BETA March 1997.
by Mark Bowers
The ancient Greeks were the first to enumerate the 5 senses: vision, hearing, taste, smell and touch. Aristotle further divided the sense of touch into hard-soft, hot-cold and rough-smooth components, quite similar to the findings of modern neurological research that supports the existence of different types of peripheral nerves in the body that carry the sensations of cold, warmth, touch and pain. HIV infection is associated with several kinds of peripheral neuropathy that affect primarily the sense of touch in the hands and feet, but may also cause more severe symptoms such as muscle weakness.
HIV does not directly infect neurons (nerve cells). Instead, it may damage the cells that surround nerves, unraveling neural insulation and slowing, garbling or stopping the transmission of information to and from the brain. Abnormal macrophage activation is associated with the pathology. Some of the drugs that are used to treat HIV or associated opportunistic infections (OI) may damage axons, the long, narrow connecting processes of neurons that communicate with muscles, tissues and organs.
Symptoms of peripheral neuropathy may arise at any time during HIV infection. Neuropathy is reported at a rate of 6-8% during the acute retroviral syndrome that often occurs shortly after infection. Neuropathy may affect people with asymptomatic HIV disease, manifesting in syndromes ranging from mononeuritis (inflammation of a single nerve) and mononeuropathy (disease of a single nerve), to polyneuropathies that affect multiple nerves and can lead to paralysis. Most commonly, peripheral neuropathy develops in people with symptomatic HIV disease or AIDS. For these individuals, the symptoms of painful, burning feet or numbness in the feet and/or hands are familiar and often disabling.
As people with HIV and AIDS who have access to
effective antiretroviral treatments continue to live
longer, more neurologic disorders are being reported.
Prompt identification and treatment of peripheral
neuropathy and other neurologic disorders may have an
important impact on the quality of this extended
lifespan.
Peripheral Neuropathies in HIV Disease
Distal (distant from the center of the body) painful neuropathy is the most common neuropathy among people with HIV disease. The hands and feet are the most commonly affected sites. According to the Multicenter AIDS Cohort Study (MACS), the number of people who report this kind of neuropathy increased from 1985 through 1992, partly because of antiretroviral drug toxicities (see sidebar on Rates of Peripheral Neuropathy for Nucleoside Analog Drugs), and partly because people with HIV are living longer. The symptoms of distal peripheral neuropathy include burning sensations in the feet and/or hands and loss of sensation. Distal neuropathy starts with nerve damage in the extremities (the areas of the body farthest from the brain or spinal cord).
Vitamin deficiencies (particularly B-1, B-6 and B-12) may cause distal painful neuropathy. Specific blood tests can measure vitamin deficiencies. Frequently, simply adding more of the deficient vitamin corrects the nutritional balance and restores normal sensation to the hands and feet. Vitamin B-1 deficiency (beriberi) produces polyneuropathy and may even cause heart failure. Vitamin B-6 (pyridoxine) supplements may be taken to prevent or treat peripheral neuropathy in people taking isoniazid (INH) for tuberculosis. Paradoxically, megadoses of pyridoxine can also cause severe sensory neuropathy, confirming the adage that "more is not always better." Vitamin B-12 (cobalamin) deficiency may produce a mild neuropathy and muscle degeneration; regular oral supplementation or intramuscular injections of cobalamin will correct this. Many physicians who specialize in HIV test B-12 blood levels once a year, and whenever neuropathy is suspected.
Magnesium supplements may also help to correct some neuropathies, according to Sally Stroud, MD, at the Houston Immunological Institute in Texas. In patients with decreased serum magnesium levels, normal thyroid and normal B-12 levels, intravenous supplementation followed by oral supplementation resulted in improvements in vibration sensation and pinprick tests, increased ankle reflex (indicating better muscle tone) and decreased use of pain medications.
Neuropathy caused by antiretroviral drugs is increasingly common among people with HIV disease. Increased reporting of peripheral neuropathy correlates with increased usage of nucleoside analog drugs. Peripheral neuropathy is a well known side effect of all of the approved nucleoside analog drugs except AZT. The highest incidence of neuropathy is associated with the use of ddC. The severity of peripheral neuropathy is related to the dose of each drug. Ethambutol, a drug used in the treatment of Mycobacterium avium complex (MAC) disease, and several drugs used for the treatment of KaposiŐs sarcoma, including vinca alkaloids, are significant causes of peripheral neuropathy as well.
A common strategy to reduce drug-related neuropathy is to reduce the dose or discontinue the offending drug. Pain (if present) generally persists for 6-8 weeks following a dose reduction or drug discontinuation. Drug-induced neuropathies are generally reversible.
Clinicians and researchers have looked for factors that put certain patients at higher risk for developing peripheral neuropathy. Carl Fichtenbaum, MD, and colleagues from the AIDS Clinical Trials Unit at Washington University School of Medicine in St. Louis, found that people with a low baseline serum vitamin B-12 level, a history of heavy alcohol consumption or previous symptoms of peripheral nerve dysfunction were more likely to develop peripheral neuropathy due to nucleoside analog drug usage than those without those histories (see BETA, March 1996, page 51).
Rarely, peripheral neuropathy is caused by exposure to various occupational toxins including solvents (e.g., hexane in gasoline and glue), mercury and acrylamide monomer. Chronic recreational inhalation of hexane has been known to cause peripheral neuropathy.
The diagnosis of peripheral neuropathy is usually a clinical one, particularly when the patient has taken a drug associated with the condition. At the recent 4th Conference on Retroviruses and Opportunistic Infections in Washington, DC, Justin McArthur, MD, from Johns Hopkins University, described a simple skin punch biopsy to help make the diagnosis. Microscopic examination of stained tissue reveals decreased numbers of fine nerve endings in the top skin layer and a decreased density of nerve fibers. Guillain-Barré Syndrome
Guillain-Barré syndrome (GBS, or ascending paralysis), while uncommon, usually occurs early in the course of HIV disease. Also known as inflammatory demyelinating polyradiculopathy (disease of the nerve root), GBS usually develops rapidly (5 days to 3 weeks) after an infection, surgery or an immunization. The symptoms are muscular weakness and sensory loss that begin in the legs and progress to the arms. GBS is a medical emergency requiring constant monitoring to ensure that respiration continues, or death can occur due to suffocation. The medical emergency lasts 14 days; recovery requires several weeks or months. However, up to 10% of all people with GBS experience a relapse after some improvement and become chronically affected. Two treatments have been clinically validated for moderate to severe GBS: blood plasma exchange and administration of intravenous gamma globulin. The usual course is 5 treatments over 5-10 days. David Simpson, MD, at Cedars Sinai Hospital in New York and Michael Olney, MD, at the University of California San Francisco, also advocate the use of prednisone, an anti-inflammatory steroid.
Elyse Singer, MD, from the University of California at Los Angeles School of Medicine, and Leonid Germaniskis, MD, from the Department of Veterans Affairs West Los Angeles Medical Center, describe a kind of peripheral neuropathy resembling GBS that is caused by Campylobacter jejuni, a pathogen that causes bacterial gastroenteritis and diarrhea. The clinical prognosis of this neuropathy is worse than GBS. Stool cultures will confirm the diagnosis. The accepted treatment is erythromycin.
Mononeuropathy affects a single nerve and the area of skin that the nerve serves. Neurologists have noted that mononeuropathies in HIV disease often occur in symmetrical pairs. For example, mononeuropathy that affects the right leg is likely to be accompanied by mononeuropathy in the same part of the left leg. However, mononeuropathies are rare in HIV disease.
Cytomegalovirus (CMV) infection is the most common viral OI in HIV/AIDS. CMV that resides in clusters of nerve cell bodies (ganglia) in the spine may produce progressive polyradiculopathy or progressive multifocal neuropathy. In either event, the spread of neuropathic symptoms is associated with previous episodes of other OI and very low CD4 cell counts. Often, people with these types of neuropathy also have CMV-related retinitis or gastroenteritis.
The symptoms of CMV-related neuropathy are burning and prickling sensations in the feet (but not the hands), absence of reflexes (ankle and knee jerk response to a tap with a rubber hammer), progressive weakness and loss of sensation and, often, pain radiating from the tailbone. Polyradiculopathy caused by untreated CMV disease can be quickly fatal. There have been no clinical studies of anti-CMV drugs for polyradiculopathy, but there is anecdotal evidence that it responds well to treatment with the antiviral drugs ganciclovir or foscarnet. According to Sally Nuessle, PharmD, of Gilead Sciences, Inc., there is no anecdotal evidence yet that CMV polyradiculopathy responds to cidofovir (Vistide).
Peripheral neuropathy occurs frequently in people with
diabetes mellitus. It is usually seen in people with
long-standing diabetes, but may affect anyone with the
disease. Dietary measures sometime correct the condition.
Treatment of neuropathy may be complex for people with
both diabetes and HIV.
Rates of Peripheral Neuropathy Associated with
Nucleoside Analog Drugs
Drug: ddC (Hivid)
Dose: 0.75 mg every 8 hours
PN Rate: 28.3%
Recommendation: Reduce or interrupt drug
for several weeks then rechallenge with a lower dose
Drug: d4T (Zerit)
Dose: 40 mg twice daily
PN Rate: 21%
Recommendation: Start at or dose reduce to
20 mg twice daily
Drug: ddI (Videx)
Dose: 750 mg daily
PN Rate: 13%
Recommendation: Interrupt for 8 weeks and
re-evaluate
Drug: 3TC (Epivir)
Dose: 150 mg twice daily
PN Rate: 12%
Recommendation: Reduce dose for several
weeks then rechallenge
Whenever possible, treatment for neuropathy should be directed at the underlying cause. If the cause is a nutritional deficiency, regular supplementation can correct it. If the cause of neuropathy is drug-related, the dose of the offending drug may be decreased or a different drug may be substituted. If the cause is related to the effects of blood sugar levels, such as diabetic neuropathy, close attention to the control of blood sugar may provide relief. If alcohol use or abuse underlies the neuropathy, addiction control may provide a solution.
In some cases, none of the above strategies is sufficient to immediately provide relief for the pain of neuropathy. Most clinicians start with pain relievers, including acetaminophen or non-steroidal anti-inflammatory drugs (ibuprofen, naprosyn and others). Over-the-counter topical anesthetics such as capsaicin may provide episodic relief for some individuals. For more persistent, less easily controlled pain, tricyclic antidepressants may be prescribed, since these alter the perception of pain. Examples include amitriptyline (Elavil), starting at 25 mg at bedtime and increased by 25 mg each week until pain is controlled. The side effects of amitriptyline are sleepiness, urinary retention and changes in blood pressure when changing body position (for example, standing up). Desipramine (Norpramin), a drug with fewer side effects, may be substituted for amitriptyline. Anticonvulsant drugs such as carbamazepine (Tegretol) at 200 mg three times a day, phenytoin (Dilantin) and gabapentin (Neurontin) are also used for some people, especially those with a "shooting" type of pain. These drugs may interfere with normal liver function and reduce or increase blood levels of protease inhibitors and other drugs used to treat HIV infection. Anticonvulsant drugs may cause bone marrow suppression, rashes, gastrointestinal upset, hepatitis (liver inflammation) and changes in consciousness.
Second-line agents for neuropathic pain control include baclofen (Lioresal), mexiletine (Mexitil) and prazosin (Minipress). Narcotics such as hydrocodone, codeine and morphine are often reserved for intractable neuropathic pain because they can cause cognitive impairment and because some people develop tolerance, which limits their effectiveness.
Practical measures are useful in neuropathic pain
control. Thick socks and loose, soft-soled shoes may be
helpful. Extreme changes in temperature may worsen the
pain of neuropathy, so warm shoes or boots are important
in winter and sandals may reduce neuropathic pain on warm
days. Sitting with shoes removed for several minutes
several times a day often provides relief. Nightly foot
soaks with either cold or hot water before bed can
relieve pain enough to allow sleep. Blanket supports that
remove the pressure of bedding from the feet may also be
helpful.
Symptoms of Neuropathy
Motor: weakness, muscle degeneration,
fasciculations (involuntary contraction or twitching of a
muscle), cramps
Sensory: loss of sensation, prickling
sensation, "pins-and-needles" sensation,
burning sensation
Autonomic: faintness (orthostatic
[standing] dizziness), increased or decreased sweating,
impotence, slowed gastrointestinal functioning
Clinical studies are evaluating the efficacy of amitriptyline, mexiletine, acupuncture and nerve growth factor for neuropathic pain. Recombinant human nerve growth factor (rhNGF) is unique among study agents, as it is designed to decrease neuropathic pain by regenerating damaged nerves.
AIDS Clinical Trials Group (ACTG) 242, a placebo-controlled study comparing mexiletine and amitriptyline for the treatment of HIV-related peripheral neuropathy, was closed in December 1996 by the Data Safety and Monitoring Board assigned to review interim results. No differences could be detected in the 3 study groups (mexiletine vs amitriptyline vs the combination). Mexiletine is an antiarrhythmic drug that is similar to the local anesthetic lidocaine. The major side effects reported in clinical studies are nausea, vomiting and heartburn (39.3%). Amitriptyline has been clinically studied for treating hereditary and diabetic neuropathic pain; its use in the treatment of HIV-related neuropathy has not yet been clinically validated.
ACTG 291, a 70-week study of rhNGF, was fully accrued in February 1997. This study compares 2 doses (0.1 microgram/kg 2 times per week or 0.3 microgram.kg 2 times per week) of injected rhNGF with placebo in 140 HIV positive individuals. Study participants may use any approved medication designed to control pain. Previous studies of rhNGF in diabetics revealed that peripheral neuropathy quickly rebounded in individuals who discontinued treatment; in an effort to minimize rebound neuropathy among study participants, Genentech has agreed to supply rhNGF to participants for an additional 48 weeks after the study concludes.
Encouraging results from a 250-person study of rhNGF for the treatment of diabetic neuropathy showed an overall reduction in pain as measured by pain scales among those who received the drug. However, no difference was detected between the 2 doses of rhNGF. The most common reported side effect was soreness at the site of injection. Community interest in rhNGF has been high for several years (see BETA, June 1993, pages 3-7).
Community Programs for Clinical Research in AIDS (CPCRA) study 022 is comparing amitriptyline with acupuncture for symptomatic relief of peripheral neuropathy. Although acupuncture has been successfully employed for centuries, previous studies of acupuncture in the relief of pain have been inconclusive because of poor study design and inadequate controls. The CPCRA study is designed to quantify the effects of acupuncture and amitriptyline on neuropathic pain, and to help determine if acupuncture or amitriptyline alone or the combination is more effective. Some study sites (including the Community Consortium in San Francisco) are only comparing acupuncture with placebo acupuncture.
As more people with HIV take advantage of treatment regimens that include nucleoside analog and protease inhibitor drugs, more people will grapple with drug-induced peripheral neuropathy. Improved prospects for survival will prompt people to assess not only increased survival but also quality of life. Controlling and potentially reversing the neuropathies that appear to be increasing in the second decade of the AIDS pandemic is no longer a secondary consideration. Novel therapies, such as rhNGF, will find their place alongside time-honored pain-control strategies such as acupuncture in the control and repair of the neural damage that HIV disease may cause at all stages of infection.
Mark Bowers is Managing Editor of Treatment Publications at the San Francisco AIDS Foundation.
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This information is designed to support, not replace, the relationship that exists between you and your doctor.