Category Archive Dr. Harun Ar Rashid

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

Nociceptors

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

Neurotransmitters

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:

• A 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 studies, evoked 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 (https://www.nap.edu/catalog/13172/relieving-pain-in-america-a-blueprint-for-transforming-prevention-care), 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.

Children

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.

References

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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

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.[rx]

• 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).[rx] Also, cervical discectomy and fusion may be associated with postoperative dysphagia.[rx][rx]

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

• Mechanical obstruction causes include Schatzki ring, esophageal stricture, esophageal carcinoma, eosinophilic esophagitis.[rx]
• 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).[rx]

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[rx]

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.

Others

• Diffuse esophageal spasm.
• Esophageal cancer.
• Eosinophilic esophagitis[rx]
• 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[rx]

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.^[rx] 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.^[rx] Patients with 2 or more of these risk factors on presentation should undergo a careful investigation to rule out malignancy.^[rx,rx]
• 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.^[rx] Type II achalasia has the best response to treatment, followed by type I achalasia, whereas type III achalasia is the most difficult to treat.^[rx,rx]
• 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.[rx]
• 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.

Medication.

• 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.[rx][rx]
• 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]

Surgery

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.[rx] 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.

References

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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. [rx][rx][rx] It can manifest in an infant as soon as the protective effect of maternal immunoglobulins wanes at around three-six months of age.

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.[rx] The disease has been associated with 544 mutations that include mainly missense mutations, insertions, deletions, and splice-site mutations.[rx]

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.[rx]

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.[rx]

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.[rx]

• 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

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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.^[rx] 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

Symptoms of Hughes Syndrome

Diagnosis of Hughes Syndrome

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:

Clinical:

• 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

Laboratory

• 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

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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?

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.

Encephalomyopathy

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?

Vision

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 (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. [rx][rx][rx][rx]

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.[rx][rx]

Types of High Altitude Sickness

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

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.)

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.[rx][rx]

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. [rx][rx][rx]

• 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

Treatments of High Altitude Cerebral Edema

Non-pharmacological

• 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.

Medication

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.[rx] 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.[rx] In addition to these established treatments, potential novel therapies have been suggested such as ibuprofen, nitrates, and intravenous (IV) iron supplementation.

Acetazolamide

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[rx].  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.[rx][rx]

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

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

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[rx,rx] or alteration in the blood–brain barrier by inflammatory mediators causing vasogenic edema.]rx] The central role of inflammation in these mechanisms has led to an interest in nonsteroidal anti-inflammatory medications such as ibuprofen.

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