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Understanding and Managing Peripheral Neuropathy

Winter/Spring 2010

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Diagnosing DSPN

DSPN is a clinical diagnosis, based on reports of symptoms, findings on physical exams, and ruling out other potential causes. If a patient reports symptoms such as pain, burning, numbness, or tingling in the feet, a neurological exam may help determine the cause of the symptoms.

A complete neurological examination includes a mental status exam (orientation to person, place, and time), assessment of cranial nerve function, motor function (strength in the hands and feet), sensory function (sensation in both hands and both feet), neurovascular examination (including pulses in the feet), reflexes, and coordination and gait. Typical findings in people with DSPN include decreased sensation to pain and temperature in the feet. Diminished ankle reflexes may also be noted.

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Many clinical conditions in addition to HIV can cause DSPN, including diabetes, alcoholism, thyroid disease, syphilis, hepatitis C, kidney disease, and vitamin B12 deficiency. A careful clinical history and laboratory testing are used to rule out these conditions. Use of neurotoxic drugs can also suggest a diagnosis of DSPN.

If an individual has atypical symptoms -- for example, an asymmetric distribution of numbness or pain, or weakness as the presenting symptom rather than sensory impairment -- additional testing may be required to reach a diagnosis.

Nerve conduction velocity (NCV) testing or electromyography (EMG) can be used to evaluate neurological symptoms. NCV checks the speed of signals transmitted through nerves using electrodes placed on the surface of the skin. NCV only detects damage to large nerves, so it may not detect DSPN, which predominantly affects small nerves.

EMG uses a thin needle electrode placed into muscle tissue to monitor electrical activity and detect whether the muscle has a normal ability to respond to electrical stimuli from nerves. In people with DSPN, EMG testing can occasionally show evidence of denervation (loss of nerve supply) in the distal (farther from the hips and shoulders) muscles of the limbs, such as those in the calves and forearms. EMG can also help distinguish DSPN from related neurological problems such as those associated with aging.

Another type of testing frequently used in DSPN research, but less frequently in clinical care, is quantitative sensory testing, a non-invasive method used to assess the ability of nerves to respond to vibration and temperature. This test provides useful information about the extent of neuropathy and whether a patient is responding to treatment.

Skin biopsy with analysis of epidermal nerve fiber density is also frequently used in DSPN research. Small skin samples are usually taken from the thigh, calf, and/or foot. Low nerve fiber density (<11 fibers/mm) in the skin has been shown to correlate with increasing severity of neuropathy symptoms and elevated risk of neuropathy progression.

As mentioned above, DSPN is a clinical diagnosis, and additional testing is not required unless the diagnosis is in question because of unusual symptoms or physical findings. Other types of neuropathy may be seen in people with HIV, but these are considerably less common than DSPN.

Inflammatory demyelinating polyneuropathy (known as Guillain-Barré syndrome in its acute form) is marked by progressive weakness of the extremities and poor reflexes at all sites. Progressive polyradiculopathy (damage to nerve roots near the spine) can be caused by the opportunistic infection cytomegalovirus or herpes simplex virus; this mostly occurs in people with CD4 counts below 200 cells/mm3. Polyradiculopathy is characterized by weakness and numbness in the feet, bowel incontinence, bladder retention (difficulty passing urine), and saddle anesthesia (lack of feeling in the perineum, the region between the anus and the scrotum or vagina).

Mononeuropathy (damage to a single nerve or nerves in a single area) may be caused by acute HIV infection or by nerve compression. Signs may include foot drop, facial droop, or paralysis of the diaphragm (the sheet of muscle in the chest used for breathing). Mononeuropathies are uncommon in people with HIV and are easily distinguishable from DSPN. Today, many cases of mononeuropathy are due to repetitive stress injuries such as carpal tunnel syndrome.


Risk Factors for DSPN

The prevalence of DSPN ranges from 9% to about 60% in the various cohorts of HIV positive individuals that have been studied. Risk factors for DSPN both before and after the introduction of HAART have been examined.

In the pre-HAART era, DSPN was associated with advanced HIV disease and severe immunosuppression. Risk factors currently associated with DSPN include older age, lower nadir (lowest-ever) CD4 cell count (especially if less than 50 cells/mm3), nutritional deficiencies, diabetes, concurrent use of neurotoxic drugs, heavy alcohol use, and low epidermal nerve fiber density. Most recent studies indicate that aging is a pivotal factor, and duration of HIV infection may also play a role.

A substudy of neurological outcomes in the Multicenter AIDS Cohort Study was initiated in 1986 to observe the incidence of HIV-associated neurocognitive impairment and sensory neuropathy. Looking at more than 1,600 men who have sex with men over the ten-year follow-up period, 213 cases of sensory neuropathy were identified, of which 66 were HIV-associated, 43 were due to drug toxicity, and 104 were mixed. Although neuropathy was associated with high viral load (above 30,000 copies/mL) and low CD4 count (less than 200 cells/mm3), after the data were adjusted for prior AIDS-defining illness or antiretroviral use, the association was no longer statistically significant.

Alejandro Arenas-Pinto of the Centre for Sexual Health & HIV Research in London and colleagues reported on data from the Delta trial, a randomized, double-blind trial conducted from 1992 to 1995 comparing NRTI monotherapy and dual-therapy regimens. The original study involved three therapeutic arms: AZT, AZT plus ddI, and AZT plus ddC. The substudy focused on time from treatment initiation to onset of peripheral neuropathy. The researchers examined whether peripheral neuropathy was associated with cumulative NRTI use or whether a brief exposure was sufficient to develop the condition.

The analysis included data from 3,195 patients; 177 new cases of peripheral neuropathy developed in the cohort. DSPN incidence was highest in the AZT/ddC group, with 6.2 cases per 100 person-years (PY), versus 3.0 cases per 100 PY in the AZT monotherapy group and 2.2 cases per 100 PY in the AZT/ddI group. The incidence of DSPN rose in the 90 days after participants were randomized to these treatment groups and started therapy, then decreased over time, suggesting that cumulative exposure to NRTIs does not increase the likelihood of developing peripheral neuropathy. Lower CD4 count and older age, but not sex, were associated with developing DSPN. The study authors hypothesized that there may be an underlying predisposition to DSPN which leads certain individuals to develop the condition within the first 90 days of exposure to a neurotoxic agent.

In a study by Kenneth Lichtenstein of the University of Colorado Health Sciences Center and colleagues, nearly 2,000 treatment-experienced participants from the HIV Outpatient Study (HOPS) cohort were followed to observe the development of peripheral neuropathy. The investigators found that older age, lower CD4 count, and higher viral load were associated with development of DSPN. The use of d4T slightly increased the risk of DSPN; however, earlier initiation of HAART -- even a regimen including d4T -- provided more protection against DSPN than withholding combination antiretroviral therapy. After six to twelve months of therapy, the incidence of DSPN reached a plateau.

Further analysis of the HOPS data revealed an increase in DSPN from 1992 to 1995 following introduction of the d-drugs, then a decrease starting with the introduction of PI- and NNRTI-based HAART in 1996. A lower nadir CD4 count was associated with higher incidence of DSPN. In the HAART era, risk factors for peripheral neuropathy included age greater than 40 years, diabetes, nadir CD4 count less than 50 cells/mm3, and viral load greater than 10,000 copies/mL.

Another HAART-era study by Catherine Cherry of Monash University in Melbourne, Australia, and colleagues enrolled 147 HIV positive adults, 76 from Johns Hopkins University in Baltimore, and 71 from Monash. The Melbourne group was enrolled first and subsequently the Baltimore group was matched according to rates of prior exposure to d4T and ddI.

At enrollment, study participants were divided into three groups: neuropathy-free, asymptomatic neuropathy (with physical signs on examination but no symptoms), and symptomatic neuropathy (with both signs and symptoms). At baseline, only 37% were characterized as neuropathy-free. Most patients had prior exposure to d-drugs (79% in the Johns Hopkins group; 83% in the Monash group). Symptomatic neuropathy was associated with history of exposure to ddI or d4T and age greater than 40 years. Race, sex, viral load, hepatitis C coinfection, and levels of lactic acid, hemoglobin A1c (a measure of glucose control over three months), and vitamin B12 were not associated with neuropathy in this study.

Investigators have tried to determine whether protease inhibitors, like the d-drugs, contribute to the development of DSPN. Jacqueline Petterson of the University of Calgary and colleagues studied a sample of HIV positive individuals with neurological disorders, dividing them into two groups: those with some form of neuropathy or neurological disorder (neurocognitive impairment, back pain, headache, etc.) and those without. Of the 221 patients studied, 101 had neuropathy; of those, 64 (29%) had DSPN related to HIV and 37 (17%) had DSPN related to antiretroviral therapy. Further analysis revealed that d-drugs and certain PIs -- namely ritonavir (Norvir), saquinavir (Invirase), and indinavir (Crixivan) -- were associated with DSPN.

However, a subsequent study by Ronald Ellis of the University of California at San Diego and colleagues yielded conflicting results. This group analyzed data from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, a large, multicenter prospective study to evaluate the neurological effects of HAART. DSPN was present in 58% of a sub-sample of participants who had been assessed for peripheral neuropathy at baseline, and 58% of these (34% of all participants) had symptoms. Patients with DSPN were older, had a lower median nadir CD4 count, and were more likely to have had an AIDS diagnosis. They were also more likely to be taking antiretroviral therapy and therefore had lower viral loads.

Participants were divided into groups based on antiretroviral use, with special attention to PI exposure. After the analysis was adjusted to account for age, CD4 nadir, viral load, and duration of antiretroviral treatment, there was no difference in rates of DPSN between the groups based on PI use. In terms of individual PIs, once adjusted for other risk factors, only amprenavir (Agenerase; now discontinued) and lopinavir/ritonavir (Kaletra) were associated with DSPN. The authors concluded that the independent risk of DSPN attributable to PIs is likely very small and should not preclude their use.

Susan Morgello of Mount Sinai School of Medicine and colleagues published data from the Manhattan HIV Brain Bank, which enrolled 187 patients between January 1999 and June 2002. Baseline neurological exams were performed and detailed clinical and psychiatric and substance use histories were obtained. The researchers found that 53% of the participants had DSPN at baseline, of whom almost one third were asymptomatic. Interestingly, opiate and sedative abuse or dependency was associated with asymptomatic DSPN.

To determine whether there is a genetic predisposition to develop DSPN, Todd Hulgan of Vanderbilt University School of Medicine and colleagues evaluated participants in ACTG 384, a study of HIV positive patients taking ddI/d4T or AZT/3TC with efavirenz (Sustiva), nelfinavir (Viracept), or both. DNA samples were available from 526 participants. Among these patients, 17 (3.2%) had peripheral neuropathy at baseline and were excluded from this analysis. Of the 509 remaining participants, 147 developed DSPN; within this group, a majority (108 patients; 73%) had been randomized to the ddI/d4T arm. Patients who developed DSPN were older and had higher baseline viral load and lower baseline CD4 count.

Geneticists use mitochondrial haplogroups to define populations with similar genetic backgrounds. The Caucasian participants from ACTG 384 were divided into the European haplogroups, and haplogroup T was identified more frequently in patients with peripheral neuropathy. In a multivariable regression analysis examining predictors of neuropathy, variables with a significant association included ddI/d4T use, older age, and haplogroup T. Between 10% and 15% of individuals of European descent belong to mitochondrial haplogroup T.

Jeffrey Canter of Vanderbilt University School of Medicine and colleagues expanded the haplogroup work from ACTG 384; they presented their results at the 2009 Conference on Retroviruses and Opportunistic Infections. Among 156 African-American ACTG 384 participants without baseline peripheral neuropathy, 51 developed DSPN. Patients with haplogroup L1c were more likely to develop DSPN than those of other sub-groups. Older age, ddI/d4T use, and haplogroup L1c were independent predictors of DSPN.

Finally, Beau Ances of Washington University School of Medicine and colleagues examined the relationship between metabolic syndrome and HIV-associated DSPN in 1,556 participants in the CHARTER study followed from 2003 through 2007. Metabolic syndrome is characterized by insulin resistance, high blood pressure, central obesity, decreased HDL ("good") cholesterol, and elevated triglycerides. In this analysis, 130 participants were found to have DSPN; however, metabolic syndrome and DSPN were not correlated. Patients with elevated triglycerides and diabetes had an increased risk of peripheral neuropathy, just as in the general population.


Neuropathy Management

The first step in DSPN management is optimal control of HIV disease with antiretroviral therapy. Although data are not entirely consistent, many studies have shown that higher viral load and lower current or nadir CD4 count are associated with peripheral neuropathy. HAART minimizes this risk by suppressing HIV replication and allowing CD4 cells to recover.

The next step is to discontinue any potentially neurotoxic agents, if possible. As discussed above, the antiretroviral agents most often associated with peripheral neuropathy are the d-drugs. Use of multiple d-drugs is particularly likely to cause problems. The ddI/d4T combination was once widely used as an NRTI "backbone" but fell out of favor due to increasing evidence of mitochondrial toxicity. U.S. treatment guidelines no longer consider ddI or d4T to be components of "preferred" or "alternative" regimens, but they are still commonly used in resource-limited settings (see table below).

Today, d-drugs are seldom used by people starting HIV therapy for the first time in high-income countries, and many treatment-experienced patients have switched to NRTIs less likely to cause neuropathy (3TC, emtricitabine, abacavir, and tenofovir). Studies indicate that neuropathy improves after stopping these drugs, but the change may be slow and incomplete.

In addition to antiretrovirals, there are many other potentially neurotoxic agents used in HIV care, including dapsone (sometimes used for Pneumocystis pneumonia prophylaxis), thalidomide (infrequently used to treat aphthous ulcers, or canker sores), isoniazid and ethambutol (tuberculosis drugs), and certain cancer chemotherapy agents (for example, vincristine).

Numbness due to DSPN may contribute to problems with walking, leading to falls and other injuries. Physical or occupational therapy may be helpful, as well as practical measures such as removing throw rugs and other fall hazards.


D-Drugs in Resource-Limited Settings

In the U.S. and other wealthier countries, d-drugs are rarely used today due to their potential mitochondrial toxicity. In lower-income countries, however, ddI and especially d4T are still frequently used because they are inexpensive, widely available, and effective as a component of first-line antiretroviral therapy.

As reported by Chi Hung of University of California at San Diego and colleagues, a 2006 survey of 23 developing countries showed that d-drugs were still used in 70% of first-line regimens and 60% of second-line regimens. In addition, patients in resource-limited settings often use generic fixed-dose coformulations containing ddI and/or d4T, so doses cannot be adjusted based on weight to minimize side effects.

The prevalence of neuropathy in resource-limited settings has been estimated at 20% to 75%. In a study presented at the 2009 Conference on Retroviruses on Opportunistic Infections, Catherine Cherry and colleagues examined incidence of DSPN in 294 patients receiving antiretroviral therapy in Australia (where d4T is rarely used), Malaysia (where it is sometimes used), and Indonesia (where it is often used). Overall, DSPN was present in 32% of the patients: 42% in Australia, 19% in Malaysia, and 34% in Indonesia.

The risk of DSPN was 20% among younger (under 40 years), shorter (height less than 170 cm or five feet, seven inches) patients; 33% among younger, taller patients; 38% among older, shorter patients; and 65% among older, taller patients. The authors proposed that height and age measurements represent a free and potentially effective means of identifying individuals at higher risk for neuropathy and prioritizing them to receive alternative agents rather than d4T.

Advocates have argued that drugs that are too toxic for use in wealthy countries should not be given to poor people either. On the eve of World AIDS Day, the World Health Organization (WHO) issued updated global antiretroviral therapy guidelines that call for phasing out d4T and replacing it with equally effective and more tolerable alternatives such as AZT or tenofovir.

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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
 
See Also
Neurological Complications of AIDS Fact Sheet
More on Neuropathy

 

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