Neuropsychiatric Sequelae of Nipah Virus Encephalitis

This is a prospective epidemiological study conducted at the National Neuroscience Institute in Singapore. Case definition is based on epidemiologic and serological diagnosis of Nipah virus infections. Patients underwent psychiatric evaluation and neuropsychological testing 2 years after the outbreak. The neurologic examination and neuroimaging were also reviewed. The research discussed in this article is essentially a late study of viral effect.

In Singapore, 13 patients (12 men and one woman) were affected by the Nipah virus outbreak. One patient died of his disease (mortality rate of 7.7%), and of the 12 surviving patients, three were lost to follow-up or did not present for imaging or psychological assessment. Nine patients underwent neuropsychiatric interview and eight patients underwent neuropsychological testing. Of the nine patients studied, there were eight males and one female; eight Chinese and one Indian; five Singaporeans and four Malaysians. Their ages ranged from 24 to 55 years (mean=40.8, SD=10.9). Seven patients worked in the abattoir and were involved either in the slaughtering of pigs or in the cleaning and processing of the carcasses. Two subjects were pig farmers from Malaysia.

Eight of nine patients suffered from neurological deficits, psychiatric sequelae or cognitive impairment; only one made a complete recovery. Table 1 summarizes the number and location of brain lesions on initial MR imaging, the residual clinical signs at 24 months, employment status at 24 months, psychiatric diagnosis, and extent of cognitive impairment detected by neuropsychological testing.

Five of the nine cases developed major depressive disorder following the encephalitis. These five cases all had cognitive and emotional symptoms of depression, like hopelessness, feelings of worthlessness and suicidal thoughts. Of the five, three became depressed shortly after their discharge from the hospital while two became depressed about 1 year after the outbreak. Four cases responded favorably to antidepressants therapy and supportive psychotherapy, while one patient refused psychiatric interventions and remained chronically depressed. There were two patients who developed personality changes, and two suffered chronic fatigue syndrome. Only one patient had no psychiatric diagnosis. Also, in this study, we found that four patients needed help coping with uncertainty. Although they had survived the initial critical period of viral encephalitis, many of them had complications arising from the illness, both physical and mental. Furthermore, recovering patients faced uncertainty and anxiety over reports of relapsed patients in Western Malaysia, although to date no such cases had been reported in the Singapore cohort.

In Nipah virus encephalitis, the diversity and multifocality of neurological manifestations are particularly striking.⁵ Histologically, widespread vascular endothelial infection and microinfarction have been demonstrated in Nipah virus infection,² and Lim et al.⁷ have proposed that the lesions seen on MRI may represent vasculitic small vessel cerebral infarction. Our series of cases would be representative of the population of post-Nipah virus encephalitis patients. There are no selection biases that may have influenced the findings in this case series.

Psychiatric sequelae, especially depression, are common and constitute a major cause of disability following recovery from viral encephalitis caused by other viruses.¹⁶ Depression, cognitive deficits, personality changes and chronic fatigue have been noted months after recovery. In our study, we found patients suffering from depressive symptoms, personality change, and chronic fatigue syndrome. None of our cases had mania, obsessive-compulsive disorder, or psychosis: these have been reported in other postencephalitis syndromes.^17,18

We find that depression following Nipah virus encephalitis is phenomenologically indistinguishable from an idiopathic depressive disorder. Sadness, anhedonia, loss of energy, weight loss, insomnia, psychomotor agitation or retardation, feelings of worthlessness or hopelessness, diminished ability to concentrate, and thoughts of death or suicide are the characteristic features. In DSM-IV symptoms that are attributable to physical causes are not counted towards a diagnosis of major depression. Our five cases of major depression all had cognitive and emotional symptoms of depression, like hopelessness, feelings of worthlessness and suicidal thoughts. The origins of the mood changes are likely to be multifactorial, including brain dysfunction, functional incapacity, and role changes in society and in the family. The patient’s premorbid personality and adequacy of family support and social resources further condition the behavioral response to the brain disorder.

Two of our patients suffered from chronic fatigue. It seems probable that infection involving the central nervous system has a greater propensity to cause fatigue. Viruses are thought to cause organic brain syndromes in two ways—one is direct action of the virus within the CNS, the other is secondary to an autoimmune or hypersensitivity reaction to the virus either within or outside the CNS.¹⁷

We found neuropsychological testing helpful in fully delineating the extent of cognitive damage. Formal testing is extremely useful in assessing the patient’s cognitive limitations, in following the progress of the disease and in treatment planning. Despite their clinical subtlety, these deficits have significant practical implications for patients’ ability to return to their normal lifestyle.¹⁸ It appears that the subjects in our study had more problems in verbal memory functions than with visual memory functions, and this pattern of verbal memory deficits may be a result of Nipah virus infection. However, an alternative explanation is that it could be easier for the subjects to compensate for visual memory loss than verbal memory loss and consequently, they had more problems in verbal memory functions.

The anatomical location of brain lesions in other organic brain diseases has been shown to be an important factor in determining which patients become depressed. Depression occurs most frequently in patients with lesions affecting the frontal and temporal lobes and the basal ganglia, particularly the caudate nuclei.¹⁶ Additionally, the number and location of MRI lesions did not correlate with the severity of clinical findings in this study.⁴ Therefore, the method of measuring lesion burden by counting the number of abnormalities visible on MRI may not be clinically useful in this new disease.