Peripheral Neuropathy
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 painful neuropathy
- Neuropathy due to nutritional deficiencies
- Neuropathy due to antiretroviral or chemotherapy drugs
- Neuropathy due to toxins (alcohol, hexane, mercury)
- Neuropathy due to other conditions (diabetes)
- Guillain-Barré syndrome
- Chronic inflammatory demyelinating polyradiculopathy
- Multiple mononeuropathies
- Acute lumbosacral polyradiculopathy
Distal Painful Neuropathy
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 KaposiÕs 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
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
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).
Diabetes
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
Treatment Options
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
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.
Conclusion
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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Page last updated 1 April 1997
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