Chong Tin Tan

Fatal encephalitis due to Nipah virus among pig-farmers in Malaysia

BACKGROUND Between February and April, 1999, an outbreak of viral encephalitis occurred among pig-farmers in Malaysia. We report findings for the first three patients who died. METHODS Samples of tissue were taken at necropsy. Blood and cerebrospinal-fluid (CSF) samples taken before death were cultured for viruses, and tested for antibodies to viruses. FINDINGS The three pig-farmers presented with fever, headache, and altered level of consciousness. Myoclonus was present in two patients. There were signs of brainstem dysfunction with hypertension and tachycardia. Rapid deterioration led to irreversible hypotension and death. A virus causing syncytial formation of vero cells was cultured from the CSF of two patients after 5 days; the virus stained positively with antibodies against Hendra virus by indirect immunofluorescence. IgM capture ELISA showed that all three patients had IgM antibodies in CSF against Hendra viral antigens. Necropsy showed widespread microinfarction in the central nervous system and other organs resulting from vasculitis-induced thrombosis. There was no clinical evidence of pulmonary involvement. Inclusion bodies likely to be of viral origin were noted in neurons near vasculitic blood vessels. INTERPRETATION The causative agent was a previously undescribed paramyxovirus related to the Hendra virus. Close contact with infected pigs may be the source of the viral transmission. Clinically and epidemiologically the infection is distinct from infection by the Hendra virus. We propose that this Hendra-like virus was the cause of the outbreak of encephalitis in Malaysia.

Clinical features of Nipah virus encephalitis among pig farmers in Malaysia.

BACKGROUND Between September 1998 and June 1999, there was an outbreak of severe viral encephalitis due to Nipah virus, a newly discovered paramyxovirus, in Malaysia. METHODS We studied the clinical features of the patients with Nipah virus encephalitis who were admitted to a medical center in Kuala Lumpur. The case definition was based on epidemiologic, clinical, cerebrospinal fluid, and neuroimaging findings. RESULTS Ninety-four patients with Nipah virus infection were seen from February to June 1999 (mean age, 37 years; ratio of male patients to female patients, 4.5 to 1). Ninety-three percent had had direct contact with pigs, usually in the two weeks before the onset of illness, suggesting that there was direct viral transmission from pigs to humans and a short incubation period. The main presenting features were fever, headache, dizziness, and vomiting. Fifty-two patients (55 percent) had a reduced level of consciousness and prominent brain-stem dysfunction. Distinctive clinical signs included segmental myoclonus, areflexia and hypotonia, hypertension, and tachycardia and thus suggest the involvement of the brain stem and the upper cervical spinal cord. The initial cerebrospinal fluid findings were abnormal in 75 percent of patients. Antibodies against Hendra virus were detected in serum or cerebrospinal fluid in 76 percent of 83 patients tested. Thirty patients (32 percent) died after rapid deterioration in their condition. An abnormal dolls-eye reflex and tachycardia were factors associated with a poor prognosis. Death was probably due to severe brain-stem involvement. Neurologic relapse occurred after initially mild disease in three patients. Fifty patients (53 percent) recovered fully, and 14 (15 percent) had persistent neurologic deficits. CONCLUSIONS Nipah virus causes a severe, rapidly progressive encephalitis with a high mortality rate and features that suggest involvement of the brain stem. The infection is associated with recent contact with pigs.

Nipah Virus Infection: Pathology and Pathogenesis of an Emerging Paramyxoviral Zoonosis

In 1998, an outbreak of acute encephalitis with high mortality rates among pig handlers in Malaysia led to the discovery of a novel paramyxovirus named Nipah virus. A multidisciplinary investigation that included epidemiology, microbiology, molecular biology, and pathology was pivotal in the discovery of this new human infection. Clinical and autopsy findings were derived from a series of 32 fatal human cases of Nipah virus infection. Diagnosis was established in all cases by a combination of immunohistochemistry (IHC) and serology. Routine histological stains, IHC, and electron microscopy were used to examine autopsy tissues. The main histopathological findings included a systemic vasculitis with extensive thrombosis and parenchymal necrosis, particularly in the central nervous system. Endothelial cell damage, necrosis, and syncytial giant cell formation were seen in affected vessels. Characteristic viral inclusions were seen by light and electron microscopy. IHC analysis showed widespread presence of Nipah virus antigens in endothelial and smooth muscle cells of blood vessels. Abundant viral antigens were also seen in various parenchymal cells, particularly in neurons. Infection of endothelial cells and neurons as well as vasculitis and thrombosis seem to be critical to the pathogenesis of this new human disease.

Relapsed and late-onset Nipah encephalitis.

An outbreak of infection with the Nipah virus, a novel paramyxovirus, occurred among pig farmers between September 1998 and June 1999 in Malaysia, involving 265 patients with 105 fatalities. This is a follow‐up study 24 months after the outbreak. Twelve survivors (7.5%) of acute encephalitis had recurrent neurological disease (relapsed encephalitis). Of those who initially had acute nonencephalitic or asymptomatic infection, 10 patients (3.4%) had late‐onset encephalitis. The mean interval between the first neurological episode and the time of initial infection was 8.4 months. Three patients had a second neurological episode. The onset of the relapsed or late‐onset encephalitis was usually acute. Common clinical features were fever, headache, seizures, and focal neurological signs. Four of the 22 relapsed and late‐onset encephalitis patients (18%) died. Magnetic resonance imaging typically showed patchy areas of confluent cortical lesions. Serial single‐photon emission computed tomography showed the evolution of focal hyperperfusion to hypoperfusion in the corresponding areas. Necropsy of 2 patients showed changes of focal encephalitis with positive immunolocalization for Nipah virus antigens but no evidence of perivenous demyelination. We concluded that a unique relapsing and remitting encephalitis or late‐onset encephalitis may result as a complication of persistent Nipah virus infection in the central nervous system.

Treatment of acute Nipah encephalitis with ribavirin

Nipah virus, a newly identified paramyxovirus caused a severe outbreak of encephalitis in Malaysia with high fatalities. We report an open‐label trial of ribavirin in 140 patients, with 54 patients who were managed prior to the availability of ribavirin or refused treatment as control. There were 45 deaths (32%) in the ribavirin arm; 29 deaths (54%) occurred in the control arm. This represents a 36% reduction in mortality (p = 0.011). There was no associated serious side effect. This study suggests that ribavirin is able to reduce the mortality of acute Nipah encephalitis.

Viral encephalitis and epilepsy.

Viral encephalitis presents with seizures not only in the acute stage but also increases the risk of late unprovoked seizures and epilepsy. Acute symptomatic and late unprovoked seizures in different viral encephalitides are reviewed here. Among the sporadic viral encephalitides, Herpes simplex encephalitis (HSE) is perhaps most frequently associated with epilepsy, which may often be severe. Seizures may be the presenting feature in 50% patients with HSE because of involvement of the highly epileptogenic frontotemporal cortex. The occurrence of seizures in HSE is associated with poor prognosis. In addition, chronic and relapsing forms of HSE have been described and these may be associated with antiepileptic drug‐resistant seizures. Among the epidemic (usually due to flaviviruses) viral encephalitides, Japanese encephalitis (JE) is most common and is associated with acute symptomatic seizures, especially in children. The reported frequency of acute symptomatic seizures in JE is 7–46%. Encephalitis due to other flaviviruses such as equine, St. Louis, and West Nile viruses may also manifest with acute symptomatic seizures. In Nipah virus encephalitis, seizures are more common in relapsed and late‐onset encephalitis in comparison to acute encephalitis (4% vs. 1.8%). Other viruses like measles, varicella, mumps, influenza, and entero‐viruses may cause seizures depending on the area of brain involved. There is no comprehensive data regarding late unprovoked seizures in different viral encephalitides. Prospective studies are required to document the risk of late unprovoked seizures and epilepsy following viral encephalitis due to different viruses as well as to determine the clinical characteristics, course, and outcome of post‐encephalitic epilepsy.

Nipah encephalitis outbreak in Malaysia, clinical features in patients from Seremban.

BACKGROUND An outbreak of viral encephalitis occurred among pig industry workers in Malaysia in September 1998 to April 1999. The encephalitis was attributed to a new paramyxovirus, Nipah virus. This is a description of the clinical features of 103 patients treated in the Seremban Hospital with characterization of the prognostic factors. METHODS Clinical case records and laboratory investigations were reviewed. The case definition was: patients from the outbreak area, direct contact or in close proximity with pigs, clinical or CSF features of encephalitis. RESULTS The mean age was 38 years, 89% were male, 58% were ethnic Chinese, 78% were pig farm owners or hired workers. The mean incubation period was 10 days. The patients typically presented with nonspecific systemic symptoms of fever, headache, myalgia and sore throat. Seizures and focal neurological signs were seen in 16% and 5% respectively. In the more severe cases, this was followed by drowsiness and deteriorating consciousness requiring ventilation in 61%. Autonomic disturbances and myoclonic jerks were common features. The mortality was high at 41%. Systolic hypertension, tachycardia and high fever were associated with poor outcome. On the other hand, 40% recovered fully. As for the other 19%, the residual neurological signs were mostly mild. CONCLUSION Nipah virus caused an encephalitis illness with short incubation period and high mortality. The prognosis for the survivors was good.

Long-term neurological and functional outcome in nipah virus infection

Nipah virus (NiV) is an emerging zoonosis. Central nervous system disease frequently results in high case‐fatality. Long‐term neurological assessments of survivors are limited. We assessed long‐term neurologic and functional outcomes of 22 patients surviving NiV illness in Bangladesh.

High mortality in Nipah encephalitis is associated with presence of virus in cerebrospinal fluid.

During the outbreak of Nipah virus encephalitis in Malaysia, stored cerebrospinal fluid (CSF) samples from 84 patients (27 fatal and 57 nonfatal cases) were cultured for the virus. The virus was isolated from 17 fatal cases and 1 nonfatal case. There were significant associations between CSF virus isolation and mortality as well as clinical features associated with poor prognosis. In addition, there was a positive linear correlation of CSF virus isolation with age. There was no significant association between CSF virus isolation and the character of the CSF, presence of Nipah‐specific antibody in the serum or CSF, duration of illness before collection of samples, or sex or ethnicity of the patients. This study suggests that high viral replication in the central nervous system may be an important factor for high mortality. Ann Neurol 2000;48:802–805

ABCB1 C3435T polymorphism and the risk of resistance to antiepileptic drugs in epilepsy: a systematic review and meta-analysis.

OBJECTIVE The C3435T, a major allelic variant of the ABCB1 gene, is proposed to play a crucial role in drug-resistance in epilepsy. The C/C genotype carriers reportedly are at higher risk of pharmacoresistance to AEDs, but only in some studies. The hypothesis of the C-variant associated risk and resistance to antiepileptic drugs (AEDs) has been hampered by conflicting results from inadequate power in case-control studies. To assess the role of C3435T polymorphism in drug-resistance in epilepsy, a systematic review and meta-analysis was conducted. METHODS Databases were obtained from the Cochrane Library, MEDLINE, EMBASE, major American and European conference abstracts, and www.google.my for genetic association studies up to February 2010. All the case-control association studies evaluating the role of ABCB1 C3435T in pharmacoresistance to AEDs were identified. The new definition of treatment outcome from International League Against Epilepsy (ILAE) was used for including studies for sub-analysis. To measure the strength of genetic association for the gene variant, the odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using models of both fixed- and random-effects for comparisons of the alleles and genotypes with co-dominant (C/C vs. T/T, C/T vs. T/T), dominant (C/C+C/T vs. T/T), and recessive (C/C vs. C/T+T/T) models in overall and in ethnicity subgroups. The 19 studies were selected for the next sub-analysis based on the new definition of drug-responsiveness and drug-resistance from ILAE. The same analysis was also performed for treatment outcome and ethnicity subgroups. RESULTS A total of 22 association studies including 3231 (47.8%) drug-resistant patients and 3524 (52.2%) drug-responsive patients or healthy controls (genotyped for C3435T) were pooled in this meta-analysis. The allelic association of ABCB1 C3435T with risk of drug-resistance was not significant under fixed-effects model, 1.06 (95% CI 0.98-1.14, p=0.12) and random-effects model, 1.10 (0.93-1.30, p=0.28) in overall and in the subgroup analysis by ethnicity. Similar results were also obtained for all genetic models in the stratified analyses by new definition of drug-resistance by ILAE and ethnicity subgroups. There was no publication bias. CONCLUSION We failed to show an association between the ABCB1 C3435T polymorphism and the risk of drug-resistance suggesting a revision in contribution of this polymorphism in the multi-drug transporters hypothesis of pharmacoresistance to AEDs in epilepsy.