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.     

Neuropsychiatric sequelae of Nipah virus encephalitis

The authors followed nine patients with Nipah virus encephalitis over the course of 24 months. Eight of the nine developed psychiatric features assigned to the encephalitis. Three patients developed major depressive disorder immediately after recovering from the encephalitis, and two developed depression approximately 1 year after the outbreak. Two patients developed personality changes, and two suffered chronic fatigue syndrome. Neuropsychological testing was accomplished in eight of the nine patients. Deficits in attention, verbal, and/or visual memory were substantial in seven of the eight patients tested. Verbal memory was more impaired than visual memory in these patients. Comparison between psychiatric and cognitive impairment and total number of brain lesions showed no discernible trends.     

The neurological manifestations of Nipah virus encephalitis, a novel paramyxovirus.

A novel Hendra-like paramyxovirus named Nipah virus (NiV) was the cause of an outbreak among workers from one abattoir who had contact with pigs. Two patients had only respiratory symptoms, while 9 patients had encephalitis, 7 of whom are described in this report. Neurological involvement was diverse and multifocal, including aseptic meningitis, diffuse encephalitis, and focal brainstem involvement. Cerebellar signs were relatively common. Magnetic resonance imaging scans of the brain showed scattered lesions. IgM antibodies against Hendra virus (HeV) were present in the serum of all patients. Two patients recovered completely. Five had residual deficits 8 weeks later.     

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.     

Nipah virus: An emergent paramyxovirus causing severe encephalitis in humans

Nipah virus is a recently emergent paramyxovirus that is capable of causing severe disease in both humans and animals. The first outbreak of Nipah virus occurred in Malaysia and Singapore in 1999 and, more recently, outbreaks were detected in Bangladesh. In humans, Nipah virus causes febrile encephalitis with respiratory syndrome that has a high mortality rate. The reservoir for Nipah virus is believed to be fruit bats, and humans are infected by contact with infected bats or by contact with an intermediate animal host such as pigs. Person to person spread of the virus has also been described. Nipah virus retains many of the genetic and biologic properties found in other paramyxoviruses, though it also has several unique characteristics. However, the virologic characteristics that allow the virus to cause severe disease over a broad host range, and the epidemiologic, environmental and virologic features that favor transmission to humans are unknown. This review summarizes what is known about the virology, epidemiology, pathology, diagnosis and control of this novel pathogen.     

Late presentation of Nipah virus encephalitis and kinetics of the humoral immune response

Nipah virus is a newly discovered paramyxovirus transmitted directly from pigs to humans. During a large encephalitis outbreak in Malaysia and Singapore in 1998-9, most patients presented acutely. A 12 year old child is described who developed encephalitis 4 months after exposure to the virus. She was diagnosed by a new indirect IgG enzyme linked immunosorbent assay (ELISA), which is also described. The late presentation and IgG subclass responses had similarities to subacute sclerosing panencephalitis. Nipah virus should be considered in patients with encephalitis even months after their possible exposure.     

Treatment of disturbances of consciousness caused by measles encephalitis with levodopa.

Results are reported of a double-blind trial with L-dopa in 39 patients with measles encephalitis. In this treatment series, L-dopa improved the state of awareness and the diffuse disturbances in the EEG. There was a significant difference too, regarding the outcome between patients treated with L-dopa and placebo. The death rate in the L-dopa-treated group was lower and there were fewer mental sequelae. It is suggested, that L-dopa should be used in patients with measles encephalitis.     

A case of non-herpetic acute limbic encephalitis in childhood--comparison with acute encephalitis with refractory repetitive partial seizures (AERRPS)

A 9-year-old boy was diagnosed as non-herpetic acute limbic encephalitis (NHALE). Four days after the gastrointestinal infection, he developed a generalized seizure accompanied with delirium and psychiatric change, which evolved into intractable seizures. These seizures were complex partial seizures or generalized tonic clonic seizures, and were highly resistant to many anticonvulsants. Magnetic resonance imaging of the brain demonstrated reversible symmetrical high-intensity lesions in the claustra on the diffusion-weighted image. Laboratory findings did not suggest herpes simplex virus infection. Further, the clinical findings were consistent with those in acute encephalitis with refractory repetitive partial seizures (AERRPS). We assume that a part of AERRPS belongs to the category of parainfectious limbic encephalitis with repetitive seizures.     

Rasmussen encephalitis and non-herpetic acute limbic encephalitis]

Rasmussen syndrome (RS) and non-herpetic acute limbic encephalitis (NHALE) have pathophysiological background related with autoimmunity to glutamate receptors (GluRs) after infections. RS and NHALE were reviewed, depending mainly on our recent studies. RS is the prototype of autoimmune-mediated epilepsy. In patients with RS, several kinds of autoantibodies against neuronal molecules, for example, GluR3, GluRepsilon2 (NMDA-R2B), etc., are reported. These autoantibodies are not specific for RS. About autoantibodies against GluR3, significance and stimulating effects to GluR3 are controversial. Autoantibodies against GluRepsilon2 were detected in all patients within six months from epilepsy onset, and in some patients at chronic stage. These data suggest that autoantibodies against GluRepsilon2 may be involved in the pathological mechanisms in the early stage, but we could not confirm the effect of the autoantibodies from RS patients on excitatory postsynaptic NMDA current using patch clump methods. However, anti-double-stranded DNA antibodies in patients with SLE are reported to cross-react with n-terminal of GluRepsilon2, and cause neuronal apoptosis in rat hippocampus, ensuing memory impairment, and emotional behavior impairment in mice. Therefore, autoantibodies against GluRepsilon2 may contribute to the cognitive and behavioral changes in RS. Concerning about cellular immunity in RS, lymphocytes stimulating tests revealed peripheral lymphocytes sensitized by antigens containing GluRepsilon2. Cytotoxic T cells (CTLs) excreting Granzyme B were reported in resected brain tissue, and we confirmed the elevated levels of Granzyme B, not in sera, but in CSF. These data suggest that CTLs activated by infection invade into CNS, and recognize neural antigens, and excrete Granzyme B. The incidence of NHALE is 4.1/1 million/year in Japanese adults. Our study in 91 adult patients with NHALE revealed the following characteristics. Mean onset age was 35.2 +/- 16.9 years old, and preceding infections existed in 68.7% of patients, and predominant symptoms at the onset were psychiatric symptoms (33.3%) and convulsions (25.0%). CSF showed slightly elevated cell counts (55.5 +/- 139.9), protein levels (48.1 +/- 36.0 mg/dl), and IgG levels (4.5 +/- 3.9 mg/dl). MRI lesions with high intensity were found in 40.8% (DWI) and 54.2% (FLAIR) of patients in various stages after onsets. Autoantibodies against GluRepsilon2 in sera were detected in approximately 60% of NHALE patients from acute to chronic stages, and the autoantibodies in CSF were detected in 51.8% (acute stage), 41.4% (recovery stage), 28.6% (chronic stage) of patients and included epitopes to n-terminal of GluRepsilon2 (NT1). These data suggest that autoantibodies against GluRepsilon2 produced in sera after infection infiltrate into CNS through damaged BBB in acute stages, and affect n-terminal of GluRepsilon2. In chronic stage, recovery of function of BBB reduces levels of the autoantibodies in CSF. Because BBB in hippocampi and amygdala are vulnerable, autoantibodies against GluRepsilon2 including epitopes to n-terminal may contribute to the limbic symptoms around onset. Among several autoantibodies related with NHALE, autoantibodies against GluRepsilon2 were found in patients around 15-34 years old, autoantibodies against VGKC were around 50.4 years old, autoantibodies against NAE were around 59 years old, autoantibodies against Hu were around 61.5 years old. These data suggest that autoantibodies related with NHALE have age-dependent heterogeneity.     

Treatment of Bickerstaff's brainstem encephalitis with immune globulin

Bickerstaff's brainstem encephalitis (BBE) is an immune disorder of unknown etiology. Previous reports of successful treatment of BBE involved steroids or plasma exchange. We describe a patient with BBE who demonstrated rapid clinical recovery after treatment with intravenous immune globulin. Our findings suggest that IVIg is an alternative treatment in BBE, especially when plasma exchange is difficult or contraindicated. Our patient also demonstrated pseudoretraction and pseudoptosis during clinical recovery, an observation which supports a differential immune attack on components of the third nerve or supranuclear regions, and expands our understanding of the pathophysiology of BBE.     

The epidemiology of acute encephalitis

Encephalitis means inflammation of the brain matter. Despite being a rare condition, encephalitis is of public health importance worldwide because it has high morbidity and mortality. Yet, many details about its epidemiology have yet to be elucidated. This review attempts to summarise what is known about the epidemiology of the infective causes of encephalitis and is based on a literature search of the Medline archives. Infection is the most common cause identified, with viruses being the most important known aetiological agents. Incidence varies between studies but is generally between 3.5 and 7.4 per 100,000 patient-years. Encephalitis affects peoples of all ages; however, incidence is higher in the paediatric population. Although both sexes are affected, most studies have shown a slight predominance in males. Encephalitis occurs worldwide; some aetiologies have a global distribution (herpesviruses) while others are geographically restricted (arboviruses). Although definite epidemiological trends are evident, it is difficult to make generalisations as few population-based studies exist, most cases are not reported to health authorities, and many possible pathogens are implicated but in most cases a cause is never found. A better understanding of the epidemiology of this devastating disease will pave the way for better prevention and control strategies.