|Year : 2015 | Volume
| Issue : 3 | Page : 245-250
Central nervous system manifestations in human immunodeficiency virus patients in the antiretroviral therapy era - Scenario from a developing country
Jency Maria Koshy1, Divya Deodhar1, Indira Brar2, Jeyaraj Pandian3, Mary John1, Aroma Oberoi4, Sangeetha Mohan4, Anna Mani1, Nitin Malhotra1, Navjot Singh1
1 Department of Medicine, Christian Medical College, Ludhiana, Punjab, India
2 Department of Infectious diseases Wayne State School of Medicine, Henry Ford Hospital, Michigan, USA
3 Department of Neurology, Christian Medical College, Ludhiana, India
4 Department of Microbiology, Christian Medical College, Ludhiana, Punjab, India
|Date of Web Publication||12-Jun-2015|
Dr. Jency Maria Koshy
Department of Medicine, Christian Medical College, Ludhiana - 141 008, Punjab
Source of Support: None, Conflict of Interest: None
Background: Central nervous system (CNS) infections associated with Human immunodeficiency virus (HIV) has decreased markedly in the developed countries. However, the scenario is different in Indian patients and is not unusual to have CNS infections as their initial presentation. Considering this, we undertook this study to look at the incidence of CNS manifestations in HIV infected patients. Materials and Methods: This was a cross sectional study conducted in the Departments of Medicine and Neurology in Christian Medical College Ludhiana, a tertiary teaching institution in North West India. All the HIV infected patients with Central nervous system manifestations who presented to our institution from 1st April 2009 to 31st of March 2014 were included in the study. The demographic and clinical profile along with the outcome of these patients was studied. Results: There were 280 patients diagnosed during this 5 year period, 43(15%) of who had CNS manifestations. The male: female ratio was 5:1. Majority of them were in the age group of 31 to 50 years of age (68.89%).In 72% of patients CNS manifestations were the initial manifestation of HIV infection.The CNS manifestations noted were cryptococcal meningitis in 20, toxoplasmosis in 3, CNS tuberculosis in 11, PMLE in 6, ischemic stroke in 4 and Diffuse B cell Lymphoma (DLBCL) with aseptic meningitis in 1. Conclusions: Even though in the era of HAART the incidence of CNS manifestations has decreased, CNS manifestations continue to be the presenting symptom for HIV infection in over 16% of the cases.
Keywords: Central nervous system, developing country, human immunodeficiency virus
|How to cite this article:|
Koshy JM, Deodhar D, Brar I, Pandian J, John M, Oberoi A, Mohan S, Mani A, Malhotra N, Singh N. Central nervous system manifestations in human immunodeficiency virus patients in the antiretroviral therapy era - Scenario from a developing country. CHRISMED J Health Res 2015;2:245-50
|How to cite this URL:|
Koshy JM, Deodhar D, Brar I, Pandian J, John M, Oberoi A, Mohan S, Mani A, Malhotra N, Singh N. Central nervous system manifestations in human immunodeficiency virus patients in the antiretroviral therapy era - Scenario from a developing country. CHRISMED J Health Res [serial online] 2015 [cited 2020 Jan 22];2:245-50. Available from: http://www.cjhr.org/text.asp?2015/2/3/245/158703
| Introduction|| |
Central nervous system (CNS) infections associated with human immunodeficiency virus (HIV) were well documented from the time HIV infection was recognized. However with the initiation of antiretroviral therapy (ART) the incidence of these has decreased markedly in the developed countries. The neurological manifestations and outcome of HIV disease is likely to be different in Indian patients because of prevailing endemic infections, malnutrition, poverty and illiteracy. It is not unusual to have CNS infections as their initial presentation to the health care. Considering this, we undertook this study to look at the incidence of CNS manifestations in HIV infected patients presenting to our institution and their in hospital outcome.
| Materials and Methods|| |
This was a cross-sectional study conducted in the Departments of Medicine and Neurology in Christian Medical College Ludhiana, a Tertiary Teaching Institution in North West India. All the HIV infected patients with CNS manifestations who presented to our institution from April 1, 2009 to March 31, 2014 were included in the study. The demographic and clinical profile along with the outcome of these patients was studied.
Human immunodeficiency virus infection was diagnosed using fourth generation ELISA kit (J. Mitra with a sensitivity of 100% and specificity of 99.95%).
Computed tomographic (CT) scan of the brain; magnetic resonance imaging (MRI) brain and cerebrospinal fluid (CSF) analysis were done when indicated.
Cryptococcal meningitis was diagnosed on the basis of detection of cryptococcal antigen in CSF or the presence of capsulated budding yeast cells on India ink preparation of CSF.  Cryptococcal antigen was detected by latex agglutination test (Biorad Pastorex Cryptoplus with sensitivity 92% and specificity 98%).
A presumptive diagnosis of toxoplasmosis was made on the basis of focal lesions on brain imaging along with detection of Toxoplasma immunoglobulin G (IgG) antibodies (Enzywell with 100% sensitivity and specificity) in serum. 
Tuberculous meningitis was diagnosed on the basis of lymphocytic predominant pleocytosis with elevated protein and decreased sugar in CSF.  It was also supported by evidence of tuberculosis (TB) elsewhere. Tuberculoma was considered when the patient presented with a ring enhancing lesion along with other features of CNS TB such as leptomeningeal enhancement, hydrocephalus, or evidence of TB elsewhere. MR spectroscopy was used to differentiate these lesions from neoplasms. ,,,,
Progressive multifocal leukoencephalopathy (PMLE) was diagnosed based on clinico-radiological findings when patients presented with focal deficits or cognitive disorders and had diffuse asymmetrical white matter lesions on the MRI of the brain.
In subjects presenting with stroke, a CSF study was carried out to rule out any infective etiology for the same.
| Results|| |
There were 280 patients diagnosed during this 5 year period, 43 (15%) of whom had CNS manifestations. The male: female ratio was 5:1. Majority of them were in the age group of 31-50 years of age (68.89%). In 72% of patients, CNS manifestations were the initial manifestation of HIV infection.
The CNS manifestations noted were cryptococcal meningitis in 20, toxoplasmosis [Figure 1] in three, CNS TB in 11, PMLE in six, ischemic stroke [Figure 2] in four and diffuse large B cell lymphoma (DLBCL) with aseptic meningitis in one [Table 1]. Coexisting opportunistic infections included TB (six-pulmonary, and four extra-pulmonary), candidiasis (oral-nine, esophageal two), two each of pneumocystis jiroveci pneumonia and herpes simplex. There were I each of histoplasmosis, cryptosporidium, herpes zoster and cytomegalovirus retinitis. The median CD4 count was 57.5 (Interquartile range (22.5-118.75).
Though the most common presentation of patients with cryptococcal meningitis was altered sensorium, few of them presented with just headache. Three of them had acellular CSF.
|Figure 2: Magnetic resonance imaging brain depicting subacute infarct involving lentiform nucleus, thalamus, internal capsule, external capsule, insular cortex and corona radiata|
Click here to view
Central nervous system TB presented as tubercular meningitis, Tuberculomas and Tubercular abscess. Most of the tuberculomas were multiple.
The patients who were diagnosed with toxoplasmosis were not on cotrimoxazole prophylaxis. One of the patient who presented with hemiparesis had multiple nodular lesions on MRI brain was initiated on anti-tubercular treatment (ATT) as the chest radiograph was suggestive of TB. The CSF was normal. However, the lesions on the MRI [Figure 3]a and b did not resolve even after 9 months of ATT. Toxoplasma IgG was 1100 IU and was initiated on pyrimethamine and sulfadoxine with which he improved both clinically and radiologically.
|Figure 3: (a) and (b) Magnetic resonance imaging with multiple nodular lesions|
Click here to view
One of the patients was diagnosed with DLBCL on bone marrow examination. She had presented with headache, seizures and altered sensorium. MRI brain did not reveal any parenchymal lesions. CSF study was suggestive of aseptic meningitis. She was advised to be initiated on ART along with chemotherapy. However, the relatives deferred treatment.
The patients who presented with stroke were 43, 45, 54 and 56 years of age. Two of them underwent CSF study, which was normal. One of the patients with middle cerebral artery infarct was diabetic, and the other patient had occlusion of the internal carotid and middle cerebral artery with evidence of intimal thickening of carotid artery on Doppler study. These findings could point towards an atherosclerotic process.
| Outcome|| |
Among the 43 patients with neurological manifestation, five of them died [Table 2]. These were patients with cryptococcal infection (3), tuberculoma (1) and stroke (1).
| Discussion|| |
Central nervous system involvement in HIV could either be due to direct effect of HIV or secondary to opportunistic diseases. In the era of highly active anti-retroviral therapy (HAART) there has been a decline in HIV-associated CNS infections.  In the developing countries, HIV patients still present with opportunistic infections as their initial presentation to the health care.
In this series, 16% of the HIV subjects presented with CNS manifestations. In previous studies, neurologic complications were noted in more than 40% of patients with HIV Infection. This was the initial presentation of 72% of the patients, as against a lower incidence of 10-20% of cases in the earlier studies.  However, autopsy studies have shown the presence of neuropathology abnormalities in up to 80%. 
There were more males in this study (Male:Female ratio = 5:1). Majority presented in the age group of 30-50 years of age, which was comparable to the study done by Patel et al.  Teja et al. and Ghate et al. also noted a higher incidence of CNS manifestations in males as compared to females. ,
The various CNS infections noted in our study were cryptococcosis, toxoplasmosis and TB. Cryptococcal meningitis was the commonest CNS manifestation observed in 7% of the HIV patients. Previous studies noted that 13% of the patients had cryptococcal meningitis.  It is not uncommon to have them presenting with benign symptoms like nausea and headache with a normal clinical examination.  Meningeal signs are absent in up to 70% of cases.  Clinicians must have a high index of suspicion for cryptococcal disease, particularly in the setting of a new onset of headache. Even if the cytology is nil, further testing in the form of India ink staining and cryptococcal antigen testing should be done.
Meningeal enhancement, focal cerebritis or cryptococcomas could be present on brain imaging.  In our cohort in addition to these changes, obstructive hydrocephalus was seen in one patient. CSF can be normal or show mononuclear pleocytosis, elevated protein, low glucose, and high opening pressure. India ink staining may reveal budding yeast with cultures growing cryptococcal neoformans.  Since the sensitivity is high, CSF cryptococcal antigen would aid in the diagnosis. 
Even with the high incidence of TB in India, there were less cases of CNS TB as compared to CNS cryptococcal disease. Diagnosis of CNS TB has always been challenging to the clinicians. Thwaite's diagnostic criteria are helpful in diagnosing patients with TB meningitis.  Tuberculomas may be found in the cerebrum, cerebellum, subarachnoid space, subdural space, or epidural space. The majority are said to be supratentorial. , Parenchymal disease may occur with or without coexistent meningitis, as was seen in our study.  Tuberculomas may be solitary or multiple. In this cohort, it was mostly multiple tuberculomas.
The tuberculomas may be indistinguishable from some lesions of toxoplasmosis or CNS lymphoma. Associated findings of cisternal enhancement, basal ganglia infarction, and/or communicating hydrocephalus favor a diagnosis of tuberculomas.  Abscesses tend to be larger than tuberculomas and have a more accelerated clinical course.  Infarction is a common complication of CNS TB, a result of spasm and thrombosis.  The findings on chest X-ray like pleural effusion, adenopathy, and cavitary infiltrates suggestive of tuberculous infection may further support the diagnosis of CNS TB.  As invasive tests are technically difficult and less acceptable for the patients, we would have to rely on these pointers for diagnosis. Response to treatment would further underpin the diagnosis.
Toxoplasma caused by Toxoplasma gondii can present as toxoplasma encephalitis in HIV-infected patients with CD4 T-cell counts <100/μL.  Earlier studies indicated that 24-47% of T. gondii-seropositive AIDS patients ultimately developed toxoplasma encephalitis. ,, The risk of toxoplasmosis decreased after the introduction of primary prophylaxis against T. gondii and effective ART.
Toxoplasmosis is one of the commonest differentials for a focal brain lesion in HIV-infected patients. Motor weakness and speech disturbances are the common focal neurological signs. Patients can also present with seizures, cranial nerve abnormalities, visual field defects, sensory disturbances, cerebellar dysfunction, meningismus, movement disorders, and neuropsychiatric manifestation. ,,
Since the burden of TB is high in developing countries, cases of Toxoplasmosis with nodular lesions are likely to be treated by physicians as CNS TB with tuberculoma. However in the setting of HIV, toxoplasmosis should be considered as the first differential when patients present with focal deficits.
Imaging studies of the brain are indispensable for diagnosis and management of patients with toxoplasma encephalitis. The ring enhancing lesions tend to involve mostly the basal ganglia and hemispheric corticomedullary junction. , However, findings on MRI and CT scans are not pathognomonic for toxoplasma encephalitis. Primary CNS lymphoma cannot be distinguished from toxoplasmosis solely on the basis of neuroradiological criteria (both present as contrast-enhancing lesions with mass effect). The presence of hyper attenuation on nonenhanced CT scans and sub-ependymal location suggests the possibility of lymphoma. 
A trial of treatment of toxoplasmosis is advisable as a clinical response can be expected within a week and radiological response within 2 weeks. MR spectroscopy, positron emission tomography and single photon emission CT studies can help in differentiating neoplastic diseases from the infective diseases. ,
Progressive multifocal leukoencephalopathy is a subacute or chronic progressive illness most often characterized by focal neurologic findings, such as hemiparesis, gait abnormalities, and visual field defects, as well as changes in mental status and personality. CT or MRI usually reveals focal or diffuse lesions in the white matter, particularly in the parieto-occipital region. Diagnosis should be based on clinical and radiographic features, supported by JC virus polymerase chain reaction (PCR). While a positive test is confirmatory, a negative CSF PCR for JC virus should not exclude the diagnosis. 
The prevalence of clinically diagnosed stroke in AIDS patients has been estimated to be 1%, with ischemic stroke constituting at least 70% of the cases. ,, The incidence of stroke was 1.4% in our series with all of them presenting as ischemic infarct. Stroke has been associated with opportunistic infections, tumors (CNS lymphoma), and advanced stages of immunosuppression.  Pathogenic mechanisms in HIV-associated ischemic stroke include cardio embolism, acquired hypercoagulability, infections, vasculitis, and HIV vasculopathy.
Patients with neurological manifestations are associated with higher mortality and morbidity. Indian studies noted a higher incidence of mortality among patients with CNS toxoplasmosis and cryptococcal meningitis, whereas western studies noted a higher mortality of 79% amongst the CNS TB patients with HIV. ,
| Conclusion|| |
Even though in the era of HAART the incidence of CNS manifestations has decreased, CNS manifestations continue to be the presenting symptom for HIV infection in over 16% of the cases. It is important to recognize the possibility of HIV infection when patients presents with these manifestations and should treat them aggressively. Since it is technically difficult to get a tissue diagnosis in CNS infections, to a large extent we can rely upon supportive evidence to diagnose and manage these patients.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]