Cryptococcal meningitis: Clinical, diagnostic and therapeutic overviews.

Cryptococcal meningitis has emerged as a leading cause of infectious morbidity and mortality in patients with AIDS. Among the human immunodeficiency virus (HIV)-seropositive subjects, cryptococcal meningitis is the second most common cause of opportunistic neuro-infection. Current trends are changing due to the marked improvement of quality and length of life produced by highly active antiretroviral therapy (HAART). The introduction of generic HAART in India has resulted in an increase in the number of individuals getting treatment for HIV infection, as the cost of highly active antiretroviral therapy (HAART) has decreased 20- fold. Cryptococcal meningitis occurs in non-HIV patients who are immunodeficient due to diabetes, cancer, solid organ transplants, chemotherapeutic drugs, hematological malignancies etc and rarely in healthy individuals with no obvious predisposing factors. Diagnosis of cryptococcal meningitis is fairly straightforward once the diagnosis is considered in the differential diagnosis of chronic meningitis. Treatment of a patient with cryptococcal infection is a challenge for both the physician and the patient, but rewarding, as many would recover with timely and adequate antifungal therapy.

Kindling & mossy fibre sprouting in the rat hippocampus following hot water induced hyperthermic seizures.

BACKGROUND & OBJECTIVES: Hot water epilepsy (HWE) is well recognized reflex epilepsy with possible genetic susceptibility. Rat model and human experimentation had proven that HWE is a type of hyperthermic seizure with possible kindling on repeated stimulation in animals. The present study was undertaken to investigate kindling associated with hyperthermic seizures induced by repeated hot water stimulation in the rat model and to prove hyperthermic kindling. METHODS: Epileptic seizures were induced in 36 male Wistar albino rats by means of hot water sprays at 48 h time intervals. Progression of seizure activity was investigated by studying the behaviour, severity and duration of the seizure. Threshold of rectal temperatures and timed latency for seizure induction were studied. Seizure discharges (EEG) were recorded from ventral hippocampus in six of these rats. Timm's staining was used to study the neuronal sprouting as a consequence of kindling. Studying the seizure threshold, latency, duration of seizure discharge and behavioural seizure following a stimulus-free interval of 30 days tested permanence of kindling. RESULTS: Following 8-12 episodes of hot water stimulations there was progressive epileptic activity manifested in the form of lowering of rectal temperature thresholds from 41.5 to 40.0 degrees C, drop in latency for developing seizures from 185 to 118 sec, increase in duration of hippocampal seizure discharge from 15 to 140 sec, along with progressive increase in complexity of EEG after discharges, increase in behavioural seizure severity from Grade 1 to 5 in all the rats, and neuronal sprouting observed in supragranular molecular layer and in stratum lacunosum. INTERPRETATION & CONCLUSION: Our study covered all aspects of kindling and provided a useful animal model for human hot water epilepsy. Hyperthermic seizures induced by hot water in the rat model kindle as demonstrated by Timm's staining.

Neuroleptospirosis - revisited: experience from a tertiary care neurological centre from south India.

BACKGROUND & OBJECTIVES: Leptospirosis is a zoonotic disease commonly reported from south India. Neurological manifestations seen in about 10-15 per cent of cases, are protean and remain unrecognized and diverse. We evaluated the pattern of nervous system involvement in leptospirosis, among patients presenting to the emergency services of a tertiary care neurological centre in south India, and also analysed the outcome and prognostic indicators. METHODS: The diagnosis of neuroleptospirosis was based on clinical and laboratory evidence of hepatorenal syndrome, and serum or CSF positivity for antileptospira antibody by a macroscopic agglutination test (MAT) and by ELISA in a limited number of samples. RESULTS: A total of 31 patients (M:F 27:4, age range 6-68 yr, mean 36.4 +/- 14.3 yr) were treated during the five year period. Acute fever with chills and rigors, headache and vomiting were the presenting manifestations; 25 patients (81%) had altered sensorium for a period ranging from 1- 8 days, four (12.9%) being deeply comatose. Eleven (35.5%) had acute symptomatic seizures at the time of presentation. Conjunctival congestion with or without haemorrhage was seen in 12 patients (38.7%), icterus in 14 (45%) and mild hepatosplenomegaly in 11 (35.5%). Early papilloedema was observed in three. Only three patients had localizing deficits. CT scan was normal in 18 of 27 (67%), while 7 (26%) had diffuse cerebral oedema. CSF pleocytosis with lymphocytic predominance (mean 50 cells/microl) and elevated protein levels (mean 115.5 +/- 67.5 mg %) were noted. Leptospira antibody was detected in serum of all, and 5 of 22 in CSF samples. Eight patients (26%) succumbed. Deep altered sensorium at presentation and raised CSF protein were two poor prognostic indicators. Pathological study of brain in five cases revealed encephalitic features and in addition immune mediated acute disseminated encephalomyelitis (ADEM) like pathology in two cases. INTERPRETATION & CONCLUSION: Neuroleptospirosis should be considered in the differential diagnosis of neuroinfections associated with hepatorenal dysfunction, in endemic areas. Leptospira antibody can be detected in CSF also in some cases. Deep altered sensorium at presentation indicates poor prognosis.

Neuropathology of HIV/AIDS with an overview of the Indian scene.

Neurological manifestations of HIV infection and AIDS are being recognized with a frequency that parallels the increasing number of AIDS cases. Next to sub-Saharan Africa, India has the second largest burden of HIV related pathology, essentially caused by HIV-1 clade C in both the geographic locales, in contrast to USA and Europe. But the true prevalence of HIV related neuroinfections and pathology is not available due to inadequate medical facilities, social stigma and ignorance that lead to underdiagnosis. Neurotuberculosis, followed by cryptococcosis and toxoplasmosis in various combinations are the major neuropathologies reflecting the endemicity and manifesting clinically by reactivation of latent infection. Discordance in the clinical prevalence of various infections, when compared to pathological studies highlight similarities in clinical, radiological modalities of diagnosis and inherent problems in establishing definitive diagnosis. Viral infections appear to be relatively rare. Inspite of heavy burden of HIV/AIDS, HIV associated neoplasia is infrequent, including primary CNS lymphomas. HIV encephalitis and HIV associated dementia are considered infrequent, though systematic studies have just been initiated in various centres. Peripheral neuropathy characteristically manifests with vasculitic neuropathy while diffuse infiltrative lymphocytosis syndrome (DILS) involving nerves has not been reported from India. Spinal cord pathology including vacuolar myelopathy is rare, even in asymptomatic cases. Till now the AIDS cases in India were drug naive but a new cohort of cases following initiation of HAART therapy as a national policy is soon emerging, altering the biology and evolution of HIV/AIDS in India. Lacunae in the epidemiology, diagnosis and study of biology of HIV/AIDS are outlined for future research.

Spectrum of epilepsy in tuberous sclerosis.

Tuberous sclerosis (TS) is an autosomal dominant disease that affects the brain, skin, eye, heart and kidney. The diagnostic criteria for tuberous sclerosis complex (TSC) have recently been revised. There are relatively few Indian studies on this disorder. Twenty-six patients diagnosed as having TS over a period of 18 years are being reported. The onset of seizures ranged from infancy to adolescence. The patterns of epilepsy encountered were generalized tonic clonic seizures (13), complex partial seizures (10), simple partial seizures (9) and myoclonic jerks (4) including infantile spasms (3). Patients often had more than one seizure type. Nineteen patients were mentally subnormal. Cutaneous manifestations were facial angiofibroma i.e. adenoma sebaceum (20), shagreen patches (7), hypopigmented macules (6), ash leaf spots (4), café-au-lait spots (2), facial hypoplasia (2) and periungual fibromas (1). One patient each had retinal phakoma and renal angiomyolipoma. CT scan revealed sub-ependymal calcifications (12), parenchymal tubers (3), cerebral edema (3) and cortical atrophy (1). One patient had enhancement of peri-ventricular sub-ependymal lesions on MRI. Anticonvulsants prescribed were phenobarbitone (20), diphenyl hydantoin (14), carbamazepine (8), sodium valproate (4), benzodiazepines (4), ACTH (2), prednisone (1), mysoline (1) and vigabatrin (1). Most patients were on combinations of anti-convulsants and response to therapy was usually not very satisfactory. However, the child treated with vigabatrin did well.

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.

Absence of GABRA1 Ala322Asp mutation in juvenile myoclonic epilepsy families from India.

An Ala322Asp mutation in the GABRA1 gene was recently reported to be responsible for causing the autosomal dominant (AD) form of juvenile myoclonic epilepsy (JME) in a French-Canadian family. To study if JME families from India exhibiting the AD mode of inheritance carry the Ala322Asp mutation, we examined 35 unrelated JME-affected individuals from such families for the Ala322Asp mutation in GABRA1. Ala322Asp mutation was not observed in any of these JME-affected individuals, suggesting that this mutation is unlikely to be a predominant mutation involved in causation of epilepsy. To evaluate the possibility of other mutation(s) in and around GABRA1 that may predispose to JME, we compared the allele frequencies at two marker loci, D5S2118 and D5S422, flanking GABRA1, in probands and 100 matched population controls. One of the allele frequencies at D5S422 shows a significant difference between the cases and controls (chi-square = 11.44, d.f. = 1, P = 0.0007), suggesting genetic association between JME and genes located in the proximity of the DNA marker.

Cryptococcosis in the immunocompromised host with special reference to AIDS.

Cryptococcosis is increasing because of an ever rising population of immunocompromised individuals especially those with acquired immune deficiency syndrome (AIDS). Cryptococcal infection of the central nervous system (CNS) were diagnosed in 149 cases over a period of 19.5 years (January 1978-June 1998). Culture was positive in all cases except three who were already on antifungal therapy. India ink mounts of cerebrospinal fluid (CSF) revealed encapsulated cryptococci in 134, and cryptococcal antigen was detected in 111 of 114 patients tested. A comparison of laboratory and certain clinical parameters in patients with and without associated HIV infection showed that a poor CSF cell response and culture of cryptococci from extra-neural sites was more often associated with HIV infection and was statistically significant. Further, presence of concomitant infection especially tuberculosis, and mortality were higher in the HIV positive group.

Profile of neurologic disorders associated with HIV/AIDS from Bangalore, south India (1989-96).

One hundred patients (95 males, 5 females, mean age at presentation 31.6 +/- 9.4 yr) with various neurological disorders associated with HIV infection during 1989-1996 were evaluated at NIMHANS, Bangalore. Eighty patients belonged to group I associated with opportunistic neuroinfections and 20 to group II--non infectious neurological disorders. Cryptococcal meningitis either alone (n = 31) or associated with tuberculous meningitis (n = 6) was the most common (46.3%) followed by neurotuberculosis either alone (n = 24) or with cerebral toxoplasmosis (n = 4) accounting for 35 per cent. Other opportunistic neuroinfections included cerebral toxoplasmosis, herpes zoster, fulminant pyogenic meningitis and neurosyphilis. Clinical characteristics, diagnostic clues, their laboratory and radiological profiles and problems encountered in diagnosis and management of these opportunistic infections are highlighted. In group II (19 males and one female; mean age of 32.6 +/- 9.4 yr), two patients had cortical dementia, three acute brain stem involvement, two epilepsy and one had features suggestive of progressive multifocal leukoencephalopathy. Two patients of group I during follow up developed cortical dementia. Six had peripheral nervous system involvement similar to Guillain-Barre syndrome. Sixty six patients (63 of group I and 3 of group II) progressed to AIDS, 33 patients from group I and one patient from group II succumbed to the disease. With the rapid increase in the incidence of HIV/AIDS and an increase in the neurological manifestations of HIV/AIDS it is important to recognise the magnitude of the problem for health planning in India.

Relationship of rectal & hippocampal temperature profiles to seizure activity in rats prone & resistant to hot water induced epilepsy.

The present study evaluates the relationship of seizure proneness, to core body and brain temperature following hot water stimulation with water of 55 degrees C in freely ambulant rats. The rectal and hippocampal temperatures were recorded in 40 rats with bathing that included the head, while 10 other rats had similar thermal stimulation, but of the body alone. Bipolar stainless steel electrodes were stereotactically implanted into the dorsal hippocampal regions which served the dual purpose of recording the seizure discharges as well as regional brain temperature. It was observed that in the seizure prone (SP) rats, the mean rate of rise in rectal temperature was 1.5 degrees C/min, whereas in the seizure resistant (SR) animals it was 0.78 degree C/ min. However, there was no noticeable difference in the rate of rise in brain temperatures between the SP and SR groups, the rate of rise being 0.3 degree C/min. In the rats subjected to hot water bath over the body (excluding the head), there was no seizure activity. Further, there was no change in the brain temperature recorded in these rats, despite the rate of rise in rectal temperature being similar to that in the SP rats. These observations indicate that two thermoregulatory factors operate in seizure proneness-viz., a rapid rise in core body temperature; and a rise in local brain temperature. Both should coexist in order to elicit a hyperthermic seizure in rats.

Effect of antiepileptic drugs and calcium channel blocker on hyperthermic seizures in rats: animal model for hot water epilepsy.

Hyperthermic seizures were elicited in groups of freely ambulant rats with jets of hot water of 55 degrees C on the head for about 10 mins. Bipolar depth EEG from the hippocampus and the behavioural seizures following the stimulation were recorded. The rectal temperature (threshold) for seizure initiation was 41.5 degrees C. The seizures were predominantly clonic jerks accompanied by large spikes and slow waves lasting for 30-60s. After 3 stimulations (once a day), Phenobarbitone (Pb) 0.02 mg/g daily, Diphenylhydantoin (DPH) 0.001 mg/g, 0.005 mg/g and 0.04 mg/g. daily and Nifedipine (Nif) 0.005 mg/g twice daily were administered intraperitoneally in different rats. During the 10-days injection trials, Pb completely suppressed seizures whereas DPH and Nif did not have any effect. One of the rats with DPH showed increased epileptic activity. After a 10 day 'washout' period' Pb and DPH were interchanged and again the rats were tested for seizures on 10 days. On changing over to Pb from DPH there was complete suppression of seizures and electrical seizure discharges. Whereas those rats which earlier had no seizure activity with Pb started showing the same on changing over to DPH.

Pathological lesions in HIV positive patients.

Pathomorphological features of 10 HIV positive individuals studied at autopsy and biopsy are described. Nine patients had evidence of neuro-AIDS and eight of them succumbed to various opportunistic infections. One surviving patient underwent a diagnostic lymph node biopsy which revealed tuberculous lymphadenopathy. Cryptococcal meningitis was the commonest CNS opportunistic infection, seen in five cases, with disseminated systemic cryptococcosis in two. The other opportunistic infections included toxoplasma encephalitis in two, with acanthamoeba infection in one patient. Pulmonary tuberculosis was noted in three patients while other bacterial infections such as meningococcal meningitis, pseudomonas septicaemia were observed in three and pneumocystis carinii pneumonia in one. One seropositive individual was clinically asymptomatic but succumbed to a road traffic accident. The brain in this case showed features of HIV associated early leucoencephalopathy. Bacterial infections caused by organisms other than Mycobacterium tuberculosis associated with AIDS are often underdiagnosed and should be considered, especially in developing countries. In cases of cryptococcal and tuberculous meningitis or multiple parasitic infections, the patients should be screened for associated HIV infection.

The role of immunological & virological techniques in the diagnosis of herpes simplex encephalitis.

The efficacy of immunological and virological methods in the diagnosis of herpes simplex encephalitis (HSE) was studied in 22 patients diagnosed as HSE by clinical, radiological EEG parameters. CSF cell counts were elevated in 14 of 18 patients with a lymphocytic predominance in 13. Virus specific IgG antibody detection by ELISA in paired CSF samples was possible in 8 of 17 patients. HSV antigen could be detected by immunohistochemical methods in the cells of the CSF and/or brain tissue in 7 of 9 patients. In four of them antemortem diagnosis was possible facilitating prompt specific antiviral therapy. Virus isolation was possible in 2 of 8 patients, one from brain biopsy tissue and the other from brain tissue obtained at autopsy. Using all the three methods, the diagnosis of HSE could be confirmed in 14 of 22 (63.6%) patients.

Prognosis of single unprovoked seizure.

201 patients (131 males and 70 females) with mean age of 18 years (range 5-55 years) who presented at median of 6 days after the onset of first unprovoked seizure were studied. They were followed for a mean period of 60 months (range 12-84 months). One hundred and fifty four (76%) patients were treated with anticonvulsant medication (group A) on a non-randomized basis and the remaining 47 patients (24%) were not treated (group B). Both the groups were comparable for age, sex, type of seizure and interval between onset of seizure and consultation. The cumulative risk of recurrence for entire study group was 24% at 1 month, 32% at 6 months, 34% at 12 months, 35% at 24 months and 36% at 36 months. The cumulative risk of recurrence in group A was 23%, 30%, 32%, 33% and 33% as compared to 28%, 36%, 40%, 43% and 45% at 1, 6, 12, 24 and 36 months respectively (p > 0.05). Maximum number of recurrences (67%) occurred within 1 month. No recurrence occurred after 36 months after the onset of first seizure. Age at onset, sex, seizure type, family history of seizure, EEG abnormalities and nature of antiepileptic drugs did not influence the risk of recurrence.

Herpes simplex encephalitis: a diagnostic and therapeutic reapprisal.

Herpes Simplex Encephalitis (HSE) appears to be underdiagnosed in India, though viral encephalitides constitutes an important entity with significant morbidity. With an upsurge in AIDS, HSE may perhaps emerge as an important opportunistic infection in future. We discuss the clinical features and laboratory evaluation of nine cases of HSE seen in the last 12 years at our center. Diagnosis was established by brain biopsy in one, virological studies in six and at autopsy in three. Immunocytochemically viral antigens could be localized in 4 biopsied/autopsied brain tissue and in CSF cells on a cytospin preparation in one. This has facilitated rapid diagnosis in our cases. Virus isolation was successful in two. Three subjects were treated with acyclovir and all survived with variable morbidity. Four patients expired and none of them had received any specific antiviral drugs. Rapid diagnosis and early treatment with acyclovir has been highlighted.