Long-term therapy of essential tremor with propranolol.

In a double-blind crossover study 12 patients with essential tremor were treated with propranolol and a placebo; 8 improved with propranolol and 3 with the placebo; the degree of improvement with propranolol was greater. In a similar study with diazepam 5 of 12 improved with diazepam and 4 of 12 with the placebo; the degree of improvement was less than that achieved with propranolol. Response in 21 patients to treatment with propranolol for 2 to 4 years was excellent in 4, good in 4 and fair in 10; the condition of 1 was unchanged and that of 2, worse. Excellent response was maintained for as long as 4 years, but response tended to deteriorate with time if initially it was less than excellent. Response decreased with increasing age. No patient 60 years of age or older had an excellent response, and the four with an excellent response were under age 55, three being under age 35; all four had had their tremor less than 12 years. Patients with essential tremor should be given a 3-month trial of propranolol at 120 mg/d; if no significant response is seen the dose should be decreased, then the drug discontinued.     

A therapeutic approach and objective test in the treatment of tremor.

Medical treatment of tremor is deceptive. The biochemical disturbance causing its appearance is not known, so that no specific treatment can be applied. Many substances have been proposed for their antitremulant properties, but clinical results must be interpreted with caution as tremor is a labile symptom which is under many influences. The authors have analysed the clinical effect of an interesting antitremulant drug and have reported an original method for measuring tremor.     

A community survey of Parkinson's disease.

In a rural community of 80,000 people 69 patients were identified as having a diagnosis of Parkinson''s disease. After interview and examination we found that 55 met the generally accepted diagnostic criteria for Parkinson''s disease, 4 had possible Parkinson''s disease, 6 had essential tremor, 2 had dementia and 2 had other conditions. The patients with Parkinson''s disease had clinical and epidemiologic characteristics similar to those of patients in previous, mainly hospital-based, studies. These characteristics included mean age at onset (63 years), frequency rate of dementia (20%) and presence of postural tremor (11%). The pattern of treatment varied, some patients receiving more medication than is usual for the severity of their illness, and some patients receiving less than is usual. Parkinson''s disease can be difficult to diagnose and manage because of the clinical variation between patients in presentation and response to treatment.     

Management of Parkinson's Disease: Combined Therapy with Levodopa and Thalamotomy

An increasing number of parkinsonian patients in whom levodopa fails to relieve tremor are being referred for thalamotomy. The literature suggests that in as many as 50 percent of patients treated with levodopa, there is no relief of tremor because of refractoriness to the medication or intractable side effects which limit dosage. Thalamotomy abolishes contralateral tremor in 90 percent of patients, with an associated mortality rate of 1 to 2 percent and morbidity of 6 percent. The relative merits and complications of levodopa and thalamotomy were reviewed and a therapeutic regimen designed in which the two approaches to treatment are combined to most effectively deal with all the symptoms of parkinsonism.     

Benign familial tremor treated with primidone.

Primidone given to a patient for epilepsy produced an unexpected reduction in benign familial tremor. Over the next eight years the drug was therefore tried in a prospective study of 20 other patients with benign familial tremor alone. Of these, six could not tolerate the drug because of vertigo and nausea but 12 obtained a good response, which in some cases was dramatic. Investigations in two patients suggested that the effect was mediated predominantly by derived phenylethylmalonamide, though primidone had some effect, since tremor recurred slightly on withdrawing the drug despite a constant or rising blood phenylethylmalonamide concentration. Primidone is highly effective in benign familial tremor. More patients with the condition are intolerant of the drug than are usually found with epilepsy.     

What happened to VIM thalamotomy for Parkinson's disease?

A prospective review of 75 of 190 parkinsonian patients undergoing unilateral thalamotomy was displayed with a computer graphics technique examining three equal consecutive groups from the pre-, early, and late L-dopa eras. Histograms for average function and scattergrams of individual patient's performance preoperatively and up to 2 years postoperatively were prepared. No ipsilateral effects or consistent iatrogenic deterioration of any function were identified. 2 years after surgery, 82% had no tremor in the contralateral fingers or hand and 7% had almost no tremor; contralateral tremor elsewhere was infrequent. Rigidity and manual dexterity improved less strikingly, the latter only reflecting abolition of tremor; locomotion, speech, facial movement and handwriting did not improve. There was no mortality, but 8% had persistent significant complications. VIM thalamotomy remains the treatment of choice for severe drug-resistant parkinsonian tremor.     

Clinicians’ Tendencies to Under-Rate Parkinsonian Tremors in the Less Affected Hand

The standard assessment method for tremor severity in Parkinson’s disease is visual observation by neurologists using clinical rating scales. This is, therefore, a subjective rating that is dependent on clinical expertise. The objective of this study was to report clinicians’ tendencies to under-rate Parkinsonian tremors in the less affected hand. This was observed through objective tremor measurement with accelerometers. Tremor amplitudes were measured objectively using tri-axis-accelerometers for both hands simultaneously in 53 patients with Parkinson’s disease during resting and postural tremors. The videotaped tremor was rated by neurologists using clinical rating scales. The tremor measured by accelerometer was compared with clinical ratings. Neurologists tended to under-rate the less affected hand in resting tremor when the contralateral hand had severe tremor in Session I. The participating neurologists corrected this tendency in Session II after being informed of it. The under-rating tendency was then repeated by other uninformed neurologists in Session III. Kappa statistics showed high inter-rater agreements and high agreements between estimated scores derived from the accelerometer signals and the mean Clinical Tremor Rating Scale evaluated in every session. Therefore, clinicians need to be aware of this under-rating tendency in visual inspection of the less affected hand in order to make accurate tremor severity assessments.     

Application of singular spectrum-based change-point analysis to EMG-onset detection

While many approaches have been proposed to identify the signal onset in EMG recordings, there is no standardized method for performing this task. Here, we propose to use a change-point detection procedure based on singular spectrum analysis to determine the onset of EMG signals. This method is suitable for automated real-time implementation, can be applied directly to the raw signal, and does not require any prior knowledge of the EMG signal’s properties. The algorithm proposed by Moskvina and Zhigljavsky (2003) was applied to EMG segments recorded from wrist and trunk muscles. Wrist EMG data was collected from 9 Parkinson’s disease patients with and without tremor, while trunk EMG data was collected from 13 healthy able-bodied individuals. Along with the change-point detection analysis, two threshold-based onset detection methods were applied, as well as visual estimates of the EMG onset by trained practitioners. In the case of wrist EMG data without tremor, the change-point analysis showed comparable or superior frequency and quality of detection results, as compared to other automatic detection methods. In the case of wrist EMG data with tremor and trunk EMG data, performance suffered because other changes occurring in these signals caused larger changes in the detection statistic than the changes caused by the initial muscle activation, suggesting that additional criteria are needed to identify the onset from the detection statistic other than its magnitude alone. Once this issue is resolved, change-point detection should provide an effective EMG-onset detection method suitable for automated real-time implementation.     

Expectation Modulates the Effect of Deep Brain Stimulation on Motor and Cognitive Function in Tremor-Dominant Parkinson's Disease

Expectation contributes to placebo and nocebo responses in Parkinson''s disease (PD). While there is evidence for expectation-induced modulations of bradykinesia, little is known about the impact of expectation on resting tremor. Subthalamic nucleus (STN) deep brain stimulation (DBS) improves cardinal PD motor symptoms including tremor whereas impairment of verbal fluency (VF) has been observed as a potential side-effect. Here we investigated how expectation modulates the effect of STN-DBS on resting tremor and its interaction with VF. In a within-subject-design, expectation of 24 tremor-dominant PD patients regarding the impact of STN-DBS on motor symptoms was manipulated by verbal suggestions (positive [placebo], negative [nocebo], neutral [control]). Patients participated with (MedON) and without (MedOFF) antiparkinsonian medication. Resting tremor was recorded by accelerometry and bradykinesia of finger tapping and diadochokinesia were assessed by a 3D ultrasound motion detection system. VF was quantified by lexical and semantic tests. In a subgroup of patients, the effect of STN-DBS on tremor was modulated by expectation, i.e. tremor decreased (placebo response) or increased (nocebo response) by at least 10% as compared to the control condition while no significant effect was observed for the overall group. Interestingly, nocebo responders in MedON were additionally characterized by significant impairment in semantic verbal fluency. In contrast, bradykinesia was not affected by expectation. These results indicate that the therapeutic effect of STN-DBS on tremor can be modulated by expectation in a subgroup of patients and suggests that tremor is also among the parkinsonian symptoms responsive to placebo and nocebo interventions. While positive expectations enhanced the effect of STN-DBS by further decreasing the magnitude of tremor, negative expectations counteracted the therapeutic effect and at the same time exacerbated a side-effect often associated with STN-DBS. The present findings underscore the potency of patients'' expectation and its relevance for therapeutic outcomes.     

Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease

Stereotactic thalamotomy of the thalamic nucleus ventralis intermedius (VIM) is routinely used for movement disorders. During this procedure, it has been observed that high-frequency (100 Hz) stimulation of VIM was able to stop the extrapyramidal tremor. In patients with bilateral tremor of extrapyramidal origin, who were resistant to drug therapy, the therapeutic protocol associated (1) a radiofrequency VIM thalamotomy for the most disabled side, and (2) a continuous VIM stimulation for the other side using stereotactically implanted electrodes, connected to subcutaneous stimulators. VIM thalamotomy relieved the tremor in all operated cases. Side effects were mild and regressive. VIM stimulation strongly decreased the tremor but failed to suppress it as completely as thalamotomy did. This was due in part to the fact that programmable stimulator frequency rate is limited to 130 Hz, while it appeared that the optimal stimulation frequency was 200 Hz. This therapeutic protocol appears to be of interest for patients with bilateral extrapyramidal movement disorders.     

Is There a Role for Combined EMG-fMRI in Exploring the Pathophysiology of Essential Tremor and Improving Functional Neurosurgery?

Background

Functional MRI combined with electromyography (EMG-fMRI) is a new technique to investigate the functional association of movement to brain activations. Thalamic stereotactic surgery is effective in reducing tremor. However, while some patients have satisfying benefit, others have only partial or temporary relief. This could be due to suboptimal targeting in some cases. By identifying tremor-related areas, EMG-fMRI could provide more insight into the pathophysiology of tremor and be potentially useful in refining surgical targeting.

Objective

Aim of the study was to evaluate whether EMG-fMRI could detect blood oxygen level dependent brain activations associated with tremor in patients with Essential Tremor. Second, we explored whether EMG-fMRI could improve the delineation of targets for stereotactic surgery.

Methods

Simultaneous EMG-fMRI was performed in six Essential Tremor patients with unilateral thalamotomy. EMG was recorded from the trembling arm (non-operated side) and from the contralateral arm (operated side). Protocols were designed to study brain activations related to voluntary muscle contractions and postural tremor.

Results

Analysis with the EMG regressor was able to show the association of voluntary movements with activity in the contralateral motor cortex and supplementary motor area, and ipsilateral cerebellum. The EMG tremor frequency regressor showed an association between tremor and activity in the ipsilateral cerebellum and contralateral thalamus. The activation spot in the thalamus varied across patients and did not correspond to the thalamic nucleus ventralis intermedius.

Conclusion

EMG-fMRI is potentially useful in detecting brain activations associated with tremor in patients with Essential Tremor. The technique must be further developed before being useful in supporting targeting for stereotactic surgery.     

帕金森病及运动障碍疾病门诊震颤患者的病因及临床表现分析

目的:总结帕金森病及运动障碍疾病门诊震颤患者的病因及临床表现,以提高门诊震颤患者的诊断率,降低误诊率,为门诊震颤诊断提供临床经验。方法:连续收集西京医院神经内科帕金森病及运动障碍疾病门诊自2015年5月至2016年7月收治的震颤患者进行横断面研究。采用SPSS19.0软件进行统计分析。结果:共纳入400例震颤患者,男性173例(43.3%),女性227例(56.8%),男女之比1:1.3,平均发病年龄54.0岁。40岁以下特发性震颤(ET)最多,41-60岁为帕金森病(PD),60岁以上帕金森病最多。震颤按临床表现形式分为静止性震颤85例(21.3%),动作性震颤137例(34.3%),混合性震颤178例(44.5%)。震颤按病因分类,占比例前三位的分别是:帕金森病(46.3%),特发性震颤(28.5%),心因性震颤(5.8%)。心因性震颤急性起病率及合并焦虑抑郁率最高,而PT画螺旋圈及书写阳性率明显低于其他病因组。结论:门诊震颤患者混合性震颤形式较多见,最常见病因为帕金森病、特发性震颤及心因性震颤;心因性震颤较其他病因所致震颤相比,急性起病率、合并焦虑抑郁率高,而画螺旋圈及书写阳性率低。震颤诊断应先明确震颤的临床特点,然后分析病因以确定诊断及治疗。     

深部脑刺激作用机制的探讨

深部脑刺激器（deep brain stimulator）,也经常被称为脑起搏器,是可植入人体设备,并连续不断地传送刺激脉冲到深部脑组织的特定区域,即所谓的深部脑刺激（deep brain stimulation,DBS）.迄今为止,深部脑刺激是治疗严重顽固抗药性运动障碍疾病（如帕金森病,原发性震颤及肌张力异常等）的最有效的外科治疗手段之一.此外,广大的科研工作者也不断地探索应用DBS治疗其他神经及精神异常（如,癫痫和强迫症）的新的临床应用.尽管应用DBS治疗运动障碍非常有效,并也迅速被探索性地应用到其他神经障碍治疗中,但其作用机制仍然不是十分清楚,成为学者们争论的热点.DBS治疗效果的作用机制通常有两种基本的观点：高频刺激抑制学说及高频刺激兴奋学说.基于最近发表的关于中枢神经系统内的高频刺激效应的资料、数据及相关评论,两种机制共存并发挥作用的DBS作用假说被提出,认为DBS通过施加高频刺激干扰并控制了核团病理性紊乱随机活动,同时施加兴奋性刺激到其他基底节的网络,以实现对帕金森病的治疗.     

Progranulin Gene Delivery Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity and akinesia/bradykinesia resulting from the progressive loss of nigrostriatal dopaminergic neurons. To date, only symptomatic treatment is available for PD patients, with no effective means of slowing or stopping the progression of the disease. Progranulin (PGRN) is a 593 amino acid multifunction protein that is widely distributed throughout the CNS, localized primarily in neurons and microglia. PGRN has been demonstrated to be a potent regulator of neuroinflammation and also acts as an autocrine neurotrophic factor, important for long-term neuronal survival. Thus, enhancing PGRN expression may strengthen the cells resistance to disease. In the present study, we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of PGRN gene delivery as a therapy for the prevention or treatment of PD. Viral vector delivery of the PGRN gene was an effective means of elevating PGRN expression in nigrostriatal neurons. When PGRN expression was elevated in the SN_C, nigrostriatal neurons were protected from MPTP toxicity in mice, along with a preservation of striatal dopamine content and turnover. Further, protection of nigrostriatal neurons by PGRN gene therapy was accompanied by reductions in markers of MPTP-induced inflammation and apoptosis as well as a complete preservation of locomotor function. We conclude that PGRN gene therapy may have beneficial effects in the treatment of PD.     

Corticomuscular Transmission of Tremor Signals by Propriospinal Neurons in Parkinson's Disease

Cortical oscillatory signals of single and double tremor frequencies act together to cause tremor in the peripheral limbs of patients with Parkinson''s disease (PD). But the corticospinal pathway that transmits the tremor signals has not been clarified, and how alternating bursts of antagonistic muscle activations are generated from the cortical oscillatory signals is not well understood. This paper investigates the plausible role of propriospinal neurons (PN) in C3–C4 in transmitting the cortical oscillatory signals to peripheral muscles. Kinematics data and surface electromyogram (EMG) of tremor in forearm were collected from PD patients. A PN network model was constructed based on known neurophysiological connections of PN. The cortical efferent signal of double tremor frequencies were integrated at the PN network, whose outputs drove the muscles of a virtual arm (VA) model to simulate tremor behaviors. The cortical efferent signal of single tremor frequency actuated muscle spindles. By comparing tremor data of PD patients and the results of model simulation, we examined two hypotheses regarding the corticospinal transmission of oscillatory signals in Parkinsonian tremor. Hypothesis I stated that the oscillatory cortical signals were transmitted via the mono-synaptic corticospinal pathways bypassing the PN network. The alternative hypothesis II stated that they were transmitted by way of PN multi-synaptic corticospinal pathway. Simulations indicated that without the PN network, the alternating burst patterns of antagonistic muscle EMGs could not be reliably generated, rejecting the first hypothesis. However, with the PN network, the alternating burst patterns of antagonist EMGs were naturally reproduced under all conditions of cortical oscillations. The results suggest that cortical commands of single and double tremor frequencies are further processed at PN to compute the alternating burst patterns in flexor and extensor muscles, and the neuromuscular dynamics demonstrated a frequency dependent damping on tremor, which may prevent tremor above 8 Hz to occur.     

The nature of essential tremor

The literature concerning essential tremor is confusing. Some accounts describe tremor of a resting type and its accompaniment by other neurological abnormalities. Critical analysis of the pertinent literature leaves some question as to the validity of these observations.Clinical analysis of 34 patients with essential tremor, personally observed during a four-year period, reveals this to be a monosymptomatic condition. The tremor was usually of both a postural and action type and resting tremor was not observed. There were no other neurological abnormalities. Serious disability was infrequent and, when present, was related to upper limb tremor. Essential tremor should be readily distinguishable from other central nervous system diseases but it may be confused with Parkinson''s disease or cerebellar ataxia.     

Neostriatal muscarinic receptor subtypes involved in the generation of tremulous jaw movements in rodents implications for cholinergic involvement in parkinsonism

Several studies have shown that a number of pharmacological and neurochemical conditions in rats can induce jaw movements that are described as "vacuous" or "tremulous". For several years, there has been some debate about the clinical significance of various drug-induced oral motor syndromes. Nevertheless, considerable evidence now indicates that the non-directed, chewing-like movements induced by cholinomimetics have many of the characteristics of parkinsonian tremor. These movements are characterized largely by vertical deflections of the jaw, which occur in the same 3-7 Hz peak frequency that is typical of parkinsonian tremor. Cholinomimetic-induced tremulous jaw movements are suppressed by a number of different antiparkinsonian drugs, including scopolamine, benztropine, L-DOPA, apomorphine, bromocriptine, ropinirole, pergolide, amantadine, diphenhydramine and clozapine. A combination of anatomical and pharmacological research in rats has implicated M4 receptors in the ventrolateral neostriatum in the generation of tremulous jaw movements. Mice also show cholinomimetic-induced jaw movements, and M4 receptor knockout mice demonstrate subtantially reduced levels of jaw movement activity, as well as increased locomotion. Taken together, these data are consistent with the hypothesis that a centrally-acting M4 antagonist may be useful as a treatment for parkinsonian symptoms, including tremor.     

EMG signal morphology and kinematic parameters in essential tremor and Parkinson’s disease patients

The aim of this work was to differentiate patients with essential tremor from patients with Parkinson’s disease. Electromyographic data from biceps brachii muscles and kinematic data from arms during isometric tension of the arms were measured from 17 patients with essential tremor, 35 patients with Parkinson’s disease and 40 healthy controls.The EMG signals were divided to smaller segments from which histograms were calculated. The histogram shape was analysed with a feature dimension reduction method, the principal component analysis, and the shape parameters were used to differentiate between different subject groups. Three parameters, RMS-amplitude, sample entropy and peak frequency were determined from the kinematic measurements of the arms.The height and the side differences of the histogram were the most effective for differentiating between essential tremor and Parkinson’s disease groups. The histogram parameters of patients with essential tremor were more similar to patients with Parkinson’s disease than healthy controls. With this method it was possible to discriminate 13/17 patients with essential tremor from 26/35 patients with Parkinson’s disease and 14/17 patients with essential tremor from 29/40 healthy controls. The kinematic parameters of patients with essential tremor were closer to parameters of patients with Parkinson’s disease compared to healthy controls. Combining EMG and kinematic analysis did not increase discrimination efficiency but provided more reliability to the discrimination of subject groups.     

Effect of Tetrabenazine on Extrapyramidal Movement Disorders

Thirty patients with various extrapyramidal movement disorders were treated for prolonged periods with 75 to 225 mg. daily of tetrabenazine. In patients with choreiform and hemiballistic motor activity the involuntary movements were diminished or abolished. In patients with cerebellar or Parkinsonian tremor the tremor was aggravated in moderately severe cases, but was uninfluenced in severe cases. In all cases the dyskinesia returned when- the drug was stopped.Side-effects were inconsiderable and disappeared on reducing the dose slightly. Hence the drug may be an important alternative to neurosurgical treatment of hyperkinesias and especially suitable for severely disabled patients.     

Carpal Tunnel Syndrome in Patients with Tremor Dominant Parkinson’s Disease

Background

Unilateral hand tremor is one of the cardinal symptoms of Parkinson’s disease. Additionally, mechanical traumatic hand movement is one of the risk factors for carpal tunnel syndrome. Our objective in this study was to examine whether repetitive mechanical movement may be related to the development of carpal tunnel syndrome in Parkinson’s disease with unilateral hand tremor using neurophysiological methods.

Methods

The study participants included 33 de novo Parkinson’s disease patients with unilateral hand tremor, and we compared the tremor hand and non-tremor hand within the same patients.

Results

Seven (21.2%) of the 33 patients had carpal tunnel syndrome. All of carpal tunnel syndrome patients showed neurophysiological abnormalities in both the hand without tremor and the hand with tremor. In addition, in patients without carpal tunnel syndrome, the sensory nerve action potential was lower in the hand without tremor than in the hand with tremor, although there were no significant differences.

Conclusions

We concluded that hand tremor in de novo Parkinson’s disease patients was not directly related to the development of carpal tunnel syndrome. In contrast, more frequent use of hand without tremor may induce mechanical loading and may be associated with CTS in the hand without tremor. Early diagnosis of Parkinson’s disease and proper education in hand use may be essential for preventing carpal tunnel syndrome in Parkinson’s disease tremor patients.