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Quantification of S-adenosylmethionine-induced tremors: a possible tremor model for Parkinson's disease.

Tremor is the most visible symptom of Parkinson's Disease (PD), and should be the appropriate parameter in models for its evaluation. Lack of reliable PD tremor models and methods to distinguish tremors from nontremor movements means that nontremor behavior such as rotation following basal ganglia damage are mostly used. Our laboratory has shown that S-adenosyl-methionine (SAM) injections into the brain of rats reliably produced tremors, rigidity, hypokinesia, and abnormal posture. Thus, SAM-induced tremors, when distinguished from nontremor activities, has the potential as a model for testing anti-PD agents. Tremor Monitor-recorded activity profiles of the rats injected with SAM showed low-amplitude signals interlaced with high-amplitude bursts of tremor episodes. Control activities were of low-medium amplitudes with no such patterns. The number of real and apparent episodes detected over 20 min were 92 +/- 12 and 84 +/- 14 lasting 470 +/- 50 and 210 +/- 50 s, indicating mean durations of 5.1, and 2.4 s, frequencies of 12 +/- 0.1 and 11 +/- 0.2 Hz, cycles (waves) per episode of 54 +/- 6 and 19 +/- 2 and amplitudes of 42.3 +/- 5 and 19.8 +/- 1 for the SAM-treated and control rats, respectively. The nontremor activities of rats injected with phosphate-buffered saline were distinguished and eliminated by raising the minimum amplitude and number of cycles to 20. This procedure is being enhanced for screening antitremor agents and for elucidating the possible mechanism for Parkinsonism.

Animals↗

Differential effects of alpha-adrenoceptor blockade on essential, physiological and isoprenaline-induced tremor: evidence for a central origin of essential tremor.

Intravenous thymoxamine reduced the power of essential tremor but increased that of physiological and isoprenaline-induced tremor. These findings indicate that essential and physiological tremor have dissimilar pathophysiological mechanisms. They also suggest that central adrenergic mechanisms are involved in the pathophysiology of essential tremor and that isoprenaline-induced tremor is not a good model of essential tremor. Furthermore, alpha-adrenoceptor blockers may be a useful therapy for essential tremor.

Adult↗

[Effect of Coretal Polfa (Oxprenolol) on parkinsonian tremor and benign essential tremor].

Coretal -- an agent blocking the beta-adrenergic receptors -- was given to 12 patients with Parkinson's syndrome with evident tremor and to 4 patients with benign essential tremor. In the group of Parkinson's syndrome the effectiveness of this treatment was evaluated by the blind method. The whole period of observation was 6 weeks, during 3 weeks the patients received Coretal 60-120 mg daily, during the next 3 weeks they were given placebo. The intensity of tremor was assessed by means of a scoring system. Improvement was achieved in 7 patients with Parkinson's syndrome and in 3 out of 4 cases of idiopathic tremor. Complete disappearance of tremor was never observed. Transient side effects were observed in 2 causes. The authors think that Coretal may be used with good result in treatment of parkinsonian tremor and benign essential tremor.

Clinical Trials as Topic↗

[Parkinsonian tremor, rigidity and flapping tremor].

Tremor occurring at rest (4-6 Hz) is considered to be one of the most characteristic symptoms in patients with Parkinson's disease. Yet, an early stages of the disease only 50% of the patients manifest resting tremor. Indeed, about 15% of Parkinsonian patients never display tremor at any stage of the disease. If tremor is present, its type is essential for differential diagnosis. Pill-rolling movement, for instance, is a hallmark of Parkinson's disease. Parkinsonian patients often show postural tremor associated with certain postures or movement, whereas flapping tremor is indicative of metabolic (ex: hepatic) encephalopathy. Parkinsonian rigidity is unique muscular rigidity. If rigidity is abolished by L-dopa or dopamine agonists, this provides a reliable sign for diagnosis of Parkinson's disease. Pathophysiology of different types of tremor is briefly discussed.

Adult↗

Yes/yes head tremor without appendicular tremor after bilateral cerebellar infarction.

We report a 67-year-old man who developed yes/yes head tremor without appendicular tremor six weeks after right occipital and bilateral cerebellar infarction. The tremor was resting-postural. Its activity increased with excitement, decreased either after ethanol, lateroflexion or rest and stopped at sleep. Four-vessel angiography revealed a well collateralised occlusion of both vertebral arteries. Needle-EMG recordings showed rhythmic, synchronous agonist/antagonist activity in both the splenius capitis and sternocleidomastoideus muscles at a frequency of 2-3 Hz. After administration of botulinum toxin A (DysportR), the tremor markedly improved and vanished completely after a booster. Since then the tremor did not reappear. Delayed-onset, yes/yes head tremor without appendicular tremor may be caused by bilateral cerebellar infarction and can be successfully relieved with botulinum toxin A.

Botulinum Toxins↗

Harmaline-induced tremor as a potential preclinical screening method for essential tremor medications.

No preclinical method to evaluate potential new medications for essential tremor (ET) is available currently. Although harmaline tremor is a well known animal model of ET, it has not found utility as a preclinical drug screen and has not been validated with anti-ET medications. We measured harmaline tremor in rats (10 mg/kg s.c.) and mice (20 mg/kg s.c.) with a load sensor under the cage floor and performed spectral analysis on 20-minute epochs. The motion power over the tremor frequency bandwidth (8-12 Hz in rats; 10-16 Hz in mice) was divided by the motion power over the full motion frequency range (0-15 Hz in rats; 0-34 Hz in mice). The use of these measures greatly reduced data variability, permitting experiments with small sample sizes. Three drugs that suppress ET (propranolol, ethanol, and octanol) all significantly suppressed harmaline-induced tremor. We propose that, with this methodology, harmaline-induced tremor may be useful as a preclinical method to identify potential medications for ET.

Animals↗

Coherence analysis differentiates between cortical myoclonic tremor and essential tremor.

Familial cortical myoclonic tremor with epilepsy (FCMTE) is characterized by a distal kinetic tremor, infrequent epileptic attacks, and autosomal dominant inheritance. The tremor is thought to originate from the motor cortex. In our patient group, a premovement cortical spike could not be established on electroencephalogram (EEG) back-averaging. Corticomuscular and intermuscular coherence analysis can demonstrate a cortical common drive to muscles. We carried out coherence analysis of electromyography (EMG) of forearm muscles and EEG of contralateral motor cortex in 7 FCMTE patients, 8 essential tremor (ET) patients, and 7 healthy controls. Results showed strong cortico- and intermuscular coherence in the 8- to 30-Hz range in the FCMTE patients, with EEG preceding EMG. Healthy controls and ET patients showed normal weak coherence around 20 Hz. The ET patients showed some additional coherence at tremor frequency (6 Hz), probably the result of sensory information flowing back to the sensorimotor cortex. These findings point to a pathological cortical drive in FCMTE patients leading to tremulous movements. Coherence analysis is an easy and useful method to differentiate FCMTE from ET. Coherence analysis is helpful when investigating a cortical common drive in cortical tremor and other movement disorders.

Adult↗

Familial cortical tremor with epilepsy: an under-recognized familial tremor.

The authors report three Japanese families presenting with cortical tremor and epilepsy. The patients showed either tremulous finger movements or seizures as the initial symptoms between 19 and 30 years of the age without progression. Postural tremor resembled essential tremor and responded to the anticonvulsants such as clonazepam, primidone and sodium valproate. Seizures were infrequent. These patients seem to have the same disorder as what the authors have described as 'familial cortical tremor with epilepsy'. Familial cortical tremor must be more common than previously thought and should be taken into consideration in the patients with 'familial essential tremor' who do not respond well to beta-blockers.

Adult↗

Tolerance and tremor rebound following long-term chronic thalamic stimulation for Parkinsonian and essential tremor.

Fifty-eight patients, 36 with essential tremor (ET) and 22 with Parkinson's disease (PD), received deep brain stimulation (DBS) in the thalamic ventral intermediate (Vim) nucleus. The mean follow-up was 17 months for ET and 21 months for PD patients. Stimulation parameters were adjusted as needed, at various intervals after surgery. Results were assessed using routine clinical evaluation and established outcome scales. All patients needed incremental increase in stimulation parameters at various intervals during the first 6-12 months after surgery. The mean voltage 1 week postoperatively was 1. 45 V in PD patients, and 1.37 V in ET patients. Twelve months later, the figures were 2.14 V in PD and 2.25 V in ET patients. At 1 year, the Essential Tremor Rating Scale (ETRS) improved from 54 to 28 (p < 0.0001). The motor part of the Unified Parkinson's Disease Rating Scale (UPDRS) improved from 37 to 26 (p < 0.01). Tremor items of the UPDRS improved more markedly (p < 0.0001). One week postoperatively 90% of PD, and 89% of ET patients were tremor free. One year later, 70% of PD and 60% of ET patients remained mostly tremor free. Upon switching off stimulation, there was a clear tendency for tremor rebound (p = 0.07) in the PD group, requiring continuous 24-hour stimulation in some patients. Permanent non-adjustable ataxia was induced by stimulation in 2 PD patients.

Electric Stimulation Therapy↗

Functional outcomes after gamma knife thalamotomy for essential tremor and MS-related tremor.

Twelve patients with a median age of 75 years underwent gamma knife thalamotomy for essential tremor (ET) (n = 9) or MS-related tremor (n = 3). All 11 evaluable patients noted improvement in action tremor. Six of eight ET patients had complete tremor arrest, and the violent action tremor in all three patients with MS was improved. One patient developed transient arm weakness. Stereotactic radiosurgery for ET and MS-related tremor is safe and effective for patients who may be poor candidates for other procedures.

Activities of Daily Living↗

Holmes tremor in association with bilateral hypertrophic olivary degeneration and palatal tremor: chronological considerations. Case report.

Hypertrophic olivary degeneration (HOD) is a rare type of neuronal degeneration involving the dento-rubro-olivary pathway and presents clinically as palatal tremor. We present a 48 year old male patient who developed Holmes' tremor and bilateral HOD five months after brainstem hemorrhage. The severe rest tremor was refractory to pharmacotherapy and botulinum toxin injections, but was markedly reduced after thalamotomy. Magnetic resonance imaging permitted visualization of HOD, which appeared as a characteristic high signal intensity in the inferior olivary nuclei on T2- and proton-density-weighted images. Enlargement of the inferior olivary nuclei was also noted. Palatal tremor was absent in that moment and appears about two months later. The delayed-onset between insult and tremor following structural lesions of the brain suggest that compensatory or secondary changes in nervous system function must contribute to tremor genesis. The literature and imaging findings of this uncommon condition are reviewed.

Cerebral Hemorrhage↗

A double-blind trial of isoniazid for essential tremor and other action tremors.

We conducted a double-blind trial of isoniazid in 11 patients with essential tremor and four patients with other types of postural action tremor. The tremor had not been helped by beta-blockers or primidone. Isoniazid was given in doses up to 1,200 mg daily, together with 100 mg pyridoxine, for four weeks. Results were assessed with subjective and objective scales. Only two patients with essential tremor appeared to benefit enough to continue the drug after the trial, and only one has benefited from its long-term use. Isoniazid may be useful in rare cases of essential tremor, but must be monitored carefully because of its toxicity.

Adrenergic beta-Antagonists↗

A new tremor mutant in the Pietrain pig: an animal model of orthostatic tremor? Clinical and neurophysiological observations.

A new tremor mutant, the "Campus syndrome" was studied in a breed of Pietrain pigs. Affected pigs showed a coarse tremor of the extremities when standing and walking, so they tended to remain recumbent, during which the tremor was suppressed. Needle electromyographic recordings of the semitendinosus muscle plus accelerometry revealed a high-amplitude 14- to 15-Hz tremor pattern activated specifically upon standing but maintained during walking. The observed syndrome thus bears similarities to the human condition of orthostatic tremor and might serve as an animal model for this as yet poorly understood disorder.

Animals↗

Asymmetry of tremor intensity and frequency in Parkinson's disease and essential tremor.

We investigated the asymmetry of tremor intensity, frequency and frequency dispersion of Parkinsonian (PT) and essential (ET) tremor using accelerometry. Data of the more and less trembling hands were statistically elaborated. We found that tremor intensity was significantly asymmetric not only in PT but also in ET, while frequency and frequency dispersion were symmetric in ET but asymmetric in PT. We conclude that bilateral assessment of frequency related tremor parameters may be used for differentiation between ET and PT, and provides further details on the central organization of tremor generators.

Aged↗

CNS pathology in the neurological mutant rats zitter, tremor and zitter-tremor double mutant (spontaneously epileptic rat, SER). Exaggeration of clinical and neuropathological phenotypes in SER.

The pathological alterations in the central nervous system (CNS) were examined in three kinds of mutant rat; the zitter (zi/zi; Zi), the tremor rat (tm/tm; Tm) and the spontaneously epileptic rat (SER) which is a double mutant carrying both zitter and tremor genes. Two major alterations demonstrated in these mutants were hypomyelination and vacuolation or spongy degeneration. Hypomyelination was observed predominantly in SER and to a lesser extent in Zi, and was accompanied by a redundant or aberrant myelin sheath formation in addition to a decreased number of myelinated fibres. This appeared to be related to the occurrence of tremor. There was no abnormality in the structure of the myelin lamellae and oligodendrocytes or any destruction of myelin sheaths by phagocytic cells. The number of radial components in CNS myelin was increased almost equally in Zi, Tm and SER. Vacuolation was prominent in SER and Tm, especially in the brainstem and thalamus. Zi also developed mild vacuolation with advancing age. Vacuolation seemed to be related to the epileptic phenomena in SER and Tm. Vacuoles consisted mainly of swollen astrocytic processes and enlargement of the extracellular space, as well as occasional enlargement of periaxonal spaces. Thus both pathological findings--the hypomyelination derived from the zitter mutation with tremor, and the vacuolation from the tremor mutation with epileptic symptoms--were mutually exaggerated in SER. It is postulated that the two different genetic loci with zi and tm mutations interact and synergistically reinforce each other both clinically and pathologically in SER.

Aging↗

Indexes for identification of abnormal tremor using computer tremor evaluation systems.

We consider methods of formulating indexes to identify abnormalities in tremor appropriate for computerized tremor analysis systems. Characterization of amplitude, frequency, and "harmonicity" are considered as well as how to combine several such characteristics into a single index to discriminate normal from abnormal tremor effectively. The methodological issues discussed here should be of interest to researchers and clinicians working with tremor in general and to both users and developers of computer tremor analysis systems.

Algorithms↗

Effects of timolol and atenolol on benign essential tremor: placebo-controlled studies based on quantitative tremor recording.

Two different beta-adrenoreceptor antagonists, atenolol and timolol, were separately compared with a placebo in the suppression of essential tremor. In two-week single-blind placebo-controlled studies with cross-over, timolol (5 mg twice daily) and atenolol (100 mg once daily) produced an equal reduction in sitting heart rate and sitting blood pressure. Timolol was effective in reducing tremor while atenolol failed to reduce tremor amplitude. These results indicate that essential tremor can be reduced but not blocked, by the adrenergic blocker timolol with both beta 1 and beta 2 blocking properties; but not by the relatively selective beta 1 blocking drug atenolol. Possibly, the tremor reduction is medicated by a peripheral effect on beta 2 adrenoreceptors.

Adult↗

Primary writing tremor: a selective action tremor.

Progressive difficulty in handwriting due to jerking movements precipitated by the act of writing beginning between the ages of 8 to 54 is reported in six patients. There was no rest tremor, but three had mild postural tremor. Specific muscle activity (especially pronation of the wrist or abduction of the fingers) elicited the tremors that persisted as long as the evocative posture or muscle activity was maintained. None had a family history of tremors, but two had a history suggestive of hypoxia at birth. Unlike benign essential tremor, the movements did not respond to propranolol HCl, but most patients were benefited both acutely and chronically by centrally active anticholinergic agents.

Adolescent↗