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|Year : 2001 | Volume
| Issue : 4 | Page : 360-5
Herpes simplex encephalitis in North West India.
Panagariya A, Jain RS, Gupta S, Garg A, Sureka RK, Mathur V
Department of Neurology, SMS Medical College and Hospital, Jaipur 302004, India.
Department of Neurology, SMS Medical College and Hospital, Jaipur 302004, India.
All patients admitted with provisional diagnosis of an encephalitic illness over a period of 30 months, were studied. Special investigations included CSF analysis, EEG, CT scan and MRI. Herpes simplex virus (HSV) antibody estimation in CSF and blood was done simultaneously using ELISA. Patients with diagnosis of cerebral venous thrombosis, cerebral malaria, tubercular meningitis etc, who resembled herpes simplex encephalitis (HSE), were excluded systematically with relevant investigations. 28 patients showed electroencephalographic, serologic and/or neuroradiological evidence of herpes simplex encephalitis. Males were affected more than females. Age ranged from 4 years to 65 years. Main clinical features included altered sensorium (100%) and seizures (89%). Serological test for HSV antibody in CSF and blood was positive in 14 patients. Fronto-temporal localisation was seen in EEG of 18 patients. CT and MRI were fairly characteristic with bilateral asymmetric fronto-temporal lesions. Patients with mild disease and who reported earlier responded well to treatment with acyclovir. Mortality was higher if treatment was delayed or if the disease was severe. Delayed treatment even in less severe cases produced neurological deficit in many survivors. Despite limitations of non-availability of CSF-PCR and serial estimation of HSV antibodies, the study is an attempt to highlight the value of high index of suspicion of HSE on clinical grounds, systematically excluding cases with different aetiologies resembling HSE and planning early antiviral therapy to reduce both mortality and morbidity associated with this fatal disease.
|How to cite this article:|
Panagariya A, Jain R S, Gupta S, Garg A, Sureka R K, Mathur V. Herpes simplex encephalitis in North West India. Neurol India 2001;49:360
occurring worldwide, contributing to 10-20% cases of viral encephalitis. Exact incidence of this disease is Herpes Simplex Encephalitis (HSE) is the most difficult to estimate, because only few patients with common cause of fatal sporadic acute encephalitis severe disease report to hospital whereas mild and self limiting cases usually go unrecognised. In India, HSE appears to be underdiagnosed, probably due to lack of awareness and diagnostic facilities. Curiously, till 1992 only occasional case reports were available. In 1993, Satish Chandra et al reported 9 cases of HSE and later in 1996 compiled data on 51 cases.
However, serological and clear epidemiological studies for viruses are not available in this part of the country, due to lack of virology research laboratories. Thus, percentage of cases of viral encephalitis and proportion of HSE are difficult to estimate. The early diagnosis of HSE is essential because early introduction of antiviral therapy can significantly decrease mortality and morbidity associated with this disease.
Patients from Rajasthan and adjoining areas of Uttar Pradesh, Haryana, Punjab with provisional diagnosis of encephalitic illness, admitted in Neurology Department of SMS Medical College, Jaipur over a period of 2½ years (March 1997 to September 1999) were studied in detail. The cases, presenting with progressive alteration of sensorium, behavioural abnormality, focal or generalised seizures with or without focal neurological deficit, preceded by a history of prodromal phase of headache, fever and other constitutional symptoms were included. Detailed neurological examination was conducted. Grading of altered sensorium was done as follows : Grade I - incoherence and mild confusion, Grade II drowsiness and moderate confusion, Grade III stupor, arousable on deep pain, Grade IV - coma, no response to external stimuli.
Special investigations included CSF analysis (cytology, biochemistry and serology), electroencephalogram (EEG), computed tomography (CT scan) and magnetic resonance imaging (MRI). HSV anti-body estimation in CSF and blood was done simultaneously with ELISA. Serial samples were not available. Only single titres were performed and interpreted. CSF polymerase chain reaction (PCR) and immuno-cytochemistry could not be done because of non-availability. All the routine investigations including haemogram, biochemistry, chest X-ray, blood film for malarial parasite and widal test were also done. A large number of cases were found to have different aetiologies like cerebral venous thrombosis, cerebral malaria, porphyria, enteric toxaemia and tubercular meningitis. The diagnosis was confirmed after relevant haematological, serological, biochemical and radiological findings. These cases were excluded from further analysis. Remaining 28 patients showed supportive evidences of HSE in the form of HSV antibody positivity in serum and CSF and/or characteristic EEG, periodic lateralised epileptiform discharges (PLED) or frontotemporal lateralisation, with neuroradiological changes on CT/MRI (bilateral asymmetric predominant frontotemporal lesion). Mini mental scale examination (MMSE) was used to estimate the level of cognitive impairment. Handicap and quality of life were graded with the Glasgow Outcome Scale [Table I].
Salient features of clinical profile, therapeutic response as well as prognostic observations are shown in Tables II and III. Males were affected more than females. The youngest patient was 4 years old and the eldest 65 years. Main clinical features were seizures (89%) and altered sensorium (100%). CSF examination was abnormal in 25 (90%) cases with (64%) patients [Figure. 1]. CT scan showed asymmetric frontotemporal lesions with or without haemorrhage in 18 (64%) cases [Figure. 2]. MRI was fairly characteristic with bilateral asymmetric frontotemporal lesions in all the 16 patients, in whom it was done [Figure. 3].
Out of the 28 patients, 18 reported within one week of the onset of symptoms. Of these, 13 patients had altered sensorium (grade I-II) and the disease was acute. Acyclovir was given to them immediately. 23% patients showed good recovery (Gr.-5), and 23% patients died. The remaining 5 patients in this group were stuporosed/comatosed on admission. They were given steroids along with acyclovir. Three patients (60%) survived with moderate residual deficits (Gr.-4) and two (40%) died. Out of 10 patients who reported after one week of onset of the first symptom, 3 were stuporosed/comatosed (grade III-IV) and they died early in the course of the disease, even after treatment with acyclovir and steroids. Remaining 7 patients were treated with acyclovir alone. Four of them (57%) survived with moderate residual deficits (Gr.-4), while 3 (43%) patients died.
Recovery with respect to higher mental function was judged with MMSE. Those, who recovered had normal orientation, attention and registration, but still had poor retentive memory. Remote memory on recovery was excellent in all the survivors. Short term memory was normal in 3 patients, mildly impaired in 10 patients and severely affected in 4 patients. All the survivors had mild to moderate residual naming defects. Other domains of language like - comprehension, writing and reading were improved significantly, while 8 patients had minimal non-fluent dysphasia. Severe anxiety, impaired concentration, insomnia, irritability, fatigue, poor motivation and emotional liability were noted in 42% of the patients. 6 patients had poorly controlled simple or complex partial seizures, with secondary generalisation despite anti-convulsant treatment.
HSV is a member of family of Herpes viridae, a DNA virus. HSE is more common in older age group and neonates where it is caused by HSV-I and HSV-II respectively. Whitley et al found no characteristic racial, age, sex or seasonal predilection. In this series, disease was more common in patients of age > 40 years and < 20 years. Male : Female ratio was 2:1 and disease was more common during summer and rainy season (61%). The term HSE is usually applied to focal and severe disease (acute necrotising encephalitis), which may be insidious to violent in onset. Prodromal phase of 4-10 days with nonspecific symptoms is common in HSE. 64% cases presented with acute onset and suffered from focal and severe disease. Prodrom characterised by fever and constitutional symptoms was observed in 82% of the patients. Common neurological manifestations included altered sensorium, seizures, abnormal behaviour, focal neurological deficit, ataxia, aphasia, visual field defects and papilloedema. Patients with abnormal behaviour had marked cognitive impairment in the form of disorientation to time, place and person, excitement and purposeless motor movements, which were not goal directed. Seizures occured within one week of the onset of neurological symptoms, mostly within three days. In 5 patients, seizures were the first symptom of nervous system involvement. Atypical cases included patients without focal deficit and slowly progressive course. About 20% cases in this study were without focal deficit and 36% had subacute onset. Such cases usually come to specialist at later stage and create diagnostic confusion.
Routine CSF examination is important in establishing the diagnosis of encephalitis but does not identify the causative viral agent. It may reveal mononuclear pleocytosis (50-200/mm3 with raised proteins. Because of haemorrhagic nature of the disease, RBCs may be present in upto 84% cases. However, normal CSF findings can be seen early in the disease. Hypoglycorrhachia is uncommon and should suggest search for a different diagnosis. CSF examination was done from 4th day to 15th day of the onset of the symptoms in our patients. 25 patients (90%) had similar findings in their CSF. Antibody detection in serum and CSF samples is for rapid diagnosis of HSE. Demonstration of four fold rise or fall in antibody titres using sequential paired samples though useful, has limited value in the management of HSE, since 10-14 day's interval is necessary between the two samples. The transient nature of IgM antibodies however, makes them useful diagnostic indicators of recent primary HSV infection. Though, measurement of antibodies in single specimen of serum and CSF lacks sensitivity, we interpreted the positivity (positive for IgM and/or IgG antibody) in relation to other supportive clinical, electroencephalo-graphic and neuro-radiological evidences. CSF-PCR is the diagnostic test of choice, which has sensitivity rate as high as 98-99% and specificity of 100%., Magnetic resonance imaging appears to be the most sensitive and specific neuroimaging method for HSE. It shows hyperintense signals on T2WI in medial temporal and inferior frontal areas bilaterally. These characteristic MRI findings seen in our patients are similar to MR lesions seen in PCR confirmed HSE patients of another series. MRI showed bilateral asymetrical fronto-temporal lesions in 12 cases, while bilateral isolated temporal lesions were seen in 4 patients. All the 4 patients were below the age of 19 years. None had unilateral lesion on MR Scan. FLAIR pulse sequence is more sensitive for early diagnosis of HSE, but it was not done in our patients. CT scan is less sensitive and shows delayed positivity in the form of fronto-temporal hypodensities with or without haemorrhage. 30 - 40% patients may have normal CT scan. CT scan was normal in 7 (25%) patients in whom it was done early after the onset of symptoms. In acute stage EEG appears to be more sensitive than CT scan. No specific EEG pattern is pathognomonic for HSE, but a focal or lateralised EEG abnormality in the form of spike/sharp wave or slow waves with temporal lobe localisation in presence of encephalitis strongly raises the suspicion of HSE and was noted in 10 patients. Periodic lateralised epileptiform discharges (PLEDs) from unilateral temporal lobe appear to be the most characteristic for the diagnosis of HSE and were present in 8 cases (28.5%). Diffuse slowing, indicating encephalopathy was present in 10 patients. Demonstration of virus in the brain biopsy is 100% confirmatory test. However, brain biopsy is now rarely undertaken, because of risk of haemorrhage and other complications. Brain biopsy was not done in any of our patients.
HSE is the only form of sporadic encephalitis which has a specific antiviral therapy i.e. acyclovir. Recommended daily dose of acyclovir is 10 mg/kg, 8 hourly, intravenously for 10 days. Low doses, for lesser duration, may result in the relapse of the disease., Some authors now advocate 3 weeks of treatment. We gave intravenous acyclovir for 2 weeks. There was no relapse in the survivors of our study, till date. Cases in which treatment was started at a very early stage, when the patients were only mildly ill (awake and alert) showed good recovery., HSE, in its severe form, is a cataclysmic condition which carries a mortality of 70-80%. Full recovery without any sequelae occurs in 38-56% of patients receiving early acyclovir therapy and it reduces mortality upto 19-30%., In present series, 77% patients with mildly altered sensorium, treated early with acyclovir alone, survived, with minimal or moderate neurological deficit (Gr.-4/5). Steroids along with acyclovir were effective in critically ill patients of this group. Though our experience is with only a small number of patients, steroids could have an important role in overall recovery. However there are no control studies for guidance. In stuporosed/comatosed and severely ill cases who reported later, even steroids along with acyclovir could not prevent mortality.
Morbidity in even treated HSE is very high., Though 61% survivors of this study regained partial or full independence in activities of daily living, most of these people had persistent neurological symptoms/signs or both. Residual focal deficits (42.8%), abnormal behaviour (42.8%) and seizures (35.7%) were the major residual sequelae. Memory disturbances, anosmia, dysphasia and naming defects are the other long term residual deficits usually seen in these patients and were present in varying degrees in the survivors of this series.
Thus clinical degree of severity, the duration of illness prior to treatment with acyclovir and state of consciousness at the initiation of antiviral therapy are of prognostic significance. The limitations of this study were lack of serial antibody estimation and CSF-PCR (due to non availability). This is an attempt to highlight the value of high index of suspicion on clinical grounds, systematically excluding those cases with different aetiologies resembling HSE. Various authors have recommended initiation of specific antiviral therapy (acyclovir) in such situations.,,, Since the disease HSE is not very uncommon and carries a very high mortality and morbidity in absence of treatment, and further, since the antiviral drug, acyclovir is quite innocuous as well as effective, if used early in the course, a clinical criteria of diagnosis by exclusion and relevant supportive evidences with EEG, neuroradiology and CSF examination may prove to be practical in initiating treatment in most of the centres in Indian conditions.
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