Peripheral Nerve Function in HIV Infection: Clinical, Electrophysiologic, and Laboratory Findings

Objective  To determine the effects of immunodeficiency, nutritional status, and concurrent systemic disease on peripheral nerve function in acquired immunodeficiency syndrome.

Design  Survey of subjects infected with human immunodeficiency virus (HIV), recruited as part of a prospective study of neuromuscular complications of HIV infection.

Setting  A neuro–acquired immunodeficiency syndrome outpatient clinic in a university medical center.

Patients  A consecutive sample of 251 HIV-infected individuals. Primary care providers referred subjects to the study for evaluation of neurologic symptoms or for prospective neurologic assessment.

Main Outcome Measures  Standardized history and neurologic examination, laboratory tests (complete blood cell count, serum albumin level, vitamin B₁₂ level, and T-lymphocyte subsets), and electrophysiologic testing of sural, tibial, and ulnar nerves.

Results  The most frequent neurologic diagnosis was distal symmetrical polyneuropathy (DSP) (38%). The most common clinical features were nonpainful paresthesias (71%), abnormalities of pain and temperature perception (71%), and reduced or absent ankle reflexes (66%). Patients with DSP were significantly older (P=.009), and had lower CD4 lymphocyte cell counts (P=.004) and lower hemoglobin levels (P=.004) than those without DSP. Deterioration of values on nerve conduction studies, irrespective of the clinical diagnosis of DSP, was significantly correlated with low CD4 counts, aging, abnormal serum albumin and hemoglobin levels, and weight loss. Most of these factors co-correlated, and, with the exception of age, no single variable significantly accounted for changes in results of nerve conduction studies when the influence of other factors was eliminated.

Conclusion  The combination of several factors, including age, immunosuppression, nutritional status, and chronic disease, contributes to distal peripheral nerve dysfunction in HIV infection.

PERIPHERAL NEUROPATHY is one of the most frequent neurologic complications of human immunodeficiency virus (HIV) type I infection.¹ Distal symmetrical polyneuropathy (DSP) is the most common form of peripheral neuropathy in patients with acquired immunodeficiency syndrome (AIDS). Clinical evidence of DSP is present in more than one third of patients with AIDS, in whom other causes of polyneuropathy have been excluded.² Distal axonopathy may be detected pathologically in almost all patients with AIDS who have undergone sural nerve biopsy or autopsy.³ The most frequent symptoms of DSP are numbness, burning pain, and paresthesias, typically with a symmetrical onset in the lower extremities.⁴ While DSP is not a life-threatening condition, it markedly affects the quality of life of patients with AIDS and may limit the use of neurotoxic antiretroviral agents.⁵

The cause of DSP in AIDS is unknown. Several mechanisms have been proposed, including direct infection by HIV or cytomegalovirus,^6-8 nutritional deficiency,² critical illness neuropathy,⁹ weight loss,^2,9 vitamin B₁₂ deficiency,¹⁰ and cytokine-mediated neurotoxic effects.¹¹ It is likely that more than 1 factor contributes to the pathogenesis of DSP in AIDS.¹⁰ We report clinical, electrophysiologic, and laboratory findings in a cohort of HIV-infected patients to determine the effects of immune deficiency, nutritional status, and concurrent systemic disease on peripheral nerve function in AIDS.

We examined 251 consecutive HIV-seropositive patients from December 1, 1990, to March 31, 1994, as part of a prospective study of neuromuscular complications of HIV infection. Individuals volunteered to participate in the study without compensation. Primary care providers in the AIDS Clinic at The Mount Sinai Medical Center, New York, NY, referred patients to the study either for evaluation of neurologic symptoms (n=163) or for longitudinal neurologic assessment of asymptomatic HIV infection (n=88). The demographics of the study cohort are shown in Table 1. Age ranged from 21 to 71 years (mean±SD, 40.5±9.3); 187 subjects (75%) were men and 64 (25%) were women. The interval from diagnosis of HIV infection to evaluation was 1 to 168 months (mean, 39.4±28.5). According to the Centers for Disease Control and Prevention guidelines,¹² 46 patients (18%) were classified as asymptomatic HIV positive (stage IA, IIA), 29 (12%) as symptomatic HIV positive (stage IB, IIB), and 176 (70%) as having AIDS (stage IC, IIC, III). All subjects gave their informed consent to participate in this protocol, which was approved by the institutional review board.

The intake evaluation consisted of a standardized history and examination performed by a neurologist, serologic and immunological blood tests, and nerve conduction studies (NCSs). Height and weight were recorded at entry. The body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Weight loss, as reported by the patient, was recorded as a percentage of baseline body weight ([baseline weight − current weight]/baseline weight). Confounding variables for peripheral neuropathy were recorded, including family history, diabetes mellitus, alcohol abuse, and a variety of neurotoxins used in the treatment of HIV-related diseases, such as isoniazid, dapsone, and the nucleoside analogues didanosine, zalcitabine, and stavudine. Eighty-five patients (33%) were excluded from the analysis because of such confounding factors. Laboratory tests included complete blood cell count, serum albumin level, vitamin B₁₂ level, and T-lymphocyte subset counts.

The clinical diagnosis of DSP was based on the following criteria: (1) symptoms of distal pain, paresthesias, or numbness, with predominant symmetrical involvement of the lower extremities; (2) neurologic signs, including absent or diminished ankle reflexes relative to knee reflexes; and (3) distal reduction of vibratory, pain, or temperature sensation in a stocking-and-glove distribution. The clinical severity of DSP was based on the associated neuropathic pain and graded as mild (no analgesic required), moderate (requiring analgesics), or severe (disabling pain requiring narcotics).

The NCSs were performed with surface recording for sensory and motor nerves. Sensory NCSs of the unilateral sural and ulnar nerves were performed orthodromically. The sensory nerve action potential (SNAP) was obtained by computerized averaging of 8 responses recorded by surface disk electrodes at a distal portion of the nerve trunk. Distance was measured from the stimulating cathode to the recording cathode. Cursor measurement of the averaged potential included (1) amplitude, in microvolts; (2) latency, in milliseconds; and (3) conduction velocity (CV), in meters per second.

For motor NCSs, supramaximal nerve stimulation was applied transcutaneously to a distal and proximal segment of the unilateral tibial and ulnar nerves. The compound muscle action potential (CMAP) was recorded with surface disk electrodes. Measurements of the CMAP taken by cursor included (1) amplitude, in microvolts; (2) latency, in milliseconds; and (3) CV, in meters per second.

F-wave latencies were obtained from the unilateral ulnar and tibial motor nerves by recording the minimum latency of 10 responses; at least 10 supramaximal stimuli were applied before it was concluded that F-waves were absent. The H-reflex was obtained by retrograde submaximal stimulation of the tibial nerve at the popliteal fossa and common recording at the soleus. The minimum latency of the H-reflex was recorded.

The electrophysiologic diagnosis of distal axonal polyneuropathy was defined as reduction in SNAP amplitudes, mild and symmetrical reduction in sensory and motor conduction velocities (not less than 60% of our laboratory's lower limit of normal), or increase in late response (F-wave or H-reflex) latencies (not more than 125% of the upper limit of normal).

The χ² test was used to define the associations between the frequency of DSP and demographic variables such as sex, race, and risk factors for HIV infection or neuropathy. To evaluate the effects of selected variables on DSP frequency and NCS values, we used 2 parallel strategies: (1) to test differences between groups of patients (eg, with or without DSP) and (2) to test correlations between variables independent of patient group or diagnosis.

For analysis of immunological effects, we established 3 CD4 cell count cohorts as follows: (1) less than or equal to 0.100 × 10⁹/L (n=125 [50%]); (2) 0.101 to 0.300 × 10⁹/L (n=75 [30%]); and (3) more than 0.300 × 10⁹/L (n=51 [20%]). For the analysis of nutritional variables, we subdivided patients in 2 groups (normal and abnormal) for each of the following laboratory values: serum albumin, hemoglobin, vitamin B₁₂, and BMI. Abnormal cutoffs were derived from our laboratory's normal limits (average±2.5 SDs): 35 g/L for albumin, 120 g/L for hemoglobin, and 148 pmol/L for vitamin B₁₂. Analysis of variance was used to establish the significance of differences in DSP prevalence and mean NCS values between these groups.

We further analyzed the influence of age and immunological and nutritional markers on NCS values by means of single correlations. The NCS amplitudes, conduction velocities, and F-wave and H-reflex latencies were correlated as dependent variables with age; CD4 count, serum albumin level, hemoglobin level, vitamin B₁₂ level, BMI, and weight loss, as independent variables. We used a forward stepwise multiple regression analysis to identify the variables that contributed independently to the outcome of NCS values, when the simultaneous influence of the other variables was controlled.

The clinical evaluation at entry established numerous neurologic diagnoses, including both central and peripheral nervous system diseases. Many patients had multiple concurrent neurologic diagnoses, including myopathy (20%), myelopathy (10%), dementia (6%), and other central nervous system diseases (5%). Only 28 subjects (11%) had normal results of neurologic examination.

After subjects with confounding factors for neuropathy were excluded, 166 HIV-infected individuals were included in the analysis. There were 75 subjects in CD4 cohort 1 (defined above), 46 in cohort 2, and 40 in cohort 3. CD4 counts were evenly distributed across subjects of different sex, race, and risk factor for HIV infection. Men were significantly older than women (42.2±8.5 vs 36.0±5.7 years; P<.001). Similarly, white subjects (43.6±7.8 years) were significantly older than subjects of other races (black, 39.7±6.5 years; Hispanic, 38.4±7.9 years; P=.02), and subjects reporting homosexual-bisexual risk factor were older than those reporting other risk factors (42.6±8.1 vs 38.1±8.2 years; P=.004).

Some form of peripheral neuropathy was clinically diagnosed in 74 subjects (45%). The most common clinically diagnosed form of neuropathy was DSP, present in 63 (38%) of the subjects without confounding factors for neuropathy (Table 1). Forms of neuropathy other than DSP were mononeuropathy multiplex (11%), inflammatory demyelinating polyneuropathy (4%), progressive polyradiculopathy (1%), autonomic neuropathy (1%), and monoradiculopathy (1%).

The frequency of DSP in patients with AIDS was 48% (53/110). Patients with DSP were significantly older than those without DSP (42.2±9.5 vs 38.9±9.5 years; P=.009) and had lower hemoglobin levels (115±23 g/L vs 128±18 g/L; P=.004) and lower mean CD4 count (0.107±0.123 × 10⁹/L vs 0.264±0.234 × 10⁹/L; P=.004). As a result, the distribution of DSP was skewed toward the cohorts with a lower CD4 count, with 43 cases (57%) in group 1, 16 (34%) in group 2, and 4 (10%) in group 3. Serum albumin and B₁₂ levels, BMI, and weight loss percentages did not differ between subjects with and without DSP (Table 1). Male sex (χ²=3.75; P<.05), white race (χ²=4.41; P<.03), and homosexual risk factor (χ²=6.75; P<.007) were significantly associated with the diagnosis of DSP. Individuals of Hispanic race were diagnosed with DSP less often than expected (χ²=7.42; P<.01).

The most common symptoms in patients with clinical DSP were distal nonpainful paresthesias in 45 patients (71%), distal pain in 24 (38%), and muscle cramps in 16 (25%). These symptoms were significantly more common in patients with DSP than in those without this diagnosis (P<.001) (Table 2). While 32 patients (51%) with DSP complained of proximal weakness and 22 (35%) had cognitive impairment, the frequency of these symptoms was similar in patients without DSP. The predominant clinical signs of DSP were sensory abnormalities (pain, 45 patients [71%]; temperature, 45 [71%]; vibration, 41 [65%]) and reduced or absent ankle reflexes in 42 patients (66%). Joint position was abnormal in only 12 subjects (19%).

All patients underwent NCSs of 1 or more nerves (sural, 148; tibial motor, F-waves, and H-reflex, 166; ulnar sensory, 153; and ulnar motor and F-waves, 158). Abnormalities in results of NCSs consistent with DSP (as defined above) were detected in 77 patients (46%). Abnormal results of NCSs were present in 51 (81%) of 63 patients with clinical DSP and in 26 (25%) of 103 patients without clinical DSP. Twelve patients (19%) with clinical DSP had normal results of NCSs.

We evaluated the association between NCS values and several variables possibly related to the pathogenesis of DSP in HIV disease. This analysis was performed independent of the clinical diagnosis of DSP and demonstrated the following findings.

1. There was a significant association between CD4 cohort and several NCS values (Table 3). Patients in the lowest CD4 count cohort (group 1) had a significantly lower mean sural nerve SNAP amplitude and CV, lower mean tibial nerve CV, and increased mean tibial F-wave and H-reflex latencies. Simple correlation analysis confirmed that low CD4 counts were substantially correlated with deterioration of several NCS values (Table 4).

2. Patients with abnormal serum albumin levels had significantly lower mean sural SNAP and tibial CMAP amplitudes, lower ulnar sensory CV, and prolonged mean tibial and ulnar F-wave latency (Table 3). Patients with abnormal hemoglobin levels had significantly lower mean sural SNAP amplitude, lower mean ulnar sensory CV, and prolonged mean H-reflex latency (Table 3). The descriptive statistics in Table 4show that abnormal albumin and hemoglobin levels, when correlated with impairment on various NCSs, resulted in correlation coefficients in excess of 20% for multiple studies. Other markers of impaired nutritional status, including weight loss and reduced BMI, yielded correlations in the range or greater than 20% (in absolute value). Vitamin B₁₂ levels showed an unexpected inverse correlation with sural nerve CV and positive correlation with tibial late responses (Table 4).

3. Most NCS values were associated with age (Table 4). Age was substantially correlated with decreased amplitude of sural and ulnar SNAP and tibial CMAP, decreased CV of all nerves (tibial and ulnar motor nerve, −0.29 m/s per year; sural nerve, −0.23 m/s per year; ulnar sensory nerve, −0.12 m/s per year), and increased latency of tibial and ulnar F-wave (+0.27 ms/y) and H-reflex (+0.10 ms/y).

Most of the variables studied, with the exception of age and vitamin B₁₂ levels, were correlated with each other. Forward stepwise multiple regression analysis indicated that informative variables might differ for distinct NCSs. For example, age, CD4 count, and albumin and hemoglobin levels accounted for 30% of the variation of sural nerve SNAP amplitude, whereas weight loss, BMI, and vitamin B₁₂ levels did not add further information. However, weight loss together with age, CD4 count, and albumin levels were the major predictors of tibial F-wave variability, while hemoglobin, BMI, and vitamin B₁₂ levels were redundant. Taken all together, age and immunological and nutritional factors substantially explained NCS variations in this cohort. No single factor other than age consistently maintained a significant association with outcome across all NCSs after adjustment for other variables.

We report a survey of variables related to peripheral nerve function in the largest group of HIV-infected individuals in whom NCSs and several potential pathogenetic factors have been systematically studied. These subjects represent a broad spectrum of sex, race, risk factors, and stage of immunodeficiency in HIV disease. Although this led to substantial heterogeneity among subjects, it allowed for the assessment of differences in type and course of neuromuscular disorders as a function of demographics and disease stage.

Distal symmetrical polyneuropathy was the most common neurologic diagnosis, even after exclusion of patients with confounding factors for distal peripheral neuropathy, such as diabetes mellitus, alcoholism, and neurotoxic drugs. Primary HIV-associated DSP was present in 38% of the study cohort and 48% of patients with AIDS. The frequency of DSP in our cohort is similar to that reported in other series,^1,2,13,14 although our figures probably overestimate the frequency of DSP in the general population of HIV-infected individuals, since patients were often symptomatic and at advanced stages of HIV disease when referred to our neuromuscular clinic.

Distal paresthesias in the lower extremities were the most common symptom of DSP, while pain was reported by only one third of patients. Muscle cramps, a nonspecific symptom in AIDS,¹⁵ were significantly more common in patients with DSP. The primary signs of DSP were sensory abnormalities of pain, temperature, and vibration, and reduced or absent ankle reflexes. Our findings are comparable with those reported in previous studies, in which subjective pain was uncommon and usually present in more advanced stages of DSP.^2,13,14 Pain is often the primary inclusion criterion in clinical trials of DSP in AIDS. The low frequency and late onset of pain in our DSP cohort suggest that experimental agents, such as nerve growth factor, should also be studied in patients with nonpainful sensory neuropathy.

Subjects with DSP frequently reported weakness and cognitive impairment. Although these symptoms were not significantly more common than in patients without DSP, they suggest the presence of concurrent brain, spinal cord, or muscle disease. Several authors have reported an association between DSP and central nervous system abnormalities in AIDS.^2,13,14 There is a high incidence of DSP and dementia in progressively immunocompromised HIV-infected patients.¹ These findings are notable, since investigators have proposed that DSP, myelopathy, and dementia in AIDS may have a common pathogenesis involving the action of cytokines.¹¹

Our electrophysiologic data indicate that AIDS is associated with sensory and motor peripheral nerve dysfunction, and they confirm previous pathological studies describing peripheral nerve axonal loss, demyelination, and muscle denervation in patients with AIDS.^16-18 We found electrophysiologic abnormalities indicating distal sensory and motor axonal neuropathy in 28% of subjects without clinical evidence of DSP.⁹ Conversely, 19% of our patients with clinical DSP had normal results of NCSs, likely resulting from predominant abnormality of small nerve fibers, which are not examined well by conventional NCSs. Other diagnostic modalities, such as quantitative sensory testing and punch skin biopsy, may be useful in the examination of such patients.¹⁹

Patients with DSP were significantly older, and NCS changes were strongly associated with increased age. Although the degree of slowing of nerve conduction velocities with advancing age in our cohort of patients with HIV is comparable with that observed in control populations,^20,21 it is not clear why patients with DSP were significantly older than those without DSP. Age did not correlate with indirect markers of disease progression, such as CD4 count and time from HIV diagnosis. Age may be a predisposing factor in the development of DSP in AIDS. The association of DSP with other demographic factors (male sex, white race, homosexual-bisexual behavior) may reflect a referral bias, as white homosexual men were more likely to be specifically referred to our care for neuromuscular symptoms.

Progressive immunodeficiency was associated with peripheral nerve dysfunction. More than two thirds of our patients with DSP had a CD4 count of less than 0.100 × 10⁹/L. Independent of the clinical diagnosis of DSP, patients in the lowest CD4 cohort had significantly worse sensory and motor NCS values than patients with higher CD4 counts. There was a significant correlation between low CD4 counts and reduced amplitude and CV of several sensory and motor nerves, as well as increased latencies of late responses. These data are concordant with results of 2 large population-based cohort studies of HIV-infected subjects that have demonstrated the predictive value of CD4 levels in peripheral nervous system dysfunction.^1,22

Clinical and electrophysiologic peripheral nerve function in our subjects correlated with several markers of nutritional deficiency and chronic disease, including serum albumin and hemoglobin levels and weight loss. Unexpectedly, vitamin B₁₂ levels inversely correlated with NCS values in our cohort. This may reflect the fact that many of our patients were receiving vitamin B₁₂ supplementation at the time of evaluation. Several investigators have described the influence of nutritional factors on DSP in AIDS, with conflicting results. While So et al² demonstrated an association of weight loss with DSP in AIDS, Fuller et al¹³ did not find significant correlation between electrophysiologic abnormalities and CD4 count, BMI, or vitamin B₁₂ or albumin levels. The larger size of our study cohort may partially account for the difference in these results.

Several of the variables examined in our study have been associated with distal peripheral neuropathy in other chronic diseases. Reduced serum albumin levels correlate with abnormal peripheral nerve function in patients with primary biliary cirrhosis.²³ Weight loss in diabetic patients may be associated with a painful distal neuropathy, a condition described as "diabetic neuropathic cachexia."^24,25 A distal sensorimotor polyneuropathy may occur in critically ill patients. In such cases, nutritional deficiency is considered as a possible cause, since serum albumin levels and lymphocyte counts are reduced.^26,27 Investigators have postulated the action of an "autotoxin," which may disturb enzymatic processes in the neuron.²⁵

In conclusion, we correlated several of the mechanisms proposed in the pathogenesis of neuropathic impairment in AIDS with NCSs and found that the combination of age, immunosuppression, markers of chronic disease, and nutritional deficiency effects provide a substantial contribution to the development of DSP and electrophysiologic abnormalities in patients with AIDS. These findings are consistent with the clinical evidence that DSP is significantly more common in late stages of HIV disease, when immunodeficiency is advanced and wasting and cachexia are also common. Further studies are needed to determine the pathogenesis of DSP in AIDS, including the role of age, nutritional status, and cytokines, and to investigate therapeutic strategies such as nutritional support, nerve growth factor, and cytokine antagonists in the treatment of DSP.

Accepted for publication May 4, 1998.

This study was supported in part by grants from the National Institute of Neurological Disorders and Stroke (RO1-NS28630), National Institute of Allergy and Infectious Disease (UO1-Al-27667), and National Center for Research Resources (5M01 RR00071), Bethesda, Md; and the Aaron Diamond Foundation, New York, NY. Dr Tagliati is an Aaron Diamond Foundation Fellow.

Presented in part at the 47th Annual Meeting of the American Academy of Neurology, Seattle, Wash, May 11, 1995.

We thank Emilie Godfrey, Jessica Moise, Sam D. Chin, and the Mount Sinai Medical Center Neuromuscular Fellows for their dedicated efforts.

Reprints: David M. Simpson, MD, Department of Clinical Neurophysiology, Box 1052, The Mount Sinai Medical Center, 1 Gustave L. Levy Pl, New York, NY 10029 (e-mail: DSimpson@smtplink.mssm.edu).