Nervous system involvement in asymptomatic HIV seropositive individuals: A cognitive and electrophysiological study
Background: A significant proportion of human immunodeficiency virus (HIV) seropositive subjects may have subclinical asymptomatic involvement of the central and peripheral nervous system. Aims: To detect subclinical neurological involvement in asymptomatic HIV seropositive individuals by clinical, mini mental state examination (MMSE) and various electrophysiological tests. Material and Methods: MMSE, EEG, nerve conduction (NC), and multimodality-evoked potential studies were evaluated in 20 asymptomatic HIV seropositive subjects. Results: The majority of the subjects were young (mean age: 29.5 ± 8.9 yrs) and female (85%). The mean MMSE score was 25.8 ± 2.3, which was marginally less than that of matched controls (26.3 ± 2.4). Four subjects had a score of less than 23 suggesting subclinical cognitive impairment. EEG (n=19) was mildly abnormal in 8 cases: low alpha index (n=4), excess of fast background activity (n=3) and intermittent bursts of slow waves along with sometimes sharp waves (n=4). Motor NC studies (n=20) revealed a decreased mean nerve conduction velocity (NCV) compared to controls in the right median (P<0.05) and CP (P<0.001) nerves. Sensory NC studies revealed a decreased mean NCV in both the median (P<0.001) and sural (P<0.001) nerves compared with controls. Brainstem auditory evoked potential (BAEP) studies showed the involvement of the peripheral auditory pathway (23.5%). The somatosensory evoked potential (SSEP) study detected a delay of N20 latency in two. Only 3 subjects came for follow-up after 6 months. Conclusion: Asymptomatic HIV seropositive subjects may have subclinical central and peripheral nervous system involvement. Long-term follow-up studies are essential for better understanding of the significance of these changes.
According to a World Health Organization (WHO) estimate, the number of human immunodeficiency virus (HIV) infected persons globally was 33.5 million (1999 census) and in India the number was 3.5 million in 1998. Approximately, the number of asymptomatic HIV seropositive is three times of those with the acquired immunodeficiency syndrome (AIDS). The asymptomatic period varies from 2 to 15 years (generally 8 to 10 years). There is also a rapid upsurge in the number of HIV infected persons, especially in India in the 21st century. Hence the burden of the asymptomatic HIV seropositive group is likely to be enormous.
About 10-20% of HIV seropositive subjects present with neurological involvement and 50-70% have evidence of neurological involvement during the course of illness. Autopsy studies showed nervous system involvement in 80-90% of subjects., Studies including detailed neuropsychological assessment, various electrophysiological tests, cranial magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) have shown evidence of subclinical neurological involvement in asymptomatic HIV seropositive individuals., These observations made clinicians and researchers identify such persons and questions were raised regarding early intervention and thereby prevention of serious systemic involvement. There are no such studies from India and hence this study.
The study was conducted at the department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. Twenty asymptomatic HIV seropositive subjects (according to the standard NACO guidelines) were included in the study. Subjects were spouses of HIV-infected patients with neurological complications or from the counseling clinic, NIMHANS, Bangalore.
After obtaining informed consent, only asymptomatic subjects were included in the study. None of them were on antiretroviral drugs nor did they have any neurological or psychiatric illnesses that would interfere with the study. They did not have history of alcohol or drug abuse.
The study protocol included a detailed history and systemic and neurologic examination. All subjects and matched controls were administered Mini Mental State Examination - Folstein (MMSE) in their mothertongue. The control population for the MMSE were normal, healthy, age, sex, education and socioeconomic status-matched relatives of patients attending NIMHANS, Bangalore.
Scalp electroencephalography (EEG), nerve conduction studies (NCS), visual evoked potential (VEP), BAEP, and SSEP recordings were done using standard methods. The control values (mean ± 2.5 SD) were obtained from the electrophysiological laboratory, NIMHANS, Bangalore.
Statistical analysis was done using the student 't' test. Value of P< 0.5 was taken as the level for statistical significance.
The mean age of the subjects was 29.5 + 8.9 years (range - 21 to 58) with a male to female ratio of 3:17. The majority of the subjects were from the low socioeconomic status (income < Rs 1500 per month in 85%) and uneducated or had education till Class VII only (60%). Eighteen (90%) of the spouses were HIV seropositive while only 2 were seronegative for HIV. All the 20 subjects contracted HIV by heterosexual mode. All were asymptomatic. One of the subjects was a patient of migraine.
The mean MMSE score in the study group was 25.8 + 2.3 and it was 26.3 + 2.5 in the control group, the difference was not statistically significant. Four of the study subjects had a score of less than 23/30 while none from the control group scored less than 23.
Scalp EEG was done in 19 subjects. It was normal in 11 (57.9%) and was abnormal in the rest. The abnormalities were poor alpha index (21%), excess of fast background activity (15.8%) and slow background activity (10.5%), while bursts of sharp and/or slow waves were seen in 4 cases. [Table - 1]
Nerve conduction studies were performed in all the 20 subjects. The motor nerve conduction studies showed significantly reduced conduction velocities in both the median and common peroneal nerves. The minimal 'F' wave latency was prolonged, more than 2.5 SD of the control value in 1 subject. The sensory nerve conduction studies showed a decreased conduction velocity in both the median and sural nerves, and reduced amplitude of sensory nerve action potential (SNAP) of the sural nerve in the study group as compared to the controls. Nerve conduction velocities were reduced more often in the lower limb nerves (motor:common peroneal - 6, sensory:sural- 4) when compared to the upper limb nerves (motor/sensory: median - 2,1) [Table - 2].
VEP studies showed normal P100 latencies and amplitudes in all the 20 subjects [Table - 3]. BAEP studies showed increased I-III inter-peak latency in 4 subjects (23.5%) and the inter-peak latencies III-V, I-V were increased in 1 each [Figure - 1]; [Table - 3]. Lower limb SSEP studies showed increased N20 latencies in 2 subjects [Figure - 2]; [Table - 3].
Only 3 (15%) subjects came for review after 6.6 + 0.6 months. Other subjects did not respond to instructions given to them in the beginning or to the letter written to them subsequently. All the 3 cases remained asymptomatic at the end of 6 months and repeat studies showed no change in the MMSE scores and also in the EEG findings. The sensory conduction velocities of the median nerve were reduced in 2 and I-III inter-peak latency in BAEP was prolonged in 1, compared to the controls and the initial examination values.
The findings in the present study are similar to the earlier reports that subtle abnormalities in the neuropsychological assessment, EEG, nerve conduction studies, multimodality-evoked potentials, CSF, and MRI occur in a few asymptomatic HIV seropositive individuals. The main concerns about such findings are whether the subclinical involvement of the nervous system would indicate what is going to happen in future and whether specific interventions were required at this stage.,
Wilkie et al showed that 43% of asymptomatic HIV positive subjects were slow in memory and cognitive skills compared to 8% of HIV negative controls. Similarly, Marder et al found subtle neuropsychological impairment in their group of intravenous drug abusers who were HIV seropositive compared to HIV seronegative subjects. Perkins et al reported personality changes in 33% of HIV positive persons. In the present study, MMSE, a standardized screening test which can be easily administered was used though it may not be the best one to assess neuropsychological function in this subgroup of individuals. Of the 20 patients studied 4 subjects (20%) had a MMSE score less than 23/30. Whether the impaired cognitive functions in asymptomatic HIV seropositive subjects would require early intervention needs further evaluation.
Non-specific EEG abnormalities were noted in 8 (42.1%) in the form of mild changes in the background activity or seizure discharges. Enzensberger et al found that 50% of 26 asymptomatic HIV positive subjects had non-specific EEG abnormalities and 5 of them developed subacute encephalopathy subsequently. Anterior slowing of the background activity was reported in 20-30% of the subjects. It is generally agreed that mild and non-specific EEG abnormalities occur in early stages, which tend to increase with disease progression. However, it is not possible to predict the chances of developing HIV encephalopathy or seizures.
Subclinical neuropathy had been reported by Gastaut et al in 40% and 100% of asymptomatic HIV seropositive and AIDS cases respectively. Avanet et al found similar results in 10% and 53% of asymptomatic HIV positive subjects and AIDS patients respectively. The present study shows evidence of subclinical neuropathy in a few subjects which was sensorimotor. It would be worthwhile to follow up these individuals and if possible with sural nerve biopsies.
Though in the present study, evoked-potential study abnormalities were similar to most of the earlier studies, we did not find any VEP abnormalities. Hall et al found increased P100 latency in 4% of asymptomatic subjects. Pagano et al had shown central auditory pathway dysfunction in their BAEP study. Jabbari et al had found that 7 out of 73 (10%) had abnormal ankle-cortex conduction and 3 more developed abnormalities within 2 years of follow-up. Iragui et al reported SSEP abnormalities in 8% and 43% of asymptomatic HIV positive subjects and AIDS patients, respectively.
Neuroimaging and CSF abnormalities are the other abnormalities described in asymptomatic HIV seropositive subjects. White matter hyperintensities in T2 weighted images have been reported on MRI imaging in 13% to 60% subjects in various studies. CSF abnormalities in the form of mild lymphocytic pleocytosis and protein elevation have been described. Attempts have also been made to isolate virus and p24 antigen from the CSF. It is not clear why some HIV positive individuals develop neurological complications, however, recent studies show that it may be related to the deficiency of some cofactors like CXCR4 and CCR5.
The present study indicates that asymptomatic HIV seropositive subjects may have subclinical central and peripheral nervous system involvement. The significance of these findings is not clear. It is also not clear whether the subclinical nervous system involvement is a predictor for the future involvement of the nervous system as part of AIDS and whether therapeutic intervention can prevent the development of nervous system AIDS. Further studies with long-term follow-up, are needed to answer some of these questions.