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The pandemic of von Economo's disease which began in January 1917 preceded that of influenza of 1918-1919 by more than a year. Though it has been customary to link the two it seems unlikely that the latter was responsible for the former as has been proposed. It has been assumed that von Economo's disease (ED) was caused by a virus; but in fact the etiology is in question as no virus has yet been transmitted to experimental animals or cells in culture. However, the presence of oligoclonal IgG bands in the CSF of suspected cases and the finding of chronic active lesions in the brain tissue at autopsy suggests a viral etiology. Occasional, sporadic presumed cases of the disease have been reported within the last 25 years. Encephalitides due to established neurotropic viruses or to other viruses that may on occasion invade the CNS only rarely produce parkinsonism, and when they do it differs from that seen in ED. The present report reviews the overall concept of a viral etiology of Parkinson's disease with particular reference to von Economo's disease.

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A marked generalized astrogliosis was observed in the frontal and temporal white matter from a case of von Economo's disease and another of postencephalitic Parkinson's disease, which areas were otherwise devoid of any other demonstrable microscopic lesions. No similar astrocytic reaction of any severity was observed in the same areas in a number of other brain diseases or controls, except when other kinds of lesions were present in the same section, with reactive astrocytes being present within the primary or defining lesion or immediately close by. The marked astrogliosis in von Economo's and postencephalitic Parkinson's diseases in areas "distant" from the primary lesions seeming to indicate extensive pathological involvement, added to the strong qualitative and quantitative similarity of this reaction to that observed in concurrently studied cases of encephalitides caused by the human immunodeficiency virus, lend further factual support to the hypothesis of a viral etiology, albeit unspecified, in both von Economo's and postencephalitic Parkinson's diseases.

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Thirty-eight patients newly diagnosed as having Parkinson's disease (mean age, 57.3 years; mean Parkinson's disease duration, 2.7 years) in the earlier phase of the disease (mean Hoehn/Yahr stage, 2; mean motor scores, 11.4) were given selegiline (Deprenyl), 10 mg daily, and maintained on this drug alone until significant clinical worsening warranted the addition of low-dose levodopa (Sinemet, 25/100 three to four doses per day). Five of these patients were not yet receiving additional levodopa despite some worsening of motor scores. Of the 33 patients now taking combined therapy, seven have been followed up for 6 months or less. Twenty-four (92%) of the 26 patients taking combined therapy for a mean of 26 months (8.5 to 99 months) who have had Parkinson's disease for 6 years showed a dramatic improvement in their parkinsonism shortly after the addition of levodopa, with significant decreases in their rated motor scores, such improvement being maintained at their latest neurologic evaluation. Eighteen (75%) of these 24 patients responded to the combined selegiline/levodopa therapy with degrees of improvement equal to or greater than 50%, compared with their motor status at the start of combined therapy just before the addition of levodopa. This degree of "reversal" of parkinsonism on addition of levodopa (mean carbidopa/levodopa dose, 98/389 mg) was not observed in any of these same patients receiving selegiline alone for an average of 13.8 months. Four patients taking combined therapy developed mild, transient, abnormal involuntary movements, and end-of-dose pattern of response after more than 2 years of combined therapy (24.75 and 33.5 months, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

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To test the hypothesis that selegiline (L-deprenyl), a selective inhibitor of B-type monoamine oxidase, can halt the natural progression of Parkinson's disease, its use in 22 naive patients (mean age, 58 years; mean Parkinson's disease duration, 2.3 years) in the early stages (1 to 2) of the disease was studied. Patients were started and maintained on a daily dose of 10 mg of selegiline, and they underwent neurologic examinations at 3-month intervals using our center's disease staging and total rated disability scores. The criterion set for disease progression was defined as either the appearance of a new objective sign and/or a definite, persistent worsening (greater than 25%) of existing signs after the initiation of the selegiline trial. Patients remained on a regimen of selegiline [corrected] for periods ranging from 7 to 84 months. At the time of their latest neurologic examination, 17 (77%) of the 22 patients had conditions that demonstrably worsened with selegiline alone at an average of 10.8 months from the start of the drug therapy. Six of these 17 patients with worsening conditions (or 27% of the original 22) eventually required the addition of levodopa with carbidopa (Sinemet) on average at 13 months from the start of selegiline therapy; they have continued, to date, taking this combination for an additional mean follow-up period of 20.7 months. Four of the original 22 patients had relatively unchanged, stable neurologic status at the time of their latest examination (average follow-up period, 11.6 months).(ABSTRACT TRUNCATED AT 250 WORDS)

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Two hundred patients at a median age of 63 years, receiving conventional levodopa therapy for 8 years, who had had Parkinson's disease for 10 years, tried a regimen of selegiline (L-deprenyl), a type B monoamine oxidase inhibitor, at a daily dose of 10 mg, for varying periods from less than 6 months to more than 24 months (28% over 24 months). Selegiline does improve parkinsonism during the initial 6 months to 12 to 24 months of combined therapy in one third to almost half of patients with an end-of-dose type of response to long-term levodopa therapy. However, even this particular class of patients is unable to maintain such an improvement by 36 months, much less by 48 months, from the start of the selegiline trial. About one quarter of poor responders to levodopa and those with random deterioration show improvement in their parkinsonian status in the first 6 months of the selegiline trial, but their conditions quickly deteriorate by 1 year. The predominant pattern of response to previous levodopa therapy and the severity of the total disability score at the initiation of the selegiline trial were the two variables that were predictive of risk of failure with the drug. No evidence suggested that selegiline decreases the excess mortality rate of Parkinson's disease above that achieved with the use of levodopa alone. Selegiline as an adjunctive agent to conventional levodopa therapy was not unduly impressive with regard to preventing progression of Parkinson's disease.

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L-deprenyl (selegiline) has been reported as a safe effective adjunctive agent to levodopa in the control of Parkinson's symptoms, as well as a means of preventing the progressive nature of the disease process. In an ongoing study, now in its 12th year, L-deprenyl has been administered 1. as monotherapy or 2. in combination with levodopa, to previously untreated patients in the early phases of the disease; 3. added to an existing regimen of levodopa when optimal therapeutic results are not being obtained. This report reviews our experience in each of these three treatment categories. Results obtained to date, indicate that L-deprenyl administered alone does not prevent the occurrence of signs of Parkinson's disease. Its administration with levodopa, as initial therapy, allows for use of lower dosage and less side-effects of the latter agent. When L-deprenyl is added to sub-optimal responders to levodopa, it attenuates fluctuating responses, particularly those of the 'end-of-dose' variety.

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We have studied the frequency of human retrovirus antibody (HTLV-I, II, III) in the serum and CSF of patients with MS, matched controls, and patients with optic neuritis, idiopathic and postencephalitic Parkinson's disease, neuropathies, polymyositis, ALS, and postpoliomyelitis. Except for the postpoliomyelitis samples, all samples were collected prior to 1980. Contrary to a previous published report, no significant levels of antibody to HTLV-I, II, or III were found in the MS patients or controls. No retrovirus antibody was detected in patients with the other neurologic diseases.

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We have tested sera from patients with multiple sclerosis, matched controls, and those with other neurological diseases, as well as sera from patients with the acquired immunodeficiency syndrome and controls and patients with tropical spastic paraparesis (TSP) and controls for antibody to human T-lymphotropic virus type I (HTLV-I), HTLV-II, human immunodeficiency virus (HIV), simian T-lymphotropic virus type III, or simian retrovirus type I by immunofluorescent activity test, and for HTLV-I and HIV by the ELISA method. Sera from patients with multiple sclerosis and matched controls, and from patients with optic neuritis and Parkinson's or other neuromuscular diseases did not have antibody to any of the retroviruses tested. Specimens from TSP patients and some controls contained HTLV-I antibody. We conclude from our study that only TSP patients had serological evidence of infection with one of the retroviruses studied.

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The presence of viral nucleic acid sequences and antigens from a variety of conventional viruses in selected brain regions of cases of Alzheimer's disease (AD), diagnosed pathologically, was investigated using molecular hybridization and immunocytochemical techniques. Seven DNA and 4 RNA viruses were used as probes in 18 AD and 5 control brains. With Southern blot hybridization, no viral DNA sequences could be detected in the cerebral cortex. With dot blot hybridization, results were also negative, except for 2 cases, 1 a control brain, the other an AD brain, which gave a positive signal in the RNA extracted from the substantia innominata when c-DNA from measles virus was used as a probe. Four specific brain areas from each of 8 AD brains and 5 controls tested with viral probes (3 DNA and 5 RNA viruses), using immunocytochemical techniques for viral antigens, showed no positive reproducible specific reactions. These results, although negative, do not totally exclude the possibility that conventional viruses may play a role in the aetiology and pathogenesis of AD.

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A series of 203 patients with primary Parkinson's disease treated with L-DOPA, with adequate neurological documentation of mental status at serial intervals during their illness, constitutes the study population. Based on the results of the latest neurological examination, slightly less than one-third (29%) had mental impairment assessed as neurologically significant. Of the eleven clinical variables analysed (Cox regression analysis) for potential influence on the occurrence of an organic mental syndrome, four had a statistically significant effect: (1) the stage of disease at initial neurological examination; (2) the occurrence of acute confusional states; (3) the years of Parkinson's prior to L-DOPA; and (4) the total duration of L-DOPA therapy. The pathogenesis of dementia in this subgroup of Parkinson's disease is discussed.

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Eleven frozen autopsy specimens from cerebral cortex were tested for DNA-binding protein profiles. Six were Alzheimer's disease (AD) brains, 1 was Parkinson's/senile dementia of the Alzheimer's type and 4 were age-matched control brains. Proteins were extracted in a guanidine thiocyanate-containing solvent and freed of all nucleic acids by density gradient sedimentation. The proteins were separated by sodium dodecyl sulfate gel electrophoresis and transferred to nitrocellulose by electroblotting under conditions which favor renaturation of proteins containing only one type of polypeptide. The nitrocellulose was treated with partially denatured radiolabeled DNA, washed and subjected to autoradiography. An Mr = 43 000 (43 K) DNA-binding protein was detected in 5 of the 6 AD brains and was found to be absent or at least greatly reduced in any of the other 6 brains. No other DNA-binding proteins were found which could be associated with AD brains. The nature of the 43 K protein has yet to be determined.

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The Mp strain of herpes simplex virus type 1 (HSV1) induced a persistent infection in the mouse C 1300 neuronal cell line (clone N 115). C 1300 cultures infected at an MOI of 0.01 or 0.001 survived the initial infection and continued to produce infectious virus and viral antigens for 185 days and 31 days, respectively. Viral antigens were not detected in cultures no longer producing infectious virus; these "cured" cultures had comparable susceptibility to reinfection with HSV as previously uninfected C 1300 cells. While significant amounts of interferon were produced by C 1300 cells when challenged with Newcastle Disease Virus (NDV) or when treated with poly I:C, HSV-induced interferon could not be detected in either the acutely or persistently infected cell lines. The persistent state was not significantly altered by the addition of 1,000 units/ml of murine interferon alpha plus beta (MuIFN alpha + beta), nor was it affected by the addition of antibody to MuIFN. It appears that IFN does not play an important role in the establishment and/or maintenance of viral persistence in this neuronal system.

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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.

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Stereotactic intracerebral inoculation of a non-neuroadapted strain of herpes simplex virus type 1 into the left neostriatum of Sprague-Dawley rats induced clinical acute encephalitis within 3 to 5 days postinoculation, with microscopic evidence of inflammation in brain parenchyma, but with no gross areas of tissue destruction. Viral presence in brain was unequivocally confirmed by tissue culture, immunofluorescence and electron microscopy. Levels of activity of neurotransmitter synthesizing enzymes tyrosine hydroxylase (TH), glutamate decarboxylase (GAD), and choline acetyltransferase (ChAT) in the substantia nigra, caudate-putamen and frontal cortex of acutely encephalitic animals were not significantly different from those of PBS-inoculated controls; neither were there significant differences between the inoculated and non-inoculated sides of the individual animals. Our results show that locally injected herpes simplex virus may spread in brain causing neurological symptoms and death without major local structural changes or loss of neurotransmitter synthesizing enzymes. The degree and distribution of cell dysfunction and cell loss in viral encephalitis basically determine any alterations of enzyme activities specific to the involved cell population. The literature on neurotransmitter enzymes and experimental viral encephalitis is reviewed.

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The relative sensitivities of human fibroblast cultures from patients with familial Alzheimer's disease (AD), patients with Down's syndrome (Trisomy 21, T-21), and normal control (D-21) subjects, to the antiviral effect of human interferon-alpha (Hu-IFN-alpha) were compared. In confirmation of previous studies, T-21 cell lines showed significantly enhanced sensitivities to IFN compared with D-21 cells from normal controls. Fibroblast cultures from 2 familial AD patients belonging to one family exhibited sensitivities which fell within the range of response of normal D-21 cells. In contrast, fibroblasts from two other related subjects, one with familial AD and his niece "at risk", were extremely insensitive to interferon.

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