ABSTRACT
INTRODUCTION: Encephalitis lethargica (EL), an epidemic disease of the early 20th century, has continued to be diagnosed sporadically since that time, including a report of 20 new cases in 2004. Many of the recent case reports state that the primary neuropathology of acute EL consists of inflammatory changes and lesions within the midbrain, basal ganglia and substantia nigra. However, the neuropathology of acute EL cases from the epidemic period was actually much more widespread. METHODS: In order to characterize the neuropathology of acute phase EL, we developed a database of EL pathology based on 112 cases from the years 1915 to 1940, of which most died within 2 weeks of EL onset. RESULTS: Our analysis revealed that cortical damage was prevalent in 75% of the 112 cases; damage to the meninges and brainstem occurred in approximately half of the cases; and the substantia nigra was damaged in only 13% of these acute cases. We also found that after 1921, damage to cranial nerve nuclei was not reported. An analysis of the neuropathology and clinical symptoms revealed little correlation. CONCLUSIONS: Based on these findings, putative modern cases of acute EL with MRI/CT indicated lesions confined solely to the midbrain, brainstem, and/or basal ganglia should not be considered, consistent with that reported during epidemic period.
Subject(s)
Brain/pathology , Disease Outbreaks/history , Parkinson Disease, Postencephalitic/epidemiology , Parkinson Disease, Postencephalitic/pathology , Adolescent , Adult , Age Distribution , Aged , Child , Child, Preschool , Databases, Factual , Female , History, 20th Century , Humans , Infant , Infant, Newborn , Male , Middle Aged , Parkinson Disease, Postencephalitic/history , Young AdultABSTRACT
1-Methyl-4-phenyl-1,2,5,6- tetrahydropyri dine ( MPTP ) is known to cause an irreversible destruction of the dopaminergic nigrostriatal pathway and symptoms of parkinsonism in humans and in monkeys. However, MPTP has been reported to act only minimally or not at all in several other animal species. When MPTP (30 milligrams per kilogram of body weight) was administered parenterally to mice, a decrease in concentrations of neostriatal dopamine and its metabolites, a decrease in the capacity of neostriatal synaptosomal preparations to accumulate [3H]dopamine, and a disappearance of nerve cells in the zona compacta of the substantia nigra were observed. In contrast, MPTP administration had no effect on neostriatal concentrations of serotonin and its metabolites. MPTP administration thus results in biochemical and histological changes in mice similar to those reported in humans and monkeys and similar to those seen in Parkinson's disease in humans. The mouse should prove to be a useful small animal with which to study the mode of action of MPTP .
Subject(s)
Brain/drug effects , Dopamine/physiology , Pyridines/adverse effects , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , 3,4-Dihydroxyphenylacetic Acid/analysis , Animals , Brain Chemistry/drug effects , Dopamine/analysis , Homovanillic Acid/analysis , Humans , Male , Mice , Substantia Nigra/analysis , Synaptosomes/analysisABSTRACT
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting approximately 1 percent of the population over age 50. Recent studies have confirmed significant familial aggregation of PD and a large number of large multicase families have been documented. Genetic markers on chromosome 4q21-q23 were found to be linked to the PD phenotype in a large kindred with autosomal dominant PD, with a Zmax = 6.00 for marker D4S2380. This finding will facilitate identification of the gene and research on the pathogenesis of PD.
Subject(s)
Chromosome Mapping , Chromosomes, Human, Pair 4 , Parkinson Disease/genetics , Female , Genetic Linkage , Genetic Markers , Humans , Lod Score , Male , Pedigree , PhenotypeABSTRACT
Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.
Subject(s)
Nerve Tissue Proteins/genetics , Parkinson Disease/genetics , Point Mutation , Age of Onset , Amino Acid Sequence , Animals , Base Sequence , Chromosome Mapping , Chromosomes, Human, Pair 4 , Female , Genes, Dominant , Genetic Markers , Greece , Humans , Italy , Male , Molecular Sequence Data , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/physiology , Pedigree , Phenotype , Polymerase Chain Reaction , Protein Structure, Secondary , Synucleins , alpha-SynucleinABSTRACT
The first systematic genetic study of Parkinson's disease (PD) was carried out by Mjönes in 1949. His results indicated autosomal dominant transmission with 60% penetrance. These conclusions, however, were long discounted because oligosymptomatic and atypical relatives were counted as secondary cases without clear justification. Subsequent surveys of patient and twin studies failed to confirm evidence of familial concentration and the hypothesis of a genetic etiology was over-shadowed by interest in possible environmental neurotoxins. A growing accumulation of pedigrees of histologically confirmed Lewy-body PD over the past several years has refocused attention on genetic factors. Fluorodopa positron emission tomography (PET) studies in oligosymptomatic co-twins of probands and recent clinicopathologic studies of atypical cases have provided retrospective support for Mjönes' methodology. A survey of a personal series of PD patients showed that the majority of those for whom pedigree information was available were familial. This along with another recently reported series confirm Mjönes' data showing similar segregation ratios for siblings and parents, a low ratio of maternal:paternal transmission and a marked asymmetry in the distribution of ancestral secondary cases. These findings favor monogenic autosomal dominant inheritance and show reason to argue against a multifactorial etiology or heteroplasmy. The clinical evidence justifies searching for gene loci linked to PD. Available methods are briefly outlined. Preliminary investigations have examined possible allelic associations, e.g., with alleles of MAO-A and debrisoquine hydroxylase and linkage to the tyrosine hydroxylase gene on chromosome 11p15.5 has been excluded in one study of juvenile familial parkinsonism. Linkage mapping studies are presently underway.
Subject(s)
Brain/pathology , Lewy Bodies/pathology , Parkinson Disease/genetics , Female , Humans , Male , Neurons/pathology , Neurotoxins/toxicity , Parkinson Disease/pathology , Parkinson Disease/physiopathology , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/etiology , Substantia Nigra/pathologyABSTRACT
The authors found a high prevalence--43.4% of tardive dyskinesia in a sample of psychiatric outpatients, a population previously thought to be at nominal risk for development of this syndrome. There was no significant relationship between the presence of dyskinesia and age, sex, years of neuroleptic use, or various organic factors. The effects of dentures and of drug combinations are discussed, and it is noted that structured scales of dyskinesia and videotope recordings are important tools in diagnosing and following the course of dyskinesia.
Subject(s)
Ambulatory Care , Dyskinesia, Drug-Induced/epidemiology , Mental Disorders/drug therapy , Tranquilizing Agents/adverse effects , Adolescent , Adult , Age Factors , Aged , Antiparkinson Agents/administration & dosage , Dentures , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , New York City , Sex Factors , Time Factors , Tranquilizing Agents/administration & dosageABSTRACT
We tested the hypothesis that the inverse association of smoking and Parkinson's disease (PD) results from a direct pharmacologic benefit of smoking on PD. We mailed questionnaires to the 32,000 members of the United Parkinson Foundation and searched for evidence of a dose-response effect between increasing intensity of smoking and decreasing intensity of PD. Of the 6006 respondents, 3693 met our diagnostic criteria. Despite confining the analysis to subgroups where confounding effects would be minimized, we found no significant correlation between any measure of smoking and any measure of PD severity and conclude that smoking is probably not of benefit in preventing, delaying, or ameliorating PD.
Subject(s)
Parkinson Disease/etiology , Smoking , Dose-Response Relationship, Drug , Female , Humans , Male , Middle AgedABSTRACT
Apraxia of lid opening was described by Goldstein and Cogan as "a non paralytic motor abnormality characterized by the patient's difficulty in initiating the act of lid elevation." We studied six such patients with this finding accompanied by vigorous frontalis contraction and no evidence of ongoing orbicularis oculi contraction, dysfunction of the oculomotor nerve, or loss of ocular sympathetic innervation. Four patients had Parkinson's disease or atypical parkinsonism, one had progressive supranuclear palsy, and one had Shy-Drager syndrome. At onset of ocular symptoms, mean age was 64 years, and the mean duration of extrapyramidal symptoms was 9.7 years. By definition, the motor system must be intact in any apraxia. Therefore, this disorder of lid opening in patients with extrapyramidal motor dysfunction is not an apraxia, but rather involuntary levator palpebrae inhibition of supranuclear origin.
Subject(s)
Apraxias/physiopathology , Eyelid Diseases/physiopathology , Aged , Apraxias/complications , Ataxia/complications , Cerebral Infarction/complications , Dangerous Behavior/complications , Eyelid Diseases/complications , Female , Humans , Male , Middle Aged , Movement Disorders/complications , Muscle Contraction , Parkinson Disease/complications , Terminology as TopicABSTRACT
We studied a family with an extrapyramidal disorder characterized by childhood onset of lower-limb and axial dystonia, followed by parkinsonism. Dramatic response to levodopa therapy and minimal progression in adult life was seen. The family included five generations of affected members of both sexes in an autosomal dominant pattern.
Subject(s)
Dystonia/diagnosis , Parkinson Disease/diagnosis , Adult , Dystonia/drug therapy , Dystonia/genetics , Dystonia/physiopathology , Female , Humans , Levodopa/therapeutic use , Male , Middle Aged , Parkinson Disease/drug therapy , Parkinson Disease/genetics , Parkinson Disease/physiopathology , PedigreeABSTRACT
In rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal system we compared the behavioral effects of pergolide with those of L-dopa, bromocriptine, and lergotrile. In this animal model of parkinsonism, doses of 0.25 mg per kilogram pergolide (free base) induced vigorous circling for 24 hours. Pergolide was more potent than bromocriptine or lergotrile. Pretreatment with alpha-methylparatyrosine nearly abolished the effects of bromocriptine, markedly diminished the effects of lergotrile, and only partially diminished the effects of pergolide. These findings suggest that pergolide should be more effective than bromocriptine in the treatment of parkinsonism.
Subject(s)
Ergolines/therapeutic use , Parkinson Disease/drug therapy , Animals , Behavior, Animal/drug effects , Brain Diseases/chemically induced , Bromocriptine/therapeutic use , Ergolines/analogs & derivatives , Female , Hydroxydopamines , Oxidopamine , Pergolide , Rats , Rats, Inbred StrainsABSTRACT
We report the physiologic and pharmacologic analysis in two women, aged 18 and 17 years, with essential myoclonus. Both responded to benztropine mesylate and had been functioning normally. The physiologic analysis suggested ballistic movement overflow and audiogenic stimulus-sensitive myoclonus. The pharmacologic study showed a direct and mutual antagonism of physostigmine and anticholinergic agent on myoclonus, implying cholinergic hyperactivity in the pathophysiology of myoclonus.
Subject(s)
Benztropine/therapeutic use , Myoclonus/physiopathology , Parasympatholytics/therapeutic use , Tropanes/therapeutic use , Adolescent , Electroencephalography , Electromyography , Evoked Potentials, Auditory , Evoked Potentials, Somatosensory , Evoked Potentials, Visual , Female , Humans , Myoclonus/drug therapy , Physostigmine/pharmacologyABSTRACT
According to the classification scheme of Kebabian and Calne, there are two types of dopamine (DA) receptors: D1 (activation of which causes increased cyclic AMP formation) and D2 (activation of which causes no increment in cyclic AMP). It is not clear what role the different receptors play in mediating motor behavior. Using drugs that act selectively at only one receptor site, we studied the effects of D1 and D2 receptor activation in two different models of parkinsonism--the rotating rat and the reserpinized mouse. Neither the D1 agonist nor the D2 agonist, given alone, could overcome reserpine akinesia, but together they restored locomotor activity. In rats with unilateral nigrostriatal lesions, both drugs induced a rotational response, each with a distinct temporal pattern. Pretreatment with alpha-methyl-paratyrosine (an inhibitor of DA synthesis) led to decrements in the rotational response induced by D2 agonists, but not that induced by D1 agonists. The mechanism by which these DA agonists induce motor activity is different; activation of both types of DA receptors seems to be necessary for normal motor behavior.
Subject(s)
Benzazepines/therapeutic use , Ergolines/therapeutic use , Parkinson Disease/drug therapy , Receptors, Dopamine/metabolism , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine , Animals , Benzazepines/pharmacology , Disease Models, Animal , Ergolines/pharmacology , Female , Locomotion/drug effects , Mice , Mice, Inbred Strains , Parkinson Disease/metabolism , Quinpirole , Rats , Rats, Inbred Strains , Reserpine/pharmacologyABSTRACT
Zero concordance for Parkinson disease was found in the first 12 monozygotic twin pairs examined in an ongoing twin study. One co-twin (subject without Parkinson disease) had essential tremor, another had cerebral vascular disease, and a third was an alcoholic. Cigarette smoking appeared to be less frequent in the probands than in the co-twins (11.9 versus 16.1 pack-years). There was also evidence of premorbid personality differences between probands and co-twins dating back to late adolescence or early adult years. These preliminary findings suggest that genetic factors do not play a major role in the etiology of Parkinson disease and point to a prodromal onset of the disease as early as late adolescence or early adult life.
Subject(s)
Diseases in Twins , Parkinson Disease/genetics , Aged , Alcoholism/complications , Female , Humans , Male , Middle Aged , Parkinson Disease/complications , Parkinson Disease/psychology , Personality , Pregnancy , Smoking , Twins, MonozygoticABSTRACT
Deficiency of glutamate dehydrogenase appears to be associated with a chronic progressive degenerative disorder manifesting parkinsonian extrapyramidal features, ataxia, supranuclear oculomotor dysfunction, a peripheral neuropathy and, in some cases, amyotrophy. The clinical features resemble those of the Dejerine-Thomas type of olivopontocerebellar atrophy. The data suggest autosomal dominant inheritance with low penetrance. Measurement of leukocyte glutamate dehydrogenase should be routinely performed in the evaluation of newly diagnosed or atypical cases of parkinsonism.
Subject(s)
Cerebellar Diseases/enzymology , Glutamate Dehydrogenase/deficiency , Ophthalmoplegia/enzymology , Parkinson Disease/enzymology , Aged , Atrophy , Cerebellar Diseases/genetics , Cerebellar Diseases/physiopathology , Female , Humans , Male , Middle Aged , Olivary Nucleus/pathology , Ophthalmoplegia/genetics , Ophthalmoplegia/physiopathology , Parkinson Disease/genetics , Parkinson Disease/physiopathology , Pons/pathologyABSTRACT
Among 62 patients with progressive supranuclear palsy (PSP) seen over a 9-year period, we encountered seven who had seizure phenomena. We suggest that PSP patients have seizures more frequently than has been appreciated.
Subject(s)
Seizures/complications , Supranuclear Palsy, Progressive/complications , Aged , Aged, 80 and over , Atrophy , Brain/pathology , Electroencephalography , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neurofibrils/pathology , Seizures/pathology , Seizures/physiopathology , Supranuclear Palsy, Progressive/physiopathology , Tomography, X-Ray ComputedABSTRACT
There have been three reports since 1969 of members of a "W" family with autosomal dominant spinocerebellar ataxia (SCA), and various conclusions have been drawn about the nosology. This pedigree has been traced back over 300 years through 11 generations. Although phenotypically similar to the disorder in the Schut-Swier, Nino, and other kindreds, the disorder in the W family is not linked to the SCA1 locus on chromosome 6, as reported in those hereditary ataxia pedigrees. The W family represents the largest such North American kindred yet reported. We examined 33 family members of a distantly related branch of the W family, determined the cumulative age of onset, and projected the number of present-day gene carriers. Two cases illustrate the spectrum of symptoms among family members. Age of onset and presenting symptom, however, seem to correlate both in our patients and in those previously reported. Between 2,000 and 5,000 individuals are estimated to be at risk of developing the disorder within this pedigree alone. The pedigree reported here will be valuable in the identification and cloning of a gene for hereditary ataxia, designated "SCA2" at the Eleventh International Workshop on Human Gene Mapping.
Subject(s)
Chromosomes, Human, Pair 6 , Spinocerebellar Degenerations/genetics , Adult , Aged , Chromosome Mapping , Female , Genes, Dominant , Humans , Male , Middle Aged , Pedigree , United StatesABSTRACT
By neurophysiologic investigations, we evaluated 20 patients with olivopontocerebellar atrophy (OPCA), comprising 8 with glutamate dehydrogenase (GDH) deficiency and 12 with normal GDH activity. We found sensorimotor, predominantly sensory axonal neuropathy distally in the legs, and peripheral auditory nerve dysfunction (prolonged wave I but normal interpeak latencies in brainstem auditory evoked response) in GDH-deficient patients. These findings seem distinctive enough to serve as the electrophysiologic marker for diagnosis and monitoring of treatment and progression of the disease. The pattern-reversal visual and median nerve somatosensory evoked responses did not differ among the patients and controls.
Subject(s)
Cerebellar Ataxia/diagnosis , Glutamate Dehydrogenase/deficiency , Olivary Nucleus/physiopathology , Pons/physiopathology , Aged , Brain Stem/physiopathology , Cerebellar Ataxia/physiopathology , Diagnosis, Differential , Electromyography , Evoked Potentials, Auditory , Evoked Potentials, Somatosensory , Evoked Potentials, Visual , Female , H-Reflex , Humans , Male , Median Nerve/physiopathology , Middle Aged , Neural ConductionABSTRACT
To explore possible risk factors for progressive supranuclear palsy (PSP), we conducted a case-control study of 50 cases in New Jersey. Two neurologists confirmed the diagnosis in the 41 living patients. Two hospital controls were matched by age, sex, race, date of death, and relationship of next-to-kin to each case. A structured interview was administered in person to the next-of-kin of cases and controls. Genetic, viral, toxic, medical, surgical, and personality factors were investigated. Cases lived in areas with low population as adults significantly more frequently than controls. The study identified no other factors associated with PSP including a history of stroke, hypertension, or smoking.
Subject(s)
Supranuclear Palsy, Progressive/etiology , Adult , Aged , Craniocerebral Trauma/complications , Environmental Exposure , Female , Humans , Male , Middle Aged , Risk Factors , Smoking , Supranuclear Palsy, Progressive/geneticsABSTRACT
We surveyed neurologists and chronic care facilities in and near two New Jersey counties with a combined population of 799,022, regarding cases of progressive supranuclear palsy. All suspected cases were examined personally, using rigid criteria. The prevalence ratio was 1.39/100,000. A total of 50 New Jersey cases yielded median intervals to onset of requiring gait assistance, 3.1 years; visual symptoms, 3.9 years; dysarthria, 3.4 years; dysphagia, 4.4 years; requiring wheelchair, 8.2 years; and death, 9.7 years.
Subject(s)
Supranuclear Palsy, Progressive/epidemiology , Humans , New Jersey , Supranuclear Palsy, Progressive/mortality , Supranuclear Palsy, Progressive/physiopathology , Time FactorsABSTRACT
We report two patients with a primarily akinetic form of parkinsonism who were nonresponsive to treatment with levodopa. At autopsy, both patients had many Lewy bodies in brainstem and diencephalic nuclei, with sparse Lewy bodies in association cortices and more numerous Lewy bodies in the limbic cortices, consistent with the transitional form of Lewy body disease. These cases emphasize that (1) Lewy body Parkinson's disease cannot be excluded on the basis of atypical presentation or levodopa nonresponsiveness, and (2) the clinicopathologic spectrum of Lewy body disease is varied.