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Neurophysiol Clin (1992) 22, 393-401 © Elsevier, Paris

Memoir

Peripheral and central n e r v o u s system a n o m a l i e s in H I V - 1 infection: an e l e c t r o p h y s i o l o g i c a l study F Pinto 1, A Grippo

1,

p Ghidini 1, F Mazzotta 2, M Di Pietro 2

Department o f Neurological and Psychiatric Sciences, Viale Morgagni 85 University o f Florence, Italy; 1Unit for Infectious Diseases, USL IOD, Florence, Italy (Received 13 January 1992; accepted 13 July 1992)

Summary - This study explored the neurophysiological changes in 87 HIV1 + (20 AIDS, 24 ARC, 24 LAS and 19 AC) patients showing no clinical evidence of neurological impairment. Tracing somatosensory responses by recording SEPs from upper and lower limbs, we found a slowing of both peripheral and central nerve conduction. Peripheral alterations occurred in virtually all patients of the AIDS group. Central anomalies, confined largely to the lower spinal cord, manifested themselves only during the later stages of the disease (ARC and AIDS) and then only in about half of our sample. More marked neurotropic varieties of HIV1 may account for these differences. We feel that SEP studies can serve to reveal pre-clinical NS involvement in HIV1 + subjects and should be included among research strategies aimed at tracing the evolution of AIDS. A I D S / myelopathy / neuropathy / somatosensory evoked potentials

R~sum~ - Anomalies du systi~me nerveux central et p~riph~rique dans I'infection ~ V I H : donn~es neurophysiologiques. Les auteurs prdsentent les donndes d'une dtude neurophysiologique ayant port~ sur 87 sujets infect~s par le VIII 1 (19 porteurs asymptomatiques, 24 lymphad~nopathies gdn~ralis~es persistantes ou LGP, 24 syndromes apparentds au sida ou A R C et 20 sida indemnes de tout symptOme pouvant ~voquer une altdration du systbme nerveux central (SNC) et/ou pdriphdrique (SNP). IIs ont ~tudid les vitesses de conduction nerveuse motriees et sensitives des nerfs p~riphOriques et les potentiels ~voqu~s somesthdsiques (PES) aprbs stimulation des membres supdrieurs et infdrieurs. Leurs r~sultats montrent l'existence d'alt~rations significatives du SNP chez tousles malades du groupe sida. Les anomalies des PES t~moignent d'altdrations de la conduction centrale concernant essentiellement la moelle dorso-lombaire et n'int~ressant que la moiti~ environ des sujets des groupes A R C et sida. L "existence de diverses souches de VIII 1, dont certaines ont un neurotropisme plus marque, pourrait expliquer que parmi des sujets appartenant ~ un m~me groupe de la classification des CDC une partie seulement d'entre eux peuvent presenter des alterations infracliniques du syst~me nerveux. Par ailleurs, l'dtude des PES, en r~v~lant des sous-groupes de sujets ayant une altdration neurologique infraclinique, pourrait constituer un des ~l~ments prddietifs de l'~volution du sida. infection/t VIH / syst~me nerveux p~riph~rique / syst~me nerveux central

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F Pinto et al

Introduction The involvement of the Nervous System (NS) during HIV-1 infection and neurological deficits is a common occurrence which has been described in HIV-1 seropositive patients without other clinical manifestations of immunodeficiency (Ho et al, 1985). Although both peripheral (PNS) and central nervous system (CNS) abnormalities are observed during the course of HIV-1 infection, a general agreement on a definite neurotropism of HIV-1 does not exist. Petito et al (1985), in a series o f post mortem examinations of patients who died from AIDS, discovered a vacuolar myelopathy affecting at various degrees the posterior and lateral tracts in 22% of cases, of whom only the most severe had been preceded by neurological symptoms. The neuropathological report fits the alterations of nerve conduction shown by Helweg-Larsen et al (1988). He found an increase of the latencies of spinal and cortical SEP components from Posterior Tibial Nerve in 70% of AIDS patients. Similar alterations of conduction velocity in the spinal somatosensory pathways from lower limbs have been described in HIV-1 seropositive patients, also in pre-AIDS stages of the infection (Comi et al, 1987; Somma-Mauvais et al, 1990). Direct evidence of HIV-1 in the spinal cord is however limited (Ho et al, 1985). Some of the clinical features of HIV-1 related myelopathy may be secondary to co-existing peripheral neuropathy, a condition which frequently appears at any stage of the infection (Lipkin et al, 1985; Cornblath et al, 1987; Gastaut et al, 1987). Most of the above mentioned studies were conducted in patients showing symptoms of neurological involvement. As the time and route of HIV-1 entrance in the CNS are not fully understood (Carne et al, 1985), one also expects to find evidence of NS dysfunction in neurologically asymptomatic patients. Neurophysiological techniques have proved sensitive enough to reveal such subclinical alterations. Changes reported include early neuronographic modifications (Smith et al, 1988; Fuller et al, 1991) as well as anomalies in electroencephalogram (Parisi et al, 1989; Koralnik et al, 1990) and event-related potentials (Goodin et al, 1990; O11o et al, 1991). We therefore explored conduction along peripheral and central pathways in HIV-1 seropositive patients without clinical evidence of neurological impairment, on the assumption that their conduction velocity would be decreased and that such decrements would occur more frequently than generally estimated.

Subjects and methods We studied 54 male and 33 female patients, aged 21 to 48, who were being cared for by the regional AIDS center of Florence. They were divided into four groups on the basis of the Centers for Disease Control criteria (1985): 19 patients asymptomatic HIV-1 + (AC); 25 with LAS; 24 with ARC; 19 with AIDS. All patients underwent a neurological examination and only those free from clinical signs entered the study. Two experienced neurologists, working independently, carried out the examination. One carried out the neurophysiological testing while the other conducted the clinical

EMG and PES in HIV-I infection

395

assessment which included tests of limb strength, tendon reflexes, pallesthesia, two-point discrimination, position sense and sphincter function. Serum samples were analyzed for antibodies to HIV-1 by means of Elisa and those proving to be positive were further studied by Western Blot analysis; peripheral blood CD4 and CD8 lymphocytes and the CD4/CD8 ratio were also available for all patients. We tested the serum for vitamin B12 and folates, total and fractional proteins, and hepatic function to exclude metabolic conditions that might interfere with nervous functions. Twenty-five age- and sexmatched volunteers constituted the control group. For the peripheral nervous system, conduction velocity studies were performed by means of surface electrodes. We measured the following parameters: motor and sensory conduction velocity in the median, deep peroneal and sural nerves, the amplitude and distal latency of muscle action potentials (MAP) from abductor pollicis brevis and extensor digitorum brevis, together with sensory nerve action potentials (SNAP), both in median and sural nerves. SEPs were obtained from the median nerve following stimulation at the wrist and from the posterior tibial nerve by stimulating the ankle. Square pulses, 0.2 s in duration, were administered at a rate of 5 Hz for the upper limbs and 3 Hz for the lower limbs; the band pass was 5-500 Hz ( - 12dB) for the upper limb and 10-5000 ( - 12dB) for the lower. Two series of 1000 responses were averaged for each test. The active electrodes for median nerve SEPs were positioned on Erb's point, on the cervical spine (Cv6) and the controlateral parietal projection area, with both cephalic (Fz) and extracephalic (opposite shoulder) references. Absolute latencies and amplitudes of subcortical components (near field N10, N1 l, N13 and far field PI4) as well as cortical N20 were measured. For SEPs from the posterior tibial nerve, the active electrodes were positioned on Cz', referred to Fz. We also recorded signal responses with active electrodes on L2 and D10, referred 4 cm rostrally. The compound nerve action potential was obtained at the popliteal fossa. We measured absolute latencies at each level and calculated the central conduction time (CCT) between the spinal response at L2 and the early cortical component (P1). We used a similar procedure to record SEPs from the median nerve and measured the latencies of N9, N13 and N20, taking the N13-N20 interval as the measure of CCT. Values exceeding those of our normal control group by 2.5 SDs or more, were defined as pathological.

Results T h e d a t a on o u r s a m p l e ' s risk f a c t o r s are s u m m a r i z e d in t a b l e I. A l t h o u g h s o m e o f o u r cases h a d previously c o m p l a i n e d o f paresthesias o f the lower limbs, the neurological e x a m i n a t i o n was n o r m a l in all subjects. A m o n g sensory functions tested were pain, t e m p e r a t u r e a n d v i b r a t o r y sensitivity, p o s i t i o n sense, a n d two- p o i n t discrimin a t i o n . T e n d o n reflexes, m u s c l e s t r e n g t h a n d t r o p h i s m were also n o r m a l . M waves a n d s e n s o r y nerve a c t i o n p o t e n t i a l s c o u l d be r e c o r d e d f r o m all patients. T h e M a n n - W h i t n e y test showed no significant a m p l i t u d e differences a m o n g the f o u r p a t i e n t g r o u p s . A s for m o t o r a n d sensory c o n d u c t i o n in the m e d i a n a n d sural nerve, o n l y the A I D S g r o u p h a d a l t e r e d values c o m p a r e d with the o t h e r g r o u p s ( P < 0.01). P e r o n e a l nerve c o n d u c t i o n velocity was slower for the L A S g r o u p t h a n the controls a n d c o n t i n u e d to decrease f o r the A R C a n d the A I D S g r o u p s (fig 1), in line

F Pinto et al

396 Table I. Epidemiological data.

Group

Mean Age

Patient Classification

CDC "85"

AC LAS ARC AIDS

Drug abusers

Homosexuals

Heterosexuals

Haemophiliacs

12 17 16 17

5 5 5 1

1 3 2 1

1 0 1 0

33 27 30 30

* For our sample, these correspond to the following CDC '87 criteria: AC = II; LAS = III; ARC = IVA & IVC2; AIDS = IVC1 & IVE.

65

+2.5

SD

60 MCV (m/s)

55 ......

O OO OO OO ......... o oo o oooo OOO

50

-2.5

O OO ............................... oo o oooo ooo oooo OOO O

SD

45 o ooo

00@@0 • OO ooeoo go

O

ooo

oo oo e

eo o@o

000

Be ogo

40

oeo og

35 / /

AC n=19

Fig 1. Peroneal

LAS n=25

ARC n=24

AIDS n=19

nerve conduction velocities in different groups of HIV1 + subjects. The broken line indicates the mean values and the solid line 2.5 SD of the control group. Filled dots refer to patients with CNS + PNS involvement.

EMG and PES in HIV-1 infection

397

with preliminary data reported elsewere (Ronchi et al, 1989). No correlation was found between peripheral alterations and serum vitamin B12. SEPs to median nerve stimulation were normal in all patients. The stimulation of nerves from the lower limb yielded normal cortical responses (P 1) in AC and LAS patients while altered responses were obtained from 19 out o f 43 A R C and AIDS patients (fig 2); the mean latency for the ARC group as a whole, as well as that for the AIDS group, did not differ significantly from the control values. C C T measured between L2 and P1 behaved in the same way as the cortical response latencies (fig 3). Nineteen subjects exhibited altered P1 values; in 16 of these the increase in latency was due to a slowing of conduction in central pathways while in the remaining three patients it indicated altered conduction in peripheral nerves. The mean value of the T4/T8 ratio did not differ significantly between subjects with and without SEP alterations. To date, we have analyzed and reported data on CSF immunological changes for only a part of our sample (Lolli et al, 1990); analysis of remaining data is in progress and will be reported in the future.

P1 LATENCY 50

PI ( m s e c )

48 46 44 42 •

40

•

•

Q• Q •

•

•

•

~

38 36 34 32 30 150

I

I

I

I

I,

I

1

155

160

165

170

175

180

185

190

height (cm) ]Fig2. Absolutelatency of principal cortical component (P1) to tibial nerve SEP. Solid line indicates mean value and dotted lines 2.5 SD; • ARC, • AIDS.

398

F Pinto et al 30

----

O

25

----

O

O O O O O

L2-PI

OO

ms

O O O

20

---.....

O

O

OO

O

OOO

OO O

O

O

OO

OO

O

OOO

OOO

OOO

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OO ............

OO ........

OO OOO

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OO .......

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0000

0

0

0000

O0

0

O0

O0

O0

O0

0

0 0

//

AC n=19

LAS

ARC

AIDS

n=25

n=24

n=19

]Fig 3. Central transmission time in different groups of HIV1 + patients. The broken line indicates the mean value and the solid line 2.5 SD of the control group.

Discussion O f the various HIV-1 related C N S and P N S disorders, s o m e are opportunistic infections whereas others appear to be unique to H I V - 1 . The latter are n o w attributed to direct N S infection by the retrovirus (Dal Canto, 1988), although the exact pathogenic m e c h a n i s m is as yet u n k n o w n . N e u r o n s do not appear to be directly infected by H I V - 1 , while brain m a c r o p h a g e s m o s t likely are and act as a reservoir for the virus ( H o e t al, 1986). In the early stages o f HIV-1 infection, neurological i n v o l v e m e n t m a y occur even in individuals without detectable s y m p t o m s o f A I D S .

EMG and PES in HIV-1 infection

399

In this study we sought to document PNS involvement in the infection's different stages as well as to specify the functional spinal tract changes o f HIV-1 related myelopathy. We further explored the relationship between central and peripheral NS involvement as a means for tracing the path of HIV-1 infection within the NS. Our results from neurologically asymptomatic patients demonstrate that slowing of PNS conduction is observed in almost all HIV-1 seropositive patients. Whereas its extent increased as the infection progressed, only the lower limb motor conduction velocity in the AIDS group was significantly lower than that of controls. As for the CNS, we found no SEP alterations following upper limb stimulation, in agreement with previous studies (Helweg-Larsen et al, 1988; Smith et al, 1988), while lower limb testing revealed altered responses in 38°7o of the patients in the last two stages of the infection. Our electrophysiological data agree only in part with those o f other investigators who have also reported neurophysiological alterations in AC and LAS patients (Gastaut et al, 1989; Cazzullo et al, 1990). We, as well as other researchers found SEPs from the median nerve to be normal whereas CCT following lower-limb stimulation was increased. Thus, the preferential site of neurophysiological alteratfons in the CNS appears to be the dorso-lumbar spinal cord. Neurophysiological evidence o f CNS involvement in neurologically asymptomatic HIV-1 seropositive patients is still rather limited. Our finding that ARC and AIDS patients may have normal SEPs is in line with other reports that such patients with opportunistic infections and low T4 levels may be free from neurological deficits. On the other hand, there are infected individuals with neurological symptoms whose lymphocyte number and T4/T8 ratio show no major change. Our data, in fact, revealed no clearcut relationship between NS involvement and immunologic balance. Electrophysiologically, the patients in the ARC and AIDS groups appear to fall into two categories, namely altered and normal. Immunosuppression may not be the only factor determining the development of parenchymal NS infection in HIV-1 infected individuals. There is large variability from patient to patient in the comparative development of neurological versus systemic complications related to immunosuppression. These differences may depend, in part, on undefined host factors, perhaps genetically determined (Eales et al, 1987). However, another, perhaps even more important factor may relate to the polymorphysm of HIV-1. It is now clear that this retrovirus has a very high mutation rate and undergoes rapid genetic change, as it spreads not only in the community but also over time within an individual infected host (Hahn et al, 1986; Koyanagy et al, 1987; Cheng-Mayer et al, 1988). It is possible that one result of HIV-1 polymorphism might be variability in the neurotropism of virus strains. Viruses that are associated with neurological disease can be distinguished from those that are linked to immune deficiency. A neurotropic strain of the virus may be responsible for the bioelectrical alterations we observed, whereas in patients with intact CNS function even in the ARC and AIDS stages, a less neurotropic virus may be at work. Certain features of an isolated HIV-1 strain might indicate whether an individual will develop neurological symptoms.

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Given that research results on i m m u n o s u p p r e s s i o n and HIV-1 p o l y m o r p h i s m do not yet enable us to predict the occurrence o f neurological deficits in A I D S , we feel that the study o f SEPs can serve as a useful tool for uncovering preclinical NS involvement in HIV-1 seropositive patients.

Acknowledgment We gratefully acknowledge E Berger for her precious assistance in editing this paper. Supported by grants from the Istituts Superiore di Sanita, Progetto AIDS Contratto diricerca N ° 5203033.

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