Hemiparkinsonism-hemiatrophy syndrome may mimic early-stage cortical-basal ganglionic degeneration.
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Adult↗
Biomedical subjects
S Fahn
Publications and source records attributed to S Fahn.
Implantation of genetically modified mesencephalic fetal cells into the rat striatum.
Transplantation of dopamine (DA) cells into the rat model of hemiparkinsonism induced by intranigral 6-hydroxydopamine (6-OHDA) injections has so far focused mainly on DA replacement via a pump-like mechanism. In the present study, we employed a model of hemiparkinsonism that uses an intrastriatal approach to lesioning the nigrostriatal DA pathway to assess the possibility of using cell transplantation to cause regeneration of that system. Toward that end, we transplanted two types of cells on the side of the 6-OHDA-induced lesions: 1) nonmodified fetal mesencephalic cells and 2) fetal mesencephalic cells that have been infected with a retrovirus vector containing a PKC beta 1 cDNA. Both types of cells cause behavioral improvement although the changes were more prominent and occurred earlier in the PKC-modified groups. Tyrosine hydroxylase (TH) immunocytochemistry revealed significantly cell survival in both groups of animals; in situ hybridization studies confirmed the continuous expression of TH mRNA in both groups. Interestingly, long TH-positive axons were observed only in the striata of animals implanted with PKC-modified cells. More importantly, surviving endogenous nigral TH-positive cell bodies were found only on the lesioned side in the latter group. The observations in these animals were associated with significantly smaller decreases in [3H]mazindol-labeled DA uptake sites in both the striata and substantia nigra pars compacta on the side ipsilateral to the 6-OHDA-induced lesions. Furthermore, immunohistochemical studies revealed increased gliosis in the striata of animals grafted with the PKC-modified cells. When taken together, these results indicate that transplantation of normal fetal mesencephalic cells can cause behavioral improvement by providing DA to the host striata whereas PKC-modified cells can, in addition, prevent the progressive degeneration of or cause regeneration of the dying nigrostriatal DA neurons in this model of hemiparkinsonism. These results are discussed in terms of their support for a role for second messenger systems and glial cells, as well as extracellular matrix molecules in the regeneration of the CNS.
Amphetamine↗
The autosomal dominant dystonias.
Dystonia is a term used to describe a specific set of abnormal movements that can occur as a symptom of a variety of neurologic disorders, but also as a disease entity in its own right. This review focuses on the primary dystonias and delineates the genetic contribution to these disorders. Included is a description of the well recognized forms of primary dystonias which manifest autosomal dominant inheritance, especially the "classic" type of early onset, generalized torsion dystonia, but also other clinically distinct forms such as myoclonic dystonia, paroxysmal dystonia, and DOPA-responsive dystonia. Also, a summary of the molecular genetic studies pertinent to these disorders and a discussion of the implications of recent genetic research for delineating the wide spectrum of this phenotypically and genetically heterogeneous group of diseases are forthcoming.
Alleles↗
Motor blocks in Parkinson's disease.
Freezing episodes and related phenomena (as a general term, motor blocks [MBs]) are poorly understood, particularly disabling, and a therapeutically frustrating problem in Parkinson's disease (PD). Epidemiologic and clinical characteristics of MBs, as well as risk factors to develop MBs, have never been fully addressed. Herein, we report our database survey on 990 PD patients, of whom 318 (32%) had MBs. The majority of MBs were linked to gait. Start hesitation occurred in 86%, blocking on turning in 45%, and blocking in narrow spaces in 25% of patients. Initial parkinsonian symptoms in the upper body and tremor as the initial motor symptom were less likely to be associated with the presence of MBs (odds ratios [OR] 0.6 and 0.7, respectively), while initial symptoms affecting gait or trunk had higher association with MBs (OR = 1.58). Longer disease duration, higher Hoehn and Yahr stage, and longer duration of levodopa treatment are all significantly associated with the presence of MBs. We observed significant association between the existence of MBs and levodopa-induced dyskinesias to suggest similar pathophysiology. We propose that MBs in PD are abnormal retrieval or execution of complex motor tasks that can occur as a result of disease progression or as short- or long-term side effects of levodopa treatment.
Dyskinesia, Drug-Induced↗
Abductor laryngeal dystonia: a series treated with botulinum toxin.
Abductor laryngeal dystonia (LD) is characterized by a hoarse voice quality which is broken up by breathy or whispered portions. Botulinum toxin injection (Botox) has been a safe and effective treatment for adductor laryngeal dystonia and is currently accepted medical therapy. As an extension of the established treatment program, in 1989 treatment of abductor LD was initiated. Thirty-two patients have been treated by sequential percutaneous electromyogram-guided (EMG) injections of the posterior cricoarytenoid (PCA) muscles. Most patients required treatment of both PCA muscles and improved to an average of 70% of normal voice. Patients who had a preexisting tremor, evidence of dystonia in other muscle groups, vocal tremor, or respiratory dysrhythmia had less improvement. Ten patients also required injection of the cricothyroid muscles and/or type I laryngoplasty.
Adolescent↗
Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity.
Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mammals causes damage to the nigrostriatal dopaminergic pathway similar to that observed in Parkinson's disease. It has been suggested that the mechanism by which MPTP kills dopamine (DA) neurons involves an energy crisis due to the inhibition of mitochondrial complex I. In addition, superoxide radicals (O2-), generated subsequent to the blockade of mitochondrial complex I, may also be involved in MPTP-induced neurotoxicity. Superoxide dismutase (SOD) is a scavenger enzyme that protects cells from the hazard of O2- radicals. To evaluate further the role of O2- radical in MPTP-induced toxicity, we tested the effects of MPTP in transgenic mice with increased SOD activity. In nontransgenic littermates with normal SOD activity, MPTP injection causes a marked reduction in striatal levels of DA and its metabolites as well as in striatal and nigral 3H-DA uptake; these findings are consistent with a loss in dopaminergic neurons. In contrast, in transgenic mice with increased SOD activity, MPTP injection does not cause any significant changes either in levels of DA and metabolites or in 3H-DA uptake. We show that this lack of toxicity is not due to a lower delivery of MPTP to the brain following its intraperitoneal injection, to reduced brain biotransformation of MPTP to N-methyl-4-phenylpyridinium ion (MPP+), to diminished striatal mitochondrial monoamine oxidase B activity, to decreased synaptosomal uptake of MPP+, to lower potency of MPP+ to inhibit the complex I of the mitochondrial electron transport chain, or to faster brain elimination of MPP+. These results suggest that increased SOD activity is, most likely, the protective factor that confers resistance to transgenic mice against MPTP-induced neurotoxicity. Thus, this study provides further evidence that some of the deleterious effects of MPTP may be mediated by O2- radicals. The similarity between the MPTP model and Parkinson's disease further raises the possibility that oxy-radicals may play a significant role in the etiology of this neurodegenerative disorder.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
[Botulinum toxin as a powerful new tool in the treatment of focal dystonia].
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Botulinum Toxins↗
Sham transplantation protects against 6-hydroxydopamine-induced dopaminergic toxicity in rats: behavioral and morphological evidence.
Administration of the neurotoxin 6-hydroxydopamine (6-OHDA) to rat brain causes biochemical and neuroanatomical changes to the nigrostriatal dopaminergic pathway similar to those observed in Parkinson's disease (PD). Although the cause of PD is unknown, it has been hypothesized that the neurodegenerative changes seen in PD might result from exposure to a neurotoxin. Therefore, strategies for limiting neurotoxin-induced dopaminergic damages, like those caused by 6-OHDA, may be of both clinical and basic interest. Accordingly, we tested the ability of both fetal neural (striatum) and fetal non-neural (liver) tissue implants to protect the rat striatum against the toxic effects of a subsequent intrastriatal injection of 6-OHDA. Non-grafted rats (lesion only) showed amphetamine-induced rotational behavior and a decrease in striatal [3H]mazindol-labeled dopamine uptake sites after 6-OHDA injection. In contrast, the animals grafted with striatum or liver showed no behavioral or biochemical changes. Interestingly, sham-transplanted control animals were also protected against the 6-OHDA-induced toxicity. These results suggest that the resistance of the dopaminergic system against 6-OHDA neurotoxicity observed in grafted and sham-transplanted animals is likely to be related to the surgical procedure itself. This observation points to a possible role for surgery-related events in the clinical improvement described in PD patients who underwent intracerebral transplantation.
Analysis of Variance↗
Genetic mapping of "Lubag" (X-linked dystonia-parkinsonism) in a Filipino kindred to the pericentromeric region of the X chromosome.
"Lubag" is an X-linked disorder causing dystonia and parkinsonism that has only been described in families from the Philippines, principally from the island of Panay. We have established linkage between the disease phenotype "lubag" and DNA markers which span the Xp11.22-Xq21.3 region by using a large Filipino family with 8 affected men in three generations. These DNA markers define an interval of about 20 centimorgans in the pericentromeric region of the X chromosome as the most likely site of the disease locus XDPD (X-linked dystonia-parkinsonism). XDPD has a maximum multipoint log likelihood ratio score (Zmax) of about 4.6 over the interval from Xq12 to Xq21.31 (DXS159-DXYS1X). The co-occurrence of dystonia and parkinsonism in lubag and in other known disorders suggests there may be a common pathogenetic mechanism. Identification of the genetic defect in this family may provide an important clue toward understanding the pathogenesis and pathophysiology of both dystonia and parkinsonism.
Adult↗
Idiopathic cervical dystonia: clinical characteristics.
We reviewed detailed clinical features of 266 patients with idiopathic cervical dystonia, commonly called spasmodic torticollis. Mean age at onset (41 years), female-to-male ratio (1.9:1), clustering of onset between ages 30 and 59 (70%), familial history of dystonia (12%), and remissions (9.8%) were similar to those found in previous studies. In contrast to the single prior large clinical study of this disorder, no predominance of right-handers or significant thyroid disease was found. Pain, which occurred in 75% of patients and contributed to disability score (p less than 0.01), distinguishes this syndrome from all other focal dystonias. Pain was also strongly associated with constant (vs. intermittent) head turning, severity of head turning, and presence of spasm. Eighty-three percent of patients had deviation of the head of greater than 75% of the time when sitting with the head unsupported (constant head deviation at rest). Of the 97% who had head turning, 81% also had head tilting in various combinations. The 23% with hand tremor had an older age at onset (mean, 46 vs. 41 years; p less than 0.05). An earlier age at onset (p less than 0.05) was seen in patients with a family history of dystonia (mean, 36 years), with trauma shortly preceding symptoms (mean, 36 years), with a change in the direction of head turning (mean, 30 years), and with remissions (mean, 33 years). Jerky movements or forced transient spasms of the head occurred in 62% of the patients, and these patients would be the ones for whom the designation "spasmodic torticollis" could logically apply.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Hereditary essential myoclonus in a large Norwegian family.
We examined 56 members of a large Norwegian family with hereditary essential myoclonus, affecting mainly the neck and upper parts of the body, and inherited in an autosomal-dominant pattern. We observed definite myoclonus in nine individuals, probable myoclonus in one, and possible myoclonus in one. There were two other living members who had a history compatible with myoclonus but who had developed a permanent remission, so we did not observe the movements, and two who had involuntary movements only with stress. Writing usually increased the myoclonus in the neck and trunk, but did not produce myoclonus in the arm used for writing. Having a conversation with an individual who was aware of being watched would also usually increase the myoclonus. Alcohol ameliorated the myoclonus in many, but not all, affected members. Activities such as walking and concentrating during reading would usually reduce the myoclonus. Three living members with definite myoclonus also had features of mild focal dystonia, either spasmodic torticollis or blepharospasm, indicating that focal dystonia may exist as part of the clinical spectrum in hereditary essential myoclonus. In addition to examining the members of the family, we videotaped them and obtained blood samples for molecular genetic analysis.
Adolescent↗
Intraventricular infusion of epidermal growth factor restores dopaminergic pathway in hemiparkinsonian rats.
We assessed the effect of a 35-day delayed intracerebroventricular (ICV) infusion of epidermal growth factor (EGF) on the survival and function of the substantia nigra (SN) dopaminergic neurons after a unilateral mechanical transection of rat nigrostriatal pathway. EGF infusion for 28 days resulted in a twofold increase in the number of surviving tyrosine-hydroxylase (TH)-positive SN neurons and a significant increase in ipsilateral striatal TH-positive fiber staining compared to controls at 200 days following the injury. In addition, there was a persistent enhancement of behavioral recovery, as indicated by a reduction in amphetamine-induced rotations. We conclude that EGF exerts a neurotrophic effect on the dopaminergic neurons in this experimental model of parkinsonism.
Animals↗
What is it? Case 2, 1991: unusual tremor, myoclonus, and a limping gait.
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Adult↗
What is it? Case 3, 1991: moaning in a man with parkinsonian signs.
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Diagnosis, Differential↗
Distant effects of locally injected botulinum toxin: a double-blind study of single fiber EMG changes.
We used single fiber electromyography (SFEMG) to study 42 patients who had enrolled in a double-blind, placebo-controlled trial undertaken to assess the efficacy of botulinum toxin (BTX) injection of neck muscles to treat torticollis. SFEMG in a limb muscle was performed before treatment, 2, and 12 weeks after injection of placebo or BTX. Before treatment, the mean jitter was 26.8 microsec in patients who were to receive BTX, and 25.7 microsec in the placebo group. Two weeks after injection, mean jitter in the group receiving BTX was 43.6 microsec. In the placebo group, it was 26.5 microsec (P = less than .05). Twelve weeks after injection, mean jitter in the BTX group was 35.5; for the placebo group it was 24.5. Fiber density did not change in any patient during the study. There were no remote clinical effects of BTX. Injection of BTX into muscles affected with focal dystonia is a promising and safe treatment, but there are subclinical effects on uninjected muscles.
Adult↗
Partial attenuation of chronic fluphenazine-induced changes in regional monoamine metabolism by D-alpha-tocopherol in rat brain.
Recent evidence has suggested a role for free radicals in tardive dyskinesia. We, therefore, investigated the effects of chronic administration of fluphenazine decanoate (FLU) and/or vitamin E (VIT E) on regional monoamine metabolism in rat brain. Chronic FLU caused significant increases in dopamine (DA) in nucleus accumbens and brainstem, significant decreases in dihydroxyphenylacetic acid (DOPAC) in frontal cortex, nucleus accumbens and hippocampus and significant decreases in homovanillic acid (HVA) in nucleus accumbens, caudate-putamen and brainstem. Coadministration of FLU and VIT E normalized HVA in caudate-putamen, nucleus accumbens and brainstem as well as DOPAC in nucleus accumbens and hippocampus. Chronic FLU caused significant increases in norepinephrine (NE) levels in all regions studied. VIT E attenuated FLU-induced increases in NE levels in nucleus accumbens and hippocampus. Significant increases in serotonin (5-HT) levels occurred in nucleus accumbens and hippocampus whereas significant decreases in 5-hydroxyindole-acetic acid (5-HIAA) occurred in all brain regions after chronic FLU. Coadministration of VIT E attenuated the changes observed in hippocampal 5-HIAA but potentiated the FLU-induced increases in 5-HT in this region. Our data suggest that VIT E can attenuate some of the FLU-induced changes in monoamine metabolism. Results are discussed in relation to possible involvement of free radicals in monoamine metabolism during chronic neuroleptic use.
3,4-Dihydroxyphenylacetic Acid↗
An open trial of high-dosage antioxidants in early Parkinson's disease.
High dosages of tocopherol and ascorbate were administered to patients with early Parkinson's disease as a preliminary open-labeled trial for the eventual controlled double-blind study evaluating antioxidants as a test of the endogenous toxin hypothesis of the etiology of Parkinson's disease. The primary endpoint of the trial was the need to treat patients with levodopa. The time when levodopa became necessary in the treated patients was compared with another group of patients followed elsewhere and not taking antioxidants. The time when levodopa became necessary was extended by 2.5 y in the group taking antioxidants. The results of this pilot study suggest that the progression of Parkinson's disease may be slowed by the administration of these antioxidants. A large multicenter, controlled clinical trial currently underway in North America evaluating tocopherol and deprenyl has the potential to confirm these results.
Adult↗