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.

Immune-mediated extrapyramidal movement disorders, including Sydenham chorea.

Immune-mediated extrapyramidal movement disorders typically occur in previously healthy children. Immune-mediated movement disorders may occur as a postinfectious, paraneoplastic, or idiopathic process. Sydenham chorea (SC) is the classical poststreptococcal movement and psychiatric disorder, and may be associated with other features of rheumatic fever. The outcome is typically good, although residual chorea, psychiatric disturbance, and relapses are possible. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a syndrome of streptococcal-induced tics and obsessive-compulsive disorder. Although a number of investigators have reported an association between streptococcal infection and neuropsychiatric syndromes, the PANDAS hypothesis is controversial. Encephalitis lethargica is an encephalitic illness with parkinsonism, dyskinesias, and psychiatric disturbance as dominant features. The exact disease mechanism is not understood, although an autoimmune process is suspected. NMDA-R encephalitis is a new entity characterized by encephalitis with dramatic psychiatric disturbance, dyskinesias, cognitive alteration, and seizures. Patients have autoantibodies against the NMDA-R that appear to be pathogenic: immune therapies appear warranted to minimize disability. Movement disorders are also described associated with systemic lupus erythematosus and antiphospholipid syndrome. The differential diagnosis and investigation approach of acute-onset movement disorders are also discussed.

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.

Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity.

In 1916, von Economo first described encephalitis lethargica (EL), a CNS disorder presenting with pharyngitis followed by sleep disorder, basal ganglia signs (particularly parkinsonism) and neuropsychiatric sequelae. Since the 1916-1927 epidemic, only sporadic cases have been described. Pathological studies revealed an encephalitis of the midbrain and basal ganglia, with lymphocyte (predominantly plasma cell) infiltration. The EL epidemic occurred during the same time period as the 1918 influenza pandemic, and the two outbreaks have been linked in the medical literature. However, von Economo and other contemporary scientists thought that the 1918 influenza virus was not the cause of EL. Recent examination of archived EL brain material has failed to demonstrate influenza RNA, adding to the evidence that EL was not an invasive influenza encephalitis. By contrast, the findings of intrathecal oligoclonal bands (OCB) and beneficial effects of steroid treatments have provoked the hypothesis that EL may be immune-mediated. We have recently seen 20 patients with a similar EL phenotype, 55% of whom had a preceding pharyngitis. The patients had remarkable similarity to the historical descriptions of EL: sleep disorder (somnolence, sleep inversion or insomnia), lethargy, parkinsonism, dyskinesias and neuropsychiatric symptoms. CSF examination commonly showed elevated protein and OCB (75 and 69% respectively). Investigation found no evidence of viral encephalitis or other recognized causes of rapid-onset parkinsonism. MRI of the brain was normal in 60% but showed inflammatory changes localized to the deep grey matter in 40% of patients. We investigated the possibility that this phenotype could be a postinfectious autoimmune CNS disorder, and therefore similar to Sydenham's chorea. Anti-streptolysin-O titres were elevated in 65% of patients. Furthermore, western immunoblotting showed that 95% of EL patients had autoantibodies reactive against human basal ganglia antigens. These antibodies were also present in the CSF in four patients tested. By contrast, antibodies reactive against the basal ganglia were found in only 2-4% of child and adult controls (n = 173, P < 0.0001). Rather than showing polyspecific binding, these antibodies bound to common neural autoantigens of molecular weight 40, 45, 60 and 98 kDa. Regional tissue comparisons showed that the majority of these autoantigens were specific to or enriched in CNS tissue. Immunohistochemistry with secondary staining localized antibody binding to neurons rather than glial populations. Further investigation is required to determine whether these antibodies affect neuronal function (i.e. whether they are pathogenic anti-neuronal antibodies). Histopathology in one case demonstrated striatal encephalitis with perivenous B- and T-lymphocytic infiltration. We believe an EL-like syndrome is still prevalent, and propose that this syndrome may be secondary to autoimmunity against deep grey matter neurons.

Anti-tau-positive glial fibrillary tangles in the brain of postencephalitic parkinsonism of Economo type.

Tau-immunoreactive astrocytes have been reported in the brain of progressive supranuclear palsy (PSP) and are referred to as glial fibrillary tangles (GFTs). We found a number of GFTs in the heavily degenerated brain region in four cases of postencephalitic parkinsonism of Economo (PPE) with a clinical history of over a half-century. GFTs had the appearance of tufts of spider-like radiating fibers or small thorn-like feature by Gallyas-Braak method and also by anti-tau immunostaining.

Circulating antibody to Nocardia in the serum of patients with Parkinson's disease.

Nocardia is a genus of aerobic Gram-positive bacteria which forms filamentous cells that fragmented into rod-shaped or coccoid elements or L-forms. According to the literature N. asteroides causes encephalitis with parkinsonian features, and it may be an unknown etiologic agent causing encephalitis with a parkinsonian syndrome. Because there are no reliable immunologic tests routinely used for diagnosing nocardial infection, less severe CNS infections with nocardiae may not be recognized or may be attributed to unknown or incorrect etiologic agents. Recently, it was shown that sublethal doses of N. asteroides causes an L-DOPA-responsive movement disorder with Lewy-like bodies in mice. In this study, we detected antibodies to nocardia in the serum of patients with Parkinson's disease (PD). Sera was diluted in PBS and added in two-fold dilutions to coccoid and rod-shaped cells of nocardia attached to nonfluorescence slides. IF test demonstrated antibodies to coccoid and rod-shaped cells of nocardia in the serum from 20/20 patients with PD at a titer greater than 1:10, and 14 controls showed 10 positively. The results suggested that not only PD patients but also age-matched healthy volunteers are routinely exposed to and naturally infected with nocardia-related microorganisms. A further reliable immunologic test will be required.

Monoclonal antibodies to Alzheimer neurofibrillary tangles. 2. Demonstration of a common antigenic determinant between ANT and neurofibrillary degeneration in progressive supranuclear palsy.

Neurofibrillary degeneration is an argyrophilic intraneuronal lesion found in several unrelated neurologic conditions. The relationship between different types of neurofibrillary tangles is investigated with two monoclonal antibodies raised against Alzheimer neurofibrillary tangles (anti-ANT). Using the peroxidase-antiperoxidase technique, the authors demonstrate that neurofibrillary tangles of progressive supranuclear palsy, containing 15-nm straight filaments, share an antigenic determinant with ANTs. Ultrastructural studies localize the antigenic determinant to filamentous elements in the parakarya. The determinant is not present in normal brain, aluminum-induced experimental tangles in the rabbit, Lewy bodies, Hirano bodies, or axonal filamentous inclusions of amyotrophic lateral sclerosis and giant axonal neuropathy. It is, however, present in ANTs regardless of the pathologic condition in which they are found, including Alzheimer's disease, Down's syndrome, and postencephalitic Parkinson's disease.

Antineurofilament antibodies in postencephalitic and idiopathic Parkinson's disease.

Autoantibodies to neurofilaments were found by the immunofluorescence technique in serum of patients with postencephalitic (von Economo's) and idiopathic Parkinson's disease in the same proportion as in age-matched neurological and non-neurological controls. In addition, similar neurofibrillary staining was detected in age groups of 29 years and younger, but rarely in the first year of life. Persons over 70, with or without disease, showed a prevalence of antibodies significantly higher than in persons under 70. Serum from 1 case of Alzheimer's disease out of 4 tested, was positive for neurofilament antibodies; serum from the only case of Creutzfeldt-Jakob disease tested was negative. A total of 298 serum specimens, each from a different person, was tested. The use of cryostat-frozen longitudinal sections of normal rat spinal cord as a substrate has been confirmed to be an effective, reproducible and simple procedure for the detection of antineurofilament antibodies in human sera by indirect immunofluorescence.

The viral hypothesis in parkinsonism.

The most crucial unanswered question in Parkinson's disease is its fundamental cause. Since Carlsson's original suggestion that dopamine may be a transmitter in the central nervous system involved in the control of motor function and that it may be involved in the Parkinsonian syndrome (Carlsson, 1959), and the now-classic paper by Ehringer and Hornykiewicz (1960) which definitively showed the significant reduction of dopamine concentration in the neostriatum of cases of idiopathic Parkinson and postencephalitic parkinsonism, the vast amount of work on the subject has focused on the biochemical and pharmacologic correlates of this dopaminergic system failure involving particularly the nigrostriatal pathways. The concept of a specific neurotransmitter deficiency associated with a specific neurological syndrome potentially amenable to replacement therapy, has appropriately generated a considerable degree of clinical and research interest for over 20 years, but, with few exceptions, there has been hardly any focused or concerted research effort on looking at direct causal factors or primary initiating events in this disease process. As in Alzheimer's disease, another of the degenerative diseases of the brain of unknown origin with a specific biochemical substrate, any etiologic hypothesis for Parkinson's disease--whether a virus, an age-related immune system dysfunction, a genetic factor, a "trophic" substance, or a toxin--would have to explain the selective involvement of specific transmitter-defined neuronal pathways, the non-specificity of the brain lesions that define the disease, and the clinical involvement of a sizeable segment of the aging population. Of the several plausible hypotheses mentioned earlier, which are not necessarily mutually exclusive, we would like to critically consider the possibility of a viral cause.

HLA-B14 antigen and postencephalitic Parkinson's disease. Their association in an American-Jewish ethnic group.

Eighteen unrelated American-Jewish patients of Eastern European extraction who had classical postencephalitic Parkinson's disease were typed for HLA-A, HLA-B, and HLA-C antigenic determinants. Compared with 147 ethnically matched controls, the HLA-B14 antigen showed a highly significantly increased frequency in the postencephalitic Parkinson's group (corrected P = .001). This association, though not necessarily reflecting genetic susceptibility to the disease, strongly suggests such a possibility in the pathogenesis of at least this particular variant of parkinsonism.

Antibodies against arboviruses in postencephalitic and idiopathic Parkinson's disease.

Serum and CSF from patients with classic von Economo's postencephalitic Parkinson's disease, idiopathic Parkinson's disease and non-Parkinsonian neurological controls were tested for hemagglutination-inhibition antibodies to 17 arboviruses. All 35 CSF specimens from patients with idiopathic Parkinson's disease and controls were negative (ie, no inhibition of hemagglutination) with all the antigens. Of the total of 124 serums from the three study groups, 105 were also negative with all antigens tested. The only positive results were given by 19 serum specimens against one or more of group B arbovirus antigens, and/or against Batai and western equine encephalomyelitis antigens. There were no definitive differences in the distribution of these positive serum titers among controls, idiopathic Parkinson's, and postencephalitic Parkinson's cases. A causal relationship of the arboviruses tested with either the classical postencephalitic or idiopathic Parkinson's disease is not supported by the results of this study.

Influenza virus antibodies in Parkinsonism. Comparison of postencephalic and idiopathic Parkinson patients and matched controls.

Hemagglutination inhibiting antibodies to four influenza virus strains: A/Swine/1976/30 (HswN1), A/PR/8/34 (HON1), A/England/1/51 (H1N), and A/Singapore/1/57 (H2N2), were studied in blood serum specimens from 20 patients with postencephalitic and 55 patients with idiopathic Parkinson disease and their age- and sex-matched controls. No significant differences were observed in the distribution or the mean titers of antibodies to any of the four strains tested, when the postencephalitic patients and their controls were compared. The postencephalitic group was also similar to the idiopathic group with regard to the influenza antibodies.