Anita B. Venkataramana, MBBS

Neuropathy associated with NRTI use is difficult to distinguish clinically from DSP, and the conditions can coexist.

 DSP affects approximately 35% of patients with AIDS.

 However, in a recent study, 55% of patients had DSP: 20% were asymptomatic and had signs of neuropathy, and the remaining 35% had signs and symptoms of neuropathy.

Symptoms are typically limited to the feet but often extend to the lower extremities. Affected persons can present with a myriad of symptoms, which include burning dysesthesias and debilitating paresthesias. HIV-associated sensory neuropathies are distinct from other neuropathies in the prominence of spontaneous and evoked pain. Often, patients do not have any symptoms and signs can be elicited only on examination.

Other types of neuropathies that occur in HIV infection include chronic inflammatory demyelinating polyneuropathy and acute inflammatory demyelinating polyneuropathy. Both are relatively uncommon; the latter is typically experienced at the time of seroconversion. A variety of infectious polyradiculopathies, such as those associated with Cytomegalovirus infection and syphilis, are also uncommonly encountered.

Sensory neuropathies develop in up to 35% of persons with HIV/AIDS.

 Affected patients should be identified, and treatment strategies for alleviating painful symptoms should be implemented. Screening tests are used routinely in the HIV clinic. 

Ideally, screening tools should be quick and easy to administer at the bedside, simple to interpret, and inexpensive. One such tool, developed by the AIDS Clinical Trials Group, is the Subjective Peripheral Neuropathy Screen (SPNS). It has been used widely to screen for neuropathies in persons with HIV/AIDS.

The advantage of the SPNS is that it can be used by both neurologists and nonspecialists. Despite its simplicity, pertinent information can be obtained. The SPNS is a 3-item questionnaire that identifies HIV-related sensory neuropathy (HIV-SN). It covers symptoms of pain, aching or burning, numbness, and paresthesias in the legs. It focuses on symptoms that patients may not report freely but will usually describe when asked directly by an examiner. 

The criteria for defining HIV-SN are the presence of any one of the symptoms cited on the questionnaire (Figure 1), along with physical examination findings that reveal loss of or decreased ankle reflexes, diminished vibration threshold in the great toes of less than 10 seconds, and a stocking pattern of sensory disturbance.

An expanded version of the same scale was used in a study

 authored by Julie H. McArthur, MS, CRNP, currently a research associate at Johns Hopkins. The goal of the study was to determine the reliability, validity, and diagnostic efficiency of the SPNS. In evaluating data on 39 HIV-positive patients with painful sensory neuropathy and 44 HIV-positive controls, McArthur found that numbness had the greatest diagnostic utility for identifying peripheral neuropathy. She also found that upper extremity symptoms were not important determinants for evaluating symptoms of DSP. Therefore, the scale was modified to assess lower extremity symptoms only.

We report on a study that assessed the sensitivity and specificity of the SPNS in HIV-associated neuropathy. Findings were drawn from analysis of a database of patients with HIV/AIDS. 

This study was a retrospective analysis of data collected from the Johns Hopkins University HIV neurology database. Patients who were seen for any neurologic complaint were eligible for inclusion in the study. The modified SPNS was administered to 75 patients from the HIV neurology outpatient clinic. Because direct questioning by the examiner or assistant appears to be important for patient understanding, the questions were not self-administered.

Patients were asked to grade the severity of each symptom on a scale of 1 (mild) to 10 (severe). They also had to say whether they had experienced symptoms in the past. A score of 00 was given if the patient did not currently have symptoms. A separate coding was recorded if the patient had never experienced symptoms.

Relevant information gathered from the patient history included CD4

 T-cell count, plasma HIV RNA viral load, Memorial Sloan-Kettering (MSK) score for dementia,

 HIV risk factors, neuropathy details, CNS opportunistic infections, and education level.

Patients were divided into 2 groups: those with HIV-associated sensory neuropathies and HIV-positive patients without evidence of neuropathy, according to findings of a detailed neurologic examination. A positive SPNS, along with any clinical sign of neuropathy, suggested the presence of a peripheral neuropathic process. The neurologic examination was performed in a standard manner by a neurologist.

To determine the optimal threshold for detecting sensory neuropathy in this population, a receiver operating characteristic (ROC) curve was used to examine the relationship between the sensitivity and the specificity of the SPNS at various total scores.

 An ROC curve plots the sensitivity of a test versus its false-positive rate for various points (ie, definitely present and probably present to definitely absent) and is especially applicable when test results are interpreted subjectively. 

The curve is a graphic representation of the trade-off between the false-negative and false-positive rates for every possible cutoff. The position of the cutoff determines the number of true positives, true negatives, false positives, and false negatives. Although an increase in sensitivity (true positives) allows more cases of a certain condition to be identified, the clinician sacrifices accuracy in distinguishing those without the condition (ie, specificity). By convention, these plots show the false-positive rate (1 minus specificity) on the x-axis and the true-positive rate (sensitivity, or 1 minus the false-negative rate) on the y-axis.

Based on the ROC curve, an optimal threshold score was determined and the sensitivity, specificity, and diagnostic efficiency of the SPNS were calculated. In addition, the area under the curve (AUC) provided a measure of how well this test discriminates between those with and those without neuropathy, with an AUC of 1.00 indicating perfect discrimination.

Of the 75 persons who participated in this questionnaire-based review, 32 had symptoms (pain, paresthesias, and numbness) consistent with HIV-associated neuropathy.

 The remaining 43 persons were symptom-free and were designated as controls. Demographic and clinical characteristics were similar in the HIV-neuropathy group and the HIV-seropositive control group of non-neuropathic patients (Table). Patients with neuropathy were more likely to be older (difference in median age at presentation: 6.5 years; Wilcoxon rank-sum test score = 1404; 

Patients were divided into 3 subgroups according to diagnosis. The most common category was HIV-related DSP, which was diagnosed in 59% of participants, followed by ATN, which was diagnosed in 38%. The cause of neuropathy was not determined in the remaining participants.

Glucose intolerance testing was not routinely performed. If there had been any evidence of a myelopathy, such as brisk reflexes that were associated with spasticity or weakness of the lower extremities, the patient's vitamin B

 level would have been assessed. Routine testing for vitamin B

 was not conducted because it has not proved helpful.

The extent of overlap between the 2 groups was not determined in this retrospective review; the ATN group had toxic antiretroviral exposure, and those without a history of antiretroviral use were deemed to have DSP.

 cell count was higher in the neuropathic group (281/µL; interquartile range [IQR], 97 to 387) than in the non-neuropathic group (239/µL; IQR, 101 to 410), but the latter group had a higher median HIV RNA level than did the neuropathic group. None of the differences were significant.

Only 15% of patients in the neuropathic group and 11% of the HIV-seropositive controls had undetectable HIV RNA levels (not significantly different).

 The risk factor for infection in the study population was injection drug use.

An MSK score was available for all patients. An MSK score of 0 was considered normal. Fifty percent of the neuropathic patients and 77% of the controls had MSK scores ranging from 0 to 0.5. Twenty-five percent of patients in the HIV-SN group and 19% of HIV-seropositive controls had scores of 2 or 3 (indicating moderate to severe dementia) (chi-square = 8.06; 

Five patients in the neuropathic group had CNS opportunistic infections: 4 patients had toxoplasmosis, and 1 patient had an unspecified intracranial mass lesion. None of the controls had CNS infections.

Hepatitis C virus (HCV) is associated with various peripheral neuropathies independent of HIV infection. The degree to which HCV contributes to the development of HIV-associated DSP is unclear. We found that 10 of 33 (almost 30%) neuropathic patients had HCV coinfection. Only 1 patient in the neuropathic group was infected with hepatitis B virus. We also found that 20% of patients who did not experience neuropathy had HIV-HCV coinfection.

To determine the psychometric properties of the SPNS in identifying persons known to have HIV-associated neuropathy, an ROC curve was fit to the observed total-score data (Figure 2). The SPNS had a sensitivity of 47% and a specificity of 83%. The positive predictive value was 70%, with a negative predictive value of 67%.

A subanalysis was conducted to determine whether any one of the 3 individual subtests of the SPNS (pain, paresthesia, or numbness) was better than the total SPNS in discriminating between patients with and without HIV-SN.

On the paresthesia and numbness subscales, the distribution of scores for those without HIV-SN, in all but one case, was zero. This lack of dispersion made the use of the ROC curve analysis problematic in these subscales. With respect to the pain subscale, however, the majority of non-neuropathic patients reported no pain, and there appeared to be a suitable distribution of scores in both the HIV-SN and non-neuropathic HIV-seropositive groups (Figure 3). The optimal threshold score was 10 or more points (sensitivity 96%, specificity 57%).

This study describes the performance characteristics of the modified SPNS. Overall, the modified SPNS has a sensitivity of 47% and a specificity of 83%, which makes it relatively insensitive as a screening measure. (Most "good" screening tests have sensitivities of more than 90%.) On the other hand, the scale is easy to administer and interpret, which makes it favorable for rapid screening. Because of these characteristics, the SPNS may be particularly useful to nonspecialists in efficiently identifying sensory neuropathies in HIV-positive patients. The SPNS can be performed routinely during regular health maintenance visits as a means to identify neuropathic symptoms early.

Specificity tests for the number of patients who do not have disease and is reflective of the positive predictive value: if the specificity is high, the positive predictive value will also be high. Thus, this scale can accurately identify patients with neuropathy because of its high specificity. Moreover, the sensitivity and specificity of each subscale was determined; the sensitivity for pain and numbness was 96% and 100%, respectively.

In contrast, the specificity for pain was 57% and for numbness, 58%; the overall specificity was only 47%. Surprisingly, paresthesia did not appear to be a useful symptom for determining the presence of neuropathy because there was insufficient variability in the scores. The most common cause of neuropathy in the patients in this study was related to HIV infection (59%).

The non-neuropathic group had a slightly lower CD4

 T-cell count and a higher HIV RNA viral load than did the neuropathic group. Undetectable HIV RNA levels were found in 19% of patients with neuropathy, compared with 11% in the seropositive controls. The reason for this difference may be related to NRTI use in the neuropathic group.

Injection drug use was significantly higher in the neuropathic group than were other risk factors, such as blood transfusion and sexual contact. No CNS opportunistic infections were found in the non-neuropathic group. None of the risk factors typically associated with HIV-SN (eg, CD4

 cell count, viral load) differed significantly between patients with neuropathy and those without neuropathy.

Peripheral neuropathy is prevalent in both HIV-seronegative and HIV-seropositive injection drug users (IDUs).

 Seronegative IDUs had 3 or 4 times the reported prevalence as non-IDUs. Neuropathic symptoms were absent in 81% of these patients. Toxic neuropathies from NRTI use may develop in those with preexisting peripheral neuropathies.

HIV-HCV coinfection was observed in 30% of the neuropathic patients and 20% of the seropositive controls. Neuropathies have been associated with HCV infection. The pathology of HCV-related neuropathy comprises a mild distal neuropathy with relatively minor neurologic deficits, probably attributed to occlusion of the vasa nervorum caused by intravascular deposits of cryoglobulins; a severe distal symmetric sensorimotor neuropathy; or an overlapping mononeuritis multiplex associated with necrotizing vasculitis.

 A combination of nutritional impairment, older age, and immunosuppression contributes to the development of DSP in persons with AIDS.

Sensory neuropathies have been well studied with various testing modalities in HIV-infected patients. Thermosensory evaluation is a sensitive tool that can detect early, small-diameter nerve fiber disease before the onset of clinically evident peripheral neuropathy.

Quantitative sensory testing (QST) techniques have been developed to quantify sensory function in patients with neurologic diseases. QST devices are useful for testing vibratory, thermal, or electric impulses and for measuring sensory impairment in both clinical and research studies.

 QST is not included in routine initial investigations in clinical practice because the tests are cumbersome, require special testing equipment, and are time-consuming.

Skin biopsy, which can determine intraepidermal nerve fiber (IENF) density in small-fiber neuropathies, is another tool for evaluating neuropathic symptoms. Lower IENF densities are commonly found at the distal leg rather than at the proximal leg. This indicates a length-dependent neuropathy,

 such as that typically seen with HIV infection. An inverse relationship exists between IENF density and neuropathic symptoms,

 measured by both patients' and physicians' global pain assessments. A valid objective measure of peripheral nerve function used in diabetic neuropathy--the total neuropathy score--is a composite of both nerve conduction testing and QST

 and is used in the clinical research setting.

A limitation of our study is the small number of patients included; a larger population should be tested to validate the findings. Another limitation is that nutritional status, which can be a contributing factor in nerve dysfunction among HIV-infected patients,

 had not been determined for the study population.

Although the modified SPNS used in this study can determine the presence or absence of neuropathic symptoms, it is by no means a substitute for a thorough clinical history and physical examination. Overall, the modified SPNS has a high specificity, but it has a relatively low sensitivity, with a good positive predictive value when used as a screening test for HIV-associated sensory neuropathies.	*

This work was supported by an R01 grant to Justin McArthur, HIV-sensory neuropathies: risk factors, immunopathology NS44807, and the General Clinical Research Center (Michael Klag PI, RR00522).

The article is reprinted with permission from the July 2005 issue of 

1. Bacellar H, Munoz A, Miller EN, et al. Temporal trends in the incidence of HIV-1-related neurologic diseases: Multicenter AIDS Cohort Study, 1985-1992. 

2. So YT, Holtzman DM, Abrams DI, Olney RK. Peripheral neuropathy associated with acquired immunodeficiency syndrome. Prevalence and clinical features from a population-based survey. 

3. Schifitto G, McDermott MP, McArthur JC, et al. Incidence of and risk factors for HIV-associated distal sensory polyneuropathy. 

4. McArthur JH. The reliability and validity of the subjective peripheral neuropathy screen. 

5. Brew BJ, Rosenblum M, Price RW. AIDS dementia complex and primary HIV brain infection. 

6. Metz CE. Basic principles of ROC analysis. 

7. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. 

8. Janssen RS, Cornblath DR, Epstein LG, et al. Nomenclature and research case definitions for neurological manifestations of human immunodeficiency virus type-1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force

9. Royal W 3rd, Updike M, Selnes OA, et al. HIV-1 infection and nervous system abnormalities among a cohort of intravenous drug users. 

10. Berger AR, Schaumburg HH, Gourevitch MN, et al. Prevalence of peripheral neuropathy in injection drug users. 

11. Garcia-Bragado F, Fernandez JM, Navarro C, et al. Peripheral neuropathy in essential mixed cryoglobulinemia. 

12. Tagliati M, Grinnell J, Godbold J, Simpson DM. Peripheral nerve function in HIV infection: clinical, electrophysiologic, and laboratory findings. 

13. Huengsberg M, Winer JB, Ross JD, Shahmanesh M. Thermosensory threshold: a sensitive test of HIV associated peripheral neuropathy? 

14. Shy ME, Frohman EM, So YT, et al. Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. 

15. Holland NR, Stocks A, Hauer P, et al. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. 

16. Polydefkis M, Yiannoutsos CT, Cohen BA, et al. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. 

17. Cornblath DR, Chaudhry V, Carter K, et al. Total neuropathy score: validation and reliability study. 

Articles

HIV/AIDS, peripheral neuropathy, sensory neuropathies, subjective peripheral neuropathy screen

Author | Anita B. Venkataramana, MBBS

Articles

Diagnostic Utility of the Subjective Peripheral Neuropathy Screen in HIV-Infected Patients