations by a cardiologist.

Other potential health issues

People with a mitochondrial disease may experience gastrointestinal problems, diabetes, and/or kidney problems.  Some of these problems are direct effects of mitochondrial defects in the digestive system, pancreas (in diabetes), or kidneys, and others are indirect effects of mitochondrial defects in other tissues.  For example, myoglobinuria stresses the kidneys’ ability to filter waste from the blood and can cause kidney damage.

What issues are of special concern in children?


Although gradual paralysis of eye movements (PEO) and ptosis typically cause only mild visual impairment in adults, they are potentially more harmful in children with mitochondrial myopathies.

Because the development of the brain is sensitive to childhood experiences, either PEO or ptosis during childhood can cause permanent damage to the brain’s visual system.  It is important for children with signs of PEO or ptosis to have their vision checked by a specialist.

Developmental delays

Due to muscle weakness, brain abnormalities, or a combination of both, children with mitochondrial diseases may have difficulty developing certain skills.  For example, they might take an unusually long time to reach motor milestones such as sitting, crawling, and walking.  As they get older, they may be unable to get around as easily as other children their age, and may have speech problems and/or learning disabilities.  Children affected by these problems may benefit from early intervention and services such as physical and speech therapy, and possibly an individualized education program at school.

Are there specific treatments for the mitochondrial myopathies?

Instead of focusing on specific complications of mitochondrial disease, some treatments under investigation aim at fixing or bypassing the defective mitochondria.  These treatments are nutritional supplements based on three natural substances involved in ATP production in our cells.

One substance, creatine, normally acts as a reserve for ATP by forming a compound called creatine phosphate (also called phosphocreatine).  When a cell’s demand for ATP exceeds the amount its mitochondria can produce, creatine can release phosphate (the “P” in ATP) to rapidly enhance the ATP supply.  In fact, creatine phosphate typically provides the initial burst of ATP required for strenuous muscle activity.

Another substance, carnitine, generally improves the efficiency of ATP production by helping import certain fuel molecules into mitochondria and cleaning up some of the toxic byproducts of ATP production.  Carnitine is available as an over-the-counter supplement called L-carnitine.

Finally, coenzyme Q10, also called CoQ10 or ubiquinone, is a component of the mitochondrial respiratory chain (which uses oxygen to manufacture ATP).  CoQ10 is also an antioxidant.  Some mitochondrial diseases are caused by CoQ10 deficiency, and CoQ10 supplementation is clearly beneficial in these cases.  It might provide some relief from other mitochondrial diseases.

Creatine, L-carnitine, and CoQ10 supplements often are combined into a “cocktail” for treating mitochondrial disease.  Although there is a need for careful studies to confirm the value of this treatment, some people with mitochondrial disease have reported modest benefits.

How are mitochondrial myopathies inherited?

The inheritance of mitochondrial diseases is complex, and often a mitochondrial myopathy can be difficult to trace through a family tree.  In fact, many cases of mitochondrial disease are sporadic, meaning that they occur without any family history.

To understand how mitochondrial diseases are inherited, it is important to know that there are two types of genes essential to mitochondria. The first type is housed within the nucleus—a compartment within our cells that contains most of our genetic material, or DNA. The second type resides exclusively within DNA contained inside the mitochondria.

Mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) can cause mitochondrial disease.

Nuclear DNA is packaged into structures called chromosomes—22 pairs of non-sex-related chromosomes (called autosomes) and a single pair of sex chromosomes (XX in females and XY in males).  This means that except for genes on the X chromosome, everyone has two copies of the genes in DNA, with one copy inherited from each parent.  There are three inheritance patterns seen for diseases caused by DNA mutations:

  • Autosomal recessive means that it takes two mutant copies of a gene—one inherited from each parent—to cause the disease.
  • Autosomal dominant means it takes just one mutant copy of a gene—inherited from one parent—to cause the disease.
  • Usually, X-linked diseases appear only in males.  An affected male’s mother and any daughters he has will carry the gene for the disease but typically will not have symptoms.

Unlike nDNA, mtDNA passes only from mother to child.  This is because during conception, when the sperm fuses with the egg, the sperm’s mitochondria and its mtDNA are destroyed.  Mitochondrial diseases caused by mtDNA mutations are unique because they are inherited in a maternal pattern.  A mother can pass defective mtDNA to any of her children, but only her daughters—and not her sons—will pass it to the next generation.

Another unique feature of mtDNA diseases arises from the fact that a typical human cell contains only one nucleus but hundreds of mitochondria.  A single cell can contain both mutant and normal mitochondria, and the balance between the two will determine the cell’s health, which can also explain the range of symptoms in mtDNA diseases.

The risk of passing on mitochondrial disease to a child depends on many factors, including whether the disease is caused by mutations in DNA or mtDNA.  To find out more about these risks, talk with a doctor or genetic counselor.

What syndromes occur with mitochondrial disease?

Some syndromes associated with mitochondrial disease are:

Barth syndrome

Onset: infancy

Features: Typical symptoms include cardiomyopathy, general muscle weakness, and a low white blood cell count, which leads to an increased risk of infection.  This syndrome was once considered uniformly fatal in infancy, but some individuals are now living much longer.

Inheritance pattern: X-linked

Chronic progressive external ophthalmoplegia (cPEO)

Onset:  usually in adolescence or early adulthood

Features:  PEO is often a symptom of mitochondrial disease.  In some people, it is a chronic, slowly progressive condition associated with instability to move the eyes and general weakness and exercise intolerance.

Inheritance pattern:  autosomal, but may occur sporadically

Kearns-Sayre syndrome (KSS)

Onset:  before age 20

Features:  PEO (usually as the initial symptom) and pigmentary retinopathy, a “salt-and-pepper” pigmentation in the retina that can affect vision.  Other common symptoms include cardiomyopathy, conduction block (a type of cardiac arrhythmia) ataxia, short stature, neuropathy, and deafness.

Inheritance pattern:  autosomal (mostly sporadic)

Leigh syndrome (MILS, or maternally inherited Leigh syndrome)

Onset: infancy or early childhood

Features: Brain abnormalities that can result in abnormal muscle tone, ataxia, seizures, impaired vision and hearing, developmental delays, and respiratory problems.  Infants with the disease have a poor prognosis.

Inheritance pattern: maternal, autosomal recessive, X-linked

Mitochondrial DNA depletion syndromes (MDDS)

Onset: infancy

Features: A myopathic form of MDDS is characterized by weakness that eventually affects the respiratory muscles.  Some forms of MDDS, such as Alpers syndrome, are marked by brain abnormalities and progressive liver disease.  The anticonvulsant sodium valproate should be used with caution in children with Alpers syndrome because it can increase the risk of liver failure.

Inheritance pattern: autosomal

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)

Onset:  childhood to early adulthood

Features:  The hallmarks of MELAS are encephalomyopathy with seizures and/or dementia, lactic acidosis, and recurrent stroke-like episodes.  These episodes are not typical strokes, which are interruptions in the brain’s blood supply that cause sudden neurological symptoms.  However, the episodes can produce stroke-like symptoms in the short term (such as temporary vision loss, difficulty speaking, or difficulty understanding speech) and lead to progressive brain injury.  The cause of the stroke-like episodes is unclear.

Inheritance pattern:  maternal

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Onset: usually before age 20

Features:This disorder is characterized by PEO, ptosis, limb weakness, and gastrointestinal (digestive) problems, including vomiting, chronic diarrhea, and abdominal pain.  Another common symptom is peripheral neuropathy (a malfunction of the nerves that can lead to sensory impairment and muscle weakness).

Inheritance pattern: autosomal recessive

Myoclonus epilepsy with ragged red fibers (MERRF)

Onset: late childhood to adolescence

Features: The most prominent symptoms of MERRF are myoclonus (muscle jerks), seizures, ataxia, and muscle weakness.  The disease also can cause hearing impairment and short stature.

Inheritance pattern: maternal

Neuropathy, ataxia, and retinitis pigmentosa (NARP)

Onset: infancy to adulthood

Features: NARP is caused by an mtDNA mutation that is also linked to MILS, and the two syndromes can occur in the same family.  In addition to the core symptoms for which it is named, NARP can involve developmental delay, seizures, and dementia.  (Retinitis pigmentosa refers to a degeneration of the retina in the eye, with resulting loss of vision).  Inheritance pattern:  maternal

Pearson syndrome

Onset: infancy

Features: This syndrome involves severe anemia and malfunction of the pancreas.  Children who have the disease usually go on to develop Kearns-Sayre syndrome.

Inheritance pattern:  autosomal (often sporadic)

How are mitochondrial diseases diagnosed?

The hallmark symptoms of mitochondrial myopathy include muscle weakness, exercise intolerance, impaired hearing and vision, ataxia, seizures, learning disabilities, heart defects, diabetes, and poor growth—none of which are unique to mitochondrial disease.  However, a combination of three or more of these symptoms in one person strongly points to mitochondrial disease, especially when the symptoms involve more than one organ system.

To evaluate the extent of these symptoms, a physician usually begins by taking the individual’s medical history.  Because mitochondrial diseases are genetic, a family history also is an important part of the diagnosis.  Physical and neurological exams also will be part of the evaluation.

The physical exam typically includes tests of strength and endurance, such as an exercise test (which can involve activities like repeatedly making a fist).  The neurological exam can include tests of reflexes, vision, speech, and basic cognitive (thinking) skills.

Typically, the doctor will order laboratory tests to look for diabetes and liver and kidney problems.  The doctor is likely to order an electrocardiogram (EKG) to check the heart for signs of arrhythmia and cardiomyopathy.

Tests may be ordered to look for abnormalities in the brain and muscles.  Diagnostic imaging that produce detailed pictures of organs, bones, and tissues, such as computed tomography (CT) or magnetic resonance imaging (MRI), might be used to inspect the brain for developmental abnormalities or signs of damage.  In an individual who has seizures, the doctor might order an electroencephalogram (EEG), which involves placing electrodes on the scalp to record brain activity.

Since lactic acidosis is a common feature of mitochondrial disease, it is routine to test for elevated lactic acid in the blood and urine.  Some cases might warrant measuring lactic acid in the cerebral spinal fluid (CSF) that fills spaces within the brain and spinal cord.  The measurement can be made by collecting CSF through a spinal tap, or estimated by MR spectroscopy—a technique that uses an MRI signal to detect changes in the level of lactic acid and other chemicals in the brain.

One of the most important tests for mitochondrial disease is the muscle biopsy, which involves removing and examining a small sample of muscle tissue.  When treated with a dye that stains mitochondria red, muscles affected by mitochondrial disease often show ragged red fibers—muscle cells (fibers) that have excessive mitochondria.  Other stains can detect the absence of essential mitochondrial enzymes in the muscle.  It also is possible to extract mitochondrial proteins from the muscle and measure their activity.

Noninvasive techniques can be used to examine muscle without taking a tissue sample.  For instance, MR spectroscopy can be used to measure levels of the organic molecule phosphocreatine and ATP (which are often depleted in muscles affected by mitochondrial disease).

Finally, genetic testing can determine whether someone has a genetic mutation that causes mitochondrial disease.  These tests use genetic material extracted from blood or from a muscle biopsy.  Although a positive test result can confirm diagnosis of a mitochondrial disorder, a negative test result can be harder to interpret.  It could mean a person has a genetic mutation that the test was not able to detect.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

In conjunction with other NIH Institutes, private organizations, and industry, NINDS supports research focused on effective treatments and cures for mitochondrial myopathies and other mitochondrial diseases.

Scientists are investigating the possible benefits of exercise programs and nutritional supplements, primarily natural and synthetic versions of CoQ10.  While CoQ10 has proven benefit for primary CoQ10 deficiency, it is unclear whether other nutritional supplements are useful for treating mitochondrial diseases.

Scientists have identified many of the genetic mutations that cause mitochondrial diseases.  They have used that knowledge to create animal models of mitochondrial disease, which can be used to investigate potential treatments.  Scientists also have designed genetic tests that allow accurate diagnosis of mitochondrial defects and provide valuable information for family planning.

Most importantly, knowing the genetic mutations that cause mitochondrial disease opens up the possibility of developing treatments that are specifically targeted.  One remarkable example where knowledge about mitochondrial disease genetics has led to a potential therapy is MNGIE.  This syndrome is caused by genetic defects in an enzyme called thymidine phosphorylase (TP).  Loss of the TP enzyme causes the body to accumulate metabolites called nucleosides.  Some of these are the building blocks for DNA, and their accumulation appears to destabilize mtDNA.  Researchers have shown that they can restore the enzyme and reduce nucleoside levels in the blood by giving individuals with MNGIE an infusion of blood-forming stem cells from a donor.  Further study is needed to establish whether this treatment affects the clinical course of MNGIE.

Scientists hope to develop unique approaches to treating mitochondrial diseases through a better understanding of mitochondrial biology.  The mitochondria in a single cell are not static; new mitochondria are born, old or damaged ones die, and two or more mitochondria can even fuse to become one.  Because people affected by mitochondrial disease often have a mixture of healthy and mutant mitochondria in their cells, effective therapy could involve getting the healthy mitochondria to take over.  It might be possible to rescue mutant mitochondria by stimulating them to fuse with healthy mitochondria.  Another approach might be to stimulate the birth of new mitochondria, encouraging the healthy ones to multiply and outnumber the mutants.  Some diabetes drugs are known to stimulate new mitochondria, and are being eyed as potential treatments for mitochondrial disorders.

Finally, scientists have developed a potential way to prevent the passage of mutant mitochondria from mother to child.  The approach would involve transferring the nDNA from a woman with mtDNA disease into another woman’s egg cell that has healthy mitochondria and has had its own nDNA removed.  Then, standard assisted reproduction techniques could be used to fertilize this egg cell and implant it into the woman who donated the nDNA.  Researchers have tested the approach in monkeys and shown that it can produce healthy offspring of an nDNA donor, with no signs of the donor’s mtDNA.



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High Altitude Cerebral Edema – Symptoms, Treatment

High Altitude Cerebral Edema (HACE) is a severe and potentially fatal manifestation of high altitude illness and is often characterized by ataxia, fatigue, and altered mental status. HACE is often thought of as an extreme form/end-stage of Acute Mountain Sickness (AMS). Although HACE represents the least common form of altitude illness, it may progress rapidly to coma and death as a result of brain herniation within 24 hours, if not promptly diagnosed and treated. 

Acute mountain sickness (AMS) is a syndrome that arises in non-acclimatized individuals who ascend to high altitudes. It is a form of acute altitude illness that occurs due to a decrease in the atmospheric partial pressure of oxygen as the altitude increases, inducing hypoxia. This includes acute mountain sickness (AMS), high-altitude cerebral oedema (HACE), and high-altitude pulmonary edema (HAPE).  This condition typically occurs at an altitude of >2500 meters; however, it can occur at lower elevations in high-risk individuals.

Types of High Altitude Sickness

High altitude oxygenation is improving oxygenation or enriching the body with additional oxygen at high altitudes.

According to the Society of Mountain Medicine (Effects of high altitude on humans), there are three altitude regions:

  • High Altitude  – 1500 to 3500 meters above sea level (4900-11500 ft.)
  • Very high altitude – 3500 to 5500 meters above sea level (11500 to 18000 ft.)
  • Extreme altitude –  above 5500 meters above sea level (18000 ft.)

High altitude (1500 to 3500 m)

  • The onset of physiologic effects of diminished inspiratory oxygen pressure (PIO2) includes decreased exercise performance and increased ventilation (lowering of arterial PaCO2).
  • Minor impairment exists in arterial oxygen transport (arterial oxygen saturation [SaO2] at least 90%, but arterial PO2 is significantly diminished).
  • Because of the large number of people who ascend rapidly to 2500 to 3500 m, high-altitude illness is common in this range.

Very high altitude (3500 to 5500 m)

  • Maximum SaO2 falls below 90% as the arterial PO2 falls below 60 mm Hg.
  • Extreme hypoxemia may occur during exercise, during sleep and in the presence of high-altitude pulmonary edema or other acute lung conditions.
  • Severe altitude illness commonly occurs in this range.

Extreme altitude (above 5500 m)

  • Marked hypoxemia, hypocapnia and alkalosis are characteristic of extreme altitudes.
  • Progressive impairment of physiologic function eventually outstrips acclimatization. As a result, no human habitation occurs above 5500 m.[]

Most people who get altitude sickness get AMS, acute mountain sickness. Higher than 10,000 feet, 75% of people will get mild symptoms. There are three categories of AMS:

  • Mild AMS – Symptoms, such as mild headache and fatigue, don’t interfere with your normal activity. Symptoms improve after a few days as your body acclimates. You can likely stay at your current elevation as your body adjusts.
  • Moderate AMS – Symptoms start to interfere with your activities. You may experience severe headaches, nausea, and difficulty with coordination. You’ll need to descend to start to feel better.
  • Severe AMS – You may feel short of breath, even at rest. It can be difficult to walk. You need to descend immediately to a lower altitude and seek medical care.
  • HAPE (High-altitude pulmonary edema) – HAPE produces excess fluid on the lungs, causing breathlessness, even when resting. You feel very fatigued and weak and may feel like you’re suffocating.
  • HACE (High-altitude cerebral edema) – HACE involves excess fluid on the brain, causing brain swelling. You may experience confusion, lack of coordination, and possibly violent behavior.

Causes of High Altitude Cerebral Edema

Acute Mountain Sickness is caused by the body’s reaction to the reduced oxygen level in respired air and resultant tissue hypoxia. At baseline metabolic levels, the brain is the most sensitive organ regarding hypoxia and oxygen stress. Thus, the symptoms of Acute Mountain Sickness (discussed below) are mediated by the central nervous system (CNS). In many travelers at altitude, respirations during sleep develop a periodic pattern that may contribute to the development of symptoms.

Along with other illnesses related to altitude, HAPE occurs above 2500 meters but can occur at altitudes as low as 2000 meters. Risk factors include individual susceptibility due to low hypoxic ventilatory response (HVR), the altitude attained, a rapid rate of ascent, male sex, use of sleep medication, excessive salt ingestion, ambient cold temperature, and heavy physical exertion. Preexisting conditions such as those leading to increased pulmonary blood flow, pulmonary hypertension, increased pulmonary vascular reactivity, or patent foramen ovale may have a higher predisposition towards the development of HAPE.

  • Asthma
  • Bronchitis
  • Mucous plugging
  • Myocardial infarction
  • Pneumonia
  • Pneumothorax
  • Pulmonary embolism
  • Upper respiratory tract infection
  • Acute psychosis
  • Brain tumour
  • Carbon monoxide poisoning
  • Central nervous system infection
  • Cerebrovascular bleed or infarct
  • Cerebrovascular spasm
  • Diabetic ketoacidosis
  • Hypoglycemia
  • Hyponatremia
  • Ingestion of drugs
  • Seizure disorder
  • Coronary artery bypass
  • Eisenmenger syndrome
  • Severe symptomatic valvular heart disease
  • Severe decompensated congestive heart disease
  • Uncontrolled ventricular and supraventricular tachycardia
  • Uncontrolled hypertension
  • Unstable angina
  • History of altitude illness
  • The rate of ascent
  • The ultimate altitude reached
  • Other medical conditions such as pulmonary hypertension, chronic obstructive pulmonary disease, restrictive lung disease, pulmonary fibrosis, and congenital heart disease
  • The degree of cold
  • The amount of physical exertion
  • Use of alcohol and sleeping pills

Symptoms of High Altitude Cerebral Edema

Some symptoms of low oxygen saturation levels include:

  • Shortness of breath
  • Cyanosis
  • Extreme fatigue and weakness
  • Mental confusion
  • Headaches

Symptoms of mild, short-term altitude sickness usually begin 12 to 24 hours after arriving at high altitude. They lessen in a day or two as your body adjusts. These symptoms include:

  • Dizziness.
  • Fatigue and loss of energy.
  • Shortness of breath.
  • Loss of appetite.
  • Sleep problems.

Symptoms of moderate altitude sickness are more intense and worsen instead of improving over time:

  • Worsening fatigue, weakness, and shortness of breath.
  • Coordination problems and difficulty walking.
  • Severe headache, nausea, and vomiting.
  • Chest tightness or congestion.
  • Difficulty doing regular activities, though you may still be able to walk independently.

Severe altitude sickness is an emergency. The symptoms are similar to moderate AMS but more severe and intense. If you start experiencing these symptoms, you must be taken to a lower altitude immediately for medical care:

  • Shortness of breath, even when resting.
  • Inability to walk.
  • Confusion.
  • Fluid buildup in the lungs or brain.

HAPE, when fluid builds up in the lungs, prevents oxygen from moving around your body. You need medical treatment for HAPE. Symptoms include:

  • Cyanosis, when your skin, nails or whites of your eyes start to turn blue.
  • Confusion and irrational behavior.
  • Shortness of breath even when resting.
  • Tightness in the chest.
  • Extreme fatigue and weakness.
  • Feeling like you’re suffocating at night.
  • Persistent cough, bringing up white, watery fluid.

HACE happens when the brain tissue starts to swell from the leaking fluid. You need medical treatment for HACE. Symptoms include:

  • Headache
  • Loss of coordination.
  • Weakness.
  • Disorientation, memory loss, hallucinations.
  • Psychotic behavior.
  • Coma.

Acute high altitude illness summary

Condition Symptoms and Signs Treatment Prophylaxis
Acute mountain sickness Headache, anorexia, nausea, vomiting, dizziness, fatigue, weakness, insomnia Descent, acetazolamide, dexamethasone, supplemental oxygen Slow ascent, acetazolamide, dexamethasone
High altitude pulmonary edema Dyspnea at rest, cough, decreased exercise performance, chest pain/tightness, low pulse oximetry, central cyanosis, tachypnea, tachycardia, rales, wheezing Descent, supplemental oxygen, nifedipine, phosphodiesterase-5 inhibitors, salmeterol, portable hyperbaric chambers Slow ascent, nifedipine, phosphodiesterase-5 inhibitors, salmeterol
High altitude cerebral edema Change in mental status or ataxia in a person with AMS or HAPE Descent, dexamethasone, acetazolamide, supplemental oxygen, portable hyperbaric chambers Slow ascent, dexamethasone, acetazolamide

Diagnosis of High Altitude Cerebral Edema

History and Physical

The hallmark of Acute Mountain Sickness is a headache, with other symptoms including nausea, vomiting, loss of appetite, fatigue/malaise (particularly at rest), sleep disturbance, and dizziness/lightheadedness.  Acute Mountain Sickness symptoms can begin after only a few hours and typically present the first day at a given altitude, resolving after one to three days, even without treatment, as the body adjusts physiologically (acclimates) to the lower oxygen levels.

The presence of facial or extremity edema can be present with or without Acute Mountain Sickness symptoms and is felt to be a marker for not yet being acclimated to the altitude. Rarely, retinal hemorrhages can occur and affect visual fields.

The onset of neurological findings such as a progressive decline in cognitive/mental function, the declining level of consciousness, impaired coordination, slurred speech, and/or lassitude signify the transition from AMS to HACE.  A typical evaluation consists of an abnormal neurological exam, with ataxia often being the earliest finding.
Early symptoms may be misinterpreted as exhaustion and it is important to exclude these, as well as other disorders such as dehydration, hypoglycemia, hypothermia, or hyponatremia which all may have signs and symptoms that overlap with that of HACE.  Though rarely available, laboratory testing may show an elevated white blood cell count in the setting of HACE, whereas any number of metabolic abnormalities may be present with the aforementioned others within the differential diagnosis.
Lumbar puncture may have an increased opening pressure with otherwise normal laboratory findings. CT may show cerebral edema, but MRI is a better study to evaluate for more subtle signs of edema and can remain abnormal for days up to weeks.  To date, there has been no direct correlation between the severity of edema with clinical outcome.

The Lake Louise Score for the diagnosis of acute mountain sickness.

Symptoms Severity Score
1. Headache None 0
Mild 1
Moderate 2
Severe/incapacitating 3
2. Gastrointestinal None 0
Poor appetite or nausea 1
Moderate nausea or vomiting 2
Severe nausea or vomiting/incapacitating 3
3. Fatigue/weakness None 0
Mild 1
Moderate 2
Severe/incapacitating 3
4. Dizziness/lightheaded None 0
Mild 1
Moderate 2
Severe/incapacitating 3
5. Difficulty sleeping None 0
Not as well as usual 1
Poor night’s sleep 2
Unable to sleep 3
A diagnosis of acute mountain sickness (AMS) requires (a) score > 3, (b) presence of headache and (c) recent ascent.
High-altitude cerebral edema With AMS Altered mental status or/and ataxia
Without AMS Altered mental status and ataxia
Acute mountain sickness (AMS)
-  In the setting of a recent gain in altitude, there is the presence of headache and at least one of the following:
-  Gastrointestinal (anorexia, nausea, or vomiting)
-  Fatigue or weakness
-  Dizziness or lightheadedness
-  Difficulty sleeping
High-altitude cerebral edema (HACE)
-  Can be considered “end-stage” or severe AMS. In the setting of a recent gain in altitude, there is either —
-  the presence of a change in mental status and/ or ataxia in a person with AMS
-  or the presence of both mental status changes and ataxia in a person without AMS.
High-altitude pulmonary edema (HAPE)
In the presence of a recent gain in altitude, the presence of the following:
At least two of the following symptoms —
-  Dyspnea at rest
-  Cough
-  Weakness or decreased exercise performance
-  Chest tightness or congestion
At least two of the following signs:
-  Crackles or wheezing in at least one lung field
-  Central cyanosis
-  Tachypnea
-  Tachycardia

Treatments of High Altitude Cerebral Edema


  • Pure oxygen – Giving pure oxygen can help a person with severe breathing problems caused by altitude sickness. Physicians at mountain resorts commonly provide this treatment.
  • A Gamow bag – This portable plastic hyperbaric chamber can be inflated with a foot pump and is used when a rapid descent is not possible. It can reduce the effective altitude by up to 5,000 ft (1,500 m). It is usually used as an aid to evacuate people with severe symptoms, not to treat them at high altitudes.
  • Gradual Ascent – The recommended method for the prevention of high-altitude illness is to allow the body time to acclimatize via gradual ascent. The WMS recommends one day of travel for every 1,500 ft ascent above 10,000 ft above sea level and a day of rest every 3 to 4 days of travel.
  • Descent – Non-severe AMS: Descent is not necessary for non-severe AMS. It responds well to rest and/or pharmacological treatment. If symptoms resolve, ascent may resume. Severe AMS is AMS with incapacitating symptoms. The appropriate and definitive treatment for severe AMS is immediate descent to a lower altitude.
  • Supplemental Oxygen – If available, supplemental oxygen should be administered with oxygen saturation of above 90% as a goal for both severe AMS and HACE.  Supplemental oxygen should only be used in conjunction with evacuation or while waiting for it.
  • Portable Hyperbaric Chamber – These portable chambers are indicated for severe AMS and HACE when evacuation is delayed.  Symptoms will recur when the patient exits the chamber. However, it may temporarily improve symptoms long enough for patients to be able to assist with their evacuation.  The equipment and constant supervision make this a resource-intensive treatment, but it has the potential to save lives in remote areas where evacuation may be delayed.


Established drug treatments include acetazolamide, dexamethasone, and nifedipine. Acetazolamide is thought to be effective in treating AMS, creating an acidemia, increasing ventilation, and therefore, increasing the arterial oxygen content. Dexamethasone is effective at reducing edema and symptoms in HACE, just as it is in any other form of cerebral edema. Nifedipine is used in HAPE for its dilatory effect on the pulmonary vasculature; however, a recent study did not demonstrate any benefit over descent and supplemental oxygen in patients with HAPE. In addition to these established treatments, potential novel therapies have been suggested such as ibuprofen, nitrates, and intravenous (IV) iron supplementation.


Acetazolamide prevents AMS when taken before ascent; it can also help speed recovery if taken after symptoms have developed. The drug works by acidifying the blood and reducing the respiratory alkalosis associated with high elevations, thus increasing respiration and arterial oxygenation and speeding acclimatization. An effective dose that minimizes the common side effects of increased urination and paresthesias of the fingers and toes is 125 mg every 12 hours, beginning the day before ascent and continuing the first 2 days at elevation, or longer if ascent continues.

Acetazolamide (125mg PO every 12 hours)

  • Acetazolamide is the only medication proven to speed acclimatization. It induces metabolic acidosis by bicarbonate diuresis. This acidosis triggers compensatory hyperventilation helping acclimatization. There are two adverse effects of this medication worth considering.  First, acetazolamide increases urination frequency and therefore increases the risk of dehydration, which is a concern during high altitude travel.  Secondly, acetazolamide has a similar molecular structure to sulfa medications and should be used cautiously in patients with sulfa allergy.  Although the risk of cross-reactivity is low, travelers with sulfa allergies are recommended to undergo a trial of acetazolamide before travel.

Allergic reactions to acetazolamide are uncommon. As a nonantimicrobial sulfonamide, it does not cross-react with antimicrobial sulfonamides. However, it is best avoided by people with a history of anaphylaxis to any sulfa. People with a history of severe penicillin allergy have occasionally had allergic reactions to acetazolamide. The pediatric dose is 5 mg/kg/day in divided doses, up to 125 mg twice a day.


Dexamethasone (initial 8mg PO, IM, or IV followed in 6 hours by 4mg PO, IM, or IV every 6 hours). Dexamethasone is effective for preventing and treating AMS and HACE and prevents HAPE as well. Unlike acetazolamide, if the drug is discontinued at elevation before acclimatization, the mild rebound can occur. Acetazolamide is preferable to prevent AMS while ascending, with dexamethasone reserved as an adjunct treatment for the descent. The adult dose is 4 mg every 6 hours. An increasing trend is to use dexamethasone for “summit day” on high peaks such as Kilimanjaro and Aconcagua, in order to prevent abrupt altitude illness.

Dexamethasone (4mg PO, IM, or IV every 12 hours)

  • For those unable to take acetazolamide, dexamethasone may be used as a preventive agent.  It also may be considered for individuals involved in an unusually high-risk situation (i.e., search and rescue personnel airlifted to above 11,000 ft).  Dosages for dexamethasone is the same for PO, IM, and IV routes of administration.  If used for longer than ten days, it must be tapered slowly to prevent withdrawal symptoms.


Nifedipine both prevents and ameliorates HAPE. For prevention, it is generally reserved for people who are particularly susceptible to the condition. The adult dose for prevention or treatment is 30 mg of extended-release every 12 hours or 20 mg every 8 hours.

Painkillers or Ibuprofen

Acetaminophens, such as Tylenol, can be taken for headaches. Ibuprofen, an anti-inflammatory medicine, can also help. Other than the tight-fit hypothesis previously discussed, other possible mechanisms causing high-altitude headaches include activation of the trigeminovascular system by vasodilatation or inflammatory mediators, or alteration in the blood–brain barrier by inflammatory mediators causing vasogenic edema. The central role of inflammation in these mechanisms has led to an interest in nonsteroidal anti-inflammatory medications such as ibuprofen.


Nitric oxide (NO) regulates physiological processes in the human body, including vasodilation, immune function, platelet aggregation, glucose homeostasis, muscle contraction, and mitochondrial function.

One possible means of eliciting this effect is via dietary nitrate supplementation (ie, nitrate-rich beetroot juice). Nitrate ingestion has been shown to increase plasma concentrations of NO metabolites (nitrate and nitrite), reduce steady-state oxygen consumption, improve arterial and tissue oxygenation, enhance exercise tolerance, and improve performance, during acute normobaric hypoxia. Interestingly, under hypoxic conditions, nitrate supplementation in the form of beetroot juice resulted in faster muscle recovery and restored maximal oxidative ATP resynthesis and exercise tolerance to normoxic values, when compared to placebo.,

Both sildenafil (a selective phosphodiesterase type 5 [PDE-5] inhibitor) and bosentan (a nonselective endothelin-receptor antagonist) have been mooted as potential treatments for AMS, due to their effect on prolonging the effect of NO. Sildenafil has been demonstrated to reduce PASP, increase oxygen delivery, and minimize the decrease in exercise capacity in both normobaric hypoxia and actual high altitude. By dilating the pulmonary vascular bed, these drugs reduce the degree of hypoxic pulmonary vasoconstriction and consequent pulmonary hypertension, and therefore, the risk of HAPE.

IV iron supplementation

In hypoxic conditions, oxygen-dependent hydroxylase enzymes are unable to degrade HIF, so iron supplementation encourages the breakdown of HIF, as in normoxic conditions. This is significant as HIF is believed to coordinate the cellular inflammatory response to hypoxia.

IV iron supplementation immediately prior to ascent to high altitude resulted in a significantly lower rise in AMS score from sea level to altitude, compared to IV saline. However, there was no significant difference in absolute AMS score at altitude between the two groups. Iron supplementation is an intriguing prospect in the prophylactic management of AMS; however, its feasibility on field expeditions is questionable. Oral iron supplemental is a possible alternative that needs more investigation.

Exercise and AMS

While the exact mechanism underlying high-altitude illness remains hotly debated, exercise has been suggested as an independent risk factor for the development of AMS. High-intensity intermittent exercise on a trekking expedition was associated with increased interstitial lung fluid at 4,090 m, suggesting that exercise increases the risk of HAPE. Corroborating this, AMS scores were significantly higher in trekkers with a higher rating of perceived exertion.

Conversely, several recent chamber studies have failed to demonstrate a statistical difference in the development of AMS between rest and exercise at simulated altitude. Of note, in comparing the change in interstitial fluid between exercise in hypoxia at 4,090 m and exercise in simulated hypoxia, there was no significant increase in simulated hypoxia, while there was an increase in actual hypoxia. This suggests that chamber studies are possibly underestimating the effect of exercise on the development of AMS and HAPE and that this may be due to the difference between the normobaric hypoxia experienced in chamber studies and hypobaric hypoxia experienced at altitude.


There are a few nutritional concerns for athletes at high altitudes. First, there is an association between chronic high altitude exposure and significant weight loss. This seems to be primarily due to loss of fat-free mass, which may have significant negative effects on physical performance. Factors possibly contributing to this weight loss are decreased physical activity, hypoxia, irregular sleep pattern, cold exposure, and nutritional imbalance related to protein metabolism.,

Inspiratory muscle training

In addition to IHE and IHT, there are other potential techniques such as dietary nitrate supplementation (which has been discussed earlier) and inspiratory muscle training (IMT), which may attenuate arterial oxygen desaturation and a reduction in exercise performance during high-altitude exposure.

Acute exposure to hypoxia and the associated reduction in the arterial partial pressure of oxygen increases minute ventilation, in an attempt to normalize arterial oxygen saturation. However, this hyperventilation increases the work of breathing and in turn the demand for respiratory blood flow, making the respiratory muscles more susceptible to fatigue.

Already abroad and need to see a doctor?

The following list of resources can help international travelers identify health care providers and facilities around the world. CDC does not endorse any particular provider or medical insurance company, and accreditation does not ensure a good outcome.

  • The nearest US embassy or consulate can help travelers locate medical services and notify friends, family, or employers of an emergency. They are available for emergencies 24 hours a day, 7 days a week, overseas.
  • The Department of State maintains a list of travel medical and evacuation insurance providers.
  • The International Society of Travel Medicine maintains a directory of health care professionals with expertise in travel medicine in more than 80 countries.
  • The International Association for Medical Assistance to Travelers maintains a network of physicians, hospitals, and clinics that have agreed to provide care to members.
  • Travel agencies, hotels, and credit card companies (especially those with special privileges) may also provide information.
  • A number of countries or national travel medicine societies have websites related to travel medicine that provide access to clinicians, including the following:
    • Australia: Travel Medicine Alliance
    • Canada: Health Canada ( and
    • China: International Travel Healthcare Association
    • Great Britain: National Travel Health Network and Centre and British Global and Travel Health Association
    • South Africa: South African Society of Travel Medicine

Tips for acclimatization

  • Be sure you are in good shape before you travel – If you have significant medical problems, check with your doctor before you go; even with his approval, be sure to go slowly and listen to your body for warning symptoms. Travel is usually safe for men with mild to moderate heart or lung disease and for most with well-controlled high blood pressure or diabetes, but high altitudes are very dangerous for people with sickle cell anemia.
  • Ascend gradually – You can fly to Denver or Mexico City in one hop, but if you’re going higher, a few days of acclimation are worth your time. Above 8,000 feet, don’t go up more than 1,000 feet a day.
  • Travel high, sleep low – For example, if you ski at 9,000 feet, you’ll do best if your lodge is 1,000–1,500 feet lower. If you’re hiking, ascend in stages, and sleep at altitudes below your daily peak.
  • Limit your exercise during your first days at altitude — and take it easy throughout your trip if you have medical problems or you feel sick in any way.
  • Drink plenty of fluids – Dehydration is sneaky at altitude because you will lose lots of water through your lungs even if you don’t perspire. Drink enough to keep your urine clear and copious. Avoid alcohol or minimize your consumption, particularly for the first 48 hours at altitude. Avoid sedatives.
  • Be alert for symptoms – You can manage mild mountain sickness yourself (see “Treatment” below), but you’ll need help for anything more serious. Don’t ignore symptoms; instead, return to a lower elevation and get help.
  • Ascend gradually, if possible. Avoid going directly from low elevation to more than 9,000 ft (2,750 m) sleeping elevation in 1 day. Once above 9,000 ft (2,750 m), move sleeping elevation no higher than 1,600 ft (500 m) per day, and plan an extra day for acclimatization every 3,300 ft (1,000 m).
  • Consider using acetazolamide to speed acclimatization if abrupt ascent is unavoidable.
  • Avoid alcohol for the first 48 hours; continue caffeine if a regular user.
  • Participate in only mild exercise for the first 48 hours.
  • Having a high-elevation exposure (greater than 9,000 ft [2,750 m]) for 2 nights or more, within 30 days before the trip, is useful, but closer to the trip departure is better.
  • Dress warmly.
  • Wear sunglasses.

These steps can help your body acclimate:

  • Walk-up – Start below 10,000 feet and walk to a high altitude instead of driving or flying. If you drive or fly to an elevation higher than 10,000 feet, stay at your first stop for at least 24 hours before going higher.
  • Go slow – Once above 10,000 feet, don’t increase your altitude more than 1,000 feet a day.
  • Rest – Build a rest day into your schedule for every 3,000 feet you climb.
  • “Climb high and sleep low” – If you climb more than 1,000 feet in a day, come down to sleep at a lower altitude.
  • Know your body – Recognize the signs and symptoms of altitude sickness. Move to a lower altitude (or avoid climbing higher) if you notice any symptoms.
  • Stay hydrated – Drink 3-4 quarts of water per day.
  • Avoid alcohol – Alcohol can dehydrate your body. It also has stronger effects at higher elevations, which can impair judgment.
  • Eat carbs – Eat a diet that’s more than 70% carbohydrates.
  • Know the “don’ts – Avoid tobacco and depressant drugs, such as sleeping pills and tranquilizers.

What should I ask my doctor?

If you’re planning to travel to high altitudes, ask your healthcare provider:

  • Should I take preventive medication to avoid altitude sickness?
  • Do I have any risk factors that would prevent me from visiting high elevations?
  • What other steps can I take to prevent altitude sickness?
  • What steps should I take if I start to feel symptoms during my climb?



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Post Surgical Back Pain – Causes, Symptoms, Treatment

Post Surgical Back Pain /Failed back surgery syndrome (FBSS) is a complex set of post-surgical pain symptoms encountered after a patient has had surgery on the lumbar spine for disc-related abnormal pathology. The patient may feel present with recurrent pain and persistent pain, with or without radiculopathy, following spinal surgery. Pain may appear after surgery and persist despite the intervention for up to 3 months or more, with chronic pain. There are other name of this condition definitions for the same disorder such as postlumbar surgery syndrome, postlaminectomy syndrome, failed back syndrome, and postoperative persistent syndrome.,

Failed back surgery syndrome or “failed back syndrome” refers to persistent pain after spinal surgery about 3 months later. It man have a number of serious problems that may including iatrogenic vigorous effects in the spine or incision area such as the development of scar tissue, nerve damage, or weakening of physical structures and posture. A disability may increase and the demand for medication may also increase. This opinion piece will discuss broadly the background and scale of failed back surgery syndrome. There will be a description of the medical and psychological factors that have been reported as causes of poor outcomes from spinal surgery.

Types of Post Surgical Back Pain

Below are the types of back and neck pain people with failed back surgery syndrome may experience. In these cases, some patients have one or more types.

  • Chronic pain It may be sustained significant pain that lasts for more than 12 weeks. Chronic pain is the opposite of acute pain, which is short-term pain that may be severe. Acute pain is expected during spine surgery recovery, but the pain should fade as the spine heals.
  • Nociceptive pain – It is a Localized pain that may be dull or sharp. This is the type of pain patients may experience immediately after surgery (eg, the heightened pain felt around the incision site). When most people think of pain, nociceptive pain is what comes to mind.
  • Neuropathic pain (neuropathy) – The pain arises due to nerve-related pain is caused by damage to the nerves or spinal cord compression in the root of the nerve. Unlike nociceptive pain, which can be traced to a single site or area, neuropathic pain often shoots and moves, affecting large areas of your body and buttock. Examples of this type of pain include numbness, burning, tingling, weakness, and other abnormal sensations (called paresthesia).
  • Radicular pain (radiculopathy) A subset of nerve pain abnormality (neuropathy) is called radiculopathy, or a group of radicular pain. The characteristic of radicular pain radiate from one area to another (eg, upper back or lumber reason to the low back down the buttocks, legs, and feet, such as sciatica).

Causes of Post Surgical Back Pain

Pain in the leg likely indicates and feel nerve compression from the condition of stenosis, epidural fibrosis, or disc herniation, and it may be more while low back pain is more common in facet joint arthropathy, sacroiliac joint issues, or myofascial etiologies. Failed back surgery syndrome is a condition with a complex etiology and many factors that predispose patients towards chronic pain. These predictive factors generally divide into preoperative (patient) factors, intraoperative factors, and postoperative factors.

  • Preoperative Causes – It is previous and after causes of the patient associated with failed back surgery syndrome include anxiety, depression, or other psychiatric comorbidities, obesity, smoking, the presence of litigation or worker’s compensation claims, and physical or radiologic findings such as stenosis, fibrosis, and disc herniation.
  • Psychosocial causes – It is the second most psychological causes that have been shown to have the strongest association with the development of FBSS. Additionally, the choice of an inappropriate surgical candidate, or theory and technique, or surgical approach correlates with a higher risk of developing FBSS. Patients who have undergone multiple prior back surgeries have the highest chance of developing FBSS and a lower chance of achieving successful pain resolution with surgery than surgeons have done.
  • Intraoperative causes – It is the sense for developing failed back surgery syndrome to include operating at either the wrong way surgery vertebral level or operating at a single level while the origin of pain spans several levels, thus providing insufficient pain relief.
  • The wrong vertebral – The Vertebralcoloumn level may pertain to factors such as lumbarization, sacralization, or even more important when the etiology gets attributed to a non-attributable pathological condition. These factors represent the symptoms in clearly identifying a locus in patients with multi-segment changes. Improper technique or unconsciousness during surgery may also lead to failure of the back syndrome to relieve pain or the onset of new pain.
  • Fusion surgery considerations – The surgery to fixed the two adjuvant vertebrae such as failure to fuse and/or implant abnormality failure, or a transfer lesion to another level after a spine fusion, when the next level degenerates more pain and becomes a pain generator.
  • Lumbar decompression back surgery considerations – It is such a condition as recurrent spinal canal stenosis,  or disc herniation, PLID, inadequate decompression of a nerve root, preoperative nerve damage or postoperative that does not heal after decompressive surgery, or nerve damage that occurs during the surgery)
  • Scar tissue considerations – It causes after surgery in such as forming epidural fibrosis, which refers to a formation of scar tissue around the nerve root and spinal column
  • Postoperative rehabilitation – Due to adequate consciousness of continued pain from a secondary pain generator.
  • Post-Surgery Pain – It is the most dangerous indication of failed back surgery symptoms that happened in past a certain point certain causes of the pain from surgery should begin to remember while the effects of the surgery reducing pain should take hold. If you continue to have the same level of pain or struggle with even more pain, despite 6 weeks of recovery, it’s likely that something went wrong either during or after the procedure of back failed surgery. Your doctor may be advised to stay in touch with a pain management professional or your doctor and with your doctor and to schedule regular checkups to be sure including imaging if you’re left with a significant amount of pain and abnormality about 3 months or more after surgery.
  • Nerve Pain – All pain is “nerve pain”, but certain forms of pain due to nerve root compression specifically point towards pinched nerves, recurring disc herniation, failed spinal fusion, or the formation of scar tissue around the surgical site putting pressure on a specific nerve or nerve root all of which are possible symptoms of a failed back symptoms surgery. Each major nerve exhibits and causes different symptoms, but common issues include severe leg pain, the paresthesia to long walk or sitting, running down the side of the leg, lower back pain getting worse, etc.
  • Spasms & Joint Lockage – Another bad sign pointing towards failure or the possibility of another issue is joint lockage and muscle spasms. Muscle spasms and cramps are not too uncommon immediately after surgery, but they shouldn’t occur after recovery. If you struggle to bend your leg or get sudden spasms and cramps preventing you from walking, then you must immediately consult a professional.
  • Severe Weakness – Nerves are responsible for sending signals into the body from the brain, and lumbar disc herniation often leaves people with limb paresis (partial paralysis or immobility in the limbs). Surgery to correct disc herniation quite often relieves patients of these symptoms and gives them back more control over their limbs. While it isn’t guaranteed that any given patient makes a full recovery, continued muscle weakness – or increased muscle weakness, and partial paralysis – may be a sign of FBSS.

The most non-surgical causes include

  • Herniated nucleus propulsors (HNP) at a non-surgical site
  • Facet arthrosis
  • Spinal Stenosis
  • Spondylolysis with or without Spondylolisthesis
  • Referred to pain.
  • myofascial pain
  • segment instability
  • Epidural hematoma,
  • Recurrent HNP at the operative site,
  • Infection such as diskitis,
  • Osteomyelitis or arachnoiditis,
  • Epidural scar
  • Meningocele or CSF fistula.

Failed Back Surgery Syndrome

Symptoms of Post Surgical Back Pain

  • Persistent or recurrent pain – in the back/neck or limbs despite surgery or treatment thought likely to relieve pain.
  • Chronic radicular pain – that has recurred or persists in the same distribution despite anatomically satisfactory previous spinal surgery. (Leveque)
  • Lumbar (cervical) pain – of unknown origin either persisting despite the surgical intervention or appearing after surgical intervention for spinal (origin) pain originally in the same topographical distribution.
  • Chronic back and leg pain – that persists or recurs despite the application of the back surgery clinical pathway.
  • Radicular symptoms – in the failed back patient may be due to a multitude of reasons including herniated disc, postoperative adhesions, a thickened ligamentum flavum, spondylolisthesis with or without an associated par defect, osteophyte formation from facet arthropathy, or other degenerative changes that may lead to central or transforaminal stenosis.
  • Original symptoms return – When the symptoms surgery intended to correct come back, it may indicate failed back surgery.
  • New problems arise Spine surgery may have fixed original symptoms, but new pain (pain in a different part of the spine or a different type of pain) warrants a discussion with your doctor.
  • Reduced mobility It takes time to recover from spine surgery and that process can affect your endurance, flexibility, and movement. However, reduced mobility or limitations in movement that is different from expected or develops after the recovery period should be discussed with your doctor. An example is a limited range of motion in your neck or low back.
  • Headaches develop If they weren’t part of your medical history before your surgery, the headache may signal a nerve problem after a cervical spine (neck) procedure.

The symptoms that may indicate life-threatening conditions; include, but are not limited to: saddle anesthesia or bowel/bladder incontinence, indicative of cauda equina syndrome; fever, chills, or weight loss indicating infection; and signs of malignancy. Patients should also have an evaluation for anxiety, depression, and other psychiatric conditions due to their high comorbidity with FBSS.

Diagnosis of Post Surgical Back Pain

An accurate and thorough history and physical examination of patients with persistent pain after lower back surgery are the most crucial for correct diagnosis.


  • Allow extra time to evaluate initially or properly
  • Essential to have prior records of medical record
  • Preoperative vs.Postoperative complaints and associate test
  • Was there a new problem immediately after surgery or not?
  • Current medication usage and issues of dependency.
  • Careful assessment of the psychological status
  • Vocational status and workers’ compensation
  • Postoperative systemic complaints(often subtle)
  • Back vs Leg pain that radiates or not
  • Unusual pain pattern (reflex sympathetic dystrophy, complex regional pain, )
  • Postoperative rehabilitation (aerobic, flexibility, strengthening, body mechanics, physical therapy).
  • Relieving and exacerbating positions and activities.

Physical Examination

  • Observe closely for pain behavior as a warning of associated problems.
  • Careful neurologic exam for focal localizing findings.
  • Evaluate for the potential major joint problem as referral source (hip, knee)
  • Palpation at surgery site for hematoma, local fluid, abscess, and pseudo meningocele.
  • Examination of extremity for sympathetic or RSD -type changes.
  • Screening for neural tension signs (SLR, Adson’s test)
  • Long tract signs (Babinski’s sign, clonus, Hoffman’s sign)
  • Vascular assessment (diabetics, elderly patients)
  • Local soft tissues (psoas muscle, iliotibial band, gluteal muscles)

Manual Examination

  • Straight Leg Raising Test – A manual test for pain from a disc herniation or nucleus proposal may present with a positive sign on straight leg raise.  Focal neurological deficits in FBSS patients warrant further testing. Deficits in strength or sensation in the lower extremities may help narrow down which nerve roots are affected and cause pain.
  • Waddell signs –  are one of the vital manual tests that can be used to evaluate for psychogenic etiology of lower back pain; while the interpretation of these tests is controversial, they may be useful especially if there is a suspicion of secondary gain.
  • One leg hyperextension test/stork test – It a simple and manual or home test the patient can do it own have the patient stand on one leg and (while being supported by the provider) have them hyper-extend their back. Repeat this maneuver on both sides. If pain with hyperextension is the resulting increase positive for a pars interarticularis defect or associate abnormalities.
  • Adam test – Patient has to bend over with feet together and arms extended with palms together. The practitioner should observe from the front side of you. If a thoracic lump is present on one left side or the other right side lower back pain, it is an indication of scoliosis.There are numerous other examination techniques; however, they have mixed and anonymous evidence for inter-practitioner reliability and poor sensitivities or specificities lower back pain.

Lab test

  • Blood tests – CBC, Hb, RBS, CRP, Serum Creatinine, Serum Electrolyte.
  • Erythrocyte sedimentation rate and C-reactive protein –  may be used to evaluate for possible infection, especially in patients with constitutional symptoms or a predisposition towards infection. . Adherence to strict standards of accurate needle placement, contrast injection, as well as a limited active agent is essential in improving the sensitivity and specificity of these blocks.
  • Bone scan – It is a bone scan that may be used for detecting bone tumors or compression of nerve root fractures caused by brittle bones and osteoporosis. The patient may receive an injection of a tracer (a radioactive substance) into a vein at the same time. The tracer collects or examiner in the bones and helps the doctor detect bone problems with the aid of a special camera.
  • Electromyography (EMG) – It one kind of test that helps assess the electrical activity in a muscle and nerve impulse velocity or nerve root compression and can detect if muscle weakness results from a problem with the nerves that control the muscles. Very fine needles are inserted in muscles to measure electrical activity transmitted from the brain or spinal cord to a particular area of the body that are causing pain.
  • Evoked potential studies – It may involve two sets of electrodes are placed one set to stimulate a sensory nerve, and the other placed on the scalp to record the speed of nerve signal that is transmitted to the brain.
  • Nerve conduction studies (NCS) – It also uses two sets of electrodes to stimulate the nerve that runs to a particular muscle and record the nerve’s electrical signals to detect any nerve damage for lower right and left side back pain.


  • X-rays – are a simple and inexpensive first imaging evaluation to detect the bone and vertebrae related problem for suspected failed back surgery syndrome. X-rays are more specific use for detecting vertebral and sacroiliac defects and/or misalignment and are superior to MRIs for the detection of spondylolisthesis. Adjacent segment degeneration and loss of lordosis are common abnormalities found on radiography. However, X-rays are unable to detect spinal stenosis, the most common pathological finding in FBSS, and are also unable to evaluate soft tissue, such as intervertebral discs, epidural scarring, or fibrosis.
  • MRI – with and without gadolinium contrast is one of the latest tests that continues to be the gold standard imaging modality for failed back surgery syndrome due to its excellent ability to detect soft tissue abnormalities such as epidural fibrosis and disc herniation. Contrast is especially indicated in patients with a history of disc herniation surgery. In patients with ferromagnetic implants, a CT myelogram is used to avoid implant artifacts created on MRI.
  • CT myelography -It is a special kind when the patient has either a contraindication to having an MRI such as heart problem, open-heart surgery, or having a pacemaker device or defibrillator or be used when a standard CT or MRI is negative or equivocal. Myelography is a CT scan or an MRI with intrathecal administration of contrast for lower back pain. CT myelography visualizes a patient’s spinal nerve roots in their passage through the neuroforamina area. CT myelography can be used to assess the underlying root sleeve and nerve root compression. A CT is a poor test for the visualization of nerve roots, making it challenging to diagnose radicular disease.
  • Electromyography (EMG) – It is complete after three weeks of symptoms, not before the lower right and left back pain. Diagnostic tests such as EMG or nerve conduction studies are accurate only after three weeks of persistent symptoms of right or left lower back pain. The primary reason or why using an EMG or nerve conduction study is to identify the delayed three weeks or more time following the development of pain is because of fibrillation potentials after an acute injury in the brain and spinal cord lead to an axonal motor loss. These do not develop until two to three weeks following injury for the lower right and left back pain.
  • Cerebrospinal fluid analysis – It is a useful test for investigating the right and left lower back pain if there is an involvement of neoplasm or infectious cause or radiculopathy symptoms and radiating pain syndrome. The recommendation for lower right and left back pain in lumbar puncture is in the case of a patient with negative or nondiagnostic neuroimaging, without knowing primary cancer and its related condition, who has progressive neurological symptoms and has failed back syndrome to improve it properly.
  • Bone scintigraphy – It is a special type of test that is done when some or above mention test failed to identify the causes of right and left lower back pain with single-photon emission computed tomography (SPECT) is more sensitive in detecting facet joint lesions and bony lesion, none spurs and allows more accurate anatomical localization of lower back pain. A recent study suggested that SPECT could help to identify patients with lower back pain who would benefit from facet joint intraarticular injections []. Facet joint block (FJB)injection is an indispensable diagnostic instrument in order to identify painful or painless back pain from painless facet joints and to plan the intervention strategy.
  • Foraminal nerve root entrapment test – It is best visualized on T1-weighted MRI where are used to identify the high contrast fat tissue and the nerve root sheath that is of great help for lower and right or left ba. In here usually, a combination of hypertrophic degenerative facets with osteophytes spurs posteriorly, and vertebral osteophytes and/or disc herniation anteriorly diminishes the anteroposterior diameter of the foramen and it associate condition. Foraminal height is erased by degenerative disc disease and subsequent disc height loss or not. In this case, the normal rounded (oval) appearance of the nerve root sheath is lost in combination with loss of the surrounding fat tissue, nerve root compression should be considered to identifying the lower right and left side back pain.

Treatment of Post Surgical Back Pain

Non-Pharmacological Treatment for failed back  surgery syndrome

  • Physical therapy – Physical therapy can help the patient optimize gait and posture and can improve muscle strength and physical function., Other conservative measures that may help postoperative back pain involve psychotherapy measures including stress reduction and cognitive behavioral therapy to body and mind fit. Finally, noninvasive procedures or systems including acupuncture and scrambler therapy can be used to minimize the pain associated with FBSS., These conservative measures should be done in conjunction with medication management to optimize pain relief.
  • Transcutaneous electrical nerve stimulation – may provide an alternative/complement to medication in patients with FBSS. Its effectiveness in chronic low back pain is, however, still have controversial [, ]. Other nonpharmacological complementary therapies, such as acupuncture, manual therapy, functional restoration, and cognitive behavioral therapy, may also be utilized, although the level and supporting team most of these therapies in the management of chronic back pain is moderate at best [, ].
  • High-frequency spinal cord stimulation – This technique has been shown to be of particular value in patients with FBSS with a predominant lower back pain component.A frequency of about 5000–10,000 Hz is used. A major advantage is that patients do not have to rely on the perception of paraesthesia, itching in the affected area. There are no efficacy, cost-effectiveness, or safety data from a randomized controlled trial or comparison with conventional SCS in relation to the long-term use of this technology.
  • Dorsal root ganglion stimulation – A specially designed lead is placed around the dorsal root ganglion, via the epidural space, and this produces pleasant paraesthesia in a dermatome or part of it. The major advantages seem to be that there is no change in perception of paraesthesia with posture, and it is possible to target dermatomes that would otherwise be difficult to target with conventional SCS (foot, groin, etc.) without overspill of paraesthesia into other dermatomes. There are minimal long-term data regarding efficacy, safety, and cost-effectiveness.,
  • Peripheral nerve field stimulation – Specially designed leads have been approved for this use, especially for treating the neuropathic back pain component of FBSS. The use of this technique, in combination with conventional SCS or alone, has been published with impressive results in case series. However, cost-effectiveness and long-term efficacy are not established.
  • Radiofrequency ablation – RFA of nerves are often used to provide sustained relief that a diagnostic block or therapeutic injection cannot provide. Successfully targeting the intended nerve is achieved, maximizing the size of the lesion. This can be done by performing multiple RFA in different locations, increasing the temperature and time of the ablation, using bipolar RF or cooled RF.,
  • Neuromodulation – Spinal cord stimulation (SCS) is a treatment modality that has shown tremendous potential in the management of FBSS. The advent of SCS came just 2 years after Melzak and Wall’s 1965 groundbreaking paper on Gate Theory with Shealy and Mortimer’s case study on the complete elimination of pain in a 70-year-old male with metastatic bronchogenic carcinoma by means of electrical stimulation of the dorsal columns.,
  • Chiropractic – The results of several studies showed significant improvement for patients with failed back surgery who were managed with chiropractic care


Oral pharmacological treatment of FBSS is multimodal and increasingly controversial.

  • Anticonvulsant drugs – have gained popularity for neuropathic pain, with gabapentin (Neurontin) and pregabalin (Lyrica) being the most commonly used preparations. Gabapentin has been shown to be superior to naproxen in alleviating back and leg pain after spinal surgery []. Pregabalin plays a role in the prevention of pain before and after surgery, with its effect apparently increasing with time [].
  • Antidepressants (amitriptyline and duloxetine) []. Two-drug combinations for the treatment of neuropathic pain in adults have been shown to improve analgesic efficacy [].
  • Chemical neuromodulation – by continuous intrathecal drug delivery (IDD) based on morphine or ziconotide administration may be considered for patients preferentially with neuropathic pain who have responded to strong oral opioids in the presence of severe adverse events []
  • Epidural injections – Epidural steroid injections (ESIs) are the most commonly performed procedure in pain clinics around the world. These can be administered primarily by three approaches: transforaminal, interlaminar, or caudally, and are indicated for symptoms of radiculopathy.
  • Intrathecal drug delivery – Similar to a spinal cord stimulator, spinal drug delivery (or intrathecal drug delivery) involves implanting a small pump in the stomach and running a catheter to the spine to deliver pain medication. It is used for people with chronic back pain who need large doses of narcotics to deal with the pain. Compared to oral medication, this “pain pump” requires a smaller dose of narcotics because the medication goes directly to the area of pain.
  • Long-term Oxycodone – Naloxone is given to counteract the long-term effects of narcotic use. In one case study, Spanish research Dr. Borja Mugabure Bujedo recorded that a combination of  Oxycodone – naloxone can be a good alternative for the management of Failed Back Surgery Syndrome when other interventional or pharmacologic strategies have failed in a case report in the journal Anesthesiology and pain medicine. In this case report, higher doses than those recommended as a maximum daily ceiling (80/40 mg) were used in one selected patient with severe pain.[rx]
  • Platelet Rich Plasma Therapy in combination with Prolotherapy – Some doctors may recommend the use of Platelet Rich Plasma to help patients with failed back surgery syndrome. Platelet Rich Plasma is an injection of your concentrated blood platelets into the area of pain. The concentrated blood platelets bring healing and regenerating growth factors to the areas possibly damaged or affected by surgery. Recent research says that
  • Platelet-rich plasma (PRP) represents an additional approach – as it has shown some promise in bone regeneration, and should be explored for its potential role in limiting spinal fusion surgery failures.[rx]

Why Does Failed Back Syndrome Happen?

One of the most common situations in which we see failed back syndrome is after spinal fusion surgery. The spine is not immediately, fully fused after spinal fusion; rather, surgeons have created an environment that encourages fusion, through the use of a tissue graft between two (or more) vertebrae.

For the vertebrae to fully fuse, the spine must be stabilized and immobilized to a degree. If the environment for growing new bone tissue is not quite right, the spinal fusion may prove ineffective. This is one of the main causes of the failed back syndrome.

Another common scenario happens after a discectomy or laminectomy to relieve symptoms of a herniated disc when the patient has degenerative disc disease (DDD). The surgery may have been performed flawlessly, but DDD can affect multiple locations in the spinal column.

Sometimes patients have one disc herniation repaired only to find that another herniation has occurred after recovery from the surgery, or a more minor existing herniation was being masked by stronger symptoms, which the surgery addressed.

The risk of failed back syndrome rises with each surgery. According to a 2018 review in Asian Spine Journal, about half of initial surgeries are successful. That percentage, however, drops to 30 percent, then 15 percent, then 5 percent after the second, third, and fourth surgeries.

Aside from the choice of surgery, the number of surgeries, and the presence of other spinal conditions, the risk of the failed back syndrome can be increased by a number of factors after surgery. In the short-term, some of these include:

  • Infection
  • Nerve injury
  • Hematoma formation

In later stages, changes to the spinal column can affect the way a patient moves, which can cause further spinal problems after time.

What exercises help reduce Failed Back Syndrome pain?

There are 4 exercises your spine specialist may recommend helping you reduce failed back pain nerve pain caused by degenerative disc disease: pelvic tilt, knee to chest, lower trunk rotations, and all fours opposite arm and leg extensions. Each low-impact exercise is demonstrated in narrated videos and written instructions are provided to help you fine-tune your sciatica home exercise program.

Pelvic Tilt

Purpose: To strengthen the lower abdominal muscles and stretch the low back.

How to perform a pelvic tilt
  • Lie on your back.
  • Exhale and tighten your abdominal muscles while pushing your belly button toward the floor and flatten your lower back.
  • Hold the position for 5 seconds.
  • Repeat the pelvic tilt 10 times holding the position for 5 seconds each time.
How can I tell if I’m doing the pelvic tilt right?
  • Place your pinky finger on your hip bone and thumb on your lowest rib (same side of your body).
  • As you tighten your abdominal muscles, the amount of space between your pinky finger and thumb should get smaller.

Pelvic tilts can help strengthen the lower abdominal muscles and stretch the low back. Photo Source:

Knee to Chest

Purpose: To help reduce nerve compression in your low back, which may help alleviate lower back pain.

  • Lie on your back.
  • Starting with either your left or right knee and use your hands to gently pull the bent knee toward your chest.
  • Hold for 10 seconds.
  • Repeat the movement with the opposite knee.
  • Perform the movement 3 to 5 times holding the position for 10 seconds each time.
  • Next, use your hands to gently pull both knees toward your chest.
  • Hold for 10 seconds.
  • Repeat the movement with both knees 3 to 5 times holding the position for 10 seconds each time.

Lower Trunk Rotations

Purpose: To increase your spine’s mobility and flexibility.

  • Lie on your back with both knees bent upright and both feet flat on the floor (called the hook lying position).
  • While holding both knees together, rotate your knees to one side and hold for 3 to 5 seconds. You will feel a gentle stretching sensation on the opposite side of your lower back and hip area.
  • Next, contact your abdominal muscles and rotate both knees to the opposite side and hold for 3 to 5 seconds.
  • Repeat up to 10 times on each side.

All Fours Opposite Arm and Leg Extensions

Purpose: To strengthen your abdominal muscles, low back, and stabilize those areas.

  • Begin by positioning yourself on all fours.
  • Contract your abdominal muscles to help keep your back flat and straight.
  • Raise one leg upward behind you and straighten in outward.
  • Hold for 3 to 5 seconds.
  • Repeat the movement on your opposite side.

When you can perform this exercise 10 times with tolerable pain, you can add arm movement with each leg extension:

  • Extend the arm (opposite side from the leg) upward and outward in front of your body.
  • Hold for 3 to 5 seconds.
  • Repeat on the opposite side.
  • Perform this exercise up to 10 times.

How can these exercises work to reduce sciatic pain?

The abdominal and spinal muscles are essential components of the spine’s support system, which—anatomically, can be likened to your internal spinal brace. These 4 low-impact exercises, when performed correctly and under your spine specialist’s guidance, can help strengthen your spine and increase its flexibility and range of motion. While you cannot halt the effects of degenerative disc disease (eg, cause of bulging or herniated disc), exercise can help fortify the spine’s structural components that may reduce pain and speed healing.

Furthermore, exercise causes your body to release endorphins—hormones that interact with pain receptors in the brain that can reduce the perception of pain.



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Subtotal Hysterectomy – Indications, Contraindications

Subtotal Hysterectomy/A hysterectomy is an operation to remove the uterus. This surgery may be done for different reasons, including uterine fibroids that cause pain, bleeding, or other problems. Uterine prolapse, which is a sliding of the uterus from its normal position into the vaginal canal. Cancer of the uterus, cervix, or ovaries.

A hysterectomy is a surgery to remove a woman’s uterus (also known as the womb). The uterus is where a baby grows when a woman is pregnant. During the surgery, the whole uterus is usually removed. Your doctor may also remove your fallopian tubes and ovaries. After a hysterectomy, you no longer have menstrual periods and cannot become pregnant.

Surgeons can perform hysterectomy through more than a few different methods. Some of the generally performed routes of hysterectomy are vaginal, abdominal, laparoscopic, and robotic-assisted. Vaginal hysterectomy ranks as one of the least and minimally invasive types of hysterectomies, and it has better outcomes and fewer complications compared to other types. It should be regarded as the preferred route of hysterectomy, whenever possible. The advantages of vaginal hysterectomy include less pain, rapid recovery, faster return to work, lower costs, and lower morbidity. It is usually performed for benign hysterectomies.

Types of Hysterectomy

There are four types of hysterectomies that can be performed depending on the condition and severity of the patient. These four types are

  • Vaginal hysterectomy
  • Laparoscopic hysterectomy
  • Minilaparotomy (a “short incision”) hysterectomy
  • Abdominal hysterectomy

There are various types of hysterectomy. The type you have depends on why you need the operation and how much of your womb and surrounding reproductive system can safely be left in place.

The main types of hysterectomy are
  • Total hysterectomy – the womb and cervix (neck of the womb) are removed; this is the most commonly performed operation
  • Subtotal hysterectomy – the main body of the womb is removed, leaving the cervix in place
  • Total hysterectomy with bilateral salpingo-oophorectomy – the womb, cervix, fallopian tubes (salpingectomy) and ovaries (oophorectomy) are removed
  • Radical hysterectomy – the womb and surrounding tissues are removed, including the fallopian tubes, part of the vagina, ovaries, lymph glands, and fatty tissue.
There are several approaches that can be used for a MIP hysterectomy
  • Vaginal hysterectomy – The surgeon makes a cut in the vagina and removes the uterus through this incision. The incision is closed, leaving no visible scar.
  • Laparoscopic hysterectomy – This surgery is done using a laparoscope, which is a tube with a lighted camera, and surgical tools inserted through several small cuts made in the belly or, in the case of a single site laparoscopic procedure, one small cut made in the belly button. The surgeon performs the hysterectomy from outside the body, viewing the operation on a video screen.
  • Laparoscopic-assisted vaginal hysterectomy – The surgeon uses laparoscopic tools in the belly to assist in the removal of the uterus through an incision in the vagina.
  • Robot-assisted laparoscopic hysterectomy – This procedure is similar to a laparoscopic hysterectomy, but the surgeon controls a sophisticated robotic system of surgical tools from outside the body. Advanced technology allows the surgeon to use natural wrist movements and view the hysterectomy on a three-dimensional screen.

Anatomy and Physiology

Hysterectomy can be performed in more than a few different ways. Some of the generally performed routes of hysterectomy are vaginal, abdominal, laparoscopic, and robotic-assisted. Vaginal hysterectomy is considered as one of the least and minimally invasive types of hysterectomies, and it has better outcomes and fewer complications compared to other types. It should be regarded as the preferred route of hysterectomy, whenever possible. The advantages of vaginal hysterectomy include less pain, rapid recovery, faster return to work, lower costs, and lower morbidity. It is usually performed for benign hysterectomies.

Indications of Vaginal Hysterectomy

Hysterectomy is one of the most frequently performed surgeries in the world, and some of the most common indications for hysterectomy include:

  • Endometriosis – the growth of the uterine lining outside the uterine cavity. This inappropriate tissue growth can lead to pain and bleeding.
  • Adenomyosis – a form of endometriosis, where the uterine lining has grown into and sometimes through the uterine wall musculature. This can thicken the uterine walls and also contribute to pain and bleeding.
  • Heavy menstrual bleeding – irregular or excessive menstrual bleeding for greater than a week. It can disturb the regular quality of life and may be indicative of a more serious condition.
  • Uterine fibroids – benign growths on the uterus wall. These muscular noncancerous tumors can grow in a single form or in clusters and can cause extreme pain and bleeding.
  • Uterine prolapse – when the uterus sags down due to weakened or stretched pelvic floor muscles potentially causing the uterus to protrude out of the vagina in more severe cases.
  • Reproductive system cancer prevention – especially if there is a strong family history of reproductive system cancers (especially breast cancer in conjunction with BRCA1 or BRCA2 mutation), or as part of recovery from such cancers.
  • Gynecologic cancer – depending on the type of hysterectomy, can aid in the treatment of cancer or precancer of the endometrium, cervix, or uterus. In order to protect against or treat cancer of the ovaries, would need an oophorectomy.
  • Transgender (trans) male affirmation – aids in gender dysphoria, prevention of future gynecologic problems, and transition to obtaining new legal gender documentation.[rx]
  • Severe developmental disabilities – this treatment is controversial at best. In the United States, specific cases of sterilization due to developmental disabilities have been found by state-level Supreme Courts to violate the patient’s constitutional and common-law rights.[rx]
  • Postpartum – to remove either a severe case of placenta praevia (a placenta that has either formed over or inside the birth canal) or placenta percreta (a placenta that has grown into and through the wall of the uterus to attach itself to other organs), as well as a last resort in case of excessive obstetrical hemorrhage.[rx]
  • Chronic pelvic pain – should try to obtain pain etiology, although may have no known cause.
  • Pelvic relaxation
  • Fibroid uterus
  • Abnormal uterine bleeding
  • Pelvic pain associated with endometriosis
  • Pelvic organ prolapse
  • Benign ovarian mass
  • Gynecological cancer
  • Adenomyosis

A hysterectomy may be performed to treat

  • Abnormal uterine bleeding that is not controlled by other treatment methods
  • Severe endometriosis (uterine tissue that grows outside the uterus)
  • Uterine fibroids (benign tumors) that have increased in size, are painful or cause bleeding
  • Increased pelvic pain related to the uterus but not controlled by other treatment
  • Uterine prolapse – (uterus that has “dropped” into the vaginal canal due to weakened support muscles) that can lead to urinary incontinence or difficulty with bowel movements
  • Cervical or uterine cancer
  • Complications during childbirth (like uncontrollable bleeding)

Contraindications of Vaginal Hysterectomy

There are no absolute contraindications, but, some of the relative contraindications to vaginal hysterectomy are:

  • Pelvic radiation
  • Large uterus
  • Prior pelvic surgeries
  • Suspected severe pelvic adhesion and anatomical distortion from PID (pelvic inflammatory disease) or endometriosis.
  • Morbid obesity
  • Nulliparity
  • Lack of uterine descent


The instruments required for vaginal hysterectomy are the following:

  • long, heavy Mayo scissors
  • Short and long weighted vaginal speculums with an extra-long blade
  • Heaney right-angle retractors
  • Jorgenson scissors
  • long Allis clamps
  • Deaver retractors.
  • A long needle holder
  • Heany clamps
  • Single tooth tenaculum
  • Single-tooth tenaculum
  • Bovie extender,
  • Suction apparatus
  • A neurosurgery headlight


  • Gynecologist
  • Urogynecologists
  • Anesthesiologist
  • Anesthetic technologist
  • Nurses
  • Surgical assistants


Preparation of the patient includes the following:

  • Proper patient positioning- Vaginal hysterectomy is typically performed with the patient positioned in dorsal lithotomy with the help of either candy cane or boot-type stirrups.
  • Application of sequential compression devices or administration of anticoagulants for venous thromboembolism prophylaxis
  • Antibiotic prophylaxis- We typically use cefazolin 1 to 2 gm IV, administered within 60 min of the incision.
  • Time out (pre-procedure verification checklist) is always performed before the commencement of surgery, to confirm the correct patient, type of the operation, equipment used, and the surgeon performing the procedure, as per the standard hospital protocol.
  • The patient is examined under anesthesia for the evaluation of size, shape, mobility of the uterus; assessment of the adnexa, and other pelvic structures. Also, the degree of descent of the uterus, vaginal wall caliber, and pelvic organ prolapse, cystocele, and rectocele are assessed.
  • Betadine scrub is used for vaginal preparation before the procedure.
  • A sterile surgical drape is used to cover the patient to ensure the aseptic environment of the entire procedure.


Urinary bladder and ureteral injuries are the most common preventable complications that can occur during the hysterectomy. The technique for performing a hysterectomy is as follows:

  • Decompression of the bladder – Foley catheter is used to drain urine.
  • Injecting vasoconstricting agents – Dilute vasopressin (20 units in 100 ml of normal saline) is circumferentially injected into the proper planes of the cervicovaginal junction. The purpose of this is for hemostasis and hydrodissection.
  • A circumferential – incision is made around the cervix at the cervicovaginal intersection by using a scalpel or diathermy.
  • Dissection and deflection of the bladderanterior colpotomy – after the circumferential incision is made, the anterior aspect of the vaginal mucosa is grasped and tented up, sharp and blunt dissection is done to separate the vaginal mucosa from the cervical stroma. The peritoneum is identified, and the peritoneal cavity is entered sharply. A right angle or Deaver retractor is then placed into the peritoneal cavity and the bladder is protected.
  • Posterior cul-de-sac entry – Posterior vaginal epithelium is grasped at the previous circumferential incision with a pair of Allis clamps and tended up, the peritoneum is identified and sharply entered with Mayo scissors. Once the peritoneal cavity is opened, the vaginal mucosa is stretched or incised laterally, and a long weighted vaginal speculum is reinserted into the peritoneal cavity.
  • Uterosacral and cardinal ligament complex – Uterosacral ligaments are felt by examining with the index finger. The right-angle retractor is placed in the medial aspect of the vagina for proper exposure of this ligament, which is then clamped with Heaney clamp and cut. It is then sutured ligament, and the tail of the suture is clamped and saved for future McCall’s culdoplasty. Similarly, the cardinal ligaments are identified, clamped, cut, and suture ligated. Care be taken during clamping as the ureters are very close to the uterosacral ligaments. Clamps must be placed very close to the cervical stump. All clamps must incorporate both anterior and posterior peritoneum to prevent bleeding from collateral blood vessels.
  • Uterine vessels – The Heaney clamp is widely opened and slide off the cervix, making sure all the vasculature is incorporated into the clamp, uterine vessels are cut, and suture ligated. The author does not recommend Heaney stitch as it can cause unnecessary injury to the vascular pedicle and cause bleeding. A significant uterine descent is seen after the uterine vessel dissection.
  • Broad ligament – This is an avascular ligament, which is primarily composed of peritoneum and minor blood vessels. This ligament is clamped medially, cut, and sutured.
  • Utero-ovarian, round ligament complex, and corneal end of the Fallopian tube – The upper and the final pedicle can be clamped all together or separately. If the pedicles are too large, the round ligament can be clamped individually. As this is a large pedicle, the author recommends doubly clamping this pedicle, and two sutures are placed. First, suture tie followed by suture ligation medial to the first. Once all ligaments and vessels are cut, ligated, and secured, the uterus is delivered.
  • Evaluate all pedicles – in a clockwise fashion for adequate hemostasis.
  • Closure of the cuff and McCall’s Coloplast – As the vaginal apex is the most common site of bleeding during vaginal hysterectomy, we usually close it in the running and locking fashion to control bleeding from the vaginal edges. The author typically horizontally closes the cuff unless there is a concern for the vaginal length, in which the wound is closed in a vertical fashion.

Incorporate the uterosacral ligaments into the angle of the vaginal cuff at the time of cuff closure for the suspensory support of the vagina. This maneuver prevents future vaginal wall prolapse.

The vagina is not usually packed as it has not shown to improve bleeding or any other outcomes. A Foley catheter is left in place until the patient is ambulatory.  Diet is advanced as tolerated.


It takes time to get back to your usual self after an abdominal hysterectomy — about six weeks for most women. During that time:

  • Get plenty of rest.
  • Don’t lift anything heavy for a full six weeks after the operation.
  • Stay active after your surgery, but avoid strenuous physical activity for the first six weeks.
  • Wait six weeks to resume sexual activity.
  • Follow your doctor’s recommendations about returning to your other normal activities.

Life after a hysterectomy

A hysterectomy permanently changes some aspects of your life. For instance:

  • You’ll no longer have menstrual periods.
  • Most of the time, you’ll get relief from the symptoms that made your surgery necessary.
  • You won’t be able to become pregnant.
  • If you’re premenopausal, having your ovaries removed along with a hysterectomy starts menopause.
  • If you have a hysterectomy before menopause and you keep your ovaries, you may experience menopause at a younger than average age.
  • If you have a partial hysterectomy, your cervix remains in place, so you’re still at risk of cervical cancer. You need regular Pap tests to screen for cervical cancer.

Other parts of your life will likely return to normal or perhaps improve once you’ve recovered from your hysterectomy. For example:

  • If you had a good sex life before a hysterectomy, chances are you’ll maintain it afterward. Some women even experience more sexual pleasure after a hysterectomy. This may be due to relief from chronic pain or heavy bleeding that was caused by a uterine problem.
  • The relief of symptoms may greatly enhance your quality of life. You may have an improved sense of well-being and a chance to get on with your life.

On the other hand, you may feel a sense of loss after a hysterectomy. Premenopausal women who must have a hysterectomy to treat gynecologic cancer may experience grief and possibly depression over the loss of fertility. If sadness or negative feelings begin to interfere with your enjoyment of everyday life, talk with your doctor.

Alternative of Hysterectomy

Alternate treatment options will depend very much on the source of the problem. The surgeon may discuss alternative approaches to Hysterectomy:

Hysterectomy is major surgery. Sometimes a hysterectomy may be medically necessary, such as with prolonged heavy bleeding or certain types of cancer. But sometimes you can try other treatments first. These include:

  • Watchful waiting. You and your doctor may wish to wait if you have uterine fibroids, which tend to shrink after menopause.
  • Exercises. For uterine prolapse, you can try Kegel exercises (squeezing the pelvic floor muscles). Kegel exercises help restore tone to the muscles holding the uterus in place.
  • Medicine. Your doctor may give you medicine to help with endometriosis. Over-the-counter pain medicines taken during your period also may help with pain and bleeding. Hormonal birth control, such as the pill, shot, or vaginal ring, or a hormonal intrauterine device (IUD) may help with irregular or heavy vaginal bleeding or periods that last longer than usual.
  • Vaginal pessary (for uterine prolapse). A pessary is a rubber or plastic donut-shaped object, similar to a diaphragm used for birth control. The pessary is inserted into the vagina to hold the uterus in place. Uterine prolapse happens when the uterus drops or “falls out” because it loses support after childbirth or pelvic surgery.
  • Surgery. You and your doctor may choose to try a surgery that involves smaller or fewer cuts than a hysterectomy. The smaller cuts may help you heal faster with less scarring. Depending on your symptoms, these options may include:
    • Surgery to treat endometriosis. Laparoscopic surgery uses a thin, lighted tube with a small camera. The doctor puts the camera and surgery tools into your pelvic area through very small cuts. This surgery can remove scar tissue or growths from endometriosis without harming the surrounding healthy organs such as ovaries. You may still get pregnant after this surgery.
    • Surgery to help stop heavy or long-term vaginal bleeding.
      • Dilation and curettage (D&C) remove the lining of the uterus that builds up every month before your period. Often, a hysteroscopy is done at the same time. Your doctor inserts the hysteroscope (a thin telescope) into your uterus to see the inside of the uterine cavity. D&C may also remove noncancerous growths or polyps from the uterus. After the D&C, a new uterine lining will build up during your next menstrual cycle as usual. You may still get pregnant after this surgery.
      • Endometrial ablation destroys the lining of the uterus permanently. Depending on the size and condition of your uterus, your doctor may use tools that freeze, heat or use microwave energy to destroy the uterine lining. This surgery should not be used if you still want to become pregnant or if you have gone through menopause.
    • Surgery to remove uterine fibroids without removing the uterus. This is called a myomectomy. Depending on the location of your fibroids, the myomectomy can be done through the pelvic area or through the vagina and cervix. You may be able to get pregnant after this surgery. If your doctor recommends this surgery, ask your doctor if a power morcellator will be used. The FDA has warned against the use of power morcellators for most women.
    • Surgery to shrink fibroids without removing the uterus. This is called myolysis. The surgeon heats the fibroids, which causes them to shrink and die. Myolysis may be done laparoscopically (through very small cuts in the pelvic area). You may still get pregnant after myolysis.
  • Treatments to shrink fibroids without surgery. These treatments include uterine artery embolization (UAE) and magnetic resonance (MR)-guided focused ultrasound (MRUS). UAE puts tiny plastic or gel particles into the vessels supplying blood to the fibroid. Once the blood supply is blocked, the fibroid shrinks and dies. MR(f)US sends ultrasound waves to the fibroids that heat and shrink the fibroids. After UAE or MR(f)US, you will not be able to get pregnant.


Complications during a hysterectomy are divided into: 

A. Intraoperative complications
  • Bleeding – The most common sites of bleeding during vaginal hysterectomy are uterine vessels, Utero-ovarian ligament, and vaginal cuff.
  • Ureteral injury- The incidence of ureteral injury is about 0.5 percent.
  • Bladder injury- The prevalence of bladder injury during vaginal hysterectomy is up to 1.2 percent. It increases with risk factors like prior pelvic surgeries and concomitant bladder surgery.
  • Bowel injury- The risk is approximately 0.4 percent.
  • Nerve injuries- Most commonly, the femoral nerve, peroneal, and tibial nerves are affected by the retractors or by malposition of the legs on the stirrups.
  • Conversion to laparotomy- Instances like unexpected large pelvic masses, adhesions, and Hemorrhage unable to identify and control can increase the chances of conversion to abdominal hysterectomy.
  • Adverse reactions to anesthetics
B. Postoperative complications
  • Ileus
  • Bowel obstruction.
  • Vaginal cuff dehiscence
  • Infections like vaginal cuff cellulitis and pelvic abscess
  • Fistulas-vesicovaginal, ureterovaginal, and rectovaginal fistulas
  • Prolapse of the pelvic structures like a fallopian tube.
  • Clamping and cutting the infundibulopelvic ligament.
  • Separating the uterine vessels.
  • Separating the uterosacral-cardinal ligament complex and during the closure of vaginal apex.

N.B. The details of the management of complications of hysterectomy are outside the scope of this article.



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Peroneal Tendon Disorders – Causes, Symptoms, Treatment

Peroneal Tendon Disorders are a cause of hindfoot and lateral foot pain. There are three primary disorders of the tendons; peroneal tendonitis, peroneal subluxation, and peroneal tendon tears; these conditions are a cause of lateral ankle pain and may lead to ankle instability. The peroneal tendons are in the lateral compartment of the leg and include the peroneus longus and peroneus brevis muscles. Both receive innervation from the superficial peroneal nerve and blood supply from the peroneal artery. The peroneus brevis originates on the lateral aspect of the distal fibula and intermuscular septum and inserts onto the base of the fifth metatarsal. The peroneus longus originates at the proximal fibula and lateral tibia and inserts at the base of the first metatarsal and the medial cuneiform. The tendons occupy a common synovial sheath that runs posterior to the distal fibula, once past the fibula they each have their own synovial sheath. They run in a tunnel bordered by the superior peroneal retinaculum, the posterior fibula that has a retromalleolar groove, and the calcaneofibular ligament. Tendon relationship at the level of the ankle is the peroneus brevis anterior and medial to the peroneus longus. Sometimes anomalous anatomy can lead to a peroneal disorder such as low lying brevis muscle belly or the presence of peroneus quartus muscle. The peroneus quartus muscle most commonly runs form the peroneus brevis to the retrotrochlear eminence of the calcaneus and is associated with peroneus brevis tears, and subluxation.

Causes of Peroneal Tendon Disorders

Acute injury with a sudden contraction of the peroneal tendons can lead to acute injuries such as a tear of the tendon, or superior peroneal retinaculum, or avulsion of the tendons or the retinaculum from their attachments. If the tendons chronically subluxate, this can lead to inflammation and irritation causing tendonitis. The tendons rubbing over the posterolateral fibula can also lead to longitudinal tears of the tendons. Chronic lateral ankle stability has also been shown to lead to subluxation and subsequent tears due to increased laxity and motion of the tendons. Anatomical variants of the fibular retromalleolar groove, hindfoot alignment or cavus foot can lead to abnormal movement of the tendon leading to a predisposition towards subluxation or dislocation.


The primary function of the peroneal tendons is to evert and plantarflex at the ankle. Also, the peroneus longus will plantarflex the first ray leading to hindfoot varus during walking. Having pre-existing varus hindfoot alignment can increase strain on the peroneus longus tendon that can lead to inflammation, subluxation, and possible tears. The retromalleolar groove has different shapes; a cadaveric study showed out of 178 ankles the groove is concave in 82%, flat in 11 % and convex in 7% with a non-osseous fibrocartilaginous ridge that is on the medial side of the groove.

Peroneal Tendonitis:

  • Lateral ankle instability can cause laxity, leading to the increased motion of the tendons around the fibula with stretched superior peroneal retinaculum
  • Low lying peroneus brevis muscle belly having to go through the narrow tendon sheath

Peroneal Subluxation/Dislocation:

  • Instability can be acute from the rupture of the superior retinaculum or fibular groove avulsion or chronic. Chronic subluxation is associated with fibular groove flattening laxity of the superior retinacular ligament

Peroneal tendon tear:

  • Musculotendinous junction during forceful contraction or in the cuboid tunnel
  • Most tears are longitudinal and result from chronic subluxation over the distal fibula

Diagnosis of Peroneal Tendon Disorders

History and Physical

History is essential in differentiating the pathology of peroneal tendons. It is necessary to identify the timing, aggravating position or activity, any traumatic events if there is associated swelling, as well as a description of the pain. A common pertinent history finding is a description of snapping or popping at the lateral malleolus. Patients must undergo screening for prior steroid injections and history of recent antibiotic use; Fluoroquinolones and steroids have associations with tendon disease.

Physical exam should begin with an inspection of the ankle and foot for erythema or swelling, muscle strength testing of eversion and plantar flexion. The examiner can isolate the peroneus longus tendon by resisting active eversion through applying pressure to the medial first metatarsal head. Palpation of the tendons during ROM of the ankle. Evaluation of hindfoot biomechanics such as varus and valgus alignment should take place with the patient standing. Ankle drawer test should be done to asses ankle ligamentous stability. Another physical exam technique is to have the patient lay prone with a knee to 90 degrees flexion and examine for peroneal tendon subluxation.

Peroneal tendonitis presents with gradual onset of pain and swelling. There may be palpable fluid present in the tendon sheath with crepitation. The primary location of tenderness is along the peroneal tendons as they pass posterior and inferior to the fibular head. Tendon tears often have constant swelling, pain, or patient feeling of ankle instability or weakness. Tendon subluxation patients will have painful clicking and popping at the lateral malleolus. Subluxation may be apparent with voluntary eversion.


The primary imaging modality with any suspected peroneal tendon disorder is X-rays of the ankle. X-rays should be weight-bearing and include standard AP, mortise, and lateral ankle views. Additional X-ray views are the axillary/Harris heel view and AP, lateral and oblique views of the foot to look for other fractures and foot alignment. Findings on the x-ray that indicate peroneal pathology are avulsion from the base of the fifth metatarsal, avulsion fracture of the distal fibular groove, os peroneum, and retromalleolar groove flattening.

Ultrasound is a no radiation, inexpensive imaging modality that can provide an evaluation of the tendon in motion, as well as assist with injections. It has been shown to be effective in identifying tears as well with a sensitivity of 100 % and specificity of 85%.

MRI is the next step in evaluation with a high-quality view of the tendons with no exposure to radiation. The sensitivity is 83%, and specificity is 75% for peroneus brevis tears. Findings include fluid surrounding the tendons, discontinuity, edema of the bone, and any bony deformity.

CT scanning does expose the patient to radiation but provides better bony detail to evaluate possible bony deformity causing possible tendon dysfunction.  If x-rays indicate the possibility of fracture, peroneal tubercle, or retro trochlear eminence CT scan would be useful and determine possible management.

Treatment of Peroneal Tendon Disorders

Nonoperative treatment:

  • Nonsteroidal anti-inflammatory drugs, ice, rest or immobilization, and physical therapy. Immobilization can include cast or controlled ankle motion boot. Modification of shoe wear can also help unload the peroneal tendons with the use of a lateral heel wedge.
  • If this does not provide any improvement steroid injection around the peroneal tendon sheath can help with pain as well as assist with diagnosis.
  • PRP injections with ultrasound guidance have shown improved functional outcomes with tendinopathy in the study by Dallaudiere. Four hundred eight patients showed 23 patients with peroneal tendon disorders.

Non-operative treatment should be for 4 to 6 months to allow resolution of inflammation

Operative treatment:

If conservative treatment has failed, operative management options of each type of disorder are as follows:

Peroneal Tendonitis:

  • Open Debridement and synovectomy
  • Arthroscopic peroneal tendoscopy

Peroneal tendon subluxation:

Treatment depends on the cause of the subluxation or dislocation. Goals are to restore the fibrocartilaginous rim, the superior peroneal retinaculum, and periosteum to the fibula and obtain smooth gliding of the tendon with adequate space for motion.

  • If the superior peroneal retinaculum is torn then open or endoscopic repair or reconstruction is necessary.
  • Avulsion fracture of the fifth metatarsal or fibular groove should entail fixation or repair.
  • If the fibular groove is shallow endoscopic or open fibular groove deepening can be performed to provide a better structure for the peroneal tendons. This procedure usually addresses cases of chronic instability.
  • If there is any hindfoot varus alignment, this should also be corrected to decrease stress on the peroneus longus with hindfoot osteotomy.
  • Rerouting the peroneal tendons underneath the calcaneofibular ligament.
  • Bone block procedures that involve performing osteotomy of the fibula lateralizing it to create a bony block for the tendons.

Peroneal tendon tears:

Treatment depends on the degree of tendon torn and whether the tear is acute or chronic

  • Debridement and tubularization- partial tears of less than 50%.
  • Repair end to end of acute complete tears
  • Side-to-side anastomosis or Pulvertaft weave with chronic tears
  • Allograft reconstruction


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Test Diagnosis of Tuberculous Spondylitis – Treatment

Test Diagnosis of Tuberculous Spondylitis/Tuberculous Spondylitis also is known as Pott disease, refers to vertebral body osteomyelitis and intervertebral diskitis from tuberculosis (TB). The spine is the most frequent location of musculoskeletal tuberculosis, and commonly related symptoms are back pain and lower limb weakness/paraplegia.

Spinal tuberculosis is a destructive form of tuberculosis. It accounts for approximately half of all cases of musculoskeletal tuberculosis. Spinal tuberculosis is more common in children and young adults. The incidence of spinal tuberculosis is increasing in developed nations. Genetic susceptibility to spinal tuberculosis has recently been demonstrated. Characteristically, there is the destruction of the intervertebral disk space and the adjacent vertebral bodies, the collapse of the spinal elements, and anterior wedging leading to kyphosis and gibbus formation. The thoracic region of the vertebral column is most frequently affected. The formation of a ‘cold’ abscess around the lesion is another characteristic feature.

Types of Tuberculous Spondylitis


  • Causative agent
      • Mycobacterium tuberculosis
      • Mycobacterium bovis
  • Tuberculoma (tuberculous granuloma)
  • Tuberculous abscess
  • Miliary tuberculosis
  • Pulmonary tuberculosis
  • Primary pulmonary tuberculosis
    • Ghon focus
    • Ranke complex
    • post-primary pulmonary tuberculosis

Extrapulmonary tuberculosis, intracranial tuberculosis

  • Tuberculous leptomeningitis
  • Tuberculous pachymeningitis
  • Intracranial tuberculous granuloma
  • Intracranial tuberculous abscess
  • Tuberculous rhombencephalitis
  • Tuberculous encephalopathy
  • Tuberculous otomastoiditis
  • Tuberculous lymphadenopathy – scrofula
  • Cardiac tuberculosis
  • Tuberculous mastitis
  • Hepatic and splenic tuberculosis
  • Gastrointestinal tuberculosis
  • Tuberculous peritonitis
  • Adrenal tuberculosis
  • Genitourinary tuberculosis
  • Renal tuberculosis
    • Kerr kink
    • putty kidney
  • Bladder and ureteric tuberculosis
  • Prostatic tuberculosis
  • Scrotal tuberculosis (testes, epididymis, seminal vesicles, vas deferens)
  • Tuberculous pelvic inflammatory disease (female)
    • tuberculosis of the Fallopian tube

Skeletal Tuberculosis

  • Tuberculosis of spine (Pott’s disease)
  • Tuberculous osteomyelitis
  • Tuberculous dactylitis (spina ventosa)
  • Tuberculous arthropathy​
  • Phemister triad
  • Shoulder tuberculous arthropathy
  • Tuberculosis of tendon sheath and bursae
  • Latent TB –  In this condition, you have a TB infection, but the bacteria remain in your body in an inactive state and cause no symptoms. Latent TB, also called inactive TB or TB infection, isn’t contagious. It can turn into active TB, so treatment is important for the person with latent TB and to help control the spread of TB. An estimated 2 billion people have latent TB.
  • Active TB – This condition makes you sick and can spread to others. It can occur in the first few weeks after infection with the TB bacteria, or it might occur years later.

Causes Of Tuberculous Spondylitis

Early infection

  • begins in the metaphysics of the vertebral body
  • spreads under the anterior longitudinal ligament and leads to
  • contiguous multilevel involvement
  • skip lesion or non-contiguous segments (15%)
  • paraspinal abscess formation (50%) usually anterior and can be quite large (much more common in TB than pyogenic infections)
  • initially does not involve the disc space (distinguishes from pyogenic osteomyelitis, but can be misdiagnosed as a neoplastic lesion)

Chronic infection

Severe kyphosis

  • mean deformity in nonoperative cases is 15° in 5% of patients, the deformity is >60°
  • infection is often diagnosed late, there is often much more severe kyphosis in granulomatous spinal infections compared to pyogenic infections
  • in adults kyphosis stays static after healing of disease
  • in children, kyphosis progresses in 40% of cases because of a growth spurt

Various types of vertebral involvement in spinal tuberculosis

Type of involvement Mechanisms of involvement Radiological appearances
Paradiskal Spread of disease via the arteries Involves adjacent margins of two consecutive vertebrae. The intervening disk space is reduced
Central Spread of infection along Batson’s plexus of veins Involves central portion of a single vertebra; proximal and distal disk spaces intact
Anterior marginal Abscess extension beneath the anterior longitudinal ligament and the periosteum Begins as a destructive lesion in one of the anterior margins of the body of a vertebra, minimally involving the disk space but sparing the vertebrae on either side
Skipped lesions Spread of infection along Batson’s plexus of veins circumferentially involvement of two noncontiguous vertebral levels without destruction of the adjacent vertebral bodies and intervertebral disks
Posterior Spread via the posterior external venous plexus of vertebral veins or direct spread Involves posterior arch without the involvement of the vertebral body
Synovial Hematogenous spread through subsynovial vessels Involves synovial membrane of atlantoaxial and atlanto-occipital joints

Tuberculous Spondylitis

Symptoms Tuberculous Spondylitis

Symptoms and signs of tuberculosis

  • Cough—usually productive
  • Sputum—usually mucopurulent or purulent
  • Haemoptysis—not always a feature, volume variable
  • Breathlessness—gradual increase rather than sudden
  • Weight loss—gradual
  • Anorexia—variable
  • Fever—may be associated with night sweats
  • Malaise— the patient may realize only retrospectively when feeling better after treatment
  • Wasting and terminal cachexia—late, ominous signs

Signs and symptoms of active TB include:

  • Coughing that lasts three or more weeks
  • Coughing up blood
  • Chest pain, or pain with breathing or coughing
  • Unintentional weight loss
  • Fatigue
  • Fever
  • Night Sweats
  • Chills
  • Loss of appetite
  • The onset is gradual.
  • Back pain is localized.
  • Fever, night sweats, anorexia, and weight loss.
  • Signs may include kyphosis (common) and/or a paravertebral swelling.
  • Affected patients tend to assume a protective, upright, stiff position.
  • If there is neural involvement there will be neurological signs.

A psoas abscess may present as a lump in the groin and resemble a hernia

  • A psoas abscess most often originates from a tuberculous abscess of the lumbar vertebra that tracks from the spine inside the sheath of the psoas muscle.
  • Other causes include an extension of renal sepsis and posterior perforation of the bowel.
  • There is a tender swelling below the inguinal ligament and they are usually apyrexial.
  • The condition may be confused with a femoral hernia or enlarged inguinal lymph nodes.

Diagnosis of Tuberculous Spondylitis

The clinical presentation of spinal tuberculosis is variable. The manifestations depend upon the duration of illness, the severity of the disease, site of the lesion, and the presence of associated complications including deformity and neurological deficit. Rest pain is pathognomonic, and rarely, radicular pain can be the main presenting symptom. Constitutional symptoms including weight or appetite loss, fever, and malaise/ fatigue are less commonly associated with extrapulmonary tuberculosis than pulmonary disease.

Cold Abscess

  • These abscesses typically lack all the inflammatory signs obvious in abscesses; and hence the name. In the cervical spine, they can present in the retropharyngeal space, anterior or posterior triangles of the neck or axilla. In the thoracic spine, they may present as pre- or paravertebral abscesses; or over the chest wall. In the lumbar spine, they may track down along the psoas muscle, Petit’s triangle, Scarpa’s triangle, or the gluteal region.


  • The clinical appearance of kyphotic deformity has been classified as knuckle (one vertebral involvement), gibbous (two vertebrae), and rounded kyphosis (more than three vertebrae). Owing to the greater involvement of the anterior spinal column in TB, the spinal column progressively develops a kyphotic orientation; especially in the thoracic and thoracolumbar spine. Jain et al. observed that kyphotic deformity greater than 60 degrees leads to significant disability and can potentially inflict neurological deficits.

Neurological Deficit

  • A neurological deficit can occur either at the active stage of the disease (secondary to compression from an abscess, inflammatory tissue, sequestrum, or spinal instability) or during the healed stage (usually secondary to mechanical traction over the internal gibbus or spinal instability).
  • The initial compression in TB is secondary to vertebral body collapse, leading to anterior spinal tract involvement (exaggerated deep tendon reflexes and Babinski sign, further progression on to UMN-type motor deficit).

There were five stages of Pott paraplegia

  • Stage 1  Deficit only evident, based on the clinical examination by the clinician (ankle clonus, exaggerated deep tendon reflexes and Babinski or plantar extensor)
  • Stage 2 The patient has UMN-type of a motor deficit with spasticity, however, is still ambulatory. The anticipated motor score in tetraparesis is 60 to 100 and in paraparesis is between 80 and 100; sensory deficit involves the lateral column
  • Stage 3 – The patient is bedridden and spastic. The anticipated motor score in tetraparesis is 0 to 30, and in paraparesis is between 50 and 80; sensory deficit involves the lateral column
  • Stage 4 – The patient is bedridden with severe sensory loss/ pressure sores. The Anticipated motor score in tetraplegia is 0, and in paraplegia is between 50; sensory deficit involves posterior and lateral columns
  • Stage 5Similar to stage 4 +/- bladder/bowel involvement +/- flexor spasms/ flaccid tetraplegia/ paraplegia

Pediatric Spinal TB

Owing to the immaturity and increased flexibility of the spine in children, they are particularly prone to developing severe deformity progression. Such worsening of deformity in children can also occur after the disease has completely healed, and therefore the need to follow-up this patient population until skeletal maturity cannot be understated. Rajasekaran et al. described 4 signs of “spine at risk” in children, which include:

  • Retropulsion of the posterior aspect of the involved vertebra
  • Faceted subluxation (separation of facets on lateral radiographs)
  • Lateral translation of vertebrae (as observed on anteroposterior radiographs)
  • The toppling of one vertebra over the other (defined by a line along the anterior surface of caudal normal vertebra crossing the mid-point of the anterior surface of the cranial normal vertebral bone)

He proposed that children with two or more of these signs had posterior facet disruption and required surgical intervention. He also proposed a classification system for the progression of the deformity in children:

  • Type 1 – curves where curvature increases until growth cessation or skeletal maturity and surgical intervention was required
  • Type 2 – curves where the deformity decreased with growth progression
  • Type 3 – curves where there was minimal change in the deformity either during the active or healed phases of the disease

Atypical Presentations

  • Some of the atypical clinical presentations may include intervertebral disc prolapse, isolated abscess without skeletal involvement, and pure intraspinal granulomas. Similarly, atypical radiological presentations may include skipping lesions, concentric vertebral collapse, circumferential vertebral involvement, isolated posterior arch involvement, ivory vertebra, isolated meningeal, neural or perineural involvement without any vertebral destruction and multifocal osseous lesions.

Imaging Modalities

  • Plain radiographs (15% sensitivity) Early stages (less than 30% vertebral destruction) – not much role; later stages (beyond 30% vertebral destruction) – can present with disc space reduction, endplate rarefaction, vertebral body destruction, instability, and spinal deformity. The chest x-ray is also an important investigation, as up to thirds of these patients with spinal TB can also have a concomitant pulmonary disease.
  • The following are radiographic changes characteristic of spinal tuberculosis on plain radiography
    • Increased anterior wedging
    • Lytic destruction of the anterior portion of the vertebral body
    • Collapse of vertebral body
    • Reactive sclerosis on a progressive lytic process
    • Enlarged psoas shadow with or without calcification
  • Additional radiographic findings may include the following
    • Vertebral endplates are osteoporotic.
    • Intervertebral disks may be shrunk or destroyed.
    • Vertebral bodies show variable degrees of destruction.
    • Fusiform paravertebral shadows suggest abscess formation.
    • Bone lesions may occur at more than one level.
  • Computed tomography (CT) (100% sensitivity)  Can help in the diagnosis at a much earlier stage than plain x-rays. The types of vertebral destructive lesions by CT in spinal TB include fragmentary, osteolytic, subperiosteal, and localized sclerosis. CT scans can also aid in image-guided biopsy for establishing the diagnosis.
  • Magnetic resonance imaging (MRI) (100% sensitivity and 80% specificity) – MRI is the most useful modality in the diagnosis of spinal TB. MRI best detects the extent of soft tissue enhancement, the location of the abscess, and spinal canal compromise. Gadolinium-enhanced MRI may provide additional information regarding the diagnosis. Screening sequences involving the whole spine can also help us in identifying non-contiguous vertebral involvement. MRI can also assess response to treatment.
  • Nuclear imaging – 18 F-fluorodeoxyglucose (18F-FDG) labeled positron emission tomography (PET) scan provides evidence of functional activity in the involved tissues, based on the rationale that 18F-FDG is known to accumulate in macrophages at the inflammation site. These modalities cannot help in distinguishing tubercular infections from malignancy or other pyogenic infections.

Tuberculous Spondylitis

Laboratory Tests

  • Blood tests
  • CBC: leukocytosis
  • Elevated erythrocyte sedimentation rate: >100 mm/h
  • Erythrocyte sedimentation rate (ESR) (60% to 90% sensitivity) – is usually more than 20 mm/hour in TB and decreases with treatment response. Nevertheless, it is not a very sensitive test. C-reactive protein (CRP) (71% sensitivity) is more specific than ESR.
  • Serological examination of IgG and IgM antibody levels against TB antigen – cannot effectively distinguish between active or healed disease; natural TB infection or vaccinated persons; and is raised in both active and chronic stages of infection.
  • Acid-fast bacilli (AFB) staining (25% to 75% sensitivity and 99% specificity) Using the Ziehl-Neelsen technique, tubercle bacillus presents with a bright red stain. At least, a concentration of 1 to 10 bacteria/ ml is necessary for detection.
  • TB culture – BACTEC radiometric culture assay (56% sensitivity and 100% specificity) takes 2 weeks of incubation time; while traditional culture on Lowenstein-Jenson (LJ) medium takes up to 6 weeks (47% sensitivity and 100% specificity). Growth on the LJ medium requires a concentration of at least 10 to 100 bacteria/ml.
  • Molecular testing and polymerase chain reaction (PCR) (75% sensitivity and 97% specificity) This technique requires only a concentration of 1 to 10 bacilli/ ml. This is a very useful technique in paucibacillary, extrapulmonary TB infections.
  • Gene Xpert MTB/RIF  This is a fully automated test, which yields results within 90 minutes (82.9% sensitivity and 98% specificity). This test also helps in diagnosing resistance to rifampicin. WHO, in March 2017 recommended Xpert MTB/RIF Ultra (87.8% sensitivity and 94.8% specificity) as an investigation with good yield in pediatric and extrapulmonary patients.
  • Histopathological evaluation – Characteristic findings including caseating necrosis, epithelioid cell granuloma, and Langhans giant cells can be found in 72% to 97% of patients.

Tests to Detect Latent Tuberculosis

  • Mantoux test (40% to 55% sensitivity and 75% specificity) Skin hypersensitivity test (purified protein derivative [PPD]) has been recommended as a low-cost test in developing nations; nevertheless, it is not an accurate test in endemic countries or immunodeficient patients.
  • Interferon-gamma release assay (50% to 65% sensitivity and 85% specificity) – Measuring interferons produced in response to tubercular antigens; not useful in endemic regions.
  • Whole blood-based enzyme-linked immunosorbent assay (ELISA)

Clinico-Radiological Staging of Pott Spine (Prognostic Staging)

  • I – Predestructive stage; straightening of curvature, perivertebral muscle spasm, hyperemia on scintiscan (Duration fewer than 3 months)
  • II – Early destructive stage; disc space reduction and paradisiacal erosion, knuckle less than 10 degrees, MRI demonstrates marrow edema, and CT shows erosions or cavitations (Duration 2 to 4 months)
  • III – Mild angular kyphosis; 2 to 3 vertebrae involved and kyphosis 10 – 30 degrees (Duration 3 to 9 months)
  • IV – Moderate angular kyphosis; 2 to 3 vertebrae involved and kyphosis 30 to 60 degrees (Duration 6 to 24 months)
  • V – Severe angular kyphosis; more than 3 vertebrae involved and kyphosis greater than 60 degrees (Duration more than 24 months)

Treatment of Tuberculous Spondylitis

It is essential to classify spinal TB disease into a complicated and uncomplicated disease, based on their presentation. While uncomplicated spinal TB is essentially a medical disease; complicated TB spine patients need surgical intervention in addition to chemotherapy.

Dosages of first-line antituberculosis drugs and major adverse effects

Drug Dosage Adverse effects
Daily Twice or thrice weekly
Isoniazid 5 mg/kg oral (maximum 300 mg) 900 mg twice weekly
600 mg thrice weekly
Hepatitis, peripheral neuritis, drug-induced lupus, seizures, and hypersensitivity with rash and fever. Drug interactions with Dilantin and disulfiram
Rifampicin 10 mg/kg oral (maximum 600 mg) 10 mg/kg
600 mg twice weekly
600 mg thrice weekly
Orange body secretions, flu-like syndrome, hepatitis, thrombocytopenia, nausea, anorexia, diarrhea, renal failure, and multiple drug interactions
Pyrazinamide 25-30 mg/kg oral 30-35 mg/kg Hyperuricemia, hepatitis, rash, nausea, and anorexia
Ethambutol 25 mg/kg initial 2 months, then 15 mg/kg oral 50 mg/kg twice weekly
30 mg/kg thrice weekly
Optic neuritis and gastrointestinal discomfort
Streptomycin 15 mg/kg intravenously or intramuscularly (maximum 1.0 g) 5 days a week 15 mg/kg (maximum 1.5 g) twice weekly or thrice weekly Ototoxicity, vestibular dysfunction, nephrotoxicity, rash, and hypersensitivity reactions

First Line

All first-line anti-tuberculous drug names have a standard three-letter and a single-letter abbreviation:

  • ethambutol is EMB or E,
  • isoniazid is INH or H,
  • pyrazinamide is PZA or Z,
  • rifampicin is RMP or R,
  • streptomycin is SM or S.

First-line anti-tuberculous drug names are often remembered with the mnemonic “RIPE,” referring to the use of a rifamycin (like rifampin), isoniazid, pyrazinamide, and ethambutol. The US uses abbreviations and names that are not internationally recognized,  rifampicin is called rifampin and abbreviated RIF; streptomycin is abbreviated STM. In the US only, streptomycin is no longer considered a first-line drug by ATS/IDSA/CDC because of high rates of resistance. The WHO have made no such recommendation.

Second Line

The second-line drugs (WHO groups 2, 3, and 4) are only used to treat the disease that is resistant to first-line therapy (i.e., for extensively drug-resistant tuberculosis (XDR-TB) or multidrug-resistant tuberculosis (MDR-TB)). A drug may be classed as second-line instead of first-line for one of three possible reasons: it may be less effective than the first-line drugs (e.g., p-aminosalicylic acid); or, it may have toxic side-effects (e.g., cycloserine); or it may be effective, but unavailable in many developing countries (e.g., fluoroquinolones):

  • aminoglycosides (WHO group 2): e.g., amikacin (AMK), kanamycin (KM);
  • polypeptides (WHO group 2): e.g., capreomycin, viomycin, enviomycin;
  • fluoroquinolones (WHO group 3): e.g., ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF);
  • thioamides (WHO group 4): e.g. ethionamide, prothionamide
  • cycloserine (WHO group 4)
  • terizidone (WHO group 5)

Third Line

Third-line drugs (WHO group 5) include drugs that may be useful, but have doubtful or unproven efficacy:

  • rifabutin
  • macrolides: e.g., clarithromycin (CLR);
  • linezolid (LZD);
  • thioacetazone (T);
  • thioridazine;
  • arginine;
  • vitamin D;
  • bedaquiline.

These drugs are listed here either because they are not very effective (e.g., clarithromycin) or because their efficacy has not been proven (e.g., linezolid, R207910). Rifabutin is effective but is not included on the WHO list because for most developing countries, it is impractically expensive.


  • The mainstay of treatment in spinal TB – is chemotherapy (antitubercular treatment [ATT]). Tubercle bacilli may exist as intracellular or extracellular forms or as dormant or rapidly multiplying forms. Therefore, multi-drug treatment is essential to attack the bacilli in various stages or forms and reduce the instance of drug resistance. The duration (6, 9, 12, or 18 months) and frequency (daily versus alternate-day regimen) of administration of ATT have been controversial.
  • WHO recommends 6 months of multidrug anti-tubercular therapy – including 2 months of four- or five-drug treatment (isoniazid, rifampicin, pyrazinamide, ethambutol, and/ or streptomycin) constituting the initiation” phase, followed by 4 months of “continuation” phase therapy with a two-drug regimen including isoniazid and rifampicin.
  • The American Thoracic Spine Society – recommends a regimen involving 9 months of treatment with the same drugs (“continuation” phase extending for a period of 7 months). The Canadian Thoracic Society recommends treatment for 9 to 12 months duration.
  • Other second-line anti-tubercular drugs including –  kanamycin, capreomycin, pyrazinamide, amikacin, among others are typically indicated when there is resistance or poor tolerance to first-line medications. A recent meta-analysis has not demonstrated any difference between self-administered and directly observed treatment (directly observed therapy, short course); nevertheless WHO has continued to recommend DOTS therapy for optimum results.

Multidrug Resistance

  • MDR-TB is defined as TB infection resistant to INH and rifampicin. Extensively drug-resistant TB (XDR-TB) is defined as infection resistant to INH and rifampicin, along with resistance to a fluoroquinolone and at least one injectable second-line medication. Velayati et al. described the term “totally drug-resistant” TB, where the tubercular strain is resistant to all first- and second-line drugs.

Surgical Management

Traditionally, TB was treated by radical debridement through an anterior approach. However, following successful outcomes with multidrug chemotherapy and Medical Research Council observations,. Introduced the concept of “middle path regimen” in the treatment of tuberculosis. This regimen recommended medical management in all patients, along with surgical management necessitated in the following situations:

  • Lack of response to chemotherapy
  • Recurrent disease
  • Severe neurological weakness
  • Static or progressive neuro deficit despite a course of ATT
  • Deformity
  • Debilitating pain
  • Instability

Anterior Approach

  • As TB spine involves the anterior vertebral structures predominantly, debridement through anterior approach and fusion has been traditionally used to manage the diseased tissues directly. Nevertheless, the anterior approach has been reported to be associated with serious complications including graft-related complications (subsidence, slippage, fracture, absorption among others), approach-related complications (respiratory compromise) and even mortality. An ideal indication for anterior surgery includes patients without any posterior vertebral structure involvement, in other words, no prevertebral disease.

Posterior Approach

In modern spine surgery, posterior approaches are more preferred in TB spondylitis in view of the following reasons

  • Ease and familiarity of the approach
  • Availability of more robust pedicle screw system
  • Less approach-related morbidity
  • Ability to perform circumferential decompression through a transpedicular approach
  • Ability to perform global reconstruction through transpedicular, transplacental, costotrans versectomy or intracavitary-extrapleural approaches

Combined (Anterior and Posterior) Approach

  • Typically, this approach should be reserved for severe destructive lesions with severe deformities or inherently unstable spines only, as it is associated with significant morbidities and complications. The approaches can be performed in single or more than one stage.

Minimally Invasive Surgery

  • Recently, minimally invasive approaches including thoracoscopic debridement, minimally invasive fusion procedures and posterolateral endoscopic debridement have been demonstrated to provide an excellent outcome in TB spondylitis.

Surgery in Healed Tuberculosis

  • Surgery may be indicated in healed disease with instability or kyphotic deformity more than 60 degrees. The decision to perform surgery in such cases should be made after taking into consideration multiple factors including age, associated comorbidities, the severity of the deformity, the location of the spine involved, number of involved levels, and the surgeon’s preference.
  • Anterior approach can be particularly difficult in thoracic and thoracolumbar levels at the apex of kyphosis. Posterior approaches are the most popular and include transpedicular decancellation, Ponte’s osteotomy, pedicle subtraction osteotomy/ closing wedge osteotomy, posterior vertebral column resection, and closing opening wedge osteotomy. Combined anterior and posterior approaches may be required in more severe deformities, the disease involving two or three vertebrae or complex revision surgeries.

Differential Diagnosis

Radiological Differentials

  • Pyogenic and fungal infections
  • Neoplastic – Lytic benign, benign aggressive and malignant (primary tumors and spinal metastases): In general, spinal metastasis and primary spinal malignancies present with primary vertebral body involvement and disc space preservation as compared to TB and other infections. Tuberculosis also presents with soft tissue and perivertebral abscess, in comparison with malignant tumors.

Differentials Based on Pathological Appearance

  • Other pathologies involving granulomatous infections and clinically mimic TB include

    • Atypical bacteria – Actinomyces israelii, Nocardia asteroids, Brucella
    • Fungi – Coccidioides immitis, Blastomyces dermatitidis, Cryptococcus neoformans, Aspergillosis
    • Spirochetes – Treponema pallidum
  • Other pathologies – presenting with non-caseating granulomas include Sarcoidosis, Wegener’s granulomatosis, Crohn disease, and leprosy.

Poor Prognostic Factors in Pott Paraplegia

  • Level of disease (junctional vertebral levels) pan-vertebral involvement, long duration of neuro deficit, rapidity of progression of neuro deficit, the severity of deficit, nature of compression (abscess versus granuloma) and presence of spinal cord changes

Poor Prognosis for Deformity Progression

  • Age less than 10 years Kyphosis angle greater than 30 degrees, three or more vertebrae involved, greater than or equal to 1.5 vertebral body loss, pan-vertebral disease, and evidence of instability


  • Failure of treatment: Depends on the presentation (complicated versus uncomplicated), clinical and radiological prognostic factors, patient compliance to chemotherapy, stage of the disease, drug resistance and other patient-related factors (socio-economic factors, general health, nourishment among others)
  • Abscess
  • Neuro deficit
  • Spinal instability
  • Spinal deformity (kyphosis)
  • Systemic TB disease



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SLE – Causes, Symptoms, Diagnosis, Treatment

SLE /The Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease, with multisystemic involvement. The disease has several phenotypes, with varying clinical presentations in patients ranging from mild mucocutaneous manifestations to multiorgan and severe central nervous system involvement. Several immunopathogenic pathways play a role in the development of SLE. The lupus erythematosus (LE cell) was described by Hargraves in 1948. Several pathogenic autoantibodies have since been identified.

The systemic lupus erythematosus (SLE) is characterized by overt polyclonal B-cell activation and autoantibody (Ab) production. By contrast, cellular immune responses against all- or recall antigens are significantly impaired. Many pieces of evidence indicate that IL-10 overproduction plays a pivotal role in the disease and the contribution of the IL-10/IL-12 imbalance to the pathophysiology of SLE will be extensively discussed. The authors will further summarize the available data about the involvement of IFN-γ, TNF-α, TGF-β, and TALL-1. Other cytokines (IL-1, IL-2, IL-4, IL-6, IL-16, IL-17, and IL-18) will be briefly discussed.

Systemic Lupus Erythematosus

Types of Systemic Lupus Erythematosus

About 25% of patients with systemic lupus erythematosus (SLE) initially present with skin involvement. It is important to correctly classify cutaneous lupus erythematosus (CLE), as it helps determine the underlying type and severity of SLE. About 5–10% of patients with CLE develop SLE, and CLE is associated with less severe forms of SLE.

Skin manifestations of lupus erythematosus are commonly divided into lupus erythematosus–specific and non–specific disease. Note that four of the nine American College of Rheumatology criteria for SLE are skin signs (ie, malar/butterfly rashdiscoid plaquesphotosensitivity, and oral ulcers).

Lupus erythematosus–specific disease

Acute cutaneous lupus erythematosus

Forms of acute CLE include the following:

  • Localised acute CLE — this presents with malar or ‘butterfly’ rash (symmetrical erythema and edema of the cheeks, forehead, chin, and V of the neck but sparing the nasolabial folds or ‘smile lines’)
  • Generalised acute CLE — this presents with a widespread exanthematous eruption on the extensor surfaces, trunk, sun-exposed areas, and hands (but sparing the knuckles)
  • Toxic epidermal necrolysis-like acute CLE — this is a life-threatening variant of acute CLE that presents with a massive epidermal injury; it occurs predominantly on sun-exposed skin and has a gradual, insidious onset, unlike toxic epidermal necrolysis.

Acute CLE is typically triggered or exacerbated by exposure to ultraviolet (UV) radiation. On recovery, there may be postinflammatory hyperpigmentation without scarring.

Subacute cutaneous lupus erythematosus

The subacute cutaneous lupus erythematosus (SCLE) starts as macules or papules that progress to hyperkeratotic plaques. SCLE is photosensitive so plaques usually occur on sun-exposed skin; these plaques do not lead to scarring but can result in postinflammatory hyperpigmentation or hypopigmentation. SCLE should be monitored to exclude any progression to SLE.

Forms of SCLE include:

  • Annular SCLE — this subtype presents with slightly raised red lesions with central clearing
  • Papulosquamous SCLE — this subtype presents with eczematous or psoriasis-like lesions on sun-exposed skin.

Chronic cutaneous lupus erythematosus

Chronic CLE is not as photosensitive as acute CLE or SCLE. Forms of chronic CLE include:

  • The discoid lupus erythematosus (DLE) — this affects the face, outer ears, neck, sun-exposed areas and lips, and presents with discoid plaques (erythematous, well-demarcated plaques covered by scale) that become hyperkeratotic, leading to atrophy and scarring; there is follicular involvement, causing both reversible and irreversible (scarring) alopecia (hair loss); depigmentation of the peripheries is also common in certain ethnicities (Asian, Indian).
  • Hypertrophic or verrucous lupus erythematosus — this is a rare form of CLE presenting with severe hyperkeratosis of the extensor surfaces of the arms, upper back and face; it has overlapping features with lichen planus.
  • Mucosal lupus erythematosus — this affects 25% of patients with CLE; most commonly, painless erythematous patches on the oral mucosa develop into chronic plaques that can centrally ulcerate and also affect nasal, conjunctival and genital mucosa; oral lupus erythematosus rarely degrades to oral cancer (squamous cell carcinoma).

Drug-induced lupus erythematosus

Many drugs are thought to induce SLE and drug-induced lupus erythematosus often includes cutaneous signs. Drugs that induce lupus erythematosus include:

  • Hydralazine
  • Isoniazid
  • Chlorpromazine
  • Procainamide
  • Phenytoin
  • Minocycline
  • Anti–tumour necrosis factor medications.

Rarer types of lupus erythematosus

The rarer types of lupus erythematosus include:

  • Lupus profundus/lupus panniculitis — this is a rare form of chronic CLE with firm nodules in the lower dermis and subcutaneous tissue that causes lipodystrophy; some use the term lupus panniculitis to refer to subcutaneous involvement only, and lupus profundus when there is a combination of lupus panniculitis with DLE.
  • Chilblain lupus erythematosus — this presents with purple-red patches, papules and plaques on toes, fingers and face, and is associated with nail fold telangiectasia; it is precipitated by exposure to the cold, so often presents in winter.
  • Lupus erythematosus tumidus —this is a variant of chronic CLE with succulent or indurated erythematous plaques without surface change.

Lupus erythematosus — non–specific disease

Lupus erythematosus-nonspecific disease can relate to SLE or another autoimmune disease, but nonspecific cutaneous features are most often associated with SLE.

Common cutaneous features seen include:

  • Photosensitivity — this is an abnormal response to UV radiation that is present in 50–93% of patients with SLE
  • Mouth ulcers — these are present in 25–45% of patients with SLE
  • Non–scarring hair loss in SLE — presenting as coarse, dry hair with increased fragility (also referred to as ‘lupus hair’).

Cutaneous vascular disease is also common. Forms of cutaneous vascular disease include

  • Raynaud phenomenon — this presents with focal ulceration in the fingertips and periungual areas that can cause pitted scarring, hemorrhage and other nail fold complications
  • Vasculitis — leukocytoclastic vasculitis: urticarial vasculitis presenting with tender papules and plaques over bony prominences; and medium or large vessel vasculitis can occur, presenting with purpuric plaques with stellate borders, often with necrosis and ulceration or subcutaneous nodules
  • Thromboembolic vasculopathy — these may have a similar clinical presentation to vasculitis, but vessel occlusion is due to blood clots
  • Livedo reticularis — characterized by net-like blanching red-purple rings that commonly arise on the lower limbs
  • Erythromelalgia — characterized by burning pain in the feet and hands, and with macular erythema; it is associated with heat exposure.

Specific cutaneous SLE

Cutaneous lupus (CLE) has specific acute, subacute and chronic manifestations.

  • Typically, SLE presents with acute CLE.
  • About half of patients with subacute cutaneous LE develop mild SLE
  • Only 5% of patients with chronic CLE have SLE, as CLE presents as a skin problem without the involvement of other organs.

Acute CLE

  • Central face malar or “butterfly” violaceous erythema with a sharp cutoff at lateral margins, resolves without scarring (may result in persistent telangiectasia)
  • Bullous systemic lupus erythematosus: a blistering rash, if severe, this may resemble toxic epidermal necrolysis
  • maculopapular rash resembling morbilliform drug eruption
  • Mucosal erosions and ulcerations (lips, nose, mouth, genitals)
  • Photosensitivity: lupus rashes are mainly on sun-exposed sites. Photosensitivity can be mild to very severe with the rash appearing after minimal light exposure.
  • Diffuse hair loss (nonscarring alopecia) with brittle hair shafts

Subacute cutaneous LE

  • Flat, scaly patches resembling psoriasis, often in a network pattern
  • Annular (ring-shaped) polycyclic (overlapping circular) lesions
  • Lesions resolve with minimal scarring
  • Affects trunk and arms
  • Flares on exposure to the sun, but usually spares face and hands

Chronic CLE

  • Chronic CLE affects 25% of patients with SLE
  • Classic discoid lupus is most common: indurated hyperpigmented plaques
  • Localized (above the neck in 80%) or generalized (above and below the neck in 20%)
  • Hypertrophic (warty) lupus
  • Tumid lupus
  • Lupus panniculitis/profundus
  • Mucosal lupus (lips, nose, mouth, genitals)
  • Chilblain lupus erythematosus
  • Discoid lupus/lichen planus overlap
  • Discoid lesions and panniculitis resolve with scarring

A more thorough categorization of lupus includes the following types

  • acute cutaneous lupus erythematosus
  • subacute cutaneous lupus erythematosus
  • the discoid lupus erythematosus (chronic cutaneous
      • childhood discoid lupus erythematosus
      • generalized discoid lupus erythematosus
      • localized discoid lupus erythematosus
    • the chilblain lupus erythematosus (Hutchinson)
    • lupus erythematosus-lichen planus overlap syndrome
    • lupus erythematosus panniculitis (lupus erythematosus profundus)
    • tumid lupus erythematosus
    • the verrucous lupus erythematosus (hypertrophic lupus erythematosus)
    • cutaneous lupus mucinosis
  • complement deficiency syndromes
  • drug-induced lupus erythematosus
  • neonatal lupus erythematosus
  • systemic lupus erythematosus
The lupus erythematosus (LE)-specific cutaneous manifestations (Duesseldorf classification of cutaneous lupus erythematosus)*
Subtype Characteristics
The acute cutaneous lupus erythematosus (ACLE)
  • Localized: “butterfly rash“
  • Generalized: maculopapular exanthema
  • Oral mucous membrane: erosions, ulcers
  • Diffuse thinning of hairline (“lupus hair“)
The subacute cutaneous lupus erythematosus (SCLE)
  • Annular and/or papulosquamous/psoriasiform with the polycyclic confluence
  • Healing without scarring, vitiligo-like hypopigmentation
  • High photosensitivity
  • 70–90% anti-Ro/SSA and in 30–50% anti-La/SSB antibodies
  • ≥ 4 ACR criteria in 50%, development of a mild form of systemic lupus erythematosus in 10–15% (rare involvement of kidneys and central nervous system)
The chronic cutaneous lupus erythematosus (CCLE)
The discoid lupus erythematosus (DLE)
  • Localized (ca. 80%) or disseminated (ca. 20%)
  • Discoid erythematous plaques with firmly adherent follicular hyperkeratoses
  • Healing with scarring (on the scalp, scarring alopecia)
Chilblain lupus erythematosus (CHLE)
  • Tender, livid red swelling, sometimes with erosion/ulceration
  • Localization: symmetrical, cold-exposed areas of extremities
Lupus erythematosus profundus/panniculitis (LEP)
  • Subcutaneous, nodular/plaque-like, dense infiltrates
  • Ulceration and calcification possible, healing with scarring and deep lipoatrophy
The intermittent cutaneous lupus erythematosus (ICLE)
Lupus erythematosus tumidus (LET)
  • Erythematous, urticaria-like, edematous plaques without epidermal involvement
  • High photosensitivity
  • Variable course, healing without scarring

Causes of Systemic Lupus Erythematosus

Factors leading to SLE include:

  • Genetic predisposition, including haplotype HLA-B8, -DR3
  • Exposure to sunlight
  • Viral infection, particularly Epstein-Barr virus
  • Hormones
  • Toxins such as cigarette smoke
  • Drugs in drug-induced LE
  • Emotional upset.

The manifestations of SLE are due to loss of regulation of the patient’s immune system.

  • Nuclear proteins are not processed properly.
  • Nuclear debris accumulates within the cell.
  • This leads to the production of autoantibodies against nuclear proteins.
  • Immune complexes are not removed.
  • The complement system is activated.
  • Inflammation leads to cell and tissue injury.

Symptoms of Systemic Lupus Erythematosus

Common symptoms include:

  • Chest pain during respiration
  • Joint pain
  • Oral ulcer
  • Fatigue
  • Weight loss
  • Fever with no other cause
  • General discomfort, uneasiness, or ill feeling (malaise)
  • Hair loss
  • Sensitivity to sunlight
  • A “butterfly” facial rash, seen in about half people with SLE
  • Swollen lymph nodes


Photosensitivity is a known symptom of lupus, but its relationship to and influence on other aspects of the disease remain to be defined.[rx] Causes of photosensitivity may include:

  • Change in autoantibody location
  • Cytotoxicity
  • Induction of apoptosis with autoantigens in apoptotic blebs
  • Upregulation of adhesion molecules and cytokines
  • Induction of nitric oxide synthase expression
  • Ultraviolet-generated antigenic DNA.
  • Tumor necrosis factor-alpha

Other symptoms include

  • General – tiredness, malaise, chronic pain, fever with flares
  • Joints – arthritis or synovitis causing swelling, pain and morning stiffness
  • Lungs – pleurisy or pleural effusions
  • Heart – pericarditis or pericardial effusions
  • Kidneys – protein, casts in urine, glomerulonephritis
  • Brain – seizures, psychosis, confusion
  • Nervous system – mono neuritis multiplex, myelitis, peripheral neuropathy
  • Blood – reduced numbers of red cells, white cells and platelets
  • Cutaneous mucinosis  – characterized by indurated papules, nodules, or plaques on the trunk or arms
  • Lupus nail dystrophy presenting as nail pitting, ridging, leukonychiaonycholysis, and red lunula
  • Spontaneous chronic urticaria
  • Lichen planus
  • Acanthosis nigricans
  • Sclerodactyly (spindle-shaped fingers)
  • Erythema multiforme
  • Cutis laxa
  • Rheumatoid nodules.

Classification of SLE: the Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria

Clinical criteria

  • The acute cutaneous lupus erythematosus (including “butterfly rash“)
  • The chronic cutaneous lupus erythematosus (e.g., localized or generalized discoid lupus erythematosus)
  • Oral ulcers (on palate and/or nose)
  • Non-scarring alopecia
  • Synovitis (≥ 2 joints) or tenderness on palpation (≥ 2 joints) and morning stiffness (≥ 30 min)
  • Serositis (pleurisy or pericardial pain for more than 1 day)
  • Renal involvement (single urine: protein/creatinine ratio or 24-hour urine protein, >0.5 g)
  • Neurological involvement (e.g., seizures, psychosis, myelitis)
  • Hemolytic anemia
  • Leukopenia (<4000/μL) or lymphopenia (<1000/μL)
  • Thrombocytopenia (<100 000/μL)

Immunological criteria

  • ANA level above the laboratory reference range
  • Anti-dsDNA antibodies
  • Anti-Sm antibodies
  • Antiphospholipid antibodies (anticardiolipin and anti- β 2-glycoprotein I [IgA-, IgG- or IgM-] antibodies; false-positive VDRL [Venereal Disease Research Laboratory] test)
  • Low complement (C3, C4, or CH50)
  • Direct Coombs test (in the absence of hemolytic anemia)

systemic lupus erythematosus /SLE

Diagnosis of Systemic Lupus Erythematosus

Investigations in suspected systemic lupus erythematosus (SLE) and monitoring after diagnosis

Screening laboratory tests

  • Erythrocyte sedimentation rate
  • Blood count, differential blood count
  • Creatinine
  • Urinary status and sediment
  • Antinuclear antibodies (ANA) (HEp-2 cell test with fluorescence pattern)

Further laboratory tests after positive screening*1 (particularly in case of positive ANA)

  • Further differentiation of ANA (particularly anti-Sm, -Ro/SSA, -La/SSB, -U1RNP antibodies, etc.)
  • Anti-dsDNA antibodies (ELISA; confirmation by radioimmunoassay or immunofluorescence test with Crithidia luciliae)
  • Complement C3, C4
  • Antiphospholipid antibodies, lupus anticoagulant
  • Glomerular filtration rate; 24-hour urine (if urine protein positive), alternatively: protein/creatinine ratio in single urine sample; investigation for dysmorphic erythrocytes in sediment
  • Liver enzymes; lactate dehydrogenase; creatine kinase in presence of muscular symptoms
  • Further laboratory tests depending on clinical symptoms
  • Screening for comorbidities
  • Assessment of vaccination status (vaccination recommendations [in German] at [rx)

Follow-up (SLE: every 3 to 6 months depending on disease course; lupus nephritis: initially every 2 to 4 weeks for the first 2 to 4 months)*2

  • Medical history (including new symptoms, comedication, infections), physical examination
  • Evaluate disease activity with standardized score
  • Evaluate damage according to standardized score (1 ×/year)
  • Repeat screening for comorbidities (at least 1 ×/year)
  • Ocular examination in patients taking hydroxychloroquine or chloroquine: baseline, then every 6 months (currently being revised by the German Society of Rheumatology in light of recommendations from the USA) (, )

Laboratory tests

  • Erythrocyte sedimentation rate
  • C-reactive protein (in suspected infection or pleurisy)
  • Urine tests for hyaline casts, creatinine, protein and blood
  • Blood pressure
  • Chest X-ray, ultrasoundCT and MRI scans
  • Electrocardiograph (ECG) and echocardiography
  • Nerve and muscle testing
  • Ophthalmological examination
  • Endoscopy of the gastrointestinal tract
  • Kidney biopsy.
  • Blood count, differential blood count
  • Creatinine
  • Liver enzymes
  • Urinary status (protein/creatinine ratio, 24-hour urine and microscopic examination of urinary sediment as needed)
  • Complement C3, C4
  • Anti-dsDNA antibodies
  • Instrument-based diagnostics as needed

Modified after (2, 8), modified after (, , , , )

Using the SLICC criteria, SLE is diagnosed if the patient has either of the following over time:

  • Four criteria including ≥ one clinical criterion and ≥ one immunological criterion
  • Biopsy-proven lupus nephritis and antinuclear antibodies or anti-double-stranded DNA antibodies

These criteria depend on history, clinical examination, exclusion of other causes of the symptoms, and the results of investigations—including blood tests and biopsy of the affected tissue. Four of the 17 SLICC criteria relate to the skin.

Clinical criteria

  • Acute or subacute cutaneous lupus
  • Chronic cutaneous lupus
  • Oral ulcers
  • Nonscarring alopecia
  • Synovitis involving 2 or more joints
  • Serositis involving lungs or heart
  • Renal involvement
  • Neurological involvement
  • Hemolytic anemia
  • leukopenia or lymphopenia
  • Thrombocytopenia

Immunological criteria

  • Raised ANA level
  • A raised anti-dsDNA antibody level
  • Presence of anti-Sm
  • Positive antiphospholipid antibody (lupus anticoagulant, false-positive rapid plasma reagin, high-titer anticardiolipin antibody, positive anti–2-glycoprotein I)
  • Low complement levels
  • Positive direct Coombs’ test

SLICC Systemic Lupus International Collaborating Clinics; ANA antinuclear antibody; anti-dsDNA anti-double-stranded DNA

Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)

The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) was developed in an attempt to classify the severity of CLE. [2] A score of activity and damage due to the disease is calculated in each of 12 anatomical locations (refer to the original published paper for details).

The total activity score is made up of:

  • The degree of redness (0–3) and scale (0–2)
  • Mucous membrane involvement (0–1)
  • Recent hair loss (0–1), nonscarring alopecia (0–3)

Total damage score is made up of:

  • The degree of dyspigmentation (0–2), and scarring (0–2)
  • Persistence of dyspigmentation more than 12 months doubles the depigmentation score
  • Scalp scarring (0,3,4,5,6)

Biopsy findings

Patients with SLE often undergo skin biopsy.

  • Acute CLE: nonspecific dermatitis.
  • Subacute CLE: features of lupus noted in the epidermis and superficial dermis
  • Chronic discoid CLE: typical features of lupus with atrophy and scarring
  • Direct immunofluorescence is positive in sun-protected healthy skin in SLE

Blood tests

Multiple autoantibodies are typically present in SLE, often in high titre (see immunological criteria above). Relating to skin disease in SLE:

  • About 70% of patients with subacute CLE have positive extractable nuclear antibodies anti-Ro (also called anti-SSA) and anti-La (also called anti-SSB).
  • Anti Ro/La is also associated with Sjogren syndrome and neonatal lupus.
  • Low serum complement in SLE has been associated with urticarial vasculitis and renal disease.
  • Antiphospholipid antibodies are associated with livedo reticularis, thrombosis, and pregnancy complications (antiphospholipid syndrome).
  • Anti-annexin 1 antibodies may be a diagnostic marker for discoid CLE

Patients with SLE should also have renal, liver, and thyroid function and markers of inflammation performed, such as C-reactive protein (CRP), immunoglobulins, and rheumatoid factor.

Photoprovocation tests

  • Photoprovocation tests  – are sometimes carried out to confirm that a skin eruption is precipitated by exposure to particular wavelengths of ultraviolet or visible radiation.
  • Echocardiogram – Echocardiogram shows Pericardial effusion, mitral valve prolapse, left ventricular hypertrophy, and changes secondary to pulmonary hypertension.
  • EKG – Abnormal EKG findings include hemiblock, bundle branch block, atrioventricular block, changes secondary to pericarditis, and pericardial effusion.
  • Pulmonary function testing – Reduction in diffusion capacity for carbon monoxide, forced vital capacity, forced expiratory volume, and six-minute walk tests occur in ILD.
  • Computed tomogram – High resolution computed tomogram is very sensitive in diagnosing ILD. Common findings include ground-glass opacities, linear opacities, subpleural micronodules, septal thickening, traction bronchiectasis usually with peripheral and lower lobe predominance. Honeycombing, airspace consolidation, emphysema, and centrilobular nodules are less common findings.
  • Angiogram – Medium-sized arterial occlusions can occur in patients with Raynaud phenomenon.
  • Right heart catheterization – Definitive diagnosis of pulmonary hypertension in MCTD requires right heart catheterization demonstrating mean pulmonary arterial pressure at rest greater than 25mmHg.

Organ-specific diagnostics as required

Skin/oral mucous membrane

  • Biopsy: histology, immunofluorescence if indicated


  • Conventional X-ray
  • Arthrosonography
  • Magnetic resonance imaging (MRI)


  • Creatine kinase
  • Electromyography
  • MRI
  • Muscle biopsy


  • Sonography
  • Renal biopsy


  • Chest X-ray
  • Thoracic high-resolution computed tomography (HR-CT)
  • Lung function test including diffusion capacity
  • Bronchoalveolar lavage
  • (Transesophageal) echocardiography
  • Cardiac catheterization
  • Cardiac MRI
  • Myocardial scintigraphy
  • Coronary angiography


  • Funduscopy/special investigations in patients on antimalarials

Central and peripheral nervous system

  • Electroencephalography
  • Primarily cranial MRI, special MRI techniques if indicated
  • Computed tomography
  • Cerebrospinal fluid analysis
  • Transcranial Doppler/angiography
  • Neuropsychiatric examination
  • Measurement of nerve conduction velocity

Treatment of Systemic Lupus Erythematosus

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) Over-the-counter NSAIDs, such as naproxen sodium (Aleve) and ibuprofen (Advil, Motrin IB, others), may be used to treat pain, swelling, and fever associated with lupus. Stronger NSAIDs are available by prescription. Side effects of NSAIDs include stomach bleeding, kidney problems, and an increased risk of heart problems.
  • Antimalarial drugs – Medications commonly used to treat malaria, such as hydroxychloroquine (Plaquenil), affect the immune system and can help decrease the risk of lupus flares. Side effects can include stomach upset and, very rarely, damage to the retina of the eye. Regular eye exams are recommended when taking these medications.
  • Corticosteroids – Prednisone and other types of corticosteroids can counter the inflammation of lupus. High doses of steroids such as methylprednisolone (A-Methapred, Medrol) are often used to control serious disease that involves the kidneys and brain. Side effects include weight gain, easy bruising, thinning bones (osteoporosis), high blood pressure, diabetes, and increased risk of infection. The risk of side effects increases with higher doses and longer-term therapy.
  • Immunosuppressants Drugs that suppress the immune system may be helpful in serious cases of lupus. Examples include azathioprine (Imuran, Azasan), mycophenolate mofetil (CellCept), and methotrexate (Trexall). Potential side effects may include an increased risk of infection, liver damage, decreased fertility and an increased risk of cancer.
  • Biologics – A different type of medication, belimumab (Benlysta) administered intravenously, also reduces lupus symptoms in some people. Side effects include nausea, diarrhea and infections. Rarely, the worsening of depression can occur.
  • Rituximab (Rituxan) –  can be beneficial in cases of resistant lupus. Side effects include allergic reaction to the intravenous infusion and infections.
  • Hydroxychloroquine – Commonly used to help keep mild lupus-related problems, such as skin and joint disease, under control. This drug is also effective at preventing lupus flares.
  • Cyclophosphamide  A chemotherapy drug that has very powerful effects on reducing the activity of the immune system. It is used to treat severe forms of lupus, such as those affecting the kidneys or brain.
  • Azathioprine A medication originally used to prevent the rejection of transplanted organs. It is commonly used to treat the more serious features of lupus.
  • Methotrexate Another chemotherapy drug used to suppress the immune system. Its use is becoming increasingly popular for skin disease, arthritis, and other non-life-threatening forms of disease that have not responded to medications such as hydroxychloroquine or low doses of prednisone.
  • Belimumab – This drug weakens the immune system by targeting a protein that may reduce the abnormal B cells thought to contribute to lupus. People with active, autoantibody-positive lupus may benefit from Benlysta when given in addition to standard drug therapy.
  • Mycophenolate mofetil A drug that suppresses the immune system and is also used to prevent the rejection of transplanted organs. It is being used increasingly to treat serious features of lupus, especially those previously treated by Cytoxan.

systemic lupus erythematosus /SLE

Treatment recommendations for systemic lupus erythematosus (SLE) with no, mild, and/or moderate organ manifestations (e.g., skin, joints, serositis)
Indication Medication Level of evidence Strength of statement Dosage
First-line and basic treatment Hydroxychloroquine
ChloroquineIf indicated, initial non-steroidal anti-inflammatory drugs
2 ()


A ()



≤ 6.0–6.5 mg/kg ideal body weight/day

≤ 3.5–4.0 mg/kg ideal body weight/day
Calculation of ideal body weight:

  • Men: [Height minus 100] minus 10%

  • Women: [Height minus 100] minus 15%

If no response or no reduction of glucocorticoids ≤ 7.5 mg possible in the long term Azathioprine
mycophenolate mofetil*
4 ()

2 ()

6 ()

B ()

A ()

D ()

2–3 mg/kg body weight/day

15–20 mg/week (preferably s.c.)

2 g/day

Adjunct treatment in autoantibody-positive SLE with high disease activity despite standard treatment () Belimumab 10 mg/kg body weight i.v. infusion (1 h) initially, then after 14 days and subsequently every 4 weeks

  • According to expert opinion, not only low-dose prednisone but also hydroxychloroquine and azathioprine (particularly in lupus nephritis []) can be administered in pregnancy ().

  • In case of comedication with mycophenolate mofetil and proton pump inhibitors, the bioavailability of mycophenolate mofetil is reduced; a switch to mycophenolic acid is advisable ().

  • Proton pump inhibitors may lower the efficacy of hydroxychloroquine/chloroquine ().

  • Treatment and monitoring instructions of the DGRh (in German) for the above-mentioned medications for use by patients and physicians can be found at [rxl

Commonly Used Medications in the Treatment of Systemic Lupus Erythematosus

Drug Class Mechanism of Action Commonly Used Agents and Dosage Potential Adverse Effects Common Monitoring Parameters
NSAIDs (including salicylates) Block prostaglandin synthesis through inhibition of cyclooxygenase enzymes, producing anti-inflammatory, analgesic, and antipyretic effects Various agents and dosages Gastrointestinal irritation and bleeding, renal toxicity, hepatic toxicity, hypertension Nausea, vomiting, abdominal pain, dark/tarry stool; baseline and annual CBC, SCr, LFTs, urinalysis
Antimalarials Unclear; may interfere with T-cell activation and inhibit cytokine activity; also thought to inhibit intracellular TLRs Hydroxychloroquine PO 200–400 mg daily Macular damage, muscle weakness Funduscopy and visual field examination at baseline and every 6 to 12 months
Corticosteroids Multiple effects on immune system (e.g., blocking cytokine activation and inhibiting interleukins, γ-interferon and tumor necrosis factor-α) Prednisone PO 0.5–2 mg/kg per day
Methylprednisolone IV 500–1,000 mg daily for 3 to 6 days (acute flare)
Weight gain, hypertension, hyperglycemia, hyperlipidemia, osteoporosis, cataracts, edema, hypokalemia, muscle weakness, growth suppression, increased risk of infection, glaucoma Baseline blood pressure, bone density, glucose, potassium, lipid panel; glucose every 3 to 6 months; annual lipid panel and bone density
Immunosuppressants Multiple suppressive effect on immune system (e.g., reduction of T-cell and B-cell proliferation; DNA and RNA disruption) Cyclophosphamide PO 1–3 mg/kg per day or 0.5–1 g/m2 IV monthly with or without a corticosteroid
Azathioprine PO 1–3 mg/kg per day
Mycophenolate PO 1–3 g daily
Myelosuppression, hepatotoxicity, renal dysfunction, infertility, increased risk of infection and cancer Baseline and routine CBC, platelet count, SCr, LFTs, and urinalysis (depends on individual drug)
Monoclonal antibodies Block binding of BLyS to receptors on B cells, inhibiting survival of B cells, and reducing B-cell differentiation into immunoglobulin-producing plasma cells Belimumab IV 10 mg/kg (over a period of 1 hour), every 2 weeks for the first three doses, then every 4 weeks Nausea, diarrhea, pyrexia, nasopharyngitis, insomnia, extremity pain, depression, migraine, gastroenteritis, infection (e.g., pneumonia, UTI, cellulitis, bronchitis) Gastrointestinal complaints, infectious signs and symptoms, mood or behavioral changes, infusion reactions

BLyS = B-lymphocyte stimulator protein; CBC = complete blood count; DNA = deoxyribonucleic acid; IV = intravenous; LFTs = liver function tests; NSAIDs = nonsteroidal anti-inflammatory drugs; PO = by mouth; RNA = ribonucleic acid; SCr = serum creatinine; TLRs = toll-like receptors; UTI = urinary tract infection.

Preventative measures

The following measures are essential to reduce the chance of flares and organ damage.

  • Careful protection from sun exposure using clothing, accessories and SPF 50+ broad-spectrum sunscreens. Sunscreens alone are not adequate.
  • Smoking cessation
  • Rest when needed.

Topical therapy

Intermittent courses of potent topical corticosteroids are important in the treatment of CLE. They should be applied accurately to the skin lesions.

The calcineurin inhibitors tacrolimus ointment and pimecrolimus cream can also be used.

Systemic therapy

Treatment of SLE depends on which are the predominant organs involved in the disease. Typically, any of the following drugs may be used alone or in combination.

  • Systemic corticosteroids, such as prednisone or prednisolone. These are the mainstay of treatment in a seriously ill patient with acute LE.
  • Hydroxychloroquine and other antimalarials—response rates are about 80% in CLE.
  • Methotrexate—best response in subacute CLE and discoid CLE
  • Immunosuppressives such as azathioprine, mycophenolate and cyclophosphamide
  • Intravenous immunoglobulin
  • Aspirin is recommended for antiphospholipid syndrome.
  • Targeted biologic therapies under evaluation for SLE include belimumab (intravenous and subcutaneous formulations were registered by FDA for use in SLE in 2017) and off-label rituximab, abatacept, tocilizumab and eculizumab.

CLE is also sometimes treated with

  • Retinoids (isotretinoin and acitretin)
  • Dapsone.

Lifestyle and Home Remedies

Take steps to care for your body if you have lupus. Simple measures can help you prevent lupus flares and, should they occur, better cope with the signs and symptoms you experience. Try to:

  • See your doctor regularly – Having regular checkups instead of only seeing your doctor when your symptoms worsen may help your doctor prevent flare-ups, and can be useful in addressing routine health concerns, such as stress, diet and exercise that can be helpful in preventing lupus complications.
  • Be sun smart – Because ultraviolet light can trigger a flare, wear protective clothing — such as a hat, long-sleeved shirt and long pants — and use sunscreens with a sun protection factor (SPF) of at least 55 every time you go outside.
  • Get regular exercise – Exercise can help keep your bones strong, reduce your risk of heart attack and promote general well-being.
  • Don’t smoke – Smoking increases your risk of cardiovascular disease and can worsen the effects of lupus on your heart and blood vessels.
  • Eat a healthy diet – A healthy diet emphasizes fruits, vegetables and whole grains. Sometimes you may have dietary restrictions, especially if you have high blood pressure, kidney damage or gastrointestinal problems.
  • Ask your doctor if you need vitamin D and calcium supplements – There is some evidence to suggest that people with lupus may benefit from supplemental vitamin D. A 1,200- to 1,500-milligram calcium supplement taken daily may help keep your bones healthy.


Inflammation caused by lupus can affect many areas of your body, including your:

  • Kidneys – Lupus can cause serious kidney damage, and kidney failure is one of the leading causes of death among people with lupus.
  • Brain and central nervous system – If your brain is affected by lupus, you may experience headaches, dizziness, behavior changes, vision problems, and even strokes or seizures. Many people with lupus experience memory problems and may have difficulty expressing their thoughts.
  • Blood and blood vessels – Lupus may lead to blood problems, including anemia and an increased risk of bleeding or blood clotting. It can also cause inflammation of the blood vessels (vasculitis).
  • Lungs – Having lupus increases your chances of developing an inflammation of the chest cavity lining (pleurisy), which can make breathing painful. Bleeding into the lungs and pneumonia also are possible.
  • Heart – Lupus can cause inflammation of your heart muscle, your arteries, or heart membrane (pericarditis). The risk of cardiovascular disease and heart attacks increases greatly as well.
  • Infection – People with lupus are more vulnerable to infection because both the disease and its treatments can weaken the immune system.
  • Cancer – Having lupus appears to increase your risk of cancer; however, the risk is small.
  • Bone tissue death (avascular necrosis) – This occurs when the blood supply to a bone diminishes, often leading to tiny breaks in the bone and eventually to the bone’s collapse.
  • Pregnancy complications – Women with lupus have an increased risk of miscarriage. Lupus increases the risk of high blood pressure during pregnancy (preeclampsia) and preterm birth. To reduce the risk of these complications, doctors often recommend delaying pregnancy until your disease has been under control for at least six months.




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Early Symptoms of Knee Osteoarthritis – Treatment

Early Symptoms of Knee Osteoarthritis/Knee Osteoarthritis (OA), also known as degenerative joint disease, is typically the result of wear and tear and progressive loss of articular cartilage. It is most common in elderly women and men. Knee osteoarthritis can be divided into two types, primary and secondary. Primary osteoarthritis is articular degeneration without any apparent underlying reason. Secondary osteoarthritis is the consequence of either an abnormal concentration of force across the joint as with post-traumatic causes or abnormal articular cartilage, such as rheumatoid arthritis (RA). Osteoarthritis is typically a progressive disease that may eventually lead to disability. The intensity of the clinical symptoms may vary from each individual.

Causes of Knee Osteoarthritis

Causes of Knee Osteoarthritis

Knee osteoarthritis is classified as either primary or secondary, depending on its cause. Primary knee osteoarthritis is the result of articular cartilage degeneration without any known reason. This is typically thought of as degeneration due to age as well as wear and tear. Secondary knee osteoarthritis is the result of articular cartilage degeneration due to a known reason.

Possible Causes of Secondary Knee OA

  • Posttraumatic
  • Postsurgical
  • Congenital or malformation of the limb
  • Malposition (Varus/Valgus)
  • Scoliosis
  • Rickets
  • Hemochromatosis
  • Chondrocalcinosis
  • Ochronosis
  • Wilson disease
  • Gout
  • Pseudogout
  • Acromegaly
  • Avascular necrosis
  • Rheumatoid arthritis
  • Infectious arthritis
  • Psoriatic arthritis
  • Hemophilia
  • Paget disease
  • Sickle cell disease

Risk Factors for Knee OA


  • Articular trauma
  • Occupation – prolonged standing and repetitive knee bending
  • Muscle weakness or imbalance
  • Weight
  • Health – metabolic syndrome


  • Gender – females more common than males
  • Age
  • Genetics
  • Race

Cartilage Changes in Aging

  • Water content – decreased
  • Collagen – same
  • Proteoglycan content – decreased
  • Proteoglycan synthesis – same
  • Chondrocyte size – increased
  • Chondrocyte number – decreased
  • Modulus of elasticity – increased

Cartilage Changes in OA

  • Water content – increased
  • Collagen – disorganized
  • Proteoglycan content – decreased
  • Proteoglycan synthesis – increased
  • Chondrocyte size – same
  • Chondrocyte number – same
  • Modulus of elasticity – decreased

Matrix Metalloproteases

Responsible for cartilage matrix degradation

  • Stromelysin
  • Plasmin
  • Aggrecanase-1 (ADAMTS-4)
  • Collagenase
  • Gelatinase

Tissue inhibitors of MMPs

Control MMP activity preventing excess degradation

  • TIMP-1
  • TIMP-2
  • Alpha-2-macroglobulin

Causes of Knee Osteoarthritis

The Symptom Of Osteoarthritis (OA) Of Knee

The main symptoms of osteoarthritis of the knee are:

  • Pain (particularly when you’re moving your knee or at the end of the day – this usually gets better when you rest)
  • Stiffness (especially after rest – this usually eases after a minute or so as you get moving)
  • Crepitus, a creaking – crunching, grinding sensation when you move the joint
  • Hard swellings – (caused by osteophytes)
  • Soft swellings – (caused by extra fluid in the joint).
  • Loss of flexibility – You may not be able to move your joint through its full range of motion.
  • Grating sensation – You may hear or feel a grating sensation when you use the joint.
  • Bone spurs – These extra bits of bone, which feel like hard lumps, may form around the affected joint.
  • Instability of the knee joint, or feeling like your knee joint is “giving way”
  • Limitations in the range of movement of your knee
  • Inability to continue with activities, whether they involve day-to-day tasks or sports
  • Feeling the kneecap shift or slide out of the groove
  • Feeling the knee buckle or give way
  • Hearing a popping sound when the patella dislocates
  • Swelling
  • A change in the knee’s appearance — the knee may appear misshapen or deformed
  • Apprehension or fear when running or changing direction.

Other symptoms can include

  • your knee giving way because your muscles have become weak or the joint structure is less stable
  • your knee not moving as freely or as far as normal
  • your knees becoming bent and bowed
  • the muscles around your joint looking thin or wasted.

Diagnosis of Knee Osteoarthritis

Patients typically present to their healthcare provider with the chief complaint of knee pain. It is essential to obtain a detailed history of their symptoms. Pay careful attention to history as knee pain can be referred from the lumbar spine or the hip joint. It is equally important to obtain a detailed medical and surgical history to identify any risk factors associated with secondary knee OA.

The history of the present illness should include the following

  • Onset of symptoms
  • The specific location of pain
  • Duration of pain and symptoms
  • Characteristics of the pain
  • Alleviating and aggravating factors
  • Any radiation of pain
  • The specific timing of symptoms
  • Severity of symptoms
  • The patient’s functional activity

Clinical Symptoms of Knee OA

Knee pain

  • Typically of gradual onset
  • Worse with prolonged activity
  • Worse with repetitive bending or stairs
  • Worse with inactivity
  • Worsening over time
  • Better with rest
  • Better with ice or anti-inflammatory medication
  • Knee stiffness
  • Knee swelling
  • Decreased ambulatory capacity

Physical examination of the knee should begin with a visual inspection. With the patient standing, look for periarticular erythema and swelling, quadriceps muscle atrophy, and varus or valgus deformities. Observe gait for signs of pain or abnormal motion of the knee joint that can be indicative of ligamentous instability. Inspect the surrounding skin for the presence and location of any scars from previous surgical procedures, overlying evidence of trauma, or any soft tissue lesions.

Range of motion (ROM) testing is a very important aspect of the knee exam. Active and passive ROM with regard to flexion and extension should be assessed and documented.

Palpation along the bony and soft tissue structures is an essential part of any knee exam. The palpatory exam can be broken down into the medial, midline, and lateral structures of the knee.

Areas of focus for the medial aspect of the knee

  • Vastus medialis obliquus
  • Superomedial pole patella
  • The medial facet of the patella
  • Origin of the medial collateral ligament (MCL)
  • Midsubstance of the MCL
  • Broad insertion of the MCL
  • Medial joint line
  • Medial meniscus
  • Pes anserine tendons and bursa

Areas of focus for the midline of the knee

  • Quadricep tendon
  • Suprapatellar pouch
  • Superior pole patella
  • Patellar mobility
  • Prepatellar bursa
  • Patellar tendon
  • Tibial tubercle

Areas of focus for the lateral aspect of the knee

  • Iliotibial band
  • Lateral facet patella
  • Lateral collateral ligament (LCL)
  • Lateral joint line
  • Lateral meniscus
  • Gerdy’s tubercle

A thorough neurovascular exam should be performed and documented. It is important to assess the strength of the quadriceps and hamstring muscles as these often times will become atrophied in the presence of knee pain. A sensory exam of the femoral, peroneal, and tibial nerve should be assessed as there may be concomitant neurogenic symptoms associated. Palpation of a popliteal, dorsalis pedis and the posterior tibial pulse is important as any abnormalities may raise the concern for vascular problems.

Other knee tests may be performed, depending on the clinical suspicion based on history

Special knee tests

  • Patella apprehension – patellar instability
  • J-sign – patellar maltracking
  • Patella compression/grind – chondromalacia or patellofemoral arthritis
  • Medial McMurray – a medial meniscus tear
  • Lateral McMurray – lateral meniscus tear
  • Thessaly test – a meniscus tear
  • Lachman – anterior cruciate ligament (ACL) injury
  • Anterior drawer – ACL injury
  • Pivot shift – ACL injury
  • Posterior drawer – posterior cruciate ligament (PCL) injury
  • Posterior sag – PCL injury
  • Quadriceps active test – PCL injury
  • Valgus stress test – MCL injury
  • Varus stress test – LCL injury

Radiographic Findings of OA

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

Differential Diagnosis

Any potential cause of local or diffuse knee pain should be considered in the differential diagnosis of knee osteoarthritis.

  • Hip arthritis
  • Low back pain
  • Spinal stenosis
  • Patellofemoral syndrome
  • Meniscal tear
  • Pes anserine bursitis
  • Infections arthritis
  • Gout
  • Pseudogout
  • Iliotibial band syndrome
  • Collateral or cruciate ligament injury

Causes of Knee Osteoarthritis

Treatment of Knee Osteoarthritis

Treatment for knee osteoarthritis can be broken down into non-surgical and surgical management. Initial treatment begins with non-surgical modalities and moves to surgical treatment once the non-surgical methods are no longer effective. A wide range of non-surgical modalities is available for the treatment of knee osteoarthritis. These interventions do not alter the underlying disease process, but they may substantially diminish pain and disability.

Non-Surgical Treatment Options

  • Patient education
  • Activity modification
  • Physical therapy
  • Weight loss
  • Knee bracing
  • Acetaminophen
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • COX-2 inhibitors
  • Glucosamine and chondroitin sulfate
  • Corticosteroid injections
  • Hyaluronic acid (HA)

The first-line treatment for all patients with symptomatic knee osteoarthritis includes patient education and physical therapy. A combination of supervised exercises and a home exercise program have been shown to have the best results. These benefits are lost after 6 months if the exercises are stopped.

The American Academy of Orthopedic Surgeons (AAOS) recommends this treatment.

  • Weight loss – is valuable in all stages of knee osteoarthritis. It is indicated in patients with symptomatic arthritis with a body mass index greater than 25. The best recommendation to achieve weight loss is with diet control and low-impact aerobic exercise. There is moderate evidence for weight loss based on the AAOS guidelines.
  • Knee bracing – in the setting of osteoarthritis includes unloader-type braces which shift the load away from the involved knee compartment. This may be useful in the setting where either the lateral or medial compartment of the knee is involved such as in a valgus or varus deformity.
  • Immobilization – Your doctor may recommend that your child wear a brace for 3 to 4 weeks. This stabilizes the knee while it heals.
  • Weightbearing –  Because putting weight on the knee may cause pain and slow the healing process, your doctor may recommend using crutches for the first week or two after the injury.
  • Physical therapy – Once the knee has started to heal, your child’s doctor will recommend physical therapy to help your child regain normal motion. Specific exercises will strengthen the thigh muscles holding the knee joint in place. Your child’s commitment to the exercise program is important for a successful recovery. Typically, children return to activity 3 to 6 weeks after the injury.
  • Emergent closed reduction followed by vascular assessment/consult – indications to considered an orthopedic emergency, vascular consult indicated if pulses are absent or diminished following reduction if arterial injury confirmed by arterial duplex ultrasound or CT angiography
  • Immobilization as definitive management – successful closed reduction without vascular compromise, most cases require some form of surgical stabilization following reduction, outcomes of worse outcomes are seen with nonoperative management/prolonged immobilization will lead to loss of ROM with persistent instability.
  • Rest Your Leg – Once you’re discharged from the hospital in a legislating, your top priority is to rest your and not further inflame the injury. Of course, the arm sling not only provides support, but it also restricts movement, which is why you should keep it on even during sleep. Avoiding the temptation to move your will help the bone mend quicker and the pain fades away sooner.
    • Depending on what you do for a living and if the injury is to your dominant side, you may need to take a couple of weeks off work to recuperate.
    • Healing takes between four to six weeks in younger people and up to 12 weeks in the elderly, but it depends on the severity of the radial head fractures.
    • Athletes in good health are typically able to resume their sporting activities within two months of breaking they’re ulnar styloid depending on the severity of the break and the specific sport.
    • Sleeping on your back (with the sling on) is necessary to keep the pressure off your shoulder and prevent stressing the hip injury.

Eat Nutritiously During Your Recovery

  • All bones and tissues in the body need certain nutrients in order to heal properly and in a timely manner. Eating a nutritious and balanced diet that includes lots of minerals and vitamins are proven to help heal broken bones of all types. Therefore focus on eating lots of fresh produce (fruits and veggies), whole grains, lean meats, and fish to give your body the building blocks needed to properly repair your. In addition, drink plenty of purified water, milk, and other dairy-based beverages to augment what you eat.
  • Broken bones need ample minerals (calcium, phosphorus, magnesium, boron) and protein to become strong and healthy again.
  • Excellent sources of minerals/protein include dairy products, tofu, beans, broccoli, nuts and seeds, sardines, and salmon.
  • Important vitamins that are needed for bone healing include vitamin C (needed to make collagen), vitamin D (crucial for mineral absorption), and vitamin K (binds calcium to bones and triggers collagen formation).
  • Conversely, don’t consume food or drink that is known to impair bone/tissue healing, such as alcoholic beverages, sodas, most fast food items and foods made with lots of refined sugars and preservatives.

Follow-Up Care

  • You will need to see your doctor regularly until your fracture heals. During these visits, he or they will take x-rays to make sure the bone is healing in a good position. After the bone has healed, you will be able to gradually return to your normal activities.


  • Antibiotic – Cefuroxime or Azithromycin, or  Flucloxacillin or any others cephalosporin/quinolone antibiotic must be used to prevent infection or clotted blood remove to prevent furthers swelling and edema.
  • NSAIDs – Prescription-strength drugs that reduce both pain and inflammation. Pain medicines and anti-inflammatory drugs help to relieve pain and stiffness, allowing for increased mobility and exercise. There are many common over-the-counter medicines called non-steroidal anti-inflammatory drugs (NSAIDs). They include and KetorolacAceclofenacNaproxen, Etoricoxib.
  • Corticosteroids – Also known as oral steroids, these medications reduce inflammation.
  • Muscle Relaxants –  These medications provide relief from associated muscle spasms.
  • Neuropathic Agents – Drugs(pregabalin & gabapentin) that address neuropathic—or nerve-related—pain. This includes burning, numbness, and tingling.
  • Opioids – Also known as narcotics, these medications are intense pain relievers that should only be used under a doctor’s careful supervision.
  • Topical Medications – These prescription-strength creams, gels, ointments, patches, and sprays help relieve pain and inflammation through the skin.
  • Calcium & vitamin D3 – to improve bone health and healing fracture. As a general rule, men and women age 50 and older should consume 1,200 milligrams of calcium a day, and 600 international units of vitamin D a day.
  • Dietary supplement-to remove general weakness & improved health.
  • Antidepressants – A drug that blocks pain messages from your brain and boosts the effects of endorphins (your body’s natural painkillers).
  • Glucosamine & DiacereinChondroitin sulfate – can be used to tightening the loose tension, cartilage, ligament, and cartilage, ligament regenerate cartilage or inhabit the further degeneration of cartilage, ligament. They are structural components of articular cartilage, and the thought is that a supplement will aid in the health of articular cartilage. No strong evidence exists that these supplements are beneficial in knee OA; in fact, there is strong evidence against the use according to the AAOS guidelines. There are no major downsides to taking the supplement. If the patient understands the evidence behind these supplements and is willing to try the supplement, it is a relatively safe option. Any benefit gained from supplementation is likely due to a placebo effect.
  • Intra-articular corticosteroid injections – may be useful for symptomatic knee osteoarthritis, especially where there is a considerable inflammatory component. The delivery of the corticosteroid directly into the knee may reduce local inflammation associated with osteoarthritis and minimize the systemic effects of the steroid.
  • Intra-articular hyaluronic acid injections (HA) – injections are another injectable option for knee osteoarthritis. HA is a glycosaminoglycan that is found throughout the human body and is an important component of synovial fluid and articular cartilage. HA breaks down during the process of osteoarthritis and contributes to the loss of articular cartilage as well as stiffness and pain. Local delivery of HA into the joint acts as a lubricant and may help increase the natural production of HA in the joint.

Glucosamine With or Without Chondroitin or Chondroitin Alone

Seven studies that assessed the effects of glucosamine, chondroitin, or the combination met inclusion criteria. No studies addressed short-term outcomes of glucosamine combined with chondroitin, and no studies addressed the short- or medium-term effects of glucosamine alone.

  • Glucosamine, chondroitin –  and the combination of glucosamine plus chondroitin have shown somewhat inconsistent beneficial effects in large, multi-site placebo-controlled and head-to-head trials.
  • Glucosamine + chondroitin – Three large, multi-site RCTs and one smaller  found low strength of evidence for a medium-term effect on pain and function but moderate strength of evidence for no long-term benefit on pain and function.
    • Two of the three trials showed a medium-term benefit of glucosamine plus chondroitin on both pain and function (low strength of evidence).
    • A random-effects pooled estimate for three studies showed no effect of long-term treatment on pain compared with control (pooled effect size −0.73, 95%  −4.03; 2.57) (moderate strength of evidence).
    • A random-effects pooled estimate for all three studies showed no effect of long-term treatment on function compared with control (pooled effect size −0.45, 95%  −2.75; 1.84) (moderate strength of evidence).
  • Glucosamine alone – No RCTs met inclusion criteria for short- or medium-term outcomes. Three RCTs that assessed the effects of long-term glucosamine showed a moderate strength of evidence for no beneficial effects on pain and low strength of evidence for no benefit on function.
    • A random-effects pooled estimate of three studies showed no effect of long-term glucosamine treatment compared with control on pain (n=1007; pooled effect size −0.05, 95%  −0.22; 0.12; I2 0%) (moderate strength of evidence)
    • Effects of long-term glucosamine on function showed no consistent benefit (low strength of evidence).
  • Chondroitin alone: Three RCTs that assessed the effects of chondroitin alone on pain and function showed inconsistent effects across time and outcomes.
    • Two large RCTs showed the significant medium-term benefit of chondroitin alone for pain (low strength of evidence). Evidence was insufficient to assess medium-term effects on function.
    • Three large RCTs showed no long-term benefit of chondroitin alone on pain (moderate strength of evidence) or function (low strength of evidence).
  • No studies were identified that compared glucosamine sulfate with glucosamine hydrochloride.
  • No studies analyzed the time course of effects of glucosamine and/or chondroitin, but studies that examined effects at multiple time points showed that the maximum effects are achieved at 3 to 6 months.

Causes of Knee Osteoarthritis

Reghabilitation of Knee Osteoarthritis

Strength or Resistance Training

Ten studies that assessed strength or resistance training met inclusion criteria.

  • It is unclear whether strength and resistance training have a beneficial effect on patients with OA of the knee. Pooled analyses support a nonstatistically significant benefit, and individual study findings suggest a possible benefit on pain and function and significant benefit on total WOMAC scores.
  • Strength and resistance training had no statistically significant beneficial effect on short-term pain or function based on pooled analyses of 5 RCTs but a significant short-term beneficial effect on the composite WOMAC total score based on 3 RCTs (low strength of evidence).
  • Strength and resistance training showed a nonsignificant medium-term beneficial effect on function in a pooled analysis of 3 RCTs (low strength of evidence).
  • Evidence was insufficient to assess the long-term effects of strength and resistance training.
  • No studies assessed the effects of any factors such as sex, obesity, or disease severity on outcomes of strength and resistance training.

Cell-based therapies

  • Based on our finding of a significant effect of  in a small number of small, high RoB studies, and the number of studies that did not meet inclusion criteria because they compared PRP only to HA, we believe a large, saline-controlled trial is needed.
  • Although corticosteroids could provide an additional comparator for noninferiority, the immediate adverse effects of intraarticular injection of corticosteroids would be impossible to mask. Residual benefits that remain after the intervention is discontinued (and the effect of follow up treatment) also need to be assessed.

Agility Training

Eight RCTs that assessed the effects of agility training met inclusion criteria.

  • It is unclear whether agility training alone has any benefit for patients with knee OA. Identified studies showed inconsistent effects across time points and outcomes.
  • Agility training showed significant short-term beneficial effects on pain but not on function in 3 RCTs (low strength of evidence).
  • Agility training showed no consistent beneficial effects on medium-term pain or function.
  • Agility training showed no long-term beneficial effect on pain (3 RCTs) or function (2 RCTs) (low strength of evidence).

Aerobic Exercise

Five RCTs that assessed the effects of aerobic exercise met inclusion criteria.

  • Based on five trials, aerobic exercise alone shows no long-term benefit on function; the evidence was insufficient to draw conclusions regarding its effects on short- or medium-term outcomes or on long-term pain for patients with knee OA.
  • Evidence was insufficient to draw conclusions about the short-term effects of aerobic exercise on pain, function, and total  scores (one ).
  • Evidence was insufficient to draw conclusions about the medium-term effects of aerobic exercise on pain, function, and total  scores (two RCTs).
  • Evidence was insufficient to draw conclusions on the effects of long-term aerobic exercise on pain (2 RCTs)
  • The aerobic exercise showed no significant long-term effects on function, based on three RCTs (low evidence).

General Exercise Therapy

Six interventions that combined exercise interventions and did not fit predefined categories were identified.

  • General exercise programs appear to have beneficial medium-term effects on pain and function and long-term effects on pain for patients with knee OA, based on a relatively small number of heterogeneous RCTs.
  • Evidence was insufficient to assess the effects of general exercise therapy programs on short-term pain or function.
  • General exercise therapy programs had a beneficial effect on medium-term pain and function, based on two RCTs (low strength of evidence).
  • General exercise therapy programs showed beneficial long-term effects on pain, based on 4 RCTs (low strength of evidence), but the evidence was insufficient to assess long-term effects on function or quality of life.

Physical Therapy

  • Although there will be some pain, it is important to maintain arm motion to prevent stiffness. Often, patients will begin doing exercises for elbow motion immediately after the injury.  It is common to lose some leg strength. Once the bone begins to heal, your pain will decrease and your doctor may start gentle hip, knee exercises. These exercises will help prevent stiffness and weakness. More strenuous exercises will be started gradually once the fracture is completely healed.

Tai Chi

Three RCTs that met inclusion criteria assessed the effects of tai chi compared with resistance training or no activity. ,

  • Tai chi appears to have some short- and medium-term benefits for patients with OA of the knee, based on three small, short-term RCTs and one larger, 18-week  (total n=290).
  • Tai chi showed significant beneficial short-term effects on pain, compared with those of conventional physical therapy, in one large , but no significant effects in two small, brief RCTs (low strength of evidence).
  • Tai chi showed beneficial effects on short-term function compared with physical therapy and education but not compared with strength training, based on three RCTs (low strength of evidence).
  • Tai chi showed significant benefit for medium-term pain and function in 2 RCTs (low strength of evidence).
  • Evidence was insufficient to assess the long-term effects of tai chi on pain, function, and other outcomes.


One RCT that met inclusion criteria assessed the short-term effects of yoga.

  • It is unclear whether yoga has any benefit for patients with OA of the knee, as we identified only one small RCT (n=36).

Manual Therapy (Including Massage and Acupressure)

Nine RCTs that assessed the effects of manual therapy (including massage, self-massage, and acupressure) met inclusion criteria., ,

  • It is unclear whether manual therapies have any benefit for patients with knee OA beyond the effects of exercise alone. Across nine RCTs, benefits were inconsistent across time points and outcomes. Pooled analysis showed no statistically significant effect on short term pain, although a clinically important effect could not be ruled out, due to the wide 95% confidence intervals.
  • Manual therapy showed no statistically significant beneficial short-term effects on pain compared with treatment as usual, based on a pooled analysis of three RCTs and four additional RCTs (low strength of evidence).
  • Manual therapy showed no consistent beneficial effects on short-term function, based on four RCTs (low strength of evidence).
  • Insufficient evidence was found to assess the medium-term effects of manual therapy on pain, function, and other outcomes, based on four RCTs.
  • Manual therapy had a small beneficial effect on long-term pain of borderline significance when combined with exercise, compared with exercise alone, based on two studies that conducted a 12-month follow-up of three-month interventions (low strength of evidence).
  • Evidence was insufficient to assess effects on long-term function.

Balneotherapy and Mud Treatment

  • Four RCTs that met inclusion criteria assessed the effects of balneotherapy, mud baths, or topical mud. No studies of balneotherapy assessed short- or long-term outcomes.
  • Balneotherapy had a beneficial effect on medium-term function, and a beneficial, but the inconsistent effect on medium-term pain across two single-blind RCTs (low strength of evidence). No studies assessed the effects of balneotherapy on short- or long-term outcomes.
  • Evidence was insufficient for an effect of mud (mud baths or topical mud) on short-term outcomes.

Heat, Infrared, and Therapeutic Ultrasound

One RCT that assessed the effects of heat,one that assessed the effects of infrared, and three that assessed the effects of pulsed and continuous U/S on outcomes of interest met inclusion criteria. Only short-term effects were reported for heat and infrared, and no medium-term effects were reported for any of the interventions.

  • Insufficient evidence was identified to determine whether heat or infrared have any beneficial effects on any outcomes in patients with knee OA.
  • Insufficient evidence was identified to determine whether continuous or pulsed therapeutic ultrasound (U/S) have beneficial effects on any outcomes.


Four RCTs that compared the effects of  with those of sham-TENS and five RCTs that assessed the effects of  met inclusion criteria., No studies were identified that assessed long-term outcomes.

  • TENS showed a small but significant beneficial short-term effect on pain compared with sham controls based on a pooled analysis of four RCTs (moderate strength of evidence), but no benefit for a short-term function or other outcomes (low strength of evidence). The beneficial effect on pain was not sustained over the medium term.
  • Evidence was insufficient to assess the short-term effects of NMES combined with exercise compared with exercise alone (or NMES compared with a sham control) on pain or function, based on three RCTs.
  • Evidence was insufficient to assess the medium- and long-term effect of  on pain and function.

Pulsed Electromagnetic Field (PEMF)

Three RCTs that assessed short-term effects of PEMF on pain met inclusion criteria. No RCTs were identified that assessed medium- or long-term outcomes of PEMF.

  • PEMF had a statistically nonsignificant beneficial effect on short-term pain based on a pooled analysis of three RCTs (low SoE).
  • Evidence is insufficient to assess the effects of PEMF on short-term function or other outcomes.

Whole-Body Vibration (WBV)

Seven RCTs that met the inclusion criteria assessed the effects of  on outcomes of interest. No studies that assessed long-term effects were identified.

  • It is unclear whether WBV has a beneficial effect on patients with knee OA, as pooled analysis showed inconsistent effects on pain and function.
  •  combined with exercise demonstrated no short-term beneficial effects on pain compared with exercise performed on a stable surface or not combined with WBV, based on three RCTs (low strength of evidence).
  • Evidence is insufficient to draw conclusions on the short-term effects of WBV on function or other outcomes.
  • The -based exercise showed no beneficial medium-term effects on pain, based on pooled analysis of four RCTs (low strength of evidence).
  • The -based exercise showed a small but statistically significant medium-term beneficial effect on  function, based on a pooled analysis of 4 RCTs (n=180;  −0.26, 95% CI −0.45, 0.06) (low strength of evidence) that did not meet the  of −0.37. However, no beneficial medium-term effect was observed on the 6-minute walk, based on pooled analysis of four RCTs (low strength of evidence).

Orthoses (Knee Braces, Shoe Inserts, Custom Shoes)

Three RCTs on knee braces eight RCTs on shoe inserts, four RCTs on footwear, and one RCT on cane use met the inclusion criteria. No RCTs on the short-term effects of footwear were identified.

  • It is unclear whether knee braces – or other orthoses have a beneficial effect on patients with knee OA. Only a small number of RCTs on braces were identified, and studies of shoe inserts and specially designed shoes showed inconsistent effects across time points and outcomes.
  • Knee Braces: Evidence was insufficient to determine whether custom knee braces had significant beneficial effects on any outcomes.
  • Shoe Inserts showed no consistent beneficial effects across outcomes or follow-up times.
    • Custom shoe inserts had no consistent beneficial short-term effects on pain (based on four RCTs), function (three RCTs), or  total scores (pooled analysis of three RCTs) (low strength of evidence).
    • Shoe inserts showed no statistically significant beneficial effects on medium-term  pain (based on a pooled analysis of three RCTs) or medium-term function (based on four RCTs) (low strength of evidence).
    • Evidence was insufficient to determine the long-term effects of shoe inserts on pain, but they showed no benefit for long-term function (low strength of evidence).
  • Custom shoes: Evidence was insufficient to assess medium- or long-term effects on pain or function.
  • Cane Use: Insufficient evidence exists to assess the benefit of cane use on pain, physical function, and quality of life.

Weight Loss

Five RCTs and five single-arm trials (reported in six publications) that assessed the effects of weight loss on OA met inclusion criteria.

  • Weight loss with or without exercise has a beneficial effect on medium-term pain and function and on long-term pain but inconsistent effects across studies on long-term function and quality of life.
  • Evidence was insufficient to assess short-term effects of dieting, with or without exercise on pain and function,.
  • Weight loss had a significant beneficial effect on medium-term pain, based on two RCTs and four single-arm trials. One single-arm trial assessed and reported a dose-response effect between weight and outcomes of interest (moderate-level evidence).
  • Weight loss had a significant beneficial effect on medium-term function, based on two RCTs and three single-arm trials (low strength of evidence).
  • Weight loss had a significant long-term beneficial effect on pain based on three RCTs and one single-arm trial (low level of evidence) but inconsistent effects on function and quality of life, based on two RCTs (low strength of evidence).

Electrotherapy of Knee Osteoarthritis

Electrotherapy and electrophysical agents include pulsed short-wave therapy (pulsed electromagnetic energy, PEME), interferential therapy, laser, Transcutaneous Electrical Nerve Stimulation (TENS) and ultrasound. All are commonly used to treat the signs and symptoms of OA such as pain, trigger point tenderness, and swelling. These modalities involve the introduction of energy into affected tissue resulting in physical changes in the tissue as a result of thermal and non-thermal effects.


  • The therapeutic effects of ultrasound have been classified as relating to thermal and non-thermal effects. Thermal effects cause a rise in temperature in the tissue and non-thermal effects (cavitation, acoustic streaming) can alter the permeability of the cell membrane, which is thought to produce therapeutic benefits.
  • The potential therapeutic benefits seen in clinical practice may be more likely in the tissue which has a high collagen content, for example, a joint capsule rather than cartilage and bone which have a lower collagen content.

Pulsed shortwave therapy (Pulsed electromagnetic energy, PEME)

  • Pulsed short wave therapy has been purported to work by increasing blood flow, facilitating the resolution of inflammation, and increasing deep collagen extensibility. The application of this type of therapy can also produce thermal and non-thermal effects. The specific effect may be determined by the specific dose.

Transcutaneous Electrical Nerve Stimulation or TENS (also termed TNS)

  • TENS produces selected pulsed currents that are delivered cutaneously via electrode placement on the skin. These currents can activate specific nerve fibers potentially producing analgesic responses. TENS is recognized as a treatment modality with minimal contraindications.
  • The term AL-TENS is not commonly used in the UK. It involves switching between high and low-frequency electrical stimulation and many TENS machines now do this. The term is more specific to stimulating acupuncture points.

Interferential therapy

  • Interferential therapy can be described as the transcutaneous application of alternating medium-frequency electrical currents and may be considered a form of TENS. Interferential therapy may be useful in pain relief, promoting healing, and producing muscular contraction.


  • The laser is an acronym for Light Amplification by the Stimulated Emission of Radiation. Therapeutic applications of low intensity or low-level laser therapy at doses considered too low to affect any detectable heating of the tissue have been applied to treat musculoskeletal injury.

Surgical Treatment Options

Open Reduction

  • irreducible knee
  • posterolateral dislocation
  • open fracture-dislocation
  • obesity (may be difficult to obtain closed)
  • vascular injury

External Fixation

  • vascular repair (takes precedence)
  • open fracture-dislocation
  • compartment syndrome
  • obese (if difficult to maintain reduction)
  • polytrauma patient

Delayed Ligamentous Reconstruction/Repair

  • instability will require some kind of ligamentous repair or fixation
  • patients can be placed in a knee immobilizer until treated operatively
  • improved outcomes with early treatment (within 3 weeks)

Arthroscopy +/- Open Debridement

  • Arthroscopic or open debridement with removal of any loose bodies may be necessary for displaced osteochondral fractures or loose bodies.

MPFL Re-Attachment Or Reconstruction (Proximal Realignment)

  • Proximal realignment constitutes the reconstruction of the MPFL. In brief, to repair the ligament, a longitudinal incision is made at the border of the VMO, just anterior to the medial epicondyle. The ligament is usually re-attached to the femur using bone anchors. If the patient has had recurrent dislocations, then reconstruction may be necessary by harvesting gracilis or semitendinosus which are then attached to the patella and femur.
  • Isolated repair/reconstruction of the MPFL is not a recommendation in those with bony abnormalities including TT-TG distance greater than 20mm, convex trochlear dysplasia, severe patella alta, advanced cartilage degeneration or severe femoral anteversion.

Lateral Release (Distal Realignment)

  • A lateral release cuts the retinaculum on the lateral aspect of the knee joint. The aim is to improve the alignment of the patella by reducing the lateral pull.

Osteotomy (Distal Realignment)

  • Where there is abnormal anatomy contributing to poor patella tracking and a high TT-TG distance, the alignment correction can be through an osteotomy. The most common procedure of this type is known as the Fulkerson-type osteotomy and involves an osteotomy as well as removing the small portion of bone to which the tendon attaches and repositioning it in a more anteromedial position on the tibia.


  • Trochleoplasty is indicated in recurrent dislocators with a convex or flat trochlea. The trochlear groove is deepened to create a groove for the patella to glide through; this may take place alongside an MPFL reconstruction. Studies suggest it is not advisable in those with open growth plates or severely degenerative joints. This procedure is uncommon except in refractory cases.

High Tibial Osteotomy (HTO)

  • Osteotomy
  • Unicompartmental knee arthroplasty (UKA)
  • Total knee arthroplasty (TKA)

A high tibial osteotomy (HTO) may be indicated for unicompartmental knee osteoarthritis associated with malalignment. Typically an HTO is done for varus deformities where the medial compartment of the knee is worn and arthritic. The ideal patient for an HTO would be a young, active patient in whom arthroplasty would fail due to excessive component wear. An HTO preserves the actual knee joint, including the cruciate ligaments, and allows the patient to return to high-impact activities once healed. It does require additional healing time compared to an arthroplasty, is more prone to complications, depends on bone and fracture healing, is less reliable for pain relief, and ultimately does not replace cartilage that is already lost or repair any remaining cartilage. An osteotomy will delay the need for arthroplasty for up to 10 years.

Indications for HTO

  • Young (less than 50 years old), active patient
  • Healthy patient with good vascular status
  • Non-obese patients
  • Pain and disability interfering with daily life
  • Only one knee compartment is affected
  • A compliant patient who will be able to follow the postoperative protocol

Contraindications for HTO

  • Inflammatory arthritis
  • Obese patients
  • Knee flexion contracture greater than 15 degrees
  • Knee flexion less than 90 degrees
  • If the procedure will need greater than 20 degrees of deformity correction
  • Patellofemoral arthritis
  • Ligamentous instability

A UKA also is indicated in unicompartmental knee osteoarthritis. It is an alternative to an HTO and a TKA. It is indicated for older patients, typically 60 years or older, and relatively thin patients; although, with newer surgical techniques the indications are being pushed.

Indications for UKA

  • Older (60 years or older), lower demand patients
  • Relatively thin patients

Contraindications for UKA

  • Inflammatory arthritis
  • ACL deficiency
  • Fixed varus deformity greater than 10 degrees
  • Fixed valgus deformity greater than 5 degrees
  • Arc of motion less than 90 degrees
  • Flexion contracture greater than 10 degrees
  • Arthritis is more than one compartment
  • Younger, higher activity patients or heavy laborers
  • Patellofemoral arthritis

A TKA is the surgical treatment option for patients failing conservative management and those with osteoarthritis in more than one compartment. It is regarded as a valuable intervention for patients who have severe daily pain along with radiographic evidence of knee osteoarthritis.

Indications for TKA

  • Symptomatic knee OA in more than one compartment
  • Failed non-surgical treatment options

Contraindications for TKA


  • Active or latent knee infection
  • Presence of active infection elsewhere in the body
  • Incompetent quadriceps muscle or extensor mechanism


  • Neuropathic arthropathy
  • Poor soft-tissue coverage
  • Morbid obesity
  • Noncompliance due to major psychiatric disorder or alcohol or drug abuse
  • Insufficient bone stock for reconstruction
  • Poor health or presence of comorbidities that make the patient an unsuitable candidate for major surgery and anesthesia
  • Patient’s poor motivation or unrealistic expectations
  • Severe peripheral vascular disease

Advantages of UKA vs TKA

  • Faster rehabilitation and quicker recovery
  • Less blood loss
  • Less morbidity
  • Less expensive
  • Preservation of normal kinematics
  • Smaller incision
  • Less post-surgical pain and shorter hospital stay

Advantages of UKA vs HTO

  • Faster rehabilitation and quicker recovery
  • Improved cosmesis
  • The higher initial success rate
  • Fewer short-term complications
  • Lasts longer
  • Easier to convert to TKA

Complications of Knee Osteoarthritis

Complications associated with non-surgical treatment are largely associated with NSAID use.

Common Adverse Effects of NSAID Use

  • Stomach pain and heartburn
  • Stomach ulcers
  • A tendency to bleed, especially while taking aspirin
  • Kidney problems

Common Adverse Effects of Intra-Articular Corticosteroid Injection

  • Pain and swelling (cortisone flare)
  • Skin discoloration at the site of injection
  • Elevated blood sugar
  • Infection
  • Allergic reaction

Common Adverse Effects of Intra-Articular HA Injection

  • Injection site pain
  • Muscle pain
  • Trouble walking
  • Fever
  • Chills
  • Headache

Complications Associated with HTO

  • Recurrence of deformity
  • Loss of posterior tibial slope
  • Patella baja
  • Compartment syndrome
  • Peroneal nerve palsy
  • Malunion or nonunion
  • Infection
  • Persistent pain
  • Blood clot

Complications Associated with UKA

  • Stress fracture of the tibia
  • Tibial component collapse
  • Infection
  • Osteolysis
  • Persistent pain
  • Neurovascular injury
  • Blood clot

Complications Associated with TKA

  • Infection
  • Instability
  • Osteolysis
  • Neurovascular injury
  • Fracture
  • Extensor mechanism rupture
  • Patellar maltracking
  • Patellar clunk syndrome
  • Stiffness
  • Peroneal nerve palsy
  • Wound complications
  • Heterotopic ossification
  • Blood clot


Causes of Knee Osteoarthritis


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