Therapeutic Advances in the Treatment of Holmes Tremor: Systematic Review

ObjectiveWe aimed to formulate a practical clinical treatment algorithm for Holmes tremor (HT) by reviewing currently published clinical data.Materials and MethodsWe performed a systematic review of articles discussing the management of HT published between January 1990 and December 2018. We examined data from 89 patients published across 58 studies detailing the effects of pharmacological or surgical interventions on HT severity. Clinical outcomes were measured by a continuous 1-10 ranked scale. The majority of studies addressing treatment response were case series or case reports. No randomized control studies were identified.ResultsOur review included 24 studies focusing on pharmacologic treatments of 25 HT patients and 34 studies focusing on the effect of deep brain stimulation (DBS) in 64 patients. In the medical intervention group, the most commonly used drugs were levetiracetam, trihexyphenidyl, and levodopa. In the surgically treated group, the thalamic ventralis intermedius nucleus (VIM) and globus pallidus internus (GPi) were the most common brain targets for neuromodulation. The two targets accounted for 57.8% and 32.8% of total cases, respectively. Overall, compared to the medically treated group, DBS provided greater tremor suppression (p = 0.025) and was more effective for the management of postural tremor in HT. Moreover, GPi DBS displayed greater benefit in the resting tremor component (p = 0.042) and overall tremor reduction (p = 0.022).ConclusionsThere is a highly variable response to different medical treatments in HT without randomized clinical trials available to dictate treatment decisions. A variety of medical and surgical treatment options can be considered for the management of HT. Collaborative research between different institutions and researchers are warranted and needed to improve our understanding of the pathophysiology and management of this condition. In this review, we propose a practical treatment algorithm for HT based on currently available evidence.     

A retrospective study of the clinical and electrophysiological characteristics of 32 patients with orthostatic myoclonus

ObjectivesTo review the electrophysiological and clinical characteristics of 32 patients with orthostatic myoclonus (OM), a relatively newly identified movement disorder, and compare these characteristics to those of primary orthostatic tremor (OT) patients and patients with similar gait and balance complaints without either hyperkinesia diagnosed during the same 30-month period.MethodsThe database of the Mayo Clinic Florida Movement Disorders Electrophysiology Laboratory (MDEL) was searched for all patients referred for possible OM or OT from 6/2010 to 12/2012. All available clinical records and archived surface electromyographical data for these patients were reviewed and analyzed.Results32 patients with OM (mean age 74 years), 8 with primary OT (mean age 71), and 55 with neither orthostatic hyperkinesia (NOH) (mean age 68) were identified. All OT patients and 84% each of OM and NOH patients complained of involuntary leg movements while standing, e.g., “shaking,” “trembling,” or “jerking.” All OM and OT patients experienced symptomatic and electrophysiological abatement or attenuation of their leg hyperkinesias by leaning forward onto an object while standing.ConclusionsOM has some similarities to OT, including causing “shaky legs” subjectively in standing older patients. Novel data from this work include that, as in OT, OM essentially abates when patients remove their weight from their legs. This shared isometric phenomenon may reflect that OT and OM are on a pathophysiological continuum. Further, many patients who complain of their legs “shaking” while standing may have neither OT nor OM. Surface electromyography may be a useful adjunct in extrapolating patients complaining of “shaky legs.”     

Tremor dominant parkinsonism: Clinical description and LRRK2 mutation screening

Tremor dominant parkinsonism (TDP) is characterized by initial prominent resting and action tremor, mild parkinsonism, unpredictable response to medication, and a better prognosis than idiopathic Parkinson's disease (PD). We report on clinical features and longitudinal course of 26 patients suffering from TDP. Mean disease duration was 6.5 ± 3 years, 61.5% of patients had a positive family history of tremor, 73% did not need drug treatment, performance of 123I‐Ioflupane SPECT showed reduced striatal tracer uptake in 65.4% of patients, and odor identification testing was pathologic in all the patients tested (n = 22). Co‐occurrence of action and resting tremor were the most annoying and disabling symptoms in all the patients, whereas rigidity and/or bradykinesia were clinically irrelevant in most of them. We also sequenced the full coding region of the Leucine‐rich repeat kinase 2 gene (LRRK2) in all patients. We found a novel Val2390Met mutation that was not found in 864 chromosomes. Our results suggest a broader clinical heterogeneity related to LRRK2 mutations and points towards TDP as a subtype within the spectrum of PD, in which disabling tremor but otherwise mild parkinsonian signs and a better prognosis are the main characteristics. © 2007 Movement Disorder Society     

Familial adult myoclonus epilepsy: Clinical findings,disease course,and comorbidities

Familial adult myoclonus epilepsy (FAME) is an autosomal dominant condition characterized by the association of myoclonic tremor and epilepsy mainly with onset in adulthood. The clinical course is non-progressive or slowly progressive, as epilepsy is commonly controlled with appropriate antiseizure medication and individuals have a normal life expectancy. However, the myoclonus severity increases with age and leads to some degree of disability in the elderly. Because the non-coding repeat expansions responsible for FAME are not detected by routine genetic tests being used at this time, a clinical diagnosis accompanied by neurophysiological testing remains essential to guide the geneticist on the selection of the specific genetic technique.     

Tremor in Parkinson disease: acute response to oral levodopa

A single blind placebo-controlled study has been performed in order to investigate objectively the acute tremorolytic effect of oral L-Dopa in ten parkinsonians chronically treated with L-Dopa. Finger tremor was assessed by means of a computerized accelerometer method, at rest and during maintenance of a fixed posture. Both resting and postural tremor were significantly influenced by L-Dopa. An “acute test” with oral L-Dopa, especially when different tremor components are investigated, may be useful for identifying objectively parkinsonians whose tremor does not respond to drug therapy or shows a deterioration of drug-responsiveness.

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Sommario Uno studio controllato con placebo è stato condotto su 10 pazienti affetti da morbo di Parkinson idiopatico, in trattamento cronico con L-Dopa, allo scopo di valutare in modo obiettivo l'effetto tremorolitico della L-Dopa. Il tremore è stato valutato alle mani mediante una metodica di accelerometria computerizzata, sia in condizioni di riposo che di postura. In entrambe le condizioni l'effetto tremorolitico della L-Dopa si è rivelato significativo. Un “test acuto” con L-Dopa orale, in particolare con l'esplorazione di componenti diverse del tremore, può risultare utile per una valutazione obiettiva di casi di Parkinson che non rispondano alla terapia farmacologica o che manifestino un deterioramento della risposta alla L-Dopa.

     

脑血管疾病后Holmes震颤的临床、影像和电生理特点

目的 总结脑血管疾病后Holmes震颤的临床、影像和电生理特点。 方法 回顾性分析2015年8月-2019年8月就诊于首都医科大学附属北京天坛医院的4例脑血管疾病 所致Holmes震颤患者,对其临床、影像及电生理资料进行分析总结。 结果 4例患者中2例由高血压性脑出血引起,另外2例分别由脑动静脉畸形和脑海绵状血管瘤破裂 出血引起。Holmes震颤出现于原发病后1～24个月,表现为病灶对侧肢体震颤,以上肢多见。头颅MRI 检查显示2例患者病灶仅累及丘脑,2例同时累及丘脑和中脑。震颤分析显示静止、姿势、意向及持物 1000 g几种状态下震颤的峰频率均在2.6～3.8 Hz,意向状态震颤半宽功率高于静止状态。主动肌与 拮抗肌在静息时以同步收缩为主,姿势、意向和持物时以交替收缩为主。3例接受普拉克索治疗均有 不同程度缓解。 结论 Holmes震颤多由累及中脑、丘脑部位脑血管疾病引起,表现为2～4 Hz低频震颤,意向状态震 颤明显,部分患者多巴胺受体激动剂治疗有效。     

Autosomal dominant cortical tremor, myoclonus and epilepsy: many syndromes, one phenotype

The association of cortical tremor, myoclonus and epileptic seizures has been reported in many Japanese and European families with different acronyms. We reviewed the familial cases presenting the clinical picture of autosomal dominant cortical tremor, myoclonus and epilepsy and analysed the phenotypic differences between the pedigrees, according to the recent genetic acquisitions. We concluded that BAFME, FAME, FEME, FCTE and ADCME are the same clinical entity even if genetically heterogeneous, with Japanese families linked to 8q24 and Italian ones to 2p11.1-q12. A third locus could also be involved. Further studies should better clarify the electrophysiological features of this condition and identify the underlying molecular defects.     

A Dutch family with 'familial cortical tremor with epilepsy'. Clinical characteristics and exclusion of linkage to chromosome 8q23.3-q24.1

Objectives: To describe the clinical characteristics of a large Dutch family with cortical tremor with epilepsy (FCTE) and to test for genetic linkage of FCTE to chromosome 8q23.3–q24.1. Background: FCTE is an idiopathic generalised epilepsy of adult onset with autosomal dominant inheritance. It is characterised by kinesiogenic tremor and myoclonus of the limbs, generalised seizures, and electrophysiological findings consistent with cortical reflex myoclonus. Genetic analysis has been performed in five Japanese families. In all families, linkage was shown to chromosome 8q23.3–q24.1. Methods: Clinical and electrophysiological data of a four-generation family, suspected of autosomal dominant inherited FCTE, were collected and linkage analysis was performed. Results Clinical and electrophysiological findings were consistent with a diagnosis of FCTE. Of 41 relatives examined, 13 subjects were considered to be definitely affected, three were probably affected and ten were unaffected. In 15 relatives, the diagnosis could not be established. Linkage to chromosome 8q23.3–q24.1 was excluded. Conclusions: In this family with autosomal dominant FCTE, specific clinical and electrophysiological features were identified. Exclusion of linkage to chromosome 8q23.3–q24.1 indicates that genetic heterogeneity exists for FCTE. Received: 5 September 2001, Received in revised form: 21 November 2001, Accepted: 29 November 2001     

Autosomal dominant cortical tremor,myoclonus and epilepsy

The term ‘cortical tremor’ was first introduced by Ikeda and colleagues to indicate a postural and action‐induced shivering movement of the hands which mimics essential tremor, but presents with the electrophysiological findings of cortical reflex myoclonus. The association between autosomal dominant cortical tremor, myoclonus and epilepsy (ADCME) was first recognized in Japanese families and is now increasingly reported worldwide, although it is described using different acronyms (BAFME, FAME, FEME, FCTE and others). The disease usually takes a benign course, although drug‐resistant focal seizures or slight intellectual disability occur in some cases. Moreover, a worsening of cortical tremor and myoclonus is common in advanced age. Although not yet recognized by the International League Against Epilepsy (ILAE), this is a well‐delineated epilepsy syndrome with remarkable features that clearly distinguishes it from other myoclonus epilepsies. Moreover, genetic studies of these families show heterogeneity and different susceptible chromosomal loci have been identified.     

Tremor severity in Parkinson's disease and cortical changes of areas controlling movement sequencing: A preliminary study

There remains much to learn about the changes in cortical anatomy that are associated with tremor severity in Parkinson's disease (PD). For this reason, we used a combination of structural neuroimaging to measure cortical thickness and neurophysiological studies to analyze whether PD tremor was associated with cortex integrity. Magnetic resonance imaging and neurophysiological assessment were performed in 13 nondemented PD patients (9 women, 69.2%) with a clearly tremor‐dominant phenotype. Cortical reconstruction and volumetric segmentation were performed with the Freesurfer image analysis software. Assessment of tremor was performed by means of high‐density surface electromyography (hdEMG) and inertial measurement units (IMUs). Individual motor unit discharge patterns were identified from surface hdEMG and tremor metrics quantifying motor unit synchronization from IMUs. Increased motor unit synchronization (i.e., more severe tremor) was associated with cortical changes (i.e., atrophy) in wide‐spread cortical areas, including caudal middle frontal regions bilaterally (dorsal premotor cortices), left inferior parietal lobe (posterior parietal cortex), left lateral orbitofrontal cortex, cingulate cortex bilaterally, left posterior and transverse temporal cortex, and left occipital lobe, as well as reduced left middle temporal volume. Given that the majority of these areas are involved in controlling movement sequencing, our results support Albert's classic hypothesis that PD tremor may be the result of an involuntary activation of a program of motor behavior used in the genesis of rapid voluntary alternating movements.     

Clinical features and nigrostriatal dysfunction in patients with combined postural and resting tremors

BackgroundThe characteristics of clinical features and nigrostriatal dopaminergic dysfunction in patients with combined postural and resting tremors have been less clearly reported.MethodsThe present study examined 43 patients with a visible persistent bilateral postural tremor and a unilateral/bilateral resting tremor involving the hands and forearms. The patients had experienced tremors for more than 3 years, with no evidence of Parkinson's disease or other parkinsonian disorders. Visual and quantitative analyses of [¹⁸F] N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (FP-CIT) PET in 36 patients were performed. Seventeen age-matched normal controls were also studied.ResultsOn visual analysis, 28 patients (78%) showed normal [¹⁸F] FP-CIT uptake and eight (22%) showed significantly reduced uptake, suggesting nigrostriatal dopaminergic neuronal degeneration. The reduced [¹⁸F] FP-CIT uptake was significantly associated with earlier age-at-onset of tremor and asymmetric presentation of resting tremor. On quantitative analysis, there were statistically significant differences in the [¹⁸F] FP-CIT uptake ratio in the posterior putamen between patients with reduced uptake (2.37 ± 1.83) and patients with normal uptake (6.39 ± 1.35) (P < 0.001). However, posterior putamen uptake levels in patients with normal [¹⁸F] FP-CIT uptake on visual analysis were similar to those in normal controls (7.22 ± 1.29) (P = 0.291).ConclusionThe nigrostriatal dopaminergic dysfunction in patients with combined postural and resting tremors may be associated with earlier age-at-onset of tremor and asymmetric pattern of resting tremor, which might help to correctly diagnose patients with mixed tremors.     

磁共振测量特发性震颤和帕金森病患者基底节区核团体积的研究

目的：利用磁共振体积测量技术评价特发性震颤（ET）,帕金森病（PD）患者基底节区核团体积的变化及互相间的差异。方法：采用1．5T磁共振机测量9例ET患者、5例PD患者和8例年龄匹配正常人全脑体积、尾状核和壳核体积。比较各组之间感兴趣区体积的差异。结果：PD组双侧尾状核标化体积之和、双侧壳核标化体积之和较正常人缩小（P〈0．05）。ET组双侧尾状核标化体积,双侧壳核标化体积与正常对照组无差别。结论：PD患者存在尾状核和壳核体积的缩小,而ET患者无明显尾状核和壳核体积变化。     

Obsessive compulsive personality disorder in Progressive Supranuclear Palsy,Multiple System Atrophy and Essential Tremor

Introductionaim of the study was to evaluate the presence of the Obsessive Compulsive Personality Disorder (OCPeD) in Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and Essential Tremor (ET) and in a group of healthy subjects.Methodspatients affected by MSA, PSP and ET diagnosed according to currently accepted diagnostic criteria and a group of healthy controls were enrolled in the study. Patients with cognitive impairment were excluded from the study. The Structured Clinical Interview for Personality Disorders-II (SCID-II) has been performed to evaluate the presence of personality disorders (PeDs). The diagnosis of OCPeD was confirmed by a psychiatric interview.Resultsfifteen MSA patients (8 men and 7 women; aged 62.9 ± 7.6 years), 14 PSP patients (8 men and 6 women; aged 69.8 ± 4.4 years), 16 ET patients (10 men and 6 women; aged 70.4 ± 6.4 years) and 20 healthy subjects (10 men and 10 women; aged 65.5 ± 6.0 years) were enrolled. OCPeD was recorded in 5 (35.7%) PSP patients, 2 (13.3%) MSA patients, 2 (12.5%) ET patient and 2 (10%) controls.Conclusiona low frequency of OCPeD, close to those recorded in healthy subjects, was recorded in both MSA and ET patients. Conversely an higher frequency of OCPeD, similar to PD was found among PSP patients, supporting the possibility of an impairment of common basal ganglia network possibly involving the orbito-frontal circuits.     

Long-Term Outcome and Neuroimaging of Deep Brain Stimulation in Holmes Tremor: A Case Series

BackgroundDifferent deep brain stimulation (DBS) targets have been suggested as treatment for patients with pharmacologically refractory Holmes tremor (HT). We report the clinical and quality of life (QoL) long-term (up to nine years) outcome in four patients with HT treated with DBS (in thalamic ventral intermediate nucleus-VIM or in dentato-rubro-thalamic tract-DRTT).Materials and MethodsThe patients underwent routine clinical evaluations before and after DBS (typically annually). Tremor severity and activities of daily living (ADL) were quantified by the Fahn-Tolosa-Marin Tremor-Rating-Scale (FTMTRS). QoL was assessed using the RAND SF-36-item Health Survey (RAND SF-36). In addition, we computed, in all four patients, the VTA based on the best stimulation settings using heuristic approaches included in the open source toolbox LEAD-DBS.ResultsIn all patients, tremor and ADL improved significantly at one-year post-DBS follow-up (34–61% improvement in FTMTRS total score compared to baseline). In three out of four patients, the improvement of tremor was sustained no longer than two to three years and only in one patient was sustained up to nine years. In this patient, the largest intersection between VTA and DBS target has been observed. Scores for ADL deteriorated over the course of time, reaching worse levels compared to baseline already during the three-year post-DBS follow-up, in three out of four patients. Physical and mental health component scores of RAND SF-36 had very different outcome between patients and follow-ups and were not associated with tremor-related outcomes.ConclusionsThe benefits of DBS in HT might not be always long lasting. Although QoL slightly improved, this change seemed to be independent of the motor outcome following DBS. The estimation of DBS target and VTA proximity could be a useful tool for DBS clinicians in order to facilitate the DBS programming process and optimize DBS treatment.     

Postural instability and neuropsychiatric disturbance in the overlapping phenotype of essential tremor and Parkinson's Disease

ObjectivesThe aim of this study was to perform a comparative analysis of postural and neuropsychiatric features in patients with essential tremor (ET), various Parkinson’s disease (PD) phenotypes, and the phenotype of combined ET and PD (ET-PD).Methods169 PD patients with early (1.0–2.0) and 111 PD patients with advanced (2.5–3.0) stages based on the Hoehn and Yahr scale, 55 patients with ET and 26 patients with ET-PD were enrolled in the study. Motor and non-motor symptoms of patients with PD, ET and ET-PD were studied using standardized scales and stabilometry.ResultsPatients with ETPD had milder manifestations of parkinsonism compared to PD patients at the same stages of the disease. Patients in the advanced PD group showed more pronounced posture and balance impairment compared to all other groups assessed by standardized walking and balance scales. No difference using scales for postural assessment was found between ETPD, ET and early stage PD. Using stabilometry, we discovered that indexes of stabilometric parameters were lower in ETPD patients compared to ET and advanced PD, although no difference between ETPD and early PD was found. PD patients in early stages had lower results in most of the indexes compared to ET.ConclusionHere, we conducted for the first time a stabilometric examination of ET-PD patients, which could be helpful in differential diagnosis. This analysis helps expand understanding of the clinical manifestations of PD, ET and ET-PD.     

Familial adult myoclonus epilepsy: Neuroimaging and neuropathological findings

Familial adult myoclonus epilepsy (FAME) is characterized by cortical myoclonus and often epileptic seizures, but the pathophysiology of this condition remains uncertain. Here, we review the neuroimaging and neuropathological findings in FAME. Imaging findings, including functional magnetic resonance imaging, are in line with a cortical origin of involuntary tremulous movements (cortical myoclonic tremor) and indicate a complex pattern of cerebellar functional connectivity. Scarce neuropathological reports, mainly from a single family, provide evidence of morphological changes in the Purkinje cells. Cerebellar changes seem to be part of the syndrome, in at least some FAME pedigrees. Cortical hyperexcitability in FAME, resulting in the cardinal clinical symptoms, might be the result of decreased cortical inhibition via the cerebellothalamocortical loop. The pathological findings might share some similarities with other pentanucleotide repeat disorders. The relation with genetic findings in FAME needs to be elucidated.     

Rate of progression from mild cognitive impairment to dementia in an essential tremor cohort: A prospective,longitudinal study

BackgroundEssential tremor (ET), among the most common neurological diseases, is associated with cognitive dysfunction. Yet, nearly all knowledge of ET-related cognitive impairment is static and cross-sectional (e.g., prevalence), with virtually no dynamic information (i.e., course and progression, conversion rates, and clinical outcomes).ObjectivesTo quantify the rate of progression from mild cognitive impairment (MCI) to dementia in a cohort of elderly ET cases.Methods167 ET cases, enrolled in a prospective, longitudinal, clinical-pathological study, underwent an extensive neuropsychological testing battery at baseline (T1), 1.5 years (T2), and 3 years (T3). Results of these assessments informed clinical diagnoses of normal cognition (ET-NC), MCI (ET-MCI), and dementia (ET-D).ResultsAt baseline, 26 cases (82.7 ± 7.7 years) were diagnosed with ET-MCI and were available for follow-up at T2. At T2, three of 26 (11.5%) had converted to ET-D. At the start of T2, 23 cases (83.6 ± 7.7 years) were diagnosed with ET-MCI and were available for follow-up at T3. At T3, six of 23 (26.1%) converted to ET-D. The average annual conversion rate from ET-MCI to ET-D was 12.5%.ConclusionsThe study of cognitive impairment in ET is a nascent field, with limited data. We show that the conversion rate from ET-MCI to ET-dementia was 12.5%. Available studies on historical controls have reported conversion rates of 2.6–6.3%. Data such as these systematically fill gaps in knowledge, creating a scientifically-derived knowledge base to guide physicians and patients in clinical settings.