Back to the future: encephalitis lethargica as an autoimmune disorder?

More than 100 years after its emergence, the exact pathophysiological mechanisms underlying encephalitis lethargica (EL) are still elusive and awaiting convincing and complete elucidation. This article summarizes arguments proposed over time to support or refute the hypothesis of EL as an autoimmune neuropsychiatric disorder triggered by an infectious process. It also provides a critical evaluation of modern cases labeled as EL and a comprehensive differential diagnosis of autoimmune neurological conditions that could mimic EL. The evidence supporting the autoimmune nature of historical EL is sparse and not entirely convincing. It is possible that autoimmune mechanisms were involved in the pathogenesis of this disease as an idiosyncratic response to a yet unidentified infectious agent in genetically predisposed individuals. Although there has been an increase in the incidence of presumed autoimmune encephalomyelitis since the peak of EL pandemics, most evidence does not support an underlying autoimmune mechanism. There are significant differences between historical and recent EL cases in terms of clinical symptomatology, epidemiology, and neuropathological features, suggesting that they are different entities with only superficial similarity. The term "encephalitis lethargica," still frequently used in the medical literature, should not be used for cases occurring at present in the sporadic form. Historical EL should be kept apart from recent EL, as they differ in important aspects.

A history of oculogyric crises during the encephalitis lethargica pandemic.

A pandemic of what came to be known as encephalitis lethargica spread starting in the winter of 1916-1917 and continued into the 1930s. Neurological after-effects, namely permanent parkinsonian syndromes and various abnormal movements, permanently disabled the survivors of the one or two million victims, often children or young adults. Among them, a small proportion developed a symptom that was little known up to that point and that is currently exceptional: oculogyric crises; that is, a lateralised, dystonic upward movement of the eyes known as a tonic eye fit. This paper proposes a history of the recognition of this symptom, its inclusion in the neurological nosography, and the pathophysiological hypotheses postulated a century ago.

Post encephalitic parkinsonism following dengue viral infection.

BACKGROUND: Incidence of dengue fever as well as dengue hemorrhagic fever is increasing in Sri Lanka especially among elderly population. As the number of cases is rising, rare complications of dengue illness also can be seen in clinical practice when compared to the past few years. Prompt identification and treatment of such complications is challenging due to lack of awareness and unavailability of standard treatment. CASE PRESENTATION: 69 years old man presented with acute onset fever and was diagnosed as having dengue illness. On the 4th day of illness, the disease was progressed into dengue haemorrhagic fever and recovered uneventfully. Although he recovered from primary illness, his general condition continued to deteriorate due to new onset of features of parkinsonism. Cerebrospinal fluid analysis and electro encephalogram showed evidence of encephalitis. Cerebrospinal fluid analysis also revealed positive IgM antibodies against dengue virus. Then the diagnosis of post encephalitic parkinsonism following dengue viral infection was made and started on. He was started on SINEMET (carbidopa 10 mg and levodopa 100 mg) half tablet 6 hourly started. After 1 week of treatment he showed marked improvement and then patient was discharged with further follow up plan. CONCLUSION: Although the management of dengue illness and dengue haemorrhagic fever is straightforward, recognition and treatment of rare complications like post encephalitic parkinsonism following dengue viral infection is difficult without great clinical suspicion.

Post-Encephalitic Parkinsonism and Sleep Disorder Responsive to Immunological Treatment: A Case Report.

We describe a 70-year-old man who, after a viral encephalitis associated with pneumonia, progressively developed a parkinsonism associated with lethargy. Encephalitis manifested with persistent hiccups, seizures and impairment of consciousness. After 2 weeks, the initial neurologic symptoms subsided and the patient progressively developed movement disorders (rigidity and bradykinesia, resistant to L-DOPA), lethargy and behavioral hypersomnia. Magnetic resonance imaging showed thalamic and hippocampal signal abnormalities, immunohistochemistry on a mouse brain substrate revealed serum autoantibodies binding to the brainstem neuropil. Polysomnographic monitoring was consistent with a very severe disruption of sleep: the sleep-wake cycle was fragmented, and the NREM-REM ultradian cycle was irregular. Intravenous immune globulin therapy resulted in the complete reversal of the movement and the sleep disorders. Our observation confirms that parkinsonism and sleep disorders may be consequences of encephalitis, that an immune-mediated pathogenesis is likely, and, consequently, that immunotherapy can be beneficial in these patients. The polysomnographic monitoring suggests that lethargia, rather than a mere hypersomnia, is the result of a combination between sleep disruption and altered motor control.

Postencephalitic parkinsonism: interesting clinico-imaging correlation.

IMPORTANCE: Post-encephalitic parkinsonism (PEP) is believed to be caused by a viral illness which causes degeneration of the nerve cells in the substantia nigra, resulting in clinical parkinsonism. Although common during the period of the First World War, the diagnosis of PEP is rarely entertained today. OBSERVATION: We report an adolescent boy of PEP, who was bedridden due to severe parkinsonism following the encephalitis attack. After relevant imaging and investigation, he was treated with levodopa which made him independent from a year long total dependent condition. RELEVANCE AND CONCLUSION: Encephalitis lethargica or PEP is one of the rare parkinsonian syndromes which may be amenable to treatment. Proper diagnosis and treatment may help the patient become ambulatory from the dreaded lethargic condition.

[Lethargic encephalitis. Report of one case]. / Enfermedad de Von Economo: Caso clínico.

Lethargic encephalitis (LE) is a Central Nervous System disorder following an upper respiratory tract infection, characterized by sleep disturbances, clinical symptoms corresponding to basal ganglia involvement and in some cases, neuropsychiatric sequelae. We report a 18-year-old mole with a history of sinusitis treated with azithromycin, two weeks before, presenting with fever, headache, confusion and myoclonus. Urine analysis was positive for cannabis. Cerebro spinal fluid analysis showed mononuclear pleiocytosis (109xmm³) and an increase in protein concentration of l.6 g/dl. Forty eight hours after admission, the patient required mechanical ventilation and subsequently a status epilepticus appeared. Ten days later, fever, rigidity and resting tremor appeared. A magnetic resonance imaging showed hyperintensities in FLALR sequence in the right insular cortex. The patient continued with extreme rigidity, catatonia and mutism. Considering the possibility ofa LE, methyl prednisolone 1 g/day was administered for five consecutive days followed by prednisone 40 mg l day, observing a dramatic improvement of rigidity and tremors.

Enfermedad de Von Economo: Caso clínico / Lethargic Encephalitis: Report of one case

Lethargic encephalitis (LE) is a Central Nervous System disorder following an upper respiratory tract infection, characterized by sleep disturbances, clinical symptoms corresponding to basal ganglia involvement and in some cases, neuropsychiatric sequelae. We report a 18-year-old mole with a history of sinusitis treated with azithromycin, two weeks before, presenting with fever, headache, confusion and myoclonus. Urine analysis was positive for cannabis. Cerebro spinal fluid analysis showed mononuclear pleiocytosis (109xmm³) and an increase in protein concentration ofl.6 g/dl. Forty eight hours after admission, the patient required mechanical ventilation and subsequently a status epilepticus appeared. Ten days later, fever, rigidity and resting tremor appeared. A magnetic resonance imaging showed hyperintensities in FLALR sequence in the right insular cortex. The patient continued with extreme rigidity, catatonia and mutism. Considering the possibility ofa LE, methyl prednisolone 1 g/day was administered for five consecutive days followed by prednisone 40 mgl day, observing a dramatic improvement of rigidity and tremors.

The diagnosis of postencephalitic parkinsonism at the neurological unit of Boston City Hospital, 1930-1981.

The objective of the study is to ascertain the rationale for the diagnosis of postencephalitic parkinsonism (PEP) at Boston City Hospital's Neurological Unit (1930-1981). 5,270 discharge summaries were evaluated for the diagnoses of PEP. Sixteen cases of PEP were identified; the diagnosis of PEP was justified in approximately half of these cases based on the published criteria for distinguishing PEP from Parkinson's disease (PD). In conclusions, the absence of a clear justification for the diagnosis of PEP in many of the 16 cases suggests that the accepted relationship between encephalitis lethargica and PEP may be less definitive than currently believed.

A modern perspective on the differential diagnosis between encephalitis lethargica or anti-NMDA-receptor encephalitis.

Two cases initially diagnosed as "encephalitis lethargica" are discussed. Both cases satisfied the published diagnostic criteria for encephalitis lethargica, with neuropsychiatric features including complex movement disorder, hypoventilation and altered conscious state. On later investigation N-methyl-D-aspartate receptor antibodies were detected in both cases. With the recent descriptions of tumour related antibodies to neuronal surface antigens in NMDA-receptor encephalitis, we highlight the importance of revisiting a diagnosis which may have prognostic significance.

N-methyl-D-aspartate receptor antibodies in pediatric dyskinetic encephalitis lethargica.

Encephalitis lethargica (EL) describes an encephalitis with psychiatric, sleep, and extrapyramidal movement disorders. Dyskinetic and parkinsonian forms have been described. EL shares clinical features with the anti-N-methyl-D-aspartate receptor (NMDAR-Ab) encephalitis. We studied 20 sera from pediatric patients with contemporary EL. Ten sera (from 2 males and 8 females, aged 1.3-13 years) and 6/6 cerebrospinal fluid samples were positive for NMDAR-Ab. NMDAR-Ab-positive patients had dyskinesias, agitation, seizures, and insomnia, whereas parkinsonism and somnolence dominated in the NMDAR-Ab-negative children. We were unable to identify any tumors. The dyskinetic form of EL is an NMDAR-Ab encephalitis and can affect very young children.

Contemporary Encephalitis Lethargica: phenotype, laboratory findings and treatment outcomes.

BACKGROUND: Encephalitis lethargica (EL) is a CNS disorder that manifests with lethargy sleep cycle disturbances, extrapyramidal symptomatology, neuropsychiatric manifestations, ocular features and cardio-respiratory abnormalities. Although there have been no reported outbreaks of EL recently, a number of reports show that cases of EL are still encountered regularly. Against this background we conducted a study aiming to elucidate the clinical characteristics, describe laboratory/ neuroimaging findings (MRI, PET) and present treatment options and outcomes in sporadic EL. METHODS: Patients were diagnosed over a period of 3 years using proposed diagnostic criteria. Extensive laboratory and imaging tests were performed for exclusion of other causes. Anti-neuronal antibodies against human basal ganglia were detected with western immunoblotting and (18)F-FDG PET imaging was performed. Selected cases were videotaped. RESULTS: Our patients (M/F: 5/3) ranged from 2-28 years (mean 9.3 +/- 9.5). Encephalopathy, sleep disturbances and extrapyramidal symptoms were present in all cases. Laboratory investigations revealed CSF leukocytosis in 5/8 patients and anti-BG Ab in 4/7 patients. MRIs revealed structural abnormalities in 7/8 cases. (18)F-FDG PET showed basal ganglionic hypermetabolism in 4/7 patients. Treatment approaches included immunomodulating and symptomatic therapies. We report no mortality from EL in our series. CONCLUSIONS: There seems to be little doubt that cases of EL still occur. Diagnosis may be based on clinical suspicion and laboratory/imaging tests may lead to early initiation of immunomodulating and supporting therapies. We suggest that in addition to anti-BG Abs FDG PET should be considered as a diagnostic tool for EL.

Contemporary encephalitis lethargica presenting with agitated catatonia, stereotypy, and dystonia-parkinsonism.

Encephalitis lethargica (EL) syndrome was classically described by Von Economo and has somnolent-ophthalmoplegic, hyperkinetic, and amyostatic-akinetic forms. We describe 2 recent cases of EL characterized by an acute encephalitis with mixed movement disorders (dystonia-Parkinsonism plus stereotypy) and psychiatric disorders (agitated catatonia, coprolalia, and echo phenomena). Both patients suffered concurrent hyperkinetic and Parkinsonian features resulting in therapeutic challenges. Bradykinetic features responded to dopamine replacement therapy and both patients also had adverse affects to dopamine antagonists (oculogyric crises plus neuroleptic malignant syndrome). Investigation was unremarkable other than the presence of CSF lymphocytosis and oligoclonal bands. Despite prolonged in-patient stays and intensive care management, both patients have made complete recoveries. We believe these cases support the hypothesis that this syndrome is an inflammatory encephalitis that specifically effects dopamine neurotransmission.

Steroid-responsive encephalitis lethargica syndrome with malignant catatonia.

We report a 47-year-old man who is considered to have sporadic encephalitis lethargica (EL). He presented with hyperpyrexia, lethargy, akinetic mutism, and posture of decorticate rigidity following coma and respiratory failure. Intravenous methylprednisolone pulse therapy improved his condition rapidly and remarkably. Electroencephalography (EEG) showed severe diffuse slow waves of bilateral frontal dominancy, and paralleled the clinical course. Our patient fulfilled the diagnostic criteria for malignant catatonia, so we diagnosed secondary malignant catatonia due to EL syndrome. The effect of corticosteroid treatment remains controversial in encephalitis; however, some EL syndrome patients exhibit an excellent response to corticosteroid treatment. Therefore, EL syndrome may be secondary to autoimmunity against deep grey matter. It is important to distinguish secondary catatonia due to general medical conditions from psychiatric catatonia and to choose a treatment suitable for the medical condition.