Neurological manifestations of HIV-AIDS at a tertiary care institute in North Eastern India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.198203
Source of Support: None, Conflict of Interest: None
Background: The nervous system is among the most frequent and serious targets of human immunodeficiency virus (HIV) infection. The infection usually occurs in patients with profound immunosuppression. In 10 - 20% of the patients, the presence of a neurological disease is the first manifestation of symptomatic HIV infection.
Keywords: Cryptococcal meningitis, HIV, India, neurological manifestation, tuberculous meningitis
Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV). India appears to be a fertile soil for HIV infection because of poverty, illiteracy, malnutrition, lack of sex education, and high prevalence of sexually transmitted diseases (STDs). In India, the HIV patients have higher chances of progressing to full-blown AIDS and developing neurotuberculosis, because patients either do not take antiretroviral treatment (ART) or become ART defaulters. The AIDS epidemic in India is in an alarming phase, with patient doubling time seen in just one year. The number of HIV-positive individuals and AIDS cases may become significant in the coming years. This will affect our already burdened economy and health system.
The nervous system is extensively involved with no part of the neuraxis being immune to the virus. Thus, the knowledge of central nervous system (CNS) manifestations of HIV is very important for clinician. We know that in the last few years, HIV/AIDS has become a chronic yet manageable disease instead of remaining an incurable disease. There are only a limited number of studies published regarding the neurological manifestation of AIDS in India. Despite the high prevalence of neurological manifestations in HIV, there is not a single study examining its impact in the resource-limited communities from the northeastern part of India.
This was a retrospective observational study conducted at a tertiary care institute in northeast India over a period of 6 years from August 2008 to September 2014. Ninety-one HIV positive patients with neurological manifestations were enrolled in this study from the Neurology department of NEIGRIHMS, an autonomous tertiary care institute under the Ministry of Health and Family Welfare, Government of India. It is the apex referral center in the state of Meghalaya located in north-east India.
A detailed history was noted in each patient with special emphasis on past history of multiple sexual partners, drug abuse, penile ulcer, major surgery, blood transfusions or a history of tuberculosis, seizures, unconsciousness or headache. Detailed physical examination was carried out in each patient to look for the presence of an opportunistic infection in other organs. Fundus was examined in each patient. Routine hematological, biochemical and bacteriological testing including complete blood count, liver and kidney function tests, cerebrospinal fluid (CSF) examination (proteins, sugar, cytology), chest X-ray, special staining studies (Ziehl–Neelsen stain, India ink, etc), and specific antigen detection tests in the serum and CSF (cryptococal and toxoplasmosis antigen and VDRL) were performed along with computed tomography (CT) of the brain and magnetic resonance imaging (MRI) of the brain/spine. Viral load estimation was not performed because of financial constraints. All patients underwent reactive fluorescent treponemal antibody tests. All the enrolled participants were screened for the differential detection of HIV1 and HIV2 antibodies using a highly sensitive, visual, and rapid immunoassay (HIV TRIDOT, J. Mitra and Co. New Delhi, India).
Patients testing positive in the initial screening tests for either HIV1 or HIV2 were subjected to two different confirmatory enzyme-linked immunosorbent assay tests using two different types of antigens, as recommended by the National AIDS Control Organization (NACO). Every patient's information was kept highly confidential. All the patients included in the study had absolute CD4 levels documented whenever possible. Patients with a diagnosis of neuro-AIDS were treated according to the NACO guidelines using anti-retroviral treatment (ART), antituberculous and antifungal medications, decongestants, antibiotics, and anticonvulsants. Associated opportunistic infections were treated with respective drugs. Intensive care unit management and mechanical ventilation were provided whenever required. HIV infected patients with a CD4 count <350/µl were put on Highly Active Antiretroviral Therapy (HAART) as recommended., Chemoprophylaxis and ART was instituted as indicated. Trimethoprim–sufamethoxazole was given to prevent pneumocystis pneumonia in all patients with a CD4 lymphocyte count of <200cells/ml.
Age and sex distribution
A total of 91 patients were admitted with neurological manifestations of HIV, out of which 90% were between the age group of 18–67 years. The male:female ratio was 1:1.05. Twenty-nine patients had a primary neurological illness, whereas 62 patients had secondary illnesses.
Mode of acquisition of virus
86% patients acquired the infection through the sexual route. Multiple unprotected heterosexual contacts with commercial sex workers was the major risk factor in 77% of male patients, whereas most of the females (80%) had acquired infection from HIV-positive husbands. Only 0.8% patients acquired infection through blood or blood products, whereas a large number (9.93%) were infected through the use of intravenous drugs. Homosexual contact was responsible in 3.85% of the patients, while the mode of transmission remained unidentified in another 3.77%.
Distal symmetrical polyneuropathy (DSPN) was the most common primary neurological illness, accounting for 16.4% of primary HIV illness. AIDS dementia complex (6.59%) was another common primary neurological manifestation, which was diagnosed by Mini Mental Status Examination (MMSE) score. Cerebrovascular disease was detected in 5.49% of HIV infected individuals. Tuberculous meningitis [TBM] (43.9%) was the most common secondary CNS illness in the present study, followed by cryptococcal meningitis (14.2%). Toxoplasmosis was observed in 2.19%, progressive multifocal leucoencephalopathy in 1.09% and neurosyphilis in 6.59% of the cases. One patient had herpes simplex encephalitis (presenting with altered sensorium and seizures with bilateral orbital and temporal lobe involvement) and 2 patients had cerebral toxoplasmosis which presented with right-sided partial seizure with secondary generalization. One patient had herpes zoster, affecting T6–T8 thoracic dermatome on the left side, presenting with radicular lancinating pain [Table 1].
Out of 91 patients with a neurological manifestation, 60 (66%) presented with fever. Headache was the most common neurological symptom seen in 65 patients (72%), while 23 patients (25%) presented with a history of convulsions. Altered sensorium was the presenting complaint in 52 patients (57%). Vomiting was present in 32 (35%) patients. Twenty-seven (30%) patients presented with tingling and numbness. Forty-one (45%) patients presented with focal deficits. Bowel and bladder involvement was found in 36 (40%) patients. Signs of meningeal irritation were present in 55 (60%) patients [Table 2].
Mean CD4 count
Most of patients with CNS infections had relatively low levels of CD4 counts i.e., <200/µl. Most of the patients with HIV encephalopathy (HAD) had CD4 levels of <200/l. The mean CD4 count in cells/cubic mm in the presence of various clinical presentations was as follows: 161 ± 100.9 in DSPN, 260.7 ± 113.9 in AIDP, 110.3 ± 81.8 in tuberculous meningitis, 42.0 ± 29.60 in cryptococcal meningitis, and 57.6 ± 38.7 in toxoplasmosis [Table 3]. In HAD, the mean CD4 count was 95 ± 83.72. AIDP occurred at a higher CD4 level due to the autoimmune phenomenon. Statistically, there was no difference in the ART status and the development of neurological manifestations in HIV/AIDS patients.
It has been well-recognized that the nervous system is extensively involved in patients with HIV-AIDS with no part of the neuraxis being immune from the virus. The neurological manifestation that occurs in HIV patients may be either due to the primary pathological process of HIV infection or secondary to opportunistic infection or neoplasm. Infected macrophages infiltrate the brain parenchyma resulting in slow neuro-degeneration, especially in the hippocampus, basal ganglia, prefrontal cortex, and white matter. Damage to the CNS may be secondary to the release of neurotoxins and cytokines such as IL-1, TNF-TNF, and IL-6.
To the best of our knowledge, there has been no study regarding neurological manifestations in AIDS from north-east India. In the present study, the incidence of neurological involvement was found to be maximum in the age group of 18–67 years, which correlates with other studies. This constitutes a highly productive section of the society that is likely to affect the growth of the nation as well as future generations. A predominantly heterosexual transmission of the disease was observed in the study. Multiple partners and contact with commercial sex workers was the cause of heterosexual transmission. This is in contrast to the studies in the west, where homosexual transmission is more common.
The most common neurological complication of HIV infection in this study was tuberculous involvement of the CNS. It was seen in 40 (43.9%) patients, out of which 35 had tuberculous meningitis and 5 had intracranial tuberculomas. This is similar to the findings of other studies such as the one from Nizam Institute of Medical Sciences (NIMS) and the one by Abayom et al., in which the incidence of tuberculous involvement was 25% and 26%, respectively., The most common presenting symptoms in patients with tuberculous meningitis were fever (83%) followed by headache (79%), altered consciousness (70%), and convulsions (30%).
Cryptococcal meningitis was the most common CNS fungal infection in HIV infected patients. In the United states, approximately 5–10% patients had AIDS with cryptococcal meningitis. In our study, 13 out of 91 (14.2%) patients with neuro-AIDS had cryptococcal meningitis. Fever, headache, and vomiting were significant complaints along with altered sensorium. The causative organism, Cryptococcal neoformans, causes minimal inflammation in AIDS patients with impaired immune defense, which explains why neck rigidity and photophobia were infrequent in our study. Cryptococcal meningitis occurred in the last stages of HIV illness, particularly with CD4 counts <100 µl. CSF examination of cryptococcal meningitis patients showed the average protein levels of 120mg%, sugar of 67mg%, total cell of 40/mm 3 and lymphocytes of 92%. CSF cryptococcal antigen titre was the gold standard investigation for diagnosis in this study. Similar reports have been documented in other studies. A high index of suspicion is the key to the diagnosis of cryptococcal meningitis. The incidence of mortality following the development of cryptococcal meningitis in patients with HIV infection was 40%. The poor prognostic predictors were altered mentation at the time of diagnosis, positive India ink staining, a low CSF leukocyte count, positive blood culture, high cryptococcal antigen titres, CSF hypoglycorrhachia, and increased CSF opening pressure. Cryptococcal meningitis, toxoplasmosis, PML, and neurosyphilis were the other presenting secondary CNS illnesses, which were similar to the findings of the NIMS study and the study by Abayomi et al., In a Brazilian study and another by Deshpande et al., toxoplasmosis was the most common cause of secondary CNS manifestation., New onset seizure was the most common manifestation of toxoplasmosis followed by focal neurological deficit. MRI with contrast is the most sensitive technique to diagnose this entity. This infection generally occurred in patients with a CD4 count less than 100/cubic mm.
PML (progressive multifocal leukoencephalopathy) results from infection with human polyoma virus (JC virus), developing in 4% of patients with AIDS, and this was the initial manifestation of AIDS in 29% of these cases. However, in the present study, only one patient had history, findings and MRI picture suggestive of PML.
In the era of AIDS, there has been a dramatic rise in the number of cases of syphilis and a corresponding increase in the incidence of neurosyphilis. The association is not unexpected because both AIDS and neurosyphilis are sexually transmitted diseases. However, neurosyphilis has been reported to develop in one-third of the cases who progress to the late stages of disease. Invasion of CNS by the organism Treponema pallidum n occur at any stage of the disease. Patients with neurosyphilis had serum VDRL titers ≥1:16. Symptomatic patients showed lower CD4 cell counts (131 ± 76.8 cell/μL). The median of serum VDRL and CD4 cell counts were 1:128 and 131 cell/μL, respectively.
HIV-associated neurocognitive impairment, myelopathy, peripheral neuropathy, myopathy, and aseptic meningitis are part of the primary illnesses. In our study, DSPN was the most common primary neurological illness followed by HAD and AIDP, which is comparable with the result of NIMS study. Five patients (5.49%) were diagnosed to be having a cerebrovascular accident (CVA). Three of them had an infarct in the basal ganglia and other two had an infarct in the cerebellum. The incidence of CVA in the present study is similar to that seen in other studies. DSPN can occur in any stage of HIV infection. It is mostly seen in patients with CD4 counts less than 200. DSPN can occur due to the side-effects of ART. ADC was seen in 6.59% of our patients, which was diagnosed by the mini mental score examination (MMSE). HIV infection characteristically generates a “subcortical” pattern of neuro-cognitive dysfunction with deficits predominantly affecting executive functions, speed of information processing, attention/working memory, motor speed, new learning, and retrieval of new information. It generally occurred when CD4 count was less than 100 cell/μL.
In the present study, the mean CD4 count (in cell/μL) was 161 ± 100.9 with DSPN, 260.7 ±113.9 with AIDP, 110.3 ± 81.8 with TBM, 42.0 ± 29.60 with cryptococcal meningitis, and 57.6 ± 38.7 with toxoplasmosis. Our results are comparable with the study conducted by Deshpande. In HAD, the mean CD4 count was 95 cells/μL, which is comparable with the NIMS study in which mean CD4 count was 92 cells/μL. People living with HIV who have a CD4 cell count below 200 are at a significant risk of developing serious illnesses, which has been seen in this study too. The presence of neurological manifestations is associated with decreased CD4 counts. Cryptococcal meningitis was associated with lowest CD4 counts, and had a fatal outcome in 40% of the patients, followed by toxoplasmosis, HAD and neurosyphillis [Table 3]. In India today, the only affordable methodology is the estimation of the CD4+ cell counts. It can serve as a guide to assess the HIV status, assess the risk for the development of neurological manifestations in such patients and help in instituting timely intervention in the form of prophylaxis and treatment. The mortality was 25% in TBM, 15% in toxoplasmosis, and 40% in cryptococcal meningitis [Table 4]. In the era of HAART and specific treatment that is available for opportunistic infections, mortality in patients with HIV with neurological illness has considerably decreased.
There is no part of the neuraxis that cannot be damaged either directly or indirectly by HIV. With effective management of opportunistic infection and HIV itself, prolonged survival of these patients will lead to an increase in the prevalence of neurologic disorders. It is crucial to recognize the primary causal factor because the institution of proper therapy may dramatically alter the morbidity and improve the quality of life. However, the proper therapy for AIDS per se remains out of reach of many patients in developing countries. Hence, the importance of preventive measures and public education cannot be overemphasized.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]