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Biomedical subjects

S Fahn

Publications and source records attributed to S Fahn.

At least 127 records · Page 7Linked to original sources
PubMed1994

A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson's disease.

Three hundred and seventy-six subjects with advanced Parkinson's disease participated in a prospective, double-blind placebo-controlled study of the dopamine agonist pergolide mesylate as an adjunct to Sinemet. At 6 months, patients randomized to pergolide had a statistically significant improvement in total Parkinson's score, scores of activities of daily living, motor function, number of "off" hours, Hoehn and Yahr stage, and numerous parameters of parkinsonian function including bradykinesia, rigidity, gait, and dexterity. This benefit was obtained with the addition of a mean dose of 2.94 mg of pergolide, which permitted a 24.7% reduction in dose of levodopa. Adverse reactions were, for the most part, mild, reversible, and not of major clinical significance. No significant cardiac or electrocardiographic abnormalities were detected. This study demonstrates that pergolide mesylate, as an adjunct to levodopa, is an effective antiparkinsonian agent that provides clinical improvement while permitting a reduction in levodopa dose.

Activities of Daily Living↗
PubMed1994

Development of resistance to botulinum toxin type A in patients with torticollis.

Between 1984 and 1992, 559 patients with torticollis were treated with botulinum toxin type A (btx) injections. Twenty-four of these 559 patients (4.3%) had serological evidence of antibodies to btx by mouse neutralization assay. Some of the 559 patients had only one or two injection series, whereas others were lost to follow-up, so that the actual prevalence of serologically detectable antibodies may be higher than 4%. In addition, some patients who improved after btx injections lost benefit and stopped developing muscle atrophy from adequate doses of btx, without serological evidence of antibodies. To evaluate the risk factors for btx resistance (loss of benefit and muscle atrophy after injections with or without serological evidence of antibodies), we reviewed the records of a cohort of torticollis patients injected over 2-45 months (mean, 23 months) beginning in 1988. Eight of 76 patients (10.5%) developed btx resistance. Compared to nonresistant patients from the same cohort, these eight patients received more frequent injections, had more "booster injections" 2-3 weeks after an initial injection, and received higher doses of btx per treatment. In order to minimize the risk of developing btx resistance, therefore, we recommend that physicians wait as long as possible (at least 1 month) between btx injections, avoid booster injections, and use the smallest possible doses.

Adult↗
PubMed1994

Exclusion of the DYT1 locus in a non-Jewish family with early-onset dystonia.

The DYT1 gene on chromosome 9q34 underlies idiopathic torsion dystonia (ITD) in Jewish and non-Jewish families with childhood and adolescent-onset dystonia that usually starts in a limb, spreads to other limbs, and uncommonly involves cranial muscles. We examined 39 members of a Mennonite family of German ancestry in which seven were affected with ITD. Age at onset was 14.7 years (range 5-34 years) and symptoms began in a limb in four. The remaining three had onset in the neck, face, and larynx. Dystonia progressed to involve at least one arm and one leg in all seven and there was cranial involvement in six. Five of these six had moderate or severe speech impairment. Linkage analysis with 9q34 markers excluded the region containing the DYT1 locus in this family. This study suggests that a gene other than DYT1 underlies some cases of early limb-onset ITD. The clinical features of prominent cranial involvement and impaired speech distinguish this "non-DYT1" early-onset ITD family from the typical DYT1 phenotype.

Adolescent↗
PubMed1994

The gene for familial dystonia with myoclonic jerks responsive to alcohol is not located on the distal end of 9q.

A gene (DYT1) for susceptibility to early-onset torsion dystonia in Ashkenazi Jewish and Gentile kindreds is situated on chromosome 9q32-q34 in a 6-7 cM span between markers AK1 and ASS. To determine whether transmission of familial dystonia with myoclonic jerks responsive to alcohol was consistent with a gene in this region, we studied the 37 members of a Swedish family, of whom 20 were so affected. A lod score of < -2.00 from a two-point linkage analysis with six DNA markers covering a 30 cM span from D9S26 to D9S10 that included the region of the DYT gene indicated that this gene is not located in this region, and that two or more autosomal loci are responsible for hereditary dystonia in humans.

Alcohols↗
PubMed1994

Modulation of parkinsonian tremor by radial nerve palsy.

We analyzed rest and postural hand tremors in a Parkinson's disease patient who developed and recovered from a right radial nerve palsy at the spiral groove, and found that, despite complete paralysis of all extensors below the elbow, tremor frequencies remained unchanged while tremor amplitudes actually increased. This provides compelling evidence for a central generation of parkinsonian tremor frequency that is not influenced by the effects of peripheral modulation. In addition, the increase in tremor amplitudes may be due to disinhibited flexor activity caused by normally operating spinal segmental mechanisms interacting with central tremor generators programmed to alternate between antagonist muscles. Peripheral treatment of tremors--with muscle paralysis or botulinum toxin, for example--therefore may not be effective in stopping tremor oscillations in Parkinson's disease and may even worsen tremor amplitudes if all antagonists of a tremoring joint are not treated equally.

Aged↗
PubMed1994

Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex.

We studied the clinical features, pathology, and molecular genetics of a family (Mo) with an autosomal dominant disinhibition, frontal lobe dementia, parkinsonism, and amyotrophy. We examined seven affected members and gathered clinical information on another six. The mean onset was at age 45 years. Personality and behavioral changes (disinhibition, withdrawal, alcoholism, hyperphagia) were the first symptoms in twelve. There was early memory loss, anomia, and poor construction with preservation until late of orientation, speech, and calculations. All affected members examined had rigidity, bradykinesia, and postural instability. Mean duration to death was 13 years. We studied the neuropathology of six individuals, five of whom had been examined in life. There was atrophy and spongiform change in the frontotemporal cortex, and neuronal loss and gliosis in the substantia nigra and amygdala. Two individuals, including one with fasciculations and muscle wasting, had anterior horn cell loss. There were no Lewy bodies, neurofibrillary tangles, or amyloid plaques. We call this disorder the "disinhibition-dementia-parkinsonism-amyotrophy complex" (DDPAC), based on the clinical syndrome found in this family and linkage to chromosome 17.

Adult↗
PubMed1994

Oral and genital tardive pain syndromes.

We report the development of chronic painful oral or genital sensations in 11 patients with tardive akathisia, tardive dyskinesias, or tardive dystonia. In each case, the pain syndrome became a source of profound distress for the patient, overshadowing all other concurrent neuropsychiatric symptoms, and requiring treatment. Agents effective in treating tardive dyskinesia and tardive akathisia, such as catecholamine depletors, proved effective in reducing the painful sensations. Our observations support the concept of tardive pain as a complication of chronic neuroleptic exposure.

Aged↗
PubMed1994

Metabolic topography of the hemiparkinsonism-hemiatrophy syndrome.

We estimated regional and global metabolic rates for glucose using 18F-fluorodeoxyglucose (FDG) and PET in six patients with hemiparkinsonism-hemiatrophy syndrome (HPHA; mean age, 41.0 +/- 12.4 years). We used 18F-fluorodopa (FDOPA) and PET in two patients to quantify presynaptic nigrostriatal dopaminergic function. We compared measures of brain glucose metabolism and striatal FDOPA uptake with those calculated for 10 age-matched normal volunteers (mean age, 35.1 +/- 8.0 years) and 10 patients with typical unilateral Parkinson's disease (unilat-PD; mean age, 58.2 +/- 13.8 years). All six HPHA patients demonstrated significant metabolic reductions (> 3 SD) in the contralateral basal ganglia or frontal cortex as compared with normal control values. Mean normalized glucose metabolism was reduced in the contralateral caudate and lentiform nuclei (p < 0.005) as compared with that in unilat-PD and normal controls. In both patients studied with FDOPA, contralateral striatal uptake was significantly reduced (> 3 SD) as compared with normal control values. These results suggest that the clinical manifestations of HPHA arise through a combination of pre- and postsynaptic nigrostriatal dopaminergic dysfunction. FDG and PET may be useful in differentiating this disorder from typical unilat-PD.

Adult↗
PubMed1993

Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity.

Parkinson's disease (PD) is characterized mainly by a loss of nigrostriatal dopamine neurons. Thus far, the actual physiopathology of PD remains uncertain, although recent studies have found decreased activity of complex I, one of the enzymatic units of the mitochondrial respiratory chain, in various tissues of PD patients. Because most, if not all, of PD patients are treated chronically with levodopa, the precursor of dopamine, and because we have shown previously that catecholamines may alter mitochondrial respiration, we assessed the effects of chronic administration of levodopa on complex I activity in rat brain. We found that chronic administration of levodopa, at a dose used in PD patients, caused a significant reduction in complex I activity while it did not affect the activities of complex II, complex IV, and citrate synthase. Reduction in complex I activity correlated well with catecholamine innervation as the reduction was observed mainly in the striatum and substantia nigra and to a lesser extent in the frontal cortex but not in the cerebellum. Moreover, the levodopa-induced decrease of complex I activity was reversible since activities at 1, 3, and 7 days after the last injection showed a progressive return to control values. Incubation of whole brain mitochondria in vitro showed that both levodopa and dopamine inhibit complex I activity in a dose- and time-dependent manner. In contrast, other compounds such as homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 3-O-methyl-dopa were minimally effective. Reduced glutathione, ascorbate, superoxide dismutase, and catalase prevented the effect of levodopa and dopamine on complex I. Various inhibitors of monoamine oxidase also prevented the effect of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Ascorbic acid protects against levodopa-induced neurotoxicity on a catecholamine-rich human neuroblastoma cell line.

Levodopa, at concentrations of 0.25 x 10(-4) M or larger, is toxic for the human neuroblastoma cell NB69. Toxicity is associated with high levels of quinones, increased activity of complex II-III, and lack of changes of complex I of the mitochondrial respiratory chain. Deprenyl, which does not alter the production of quinones, has a partial protective effect. Tocopherol, 23 or 115 x 10(-6) M, lacks significant preventive effect on levodopa toxicity, but ascorbic acid, 10(-3) M, prevents levodopa toxicity and quinone formation. Deprenyl, 10(-4) M, provides additional protection in cultures treated with levodopa and ascorbic acid. Our results indicate that ascorbic acid and deprenyl prevent levodopa neurotoxicity by unrelated mechanisms. Both compounds should be considered as complementary drugs to test for slowing the progression of Parkinson's disease.

Ascorbic Acid↗
PubMed1993

Neuropathology of lubag (x-linked dystonia parkinsonism).

Lubag is an x-linked recessive dystonia parkinsonism that affects Filipino men originating principally from the Panay Island. Linkage analysis has confirmed the mode of inheritance and localized the disease gene to the proximal long arm of the x-chromosome. We studied the brain of a 34 year old Filipino man affected with lubag. He developed truncal dystonia at age 30, which subsequently generalized. With disease progression, he also presented with parkinsonism including, rigidity, bradykinesia, and impaired balance. His symptoms were largely unaffected by medication and, at age 34, he underwent a right cryothalamotomy. He died suddenly 2 days after the procedure. The principal neuropathological findings were neuronal loss and a multifocal mosaic pattern of astrocytosis restricted to the caudate and lateral putamen. Similar findings have been reported in two other men with dystonia--one Filipino and the other non-Filipino. The similar pathology of the two Filipino men suggests that this is the pathology of lubag. Recognition of this pathology in a non-Filipino man suggests that the mutation causing lubag may not be restricted to the Filipino population.

Adult↗
PubMed1993

Use of botulinum toxin type F injections to treat torticollis in patients with immunity to botulinum toxin type A.

Fifteen patients with torticollis who had been treated with repeated injections of botulinum toxin type A (botox A) developed antibodies to the toxin. This resulted in loss of benefit in the 13 patients who had improved with botox A injections and failure to develop muscle atrophy after injection in all 15 patients. Patients were then injected with botulinum toxin type F (botox F) in the same muscles that had been injected with botox A. Ten of the 15 improved after botox F injections, including 9 of the 12 patients who had improved with type A toxin. Six of 9 patients with pain had improvement in pain after botox F injections. Patients reported similar improvement with type F and type A toxins, but duration of benefit was approximately 3 months with type A and approximately 1 month with type F. Botox F is an effective treatment for torticollis in patients who are immune to botox A. The usefulness of type F toxin, however, is limited by short duration of benefit.

Adolescent↗
PubMed1993

Therapeutic trial of milacemide in patients with myoclonus and other intractable movement disorders.

We performed a therapeutic trial with the glycine precursor, milacemide, on 10 patients with intractable movement disorders. Six had myoclonus of various etiologies and one each had progressive supranuclear palsy, Filipino X-linked dystonia with parkinsonism, painful legs and moving toes, and stiff-person syndrome. Milacemide was initiated at a dose of 2,400 mg/day, orally, and increased gradually to a maximum of 4,800 mg/day. No clear-cut observable improvement occurred. There were no serious adverse effects.

Acetamides↗
PubMed1993

Striatal 18F-dopa uptake: absence of an aging effect.

L-[18F]6-Fluoro-DOPA (L-[18F]6-fluoro-3,4-dihydroxyphenylalanine; FDOPA) has been used with quantitative positron emission tomography (PET) to assess presynaptic nigrostriatal dopaminergic function in life. The relationship of estimated kinetic rate constants for striatal FDOPA uptake [Ki(FDOPA)] to the normal aging process has been the subject of conflicting reports. Resolution of this issue has been hampered by methodological differences in previous FDOPA/PET investigations. We studied 19 healthy normal subjects (aged 27-77 years) and measured striatal Ki-(FDOPA) according to each of the earlier methods. While significant correlations (p < 0.005) existed between Ki(FDOPA) values estimated by the various techniques, none correlated with normal aging. We conclude that normal striatal Ki(FDOPA) values estimated using quantitative FDOPA/PET are uncorrelated with the aging process.

Adult↗