Khean Jin Goh

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.

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

The Clinical Syndrome Associated with Lumbar Spinal Stenosis

Lumbar spinal stenosis is well defined in patho-anatomical terms but its clinical features are heterogeneous. We carried out a comprehensive retrospective review of the clinical features, radiological changes and outcome of 75 patients with radiologically diagnosed lumbar spinal stenosis in order to define its clinical spectrum. The presenting complaints were of weakness, numbness/tingling, radicular pain and neurogenic claudication in almost equal proportions. The commonest symptom was numbness or tingling of the legs. Neurogenic claudication eventually occurred in only 61%. Ninety-three per cent showed abnormalities on neurological examination, but these were generally mild with reduced ankle jerks being commonest. Imaging of the lumbar spine showed that moderate to severe central spinal stenosis correlated with complaints of weakness and abnormal motor power on clinical examination. Patients were reviewed at a mean of 4 years after diagnosis and 65% had undergone surgical decompression; this was not a prospective comparison of different treatment modalities. Overall, a third of patients felt that their symptoms had improved while a quarter felt that they had worsened. More than half had satisfactory neurological function at the time of review. Thirty-nine per cent of those treated surgically, and 25% of those managed conservatively, reported improved symptoms. A poorer functional status at review correlated with complaints of motor weakness and associated comorbid disease. Degenerative lumbar stenosis is a clinically heterogeneous neurological disorder of the lower limbs in the elderly with variable longer-term outcome. A high index of suspicion is required and neuroimaging should be obtained to confirm the diagnosis.

Botulinum toxin injection for hypertonicity of the upper extremity within 12 weeks after stroke: a randomized controlled trial.

Background. Botulinum neurotoxin type A (BoNT-A) reduces upper-extremity poststroke spasticity when given 6 or more months after stroke. Effects on functional use of the arm and hand are less apparent. Objective. To determine the effect and safety of very early use of BoNT-A for patients with upper-limb spasticity. Methods. The Asia Botulinum Toxin-A Clinical Trial Designed for Early Post-stroke Spasticity (ABCDE-S; NCT00234546) was a multicenter, randomized, placebo-controlled trial conducted in patients recruited within 2 -12 weeks of first-ever stroke. Participants with a Modified Ashworth Scale (MAS) score of 1+ or above received BoNT-A (Dysport) 500 U or placebo to one or more wrist and elbow mover muscles, plus unstructured rehabilitation. The primary outcome was the MAS score in the most affected joint 4 weeks after first injection. Follow-up was 24 weeks. Results. A total of 163 patients were enrolled and assigned to placebo (n = 83) or BoNT-A (n = 80). Mean time since stroke was about 7 weeks. At 4 weeks postinjection, BoNT-A significantly improved MAS scores. Treatment effect-size estimates increased with higher baseline MAS scores from 0.45 (Q1) to 0.70 (Q3). MAS scores for all secondary end points improved with BoNT-A versus placebo at all time points (P < .0001, all visits). The Functional Motor Assessment Scale did not reveal clinically significant differences. No group differences in adverse events were found. Interpretation. BoNT-A 500 U can provide a sustained reduction in poststroke upper-limb spasticity when combined with rehabilitation in Asian patients who have mild-to-moderate hypertonicity and voluntary movement, within 2 -12 weeks of stroke. Functional use of the arm and hand was not affected.

Serological Evidence of Possible Human Infection with Tioman virus, a Newly Described Paramyxovirus of Bat Origin

Tioman virus, a relatively new paramyxovirus, was isolated from fruit bats (Pteropus species) on Tioman Island, Malaysia, in 2001. The objective of this study was to determine the prevalence of antibodies to T. virus in island inhabitants, by use of comparative ELISA and serum neutralization assays. Of the 169 human sera analyzed, 5 (approximately 3.0%) were positive for T. virus, by comparative ELISA. Of these 5 sera, 3 (1.8% of the total) had neutralizing antibodies against T. virus, suggesting previous infection of this study population by this virus or a similar virus.

Myopathic dropped head syndrome: a syndrome of mixed aetiology.

We report two patients with myopathic dropped head syndrome, a rare and interesting neuromuscular syndrome characterised by a predominant weakness of the neck extensor muscles. The first patient, a middle aged Chinese man, presented with progressive weakness of neck extension but his clinical course later stabilised despite a lack of response to corticosteroids. Muscle biopsy revealed a necrotising myopathy with no evidence of inflammation. This patient supports the existence of an idiopathic restricted non-inflammatory myopathy, a so called isolated neck extensor myopathy syndrome which is recognised to pursue a less progressive, more benign course. Our second patient had histopathological evidence for polymyositis; there was a favourable response to steroids. Our cases underscore the fact that there may be a spectrum of pathological processes associated with the myopathic dropped head syndrome ranging from non-inflammatory muscle necrosis to a full blown inflammatory myositis.