Low dosage clozapine effects on L-dopa induced dyskinesias in parkinsonian patients

Objectives – The aim of this study was to investigate the clinical efficacy of clozapine, an atypical neuroleptic, on L-dopa induced dyskinesias of Parkinson's disease. Material and methods – In an open study, a group of 10 PD patients was treated with low dosage clozapine (mean 30 mg/day) for a 4-month period and L-dopa dyskinesias were evaluated in basal conditions and during clozapine treatment after the usual morning dose of clozapine. We utilized the AIMS for evaluation of dyskinesias and UPDRS for the assessment of motor performances. Results – Clozapine produced a significant ( P < 0.05) reduction of dyskinesias 1 week after the therapy onset. This effect was more pronunced at the end of the 2nd week and remained stable through the following months. We did not observe significant variations of motor performances. Conclusion – A low dose of clozapine appears to be beneficial for patients with L-dopa induced dyskinesias that do not respond to other drugs and therapeutic measures.     

Long-term EMG recordings differentiate between parkinsonian and essential tremor

The differential diagnosis of tremor is mainly based on clinical criteria.Nevertheless, these criteria are in some cases not sufficient to differentiate between different tremor forms. Long-term EMG has proven to be a valid and reliable method for the quantification of pathological tremors. The aim of the study was to develop a long-term EMG-based automated analysis procedure that separates parkinsonian tremor from essential tremor. Using longterm EMG tremor was recorded in 45 consecutive patients, 26 with Parkinson's disease (PD) and 19 with essential tremor (ET). Eight tremor parameters were generated automatically. By stepwise backward regression a subset of these criteria was extracted to achieve an automated classification of the tremor by a mathematical model. The obtained model was then tested on a new group of 13 patients in early stages of the disease. Significant differences between groups were found for tremor occurrence, tremor asymmetry, mean tremor frequency and standard deviation of phase of antagonistic muscles. Due to data overlap a classification of the two tremor forms was not possible based on a single tremor parameter. Using logistic regression, a linear formula based on the three parameters tremor occurrence, mean tremor frequency and standard deviation of phase was established and predicted the correct diagnosis in 93% of patients. The validation of the model on the new group of patients in early stages of the tremor disease yielded a correct diagnosis in 100% of cases. We conclude that long-term EMG recording allows a rater-independent classification of parkinsonian versus essential tremor.     

Paradoxical aspects of parkinsonian tremor

Although resting tremor is the most identifiable sign of Parkinson's disease, its underlying basis appears to be the most complex of the cardinal signs. The variable relationship of resting tremor to other symptoms of PD has implications for diagnosis, prognosis, medical and surgical treatment. Structural lesions very rarely cause classic resting tremor, with likely contributions to tremor by a network of neurons both within and outside the basal ganglia. Patients with only resting tremor show dopaminergic deficits with radioligand imaging, but severity of tremor correlates poorly in such dopamine imaging studies. Correlation of tremor severity to changes in radioligand studies is also limited by the use of mostly qualitative measures of tremor severity. A complex pharmacologic basis of parkinsonian resting tremor is supported by treatment studies. Although levodopa is clearly effective for resting tremor, several agents have shown efficacy that appears to be superior or additive to that of levodopa including anticholinergics, clozapine, pramipexole, and budipine. Although the thalamus has the greatest body of evidence supporting its role as an effective target for surgical treatment of tremor, recent studies suggest that the subthalamic nucleus may be a reasonable alternative target for patients with Parkinson's disease and severe tremor as the predominant symptom. © 2007 Movement Disorder Society     

Tremor is attenuated during walking in essential tremor with resting tremor but not parkinsonian tremor

We used accelerometry and visual examination by a neurologist to measure the intensity and frequency of hand tremor under resting, postural, writing, and walking conditions among patients with essential tremor with resting tremor (n = 11) and Parkinson’s disease (n = 38). The intensity of essential tremor was markedly attenuated during walking relative to resting. The intensity and frequency of parkinsonian tremors were higher while walking than while resting. We suggest that assessment of the intensity and frequency of tremor during walking is clinically useful for differentiating between essential tremor with resting tremor and parkinsonian tremor, especially in the early stages, when the two conditions are often difficult to distinguish. Parkinsonian tremors are known to be enhanced during walking. Our clinical experience, as well as that of others, suggests that the intensity of essential tremor with resting tremor is markedly attenuated during walking.     

Clozapine in the treatment of tremor

In an open trial 25 tremor patients were treated with clozapine in small doses (18-75 mg per day). The effect was measured with a new movement analyzer. Nine of 12 essential tremor patients were greatly improved. In six of nine patients with Parkinson tremor and in two combined essential tremor/Parkinson tremor patients tremor almost disappeared. Sedation is a major side effect, but decreases in most patients with time. The risk of agranulocytosis makes blood control necessary.     

Clozapine in the treatment of tremor in Parkinson's disease

Tremor at rest is a classic symptom of Parkinson's disease that causes significant disability and distress for the patient and is generally only weakly responsive to conventional treatment, like anticholinergic and dopaminergic medication. This study describes the treatment with Clozapine in patients with Parkinson's disease, who despite optimal antiparkinson medical therapy still have a major disabling tremor at rest. Clozapine is an "atypical" neuroleptic agent, producing fewer extra pyramidal side effects common to conventional antipsychotic drugs. Clozapine, however, has as its most serious complication agranulocytosis, and hence all patients taking Clozapine must undergo bloodtests at least several times a month. Under these frequent blood monitoring conditions, in this study Clozapine produced a substantial alleviation of parkinsonian tremor in 17 of 23 patients (73%). The beneficial response was reached with a relative low dose of Clozapine (18 mg./day), while previous antiparkinson medication was kept unchanged. The improvement of tremor at rest was noticeable generally within 2 weeks of beginning Clozapine therapy. No tolerance to the antitremor efficacy of Clozapine was seen during study-period of at least 6 months. Leucopenia developed in one patient, other major adverse events were hypersalivation and day-time drowsiness. These findings confirm the substantial antitremor efficacy of Clozapine in Parkinson's disease.     

Rest tremor suppression may separate essential from parkinsonian rest tremor

Rest tremor at 4–6 Hz is typical for classical rest tremor (PT) of Parkinson's disease (PD). But rest tremor also appears in other tremor syndromes and may therefore cause a misdiagnosis. In this study we evaluated if suppression of tremor during movement onset is a characteristic feature of Parkinsonian Tremor distinguishing PT from Essential tremor (ET) and if this sign can be reliably diagnosed.Clinically diagnosed patients with PT (n = 44) and ET (n = 22) with rest tremor were included. Video sequences were recorded according to a standardized protocol focusing on the change of tremor amplitude during transition from rest to posture (test 1) or to a target-directed movement (test 2). These videos were assessed for rest tremor suppression by 4 reviewers (2 specialists and 2 residents) blinded to the clinical diagnosis and were compared to the personal assessment of an unblinded movement disorder specialist.Rest tremor suppression was found in 39/44 PD patients and in 2/22 patients with ET during the personal assessment. Rest tremor suppression showed a high sensitivity (0.92–1.00) and an acceptable specificity (0.69–0.95) for PD tremor in both tests. The interrater-reliability of the video-sequences was good to very good (κ 0.73–0.91). Less than 3% of the video sequences were misclassified.We conclude that the assessment of the suppression of rest tremor during movement initiation is a simple and reliable tool to separate PT from rest tremor in ET also suggesting that the mechanisms of rest tremor in these two diseases are different.     

Effectiveness of bornaprine on parkinsonian tremor

The effectiveness of Bornaprine on parkinsonian tremor was evaluated in a single-blind study of mediumterm treatment. 25 patients were treated with rising doses of Bornaprine per os, one week at each dose-level. The dose at which Bornaprine was most effective was 8 mg daily and its action at this dose was mild but statistically significant. The drug was generally well tolerated in patients with idiopathic parkinsonism, but transient confusion developed in a few patients with secondary parkinsonism.

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Sommario Gli Autori hanno valutato in uno studio a singolo cieco l'efficacia della Bornaprine, sul tremore parkinsoniano durante un trattamento a medio termine. Il farmaco è stato somministrato per os a dosi crescenti da 6 a 16 mg/die ad un gruppo di 25 pazienti. La Bornaprine è stata generalmente ben tollerata in 18 dei pazienti affetti da Parkinson idiopatico mentre nei 7 pazienti affetti da parkinsonismo arteriosclerotico si è notata la frequente comparsa di transitori sintomi confusionali. L'attività tremorolitica del farmaco è apparsa modesta ma statisticamente significativa.

     

Clinical and electromyographic examinations of Parkinsonian tremor

Background: The clinical presentations of postural Parkinsonian tremor are variable and different types of tremors have been described. The aim of this study was to re-evaluate the clinical and electromyographic (EMG) pattern of different tremors in Parkinsonian patients.

Methods: One hundred and ten patients with Parkinsonian tremor were included in the study. Patients were subdivided into four groups according to the presence or absence of postural tremor, in addition to a resting tremor and its EMG pattern. The first group consisted of patients without postural tremor. The second group consisted of patients with fast postural tremor (>7 Hz). The third group consisted of patients with slow postural tremor with alternating EMG activity. Patients with slow postural tremor with synchronous EMG activity were included in the fourth group. In each limb position, the tremor of the most involved body part was graded on the Webster Tremor Scale. Surface EMG recordings of the most involved limb in all positions were performed.

Results: Postural tremor in addition to the rest one was found in 84% of the patients. The postural tremor was with lower amplitude than the rest one. The frequencies and EMG patterns of the postural tremors were different and correlated with some specific clinical symptoms. Patients with alternating postural tremor had a kinetic and intention tremor in addition.

Conclusions: Four different subtypes of Parkinsonian tremor were found according to the presence and type of postural tremor. These subtypes had some differing clinical characteristics and probably different relationships to essential tremor.     

Patients with adult-onset dystonic tremor resembling parkinsonian tremor have scans without evidence of dopaminergic deficit (SWEDDs).

We present the clinical details and dopamine transporter SPECT scan results of 10 patients with arm tremor, including a rest component and reduced arm swing on the affected side, in whom the possibility of PD had been raised. All patients had signs of dystonia or components of their arm tremor that were compatible with dystonic tremor, and none had true akinesia with fatiguing or decrement, even after a mean follow-up period of 5.8 years. All patients had normal dopamine transporter SPECT scans. Clinicians should be aware that primary adult-onset dystonia can present with an asymmetric resting arm tremor, with impaired arm swing and sometimes also facial hypomimia or a jaw tremor, but without evidence of true akinesia. Given the important consequences of misdiagnosing such patients as PD, in cases with diagnostic uncertainty functional imaging should be considered. Among patients suspected of PD, dystonic tremor may be one cause of SWEDDs (Scans Without Evidence of Dopaminergic Deficit).     

特发性震颤的临床特点分析

目的探讨特发性震颤(essential tremor,ET)的临床特点。方法对92例ET患者的临床资料进行回顾性分析。结果92例ET中男58例,女34例,发病年龄12～80岁,平均(50.2±17.3)岁,病程6个月～60年,平均(16.2±8.9)年。49例(53.3%)患者有阳性家族史,多呈常染色体显性遗传,临床主要表现为单症状的姿势性震颤,累及部位依次为手(92.4%)、头(25.0%)、咽喉部(21.7%)、下颏(15.2%)等。16.3%患者因震颤致日常生活困难。42例饮酒患者中,85.7%显示对酒精有反应性。6.5%患者并发帕金森病(Parkinson’s disease,PD)。67.3%患者小剂量普萘洛尔治疗有效。结论本组ET患者男多于女,临床表现为单症状姿势性震颤,部分病例可伴发PD,小剂量普萘洛尔治疗大多有效。     

震颤分析在帕金森病和原发性震颤鉴别诊断中的应用

目的 探讨震颤分析在帕金森病(parkinson's disease,PD)和原发性震颤(essential trem-or,ET)鉴别诊断中的应用价值.方法 选取2017年9月至2020年11月在福建省立金山医院门诊和住院确诊的PD患者27例(PD组)和ET患者23例(ET组),所有患者均至少有一侧上肢静止性或姿势性...     

Therapeutic effect of clozapine in psychotic decompensation in idiopathic Parkinson's disease

Summary Seven patients with idiopathic Parkinson's disease, aged 62 to 76 years, average duration of the disease approximately eleven years, suffering from severe hallucinosis and paranoid delusions of different degree, in whom conventional therapeutic strategies (administration of benzodiazepines and mild neuroleptics) had no antipsychotic effect, received clozapine, a non-classical highly potent neuroleptic, while blood count was strictly monitored. Paranoid ideas disappeared in all seven patients after a maximum of four days administration of 25–125 mg/day. No deterioration of parkinsonian symptoms, quantified according to UPDRS was seen. Given the protection of clozapine, we could increase the L-dopa dose in two cases, thereby improving the patients' motor function. Blood count showed no abnormalities in any of the patients during an average observation period of seventeen months.Our results support the assumption that clozapine has a potent antipsychotic effect in the treatment of psychotic decompensation in advanced Parkinson's disease in carefully selected patients. We saw no negative influence of the neurolpetic on extrapyramidal symptoms.     

Fluctuations in tremor and respiration in patients with Parkinson's disease

Fluctuations in tremor were investigated in patients with Parkinson's disease. Two patients with fluctuations of tremor (H and V) and one patient with no fluctuations in tremor (C) were tested. Blood pressure, ECG, respiration and tremor were recorded continuously for 5 min while the patients were relaxing with eyes closed, performing subtractions mentally or listening to a story. Results indicate the presence of abrupt transitions in both tremor and respiration for patients H and V. In patient V the fluctuations appear to be simultaneous, in patient H a delay exists between the onset of fluctuations in respiration and the fluctuations in tremor. In Patient C, no fluctuation was recorded in either respiration or tremor. Although the mechanisms underlying these fluctuations are not yet understood, this preliminary study has begun to characterize the qualitative changes occurring in tremor and respiratory patterns associated with Parkinson's disease. Such an approach combined with the knowledge that some temporal rhythms respond best to certain treatment strategies, may provide a new basis for therapy.     

Resting tremor only: a variant of Parkinson''s disease or of essential tremor

Resting tremor is one of the characteristic features of Parkinson's disease. However, there are a number of patients who typically have resting tremor alone for at least 5 years without development of other parkinsonian signs or symptoms. The etiology of an isolated resting tremor is still obscure. Recently, positron emission tomography was used to study these patients with isolated resting tremor, and demonstrated a markedly decreased striatal uptake of fluoro-dopa to the range of Parkinson's disease. These findings suggested the existence of a separate subtype, namely, tremulous Parkinson's disease with a manifestation of resting tremor alone. In order to confirm the existence of this subgroup of tremulous Parkinson's disease and further investigate its morphological changes and the usefulness of magnetic resonance imaging, we collected 5 patients who typically have resting tremor for at least 8 years in the absence of other features of Parkinson's disease. MRI was performed and the results of the images showed typical findings of Parkinson's disease with smudging or decreased distance between substantia nigra and red nucleus. Quantitative analysis also demonstrated a significant decrease of the above-noted distance when the resting tremor group was compared to the essential tremor group. Therefore, patients with an isolated resting tremor can have morphological abnormalities in addition to functional disturbances shown by positron emission tomography. To our knowledge, this is the first paper to report that resting tremor is a variant of Parkinson's disease rather than essential tremor, by using a double-blind method, with magnetic resonance imaging to support.     

Spike shape analysis of electromyography for parkinsonian tremor evaluation

Introduction: Standard electromyography (EMG) parameters have limited utility for evaluation of Parkinson disease (PD) tremor. Spike shape analysis (SSA) EMG parameters are more sensitive than standard EMG parameters for studying motor control mechanisms in healthy subjects. SSA of EMG has not been used to assess parkinsonian tremor. This study assessed the utility of SSA and standard time and frequency analysis for electromyographic evaluation of PD‐related resting tremor. Methods: We analyzed 1‐s periods of EMG recordings to detect nontremor and tremor signals in relaxed biceps brachii muscle of seven mild to moderate PD patients. Results: SSA revealed higher mean spike amplitude, duration, and slope and lower mean spike frequency in tremor signals than in nontremor signals. Standard EMG parameters (root mean square, median, and mean frequency) did not show differences between the tremor and nontremor signals. Conclusions: SSA of EMG data is a sensitive method for parkinsonian tremor evaluation. Muscle Nerve 52 : 1096–1098, 2015     

临床不同分期帕金森病患者震颤特点分析

目的研究不同临床分期帕金森病(PD)患者震颤的特点。方法收集2014-11—2015-05首都医科大学附属北京天坛医院神内病房临床确诊或临床诊断PD可能性大的75例患者。患者至少具有一侧上肢静止性或姿势性震颤,按照Hoehn-Yahr分期分为1~1.5期、2~2.5期、3期3组,分别检测各组患者静止、姿势及持物1000g震颤的优势频率、振幅及震颤节律形式。结果 (1)震颤优势频率:静止、姿势状态下为4~7 Hz,1~1.5期与2~2.5期、3期组间比较差异无统计学意义(P0.05)。持物1000g状态下,1~1.5期与2~2.5期、3期组间比较差异有统计学意义(P0.01),1~1.5期患者优势频率除了4~7Hz之外,还有7~10Hz、无规律及无震颤。(2)震颤振幅:随病情进展有下降趋势。(3)震颤节律形式:临床不同分期患者静止、姿势及持物1000g时震颤的节律形式均以交替形式为主,但随着病情进展,非交替节律比例有增加趋势。结论 PD患者震颤属于中枢性震颤,静止、姿势震颤优势频率为4~7Hz,不随病情进展而变化。疾病初期,持物1000g状态震颤优势频率可能受外周调节而表现多样。震颤节律不受病情进展及姿势影响。随病情进展,非交替节律比例有增加趋势,震颤振幅有下降趋势。     

Levodopa affects functional brain networks in parkinsonian resting tremor

Resting tremor in idiopathic Parkinson's disease (PD) is associated with an oscillatory network comprising cortical as well as subcortical brain areas. To shed light on the effect of levodopa on these network interactions, we investigated 10 patients with tremor‐dominant PD and reanalyzed data in 11 healthy volunteers mimicking PD resting tremor. To this end, we recorded surface electromyograms of forearm muscles and neuromagnetic activity using a 122‐channel whole‐head magnetometer (MEG). Measurements were performed after overnight withdrawal of levodopa (OFF) and 30 min after oral application of fast‐acting levodopa (ON). During OFF, patients showed the typical antagonistic resting tremor. Using the analysis tool Dynamic Imaging of Coherent Sources, we identified the oscillatory network associated with tremor comprising contralateral primary sensorimotor cortex (S1/M1), supplementary motor area (SMA), contralateral premotor cortex (PMC), thalamus, secondary somatosensory cortex (S2), posterior parietal cortex (PPC), and ipsilateral cerebellum oscillating at 8 to 10 Hz. After intake of levodopa, we found a significant decrease of cerebro‐cerebral coupling between thalamus and motor cortical areas. Similarly, in healthy controls mimicking resting tremor, we found a significant decrease of functional interaction within a thalamus–premotor–motor network during rest. However, in patients with PD, decrease of functional interaction between thalamus and PMC was significantly stronger when compared with healthy controls. These data support the hypothesis that (1) in patients with PD the basal ganglia and motor cortical structures become more closely entrained and (2) levodopa is associated with normalization of the functional interaction between thalamus and motor cortical areas. © 2008 Movement Disorder Society     

伴有快动眼睡眠行为障碍帕金森患者的震颤特征及多巴反应性

目的研究伴与不伴快动眼睡眠行为障碍(rapid eye movement sleep behavior disorder,RBD)的帕金森病(Parkinson disease,PD)患者的震颤特征及多巴反应性。方法根据2014年国际睡眠障碍分类第三版RBD的临床最低诊断标准,本研究采用RBD筛查问卷(RBD screening questionnaire,RBDSQ)量表来诊断临床很可能RBD(clinically probable RBD,cpRBD),将PD患者分为伴有cpRBD的PD(PD+cpRBD)与不伴有cpRBD的PD(PD-cpRBD)两组。对入组患者进行一般资料的收集,采用修订的H-Y分级、统一帕金森评分量表3.0版运动检查部分(UPDRS-Ⅲ)、MDS-UPDRS震颤量表对患者的运动功能进行评估,并且分别对两组患者首发侧肢体姿势性震颤、动作性震颤及静止性震颤的幅度进行评分,比较两组患者一般资料及震颤特征的差异性。对所有患者行急性左旋多巴冲击试验,将两组患者UPDRS-Ⅲ及MDS-UPDRS震颤量表评分最大改善率进行比较。结果共纳入42例伴有震颤的PD患者,PD+cpRBD组19例,PD-cpRBD组共23例,两组患者在性别、年龄、发病年龄、病程、关期UPDRS-Ⅲ评分及H-Y分级方面均无明显差异(P0.05)。与PD-cpRBD组相比,PD+cpRBD组关期震颤评分明显增高(t=2.379,P=0.022),震颤症状由首发侧肢体进展至对侧肢体的时间短(u=-2.133,P=0.033),首发侧肢体静止性震颤幅度大(u=-2.956,P=0.003),动作性震颤幅度大(u=-2.657,P=0.008)。口服左旋多巴/苄丝肼(200/50 mg)后,PD-cpRBD组的UPDRS-Ⅲ及震颤评分最大改善率均明显高于PD+cpRBD组(UPDRS-Ⅲ最大改善率u=-3.134,P=0.002;震颤评分最大改善率t=-3.189,P=0.003)。结论本研究表明,伴有cpRBD的PD患者震颤程度相对较重,以静止性震颤和动作性震颤为主,由首发侧肢体进展至对侧肢体的时间相对较短,对左旋多巴的反应性较差。     

Parkinsonian action tremor: interference with object manipulation and lacking levodopa response

It has been postulated that Parkinsonian action tremor is distinct from classical resting tremor and that it may contribute to a loss of manual dexterity in Parkinson's disease. We analyzed pinch grip coordination in 20 patients with Parkinson's disease. An object with and without an additional 500 g weight was grasped, lifted and held for a short time with opposed thumb and index finger. Force sensors recorded the force exerted by both fingers. Spectral analysis of the force traces was performed. Transition times between grasping and lifting the object were measured. 18 age matched normal volunteers served as a control group. While holding the object, there were force oscillations in the 3.5-6.5 Hz band indicating (reemerging) classical Parkinsonian tremor in 65% of the patients. This was reduced to 15-20% under levodopa. Oscillations in the 6-15 Hz band were found in 30% (50% with weight) of the patients, remaining unchanged under levodopa, and in 10% (20% with weight) of the normal controls. During lift initiation, 6-15 Hz oscillations were found in all patients and the majority of controls. The band power was positively correlated with the movement transition times in the severely akinetic patients and was significantly higher than in controls. It remained unchanged under levodopa. Our data confirm that Parkinsonian action tremor activated during complex voluntary movements is distinct from classical resting tremor. It does not show a clear levodopa response but affects dextrous movement coordination when associated with clinically severe overall akinesia.