Faculty Bibliography

BACKGROUND: Although essential tremor (ET) is one of the most common neurologic disorders, there have been few postmortem studies. We recently reported postmortem changes (torpedoes and Bergmann gliosis) in the cerebellar cortex in a few ET cases. OBJECTIVE: To describe more extensive postmortem changes in the cerebellum in another ET case. DESIGN: Case report. RESULTS: A 90-year-old woman had a 30-year history of ET. At postmortem examination, there was segmental loss of Purkinje cells, presence of torpedoes, and Bergmann gliosis in the cerebellar cortex. Moreover, there were extensive changes in the dentate nucleus, in the form of neuronal loss, neuronal atrophy, microglial clusters, and reduction in the number of efferent fibers (ie, pallor of the hilum). CONCLUSIONS: The brain in the current case exhibited more marked cerebellar pathologic features than noted in previously reported ET cases and thereby extends the described cerebellar findings in this common, yet pathologically poorly characterized, neurologic disorder.

BACKGROUND: Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls. OBJECTIVE: To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged < or =50 years) and controls participating in a familial aggregation study. PATIENTS AND METHODS: We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction. RESULTS: Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations. CONCLUSIONS: The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD.

Data regarding the clinical experience of movement disorders subspecialty training are currently not available. In order to provide information to help design a well-rounded clinical experience, we reviewed the number and types of patients seen by all clinical movement disorders fellows over the course of 1 year at Columbia University Medical Center (CUMC). We conducted a retrospective analysis of all patients seen by four full-time clinical fellows and one part-time fellow during the 2001-2002 academic year, using billing records to tabulate all clinic visits and patient charts to certify diagnosis. One thousand six hundred sixty-two patients (1,132 new and 530 follow-ups) were seen by five fellows. Each full-time fellow evaluated and treated a mean of 263 new patients, 116 follow-up patients, and 15 in-patient consultations. The part-time clinical fellow evaluated and treated 81 new patients and 65 follow-up patients. Approximately half of the new patients had idiopathic Parkinson's disease. Full-time fellows saw equivalent numbers of patients but they evaluated few patients with uncommon movement disorders. Weekly video rounds allowed all fellows to see many more patients, aiding the recognition of movement phenomenology and enhancing understanding of diagnoses and treatment strategies. Thus, CUMC fellows evaluate a large number of patients with a wide range of diagnoses within a 1-year period. Video rounds allow greater exposure to uncommon diagnoses. Similar data from other movement disorder training programs are needed to help create guidelines for formal accreditation and to improve clinical training in this subspecialty.

It is difficult to predict precisely the final neurologic outcome from cardiac arrest and accompanying cerebral hypoxia. Although rare, several movement disorders may arise as a consequence of hypoxic injury, including myoclonus, dystonia, akinetic-rigid syndromes, tremor, and chorea. Dys-function of various portions of the central nervous system, including the basal ganglia, thalamus, midbrain, and cerebellum, is implicated in the pathogenesis of these posthypoxic movement disorders. The development of animal models of posthypoxic movement disorders and of newer imaging techniques applied to human patients who have movement disorders after hypoxic episodes has improved understanding of the pathophysiology of posthypoxic movement disorders and has suggested newer treatments. Many outstanding questions remain, however. What factors promote susceptibility to the development of posthypoxic movement disorders? Why do patients who have similar clinical hypoxic insults develop markedly dis-similar movement disorders? Why are the basal ganglia especially vulnerable to cerebral hypoxia? Why do some movement disorders occur in delayed fashion and progress for years after the hypoxic insult? Is the pathogenesis of progressive posthypoxic movement disorders related to that of neurodegenerative diseases? What are the most effective medications for the various posthypoxic movement disorders? Is there a role for deep brain stimulation in the treatment of posthypoxic movement disorders? We anticipate that current and future research in the area of posthypoxic movement disorders will reveal answers to some of these important questions.