Cerebrospinal fluid and nerve conduction abnormalities in HIV positive individuals

JOURNAL

OF lHE

NEUROLOGICAL SCIENCES

ELSEVIER

Journal of the Neurological Sciences 136( 1996) 8 1-85

Cerebrospinal fluid and nerve conduction abnormalities in HIV positive individuals ’ Richard J. Barohn avbv*, Gary S. Gronseth b, Anthony A. Amato b, StephenA. McGuire b, April L. McVey b, Bruce R. LeForce b, Randall B. King b a Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-8897, USA b Department of Neurology, Wirford Hall US Air Force Medical Center, Lackland Air Force Base, San Antonio, TX. USA

Received 5 May 1995;revised 29 August 1995;accepted4 September 1995

Abstract We studied whether there was an association between nerve conduction studies (NCS), CSF, and CDCT lymphocyte parameters in a large cohort of HIV positive individuals. Two hundred and twenty-eight HIV positive individuals underwent motor and sensory nerve conduction studies, CSF evaluation, peripheral CDCT lymphocyte count, and neurologic evaluation to determine the presenceor absence of peripheral neuropathy. We compared NCS of HIV positive subjects with and without abnormal CSF parameters in the entire cohort. We also compared CSF parameters in a subset of CDCmatched patients with and without neuropathy. CSF abnormalities (in excessof laboratory norms) occured frequently in the entire study group. There was no statistically significant relationship between NCS and CSF parameters. In addition, there was no significiant difference in the CSF findings in the group of patients with clinical neuropathy compared to the group without neuropathy. However, there was an association (p < 0.05) between lower CD4 counts and NCS parameters. In general, abnormal CSF findings are not associated with deteriorating peripheral nerve function in HIV infected patients and are just as likely to be found in an HIV positive patient whether or not a peripheral neuropathy is present. Keywords: HIV; CDCT lymphocyte count; Cerebrospinal fluid; Nerve conduction studies; Peripheral neuropathy; AIDS

1. Introduction Neurologic complications of HIV infection are common (Levy et al., 1985; Snider et al., 1983). Most of these neurologic complications, both in the central and peripheral nervous system, occur late in the course of HIV infection, usually when the patient has AIDS. We have documented that lower CDCT lymphocyte count in HIV positive (HIV + ) individuals are associated with worsening nerve conduction study (NCS) parameters, even in asymptomatic patients, suggesting that immunologic compromise is a harbinger for AIDS related peripheral neuropathy (Barohn et al., 1993). It has previously been shown that cerebrospinal (CSF) abnormalities occur fre-

Corresponding author. At: Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 752358897, USA. Tel.: (214) 6486419; Fax: (214) 6489311. ’ The views expressed herein are those of the authors and do not necessarily reflect the views of the US Air Force or the Department of Defense. l

0022-510X/~/$15.00 8 1996 Elsevier Science B.V. All rights reserved SSDI 0022-5 10X(95)00294-4

quently in HIV infection, even in asymptomatic patients early in the course of infection (Marshall et al., 1988). In the present study we attempted to determine if there was a relationship between abnormal CSF findings and peripheral nerve function as measured by NCS in a large cohort of HIV + patients, In addition, we compared the CSF values in a HIV + patients with clinical evidence of peripheral neuropathy to an HIV + group without neuropathy. Our goal was two-fold. First, to ascertain if the CSF abnormalities which are commonly found in the course of HIV infection are associated with dysfunction of the peripheral nervous system. Secondly, to determine the usefulness of examining the CSF in HIV + patients with neuropathy.

2. Materials

and methods

All of the subjects in this study were U.S. Air Force active duty personnel who were found to have antibodies to the HIV virus and who underwent detailed evaluation at

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Wilford Hall Medical Center (WI-IMC). The presence of HIV antibodies was determined by ELISA and then confirmed by Western blot assay, as previously described (Marshall et al., 1988). All patients had peripheral CDCT cell lymphocyte count determinations by methods previously reported (Marshall et al., 1988). The subjectsin this study also consentedto undergo lumbar puncture for cerebrospinal fluid (CSF) analysis and nerve conduction studies (NCS). We included data from these patients in this study when the CSF analysis and NCS were performed within 30 days of one another. Patients were also examined by a board-certified neurologist for clinical evidence of nervous system involvement (RB, GG, AM, AA, BL, SM, RK) and diagnosed with a clinically apparent peripheral neuropathy if their evaluation revealed distal numbness, paresthesias,weakness,or hyporeflexia and was confirmed by abnormal nerve conduction studies. The battery of NCS consisted of median and peroneal motor, median and sural sensory, and H-reflex measurements using methods previously outlined (Barohn et al., 1993). The individual NCS parametersthat were measured consisted of the following: median and peroneal motor amplitude, distal latency, and conduction velocity; median and sural sensory amplitude and distal latency; and H-reflex latency. The following CSF parameterswere analyzed: protein level, nucleated cell count, glucose level, oligoclonal bands by agarosegel electrophoresis, IgG level, IgG index (Link and Tribbling, 1977), and IgG synthesis rate (Tourtellotte et al., 1980). Oligoclonal bands were measuredsimultaneously in CSF and serum (Paragon electrophoresis system, Beckman Inst., Bera, CA). Abnormal CSF values were based on the normative values for the laboratory at WHMC. We considered CSF parametersto be abnormal if they exceededthe following levels: nucleated cell count > 5 cells/mm3, glucose level < 40 mg%, protein level > 45 mg%, IgG level > 6 mg%, IgG index > 0.66 and IgG synthesis > 3.3 mg/day. Oligoclonal bands were considered to be present if there were 3 or more bands present in the CSF that were not present in serum. Because we previously demonstrated that lower NCS values are associated with low CD4 counts in HIV + individuals (Barohn et al., 1993), we looked for potentially confounding interactions between CD4 count and CSF parameters.We divided patients into groups basedon their peripheral CD4 count (cells/mm3: < 200, 200-399, 4OO599; 600-799, > 799) and compared the proportion of patients with abnormal CSF parametersacrossCD4 count groups using x2 contingency tables. We compared mean age and NCS index across CD4 count groups with one way ANOVA. Post-hoc analyses were performed using Tulcey’s HSD method. We considered a P value of < 0.05 significant. In order to avoid a large number of comparisons, for each patient we calculated a composite NCS value by

adding the relative distances (in standarddeviations) from the group means of each NCS parameter.This composite z-score was referred to as the NCS index. The mean NCS index and age were compared across CD4 groups by analysis of variance. We compared the NCS index of HIV + patients with normal and abnormal CSF parameters using the student’s f-test. We also carried out a secondary analysis comparing individual NCS parametersof HIV + patients with normal and abnormal CSF values using the student’s r-test. For this analysis, a Bonferroni correction was applied because of the large number of comparisons. Additionally, we compared the proportion of subjects that had abnormal CSF values in the CD4 matchedpatients with and without neuropathy using x2 contingency tables. Fisher’s exact test was used where appropriate. 3. Results

Two hundred and twenty-eight HIV + individuals had lumbar puncture for CSF evaluation and NCS within 30 days of one another. The characteristicsof this population, grouped by CD4 count are listed in Table 1. Subjectswith CSF abnormalities were common: nucleated cells 37%, protein 23%, glucose l%, IgG 29%, IgG Index 38%, IgG synthesis rate 34%, oligoclonal bands 16%. In addition, CSF abnormalities were common in all CD4 count groups. The IgG synthesis rate was the only CSF abnormality that was more common in lower CD4 count groups (see P in Table 1). While the mean CSF nucleated cell count appears to be markedly abnormal in patients with CD4 counts less than 200, this mean is skewed by a single patient with CMV polyradiculopathy (see below). The mean CSF nucleated cell count in the < 200 CD4 count group with this patient removed was 7.8 cells/mm3 (*21.0X The mean NCS index and age showed statistically significant differences across CD4 groups (see Table 1). NCS indexes were lower for patients with CD4 counts < 400, consistent with our previous results for individual NCS parameters(Barohn et al., 1993). The relationship between the NCS index and each of the CSF parameters is shown in Table 2. ‘Abnormal’ values for each CSF parameter are described in the Methods. There were no significant differences in mean NCS index in patients with or without abnormal CSF parameters. Additionally, comparison of the means of individual NCS parameters in patients with normal and abnormal CSF parametersrevealed no significant differences, after applying a Bonferroni correction. Twenty patients were identified with peripheral neuropathy in the study population. The neuropathy was a distal symmetrical polyneuropathy in 18 patients (Comblath and McArthur, 1988), chronic inflammatory demyelinating polyneuropathy in 1 patient (Barohn et al., 1989;

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Comblath et al., 19871, and 1 patient had a lumbosacral syndrome in which cypolyradiculoneuropathy tomegalovirus was cultured from the CSF (Bazan et al., 1991; Miller et al., 1990). The mean CD4 count for the patients with clinical evidence for peripheral neuropathy was 125 cells/mm3.

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There was no significant difference in the proportion of subjects with abnormal parameters( x2) when 19 patients with neuropathy were compared to 20 CD4 matched patients without peripheral neuropathy (Table 3). In Table 3, the patient with lumbosacral polyradiculoneuropathy due to CMV was excluded from the analysis because of

Table 1 Age, NCS Index and CSF parameters of study population grouped by CD4 count Parameter

CD4 count cells /mm’ >799 (N = 69) Mean

Age years NCS index Protein mg% Nucleated cells/mm3 Glucose mg% Oligoclonal bands IgG mg% IgG synthesis mg/day IgG index

600-799 (N= 52)

SD

28.5 0.9 35.3 7.2 63.3

5.3 3.7 13.5 10.5 5.2 4.3 3.0 - 0.2 7.62 0.62 0.23

400-599 (N=51)

200-399 (N=24)

<2cO (N= 32)

P

%Ab

Mean

SD

%Ab

Mean

SD

%Ab

Mean

SD

%Ab

Mean

SD%

Ab

14.5 38.2 0 7.6 18.8 19.4 27.5

28.7 0.1 39.8 6.0 63.0 5.7 4.7 0.72

5.6 3.8 14.5 7.0 8.4 4.3 14.8 0.31

25.0 41.2 1.9 17.6 32.7 38.5 42.3

31.2 0.1 38.4 6.8 63.3 5.1 2.7 0.69

6.4 3.9 14.9 9.8 6.0 3.1 9.3 0.24

24.0 41.2 0 21.6 29.4 38.0 41.2

34.5 a -0.1 40.1 6.2 61.5 7.0 6.8 0.76

9.1 3.5 15.8 7.0 6.3 5.5 14.3 0.24

33.3 37.5 0 13.0 37.5 50.0 50.0

33.7 a -3.2 a 56.9 62.3 56.4 6.2 3.8 0.69

7.7 3.4 104 318 8.9 4.1 12.5 0.22

28.1 21.9 6.3 24.0 40.7 37.0 40.7

0.30 0.41 0.09 0.19 0.17 0.04 0.25

SD = Standard deviation; %Ab = Percentage of subjects with abnormal values (see text for definition for each parameter); P = P value comparing the proportion of subjects with abnormal values across CD4 groups using x2 contigency tables. a Different from higher CD4 count groups at the < 0.05 level using ANOVA with multiple comparisons of means.

Table 2 Mean NCS Index in HIV positive patients with and without abnormal CSF parameters and CD4 counts Parameter

CD4 count Protein Nucleated cells Glucose Oligloclonal bands IiS IgG synthesis IgG index

Abnormal

Normal N

NCS Index

1% 175 142 224 182 158 146 138

0.4 0 0.3 0 0 0 0 0

P

SD

N

NCS Index

SD

3.7 3.9 3.7 3.7 3.7 3.6 3.6 3.5

32 52 84 3 34 65 74 85

-3.2 0 -0.5 -0.9 0.2 -0.1 0 0.1

3.4 3.7 4.1 3.2 4.6 4.4 4.4 4.4

0.001 0.99 0.11 0.35 0.88 0.61 0.60 0.82

N = number of subjects; SD = Standard deviation; P = P value for comparison of mean NCS index using Student’s t-test. See text for definitions of abnormal for each Parameter. For this table a CD4 count of < 200 cells/mm3 is categorized abnormal.

Table 3 Mean CD4 count, CSF parameters and NCS Index in CD4-matched HIV positive patients with and without neuropathy Parameter CD4 count cells/mm3 NCS index Protein mg% Nucleated cells/mm’ Glucose mg% Oligoclonal bands IgG mg% IgG synthesis mg/day IgG index

No neuropathy (20)

Neuropathy ( 19) Mean

SD

125 -5.3 38.7 5.8 55.2

130 4.8 19.1 8.5 7.0

6.5 4.9 0.66

4.9 14.4 0.16

%Ab

26.3 26.3 0 37.5 35.3 35.3 29.4

P

Mean

SD

%Ab

105 - 1.8 39.1 7.6 59.6

67 3.1 16.5 22 8.0

-

6.2 2.0 0.69

4.1 7.9 0.24

25 20 5.3 17.6 38.9 38.9 44.4

0.99 0.72 0.49 0.26 0.83 0.83 0.36

SD = Standard deviation; WAb = Percentage of subjects with abnormal parameters (see text for definition of abnormal for each CSF parameter). P = P value comparing the proportion of subjects with abnormal CSF parameters between the neuropathy and no-neuropathy groups using x2 contigency tables.

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markedly abnormal CSF (see below). However, these negative results persisted even when the CMV patient was included in the analysis (data not shown). This patient had a strikingly abnormal CSF: nucleated cell count 1,800 cells/mm3; protein 62 mg%; glucose 37 mg%. Of note, the patient with clinical and electrophysiologic evidence for chronic inflammatory demyelinating polyneuropathy had the following CSF values: nucleated cell count 2 cells/mm3, protein 53 mg%, glucose 54 mg%, IgG 12.9 mg%, IgG index 0.63, IgG synthesis rate 6.5 mg/day and oligoclonal bands absent. 4. Discussion

Both CSF abnormalities (Marshall et al., 1988) and peripheral neuropathy (Barohn et al., 1993; Comblath and McArthur, 1988; Miller et al., 1988; So et al., 1988) are common in HIV + patients. Several of the neuropathies involve proximal nerve and root segments,such as acute and chronic inflammatory demyelinating polyneuropathy (Barohn et al., 1989; Comblath et al., 19871, and lumbosacral polyradiculoneuropathy (Bazan et al., 1991; Miller et al., 1990; So and Olney, 1994). Even in distal symmetrical polyneuropathy (DSPN), the most common neuropathy associatedwith HIV infection (Comblath and McArthur, 1988), the pathologic processmay be due to a dorsal root ganglionitis with a subsequentretrograde degeneration of the central process and distal degeneration of the peripheral axon (Rance et al., 1988). Because of the suspected proximal nerve involvement in several of the neuropathies seen in HIV infected individuals, and becausethe CSF is frequently abnormal in diseaseprocessesthat affect proximal nerve and root segments(Asbury and Comblath, 1990; Barohn et al., 1989, 1991), we wanted to determine if there was an association between the CSF changes that are frequently seen in HIV infection (Marshall et al., 1988) and peripheral nerve status. However, in this study we found no association between the CSF parameter and the NCS index in a large cohort of HIV + patients in whom CSF abnormalities were common (Tables 1 and 2). In addition, in our 20 patients with peripheral neuropathy, predominantly DSPN, we could not detect any difference in their CSF parameterscomparedto a CD4 matched HIV infected group (Table 3). We conclude that in an HIV + patient with DSPN, CSF abnormalities are not due to the peripheral neuropathy. Even in HIV + patients who clinically are felt to have an inflammatory demyelinating polyneuropathy, especially the chronic form, we would interpret abnormal CSF values with caution, as they may not be related to the peripheral neuropathy. There are probably two exceptions concerning our caution about attributing CSF changes in an HIV + patient to a concurrent peripheral neuropathy. HIV + patients who develop acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome) may have a

Sciences 136 (1996) 81-85

significant pleocytosis rather than the typical albumin-cytologic dissociation seen in non-HIV + patients (Asbury and Comblath, 1990, Comblath et al., 1987). Another exception is patients with lumbosacral polyradiculoneuropathy due to cytomegalovirus infection, in whom CSF values are usually strikingly abnormal with high nucleated cell count and protein, and low glucose (Bazan et al., 1991; Miller et al., 1990; So and Olney, 1994). On the other hand, this study re-enforced the finding that abnormalities of CSF parametersare common in all stages of HIV infection. Abnormalities of nucleated cell count, protein, and immunoglobulins occurred in 23-38% of our population. While there was an association between CSF IgG synthesis rate and the peripheral CD4 count, no other CSF parameterwas similarly associated. We were able to demonstratea statistically significant association between lower peripheral CD4 counts and worsening nerve conduction studies by using a composite NCS index. We utilized the NCS index rather than individual NCS parametersin order to reduce the probability of finding spurious, statistically significant relationships which can result from performing a large number of comparisons. Combining individual NCS parameters in this way had the added effect of emphasizing differences between patient groups when individual NCS parameters changed in the same direction. While we previously have shown that individual worsening NCS parameters were associatedwith lower CD4 counts (Barohn et al., 1993). this study illustrates how a simple composite index of multiple NCS studies can show a similar finding. Thus, the NCS index is a useful single value that reflects the electrophysiologic results of multiple peripheral nerve measurements. In conclusion, worsening peripheral nerve function is strongly associatedwith lower CDCT lymphocyte counts, but not with abnormal CSF parameters,even though both peripheral neuropathy and CSF abnormalities are common in HIV infected individuals. In an HIV infected patient with a distal symmetrical polyneuropathy, examination of the CSF is probably not indicated on the basis of neuropathy alone as abnormalities are expected to occur just as often in the absenceof neuropathy. References Asbury, A.K., Comblath, D.R. (1990) Assessment of current diagnostic criteria for Guillain-Barn5 syndrome (supplement). Ann. Neurol., 27: S21-24. Barohn, R.J., Gronseth, G., LeForce, B.R., McVey, A., McGuire, .%A., Butzin, C.A., King, R.B. (1993) Peripheral nervous system involvement in a huge cohort of human immunodeticiency virus-infected individuals. Arch. Neural., 50: 167- 171. Barohn, R.J., Kisse.1, J.T., Warmolts, J.R., Mendell, J.R. (1989) Chronic inflammatory demyelinating polyradiculoneuropathy: clinical chamcteristics, course, and recommendations for diagnostic criteria. Arch. Neurol., 46: 878-884. Barohn, R.J., Sahenk, Z., Warmolts, J.R., Mendell, J.R. (1991) The

R J. Barohn et al./ Journal of the Neurological Bruns-Garland syndrome (diabetic amyotrophy): revisited 100 years later. Arch. Neurol., 48: 1130-l 135. Bazan, C., Jackson, C., Jinkins, J.R.. Barohn, R.J. (1991) Gadolinium-enhanced MRI in a case of cytomegalovirus polyradiculopathy. Neurology, 41: 1522-1523. Comblath, D.R., McArthur, J.C. (1988) Predominantly sensory neuropathy in patients with AIDS and AIDS-related complex. Neurology, 38: 794-7%. Comblath, D.R.. McArthur, J.C., Kennedy, P.G.E., Witte, AS., Griffin, J.W. (1987) Inflammatory demyelinating peripheral neuropathies associated with human T-cell lymphotropic virus type III infection. Ann. Neurol., 21: 32-40. Levy, R.M., Bredesen, D.E., Rosenblum, M.L. (1985) Neurological manifestations of the acquired immunodeticiency syndrome (AIDS): experience at UCSF and Review of the literature. J. Neurosurg., 62: 475-495. Link, H., Tribbling, G. (1977) Principles of albumin and IgG analyses in neurological disorders: II. Relationship of the concentration of the proteins in serum and cerebrospinal fluid. Scan. J. Clin. Lab. Invest., 37: 39l-3%. Marshall, D.W., Brcy, R.L., Cahill, W.T., Houk, R.W., Zajac, R.A.. Boswell, R.N. (1988) Spectrum of cerebrospinal fluid findings in various stages of human immunodeflciency virus infection. Arch. Neurol., 45: 954-958.

Sciences 136 (1996) 81-85

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Miller, R.G.. Parry, G.J., Pfaefel, W., Lane. W.. Liooert. R.. Kiorov, D. (1988) The spectrum of peripheral neu;bpathy associated with ARC and AIDS. Muscle Nerve, 11: 857-863 ---. Miller, R.J., Storey, J.R., Greco, C.M. (1990) Ganciclovir in the treatment of progressive AIDS-related polyradiculopathy. Neurology, 40: 569-574. Rance, N.E., McArthur, J.C., Comblath, D.R., Landstrom, D.L. Griffin, J.W., Price, D.L. (1988) Gracile tract degeneration in patients with sensory neuropathy and AIDS. Neurology, 38: 265-27 I. Snider, W.D., Simpson, D.M., Nielson, S., Gold, J.W.N., Metroka, C.E., Posner, J.B. ( 1983) Neurological complication of acquired immunodeticiency syndrome. Ann. Neurol., 14: 403-418. So, Y.T., Holtzman, D.M., Abrams, D.I., Ohtey, R.K. (1988) Peripheral neuropathy associated with acquired immunodeficiency syndrome: prevalence and clinical features from a population-based survey. Arch. Neurol., 45: 945-948. So, Y.T., Ohrey, R.K. (1994) Acute lumbosacral polyradiculopathy in acquired immunodeticiency syndrome: experience in 23 patients. Ann. Neurol., 35: 53-58. Tourtellotte, W.W., Potvin, A.R., Fleming, J.O., Murthy, K.N., Levy, J., Syndulko, K., Potvin, J.H. (1980) Multiple sclerosis: Measurement and validation of central nervous system IgG synthesis rate. Neurology, 30: 240-244.