Cerebellar axial postural tremor

Three cases are presented with a predominantly axial postural tremor, without visible palatal tremor. Tremor varied in frequency between 3 and 10 Hz, often jumping from one frequency to another in this band. All three patients had evidence of cerebellar pathology. Cases 1 and 2 developed tremor in the setting of a lateLondon, Englandonset cerebellar degeneration and after excision of a right cerebellar haemangioblastoma, respectively. Etiology was unclear in Case 3. Nevertheless, this patient had a cerebellar dysarthria. The tremor was similar to that sometimes seen in conjunction with palatal tremor, and EMG studies in Case 3 demonstrated a subclinical modulation of palatal muscle activity simultaneous with the truncal tremor. It is suggested that an axial postural tremor may be due to pathology of the cerebellum and its outflow pathways, despite the absence of clinically apparent palatal tremor.     

Progressive ataxia and palatal tremor: Two autopsy cases of a novel tauopathy

Background: Sporadic progressive ataxia and palatal tremor is a rare syndrome characterized by mid‐ to late‐adult‐onset symptomatic palatal tremor and slowly progressive cerebellar ataxia. To date, there has been only one autopsy report, which described a novel 4‐repeat tauopathy with hypertrophic olivary degeneration and tau‐positive inclusions in olivary neurons and dystrophic neuritic processes termed glomeruloid bodies. We report on 2 additional autopsy cases. Methods: Sections from selected paraffin‐embedded brain regions were stained with hematoxylin and eosin/Luxol fast blue and processed for phosphorylated tau, 3‐repeat tau, 4‐repeat tau, neurofilament, glial fibrillary acid protein, phosphorylated α‐synuclein, phosphorylated TAR DNA‐binding protein 43, beta‐amyloid, and p62 immunohistochemistry. Results: Two male patients were aged 74 and 64 years at onset. Both had clinical findings consistent with progressive ataxia and palatal tremor and T2 hyperintensity in the bilateral olives on MRI. Pathological findings included bilateral hypertrophic olivary degeneration accompanied by glomeruloid bodies, 3‐repeat and 4‐repeat tau‐positive neuronal inclusions in the olive, and additional tauopathy in the midbrain, pons, and thalamus. Cerebellar cortical degeneration was extensive, but involvement of the dentate was minimal. P62‐positive, but tau‐ and TAR DNA‐binding protein 43–negative, inclusions in the cerebellum of 1 case was also a feature. Conclusions: Whereas our findings are largely in keeping with the previously published case report, we found a more extensive and mixed 3/4‐repeat tauopathy and additional cerebellar p62 pathology, highlighting our incomplete understanding of the pathogenesis of this disease. © 2017 International Parkinson and Movement Disorder Society     

Factors associated with increased risk of head tremor in essential tremor: a community-based study in northern Manhattan.

Head tremor is one of the major expressions of essential tremor (ET). It is not well understood why some patients develop head tremor, whereas others do not. A study of the characteristics of patients with head tremor has not been undertaken. Our goal was to estimate the prevalence of head tremor and to identify demographic and clinical characteristics associated with an increased risk of head tremor in ET. Cases were ascertained from a community-based study of ET in northern Manhattan, New York. Arm tremor severity was rated with a total tremor score. Logistic regression analyses resulted in odds ratios (OR). Head tremor was present in 37 (34.9%) of 106 ET cases. Female gender was associated with a fourfold increased risk of head tremor (OR = 3.73; P = 0.005). Total tremor score was divided into quartiles; individuals in the lowest or highest quartile were four times more likely to have head tremor (OR = 4.16; P = 0.001). Individuals with both risk factors (female gender and lowest or highest total tremor score quartile) were 16 times more likely to have head tremor (OR = 15.88; P = 0.0006). Being related to a proband with head tremor marginally increased the risk of head tremor (OR = 11.30; P = 0.08). Age and tremor duration did not influence the risk of head tremor. We identified several factors that were associated with an increased risk of head tremor in ET; female gender, coexisting arm tremor that was either very mild or extremely severe, and relation to an ET case with head tremor. These disease associations require further exploration, and might provide insight into the mechanisms underlying head tremor.     

Subclinical tremor in normal controls with versus without a family history of essential tremor: data from the United States and Turkey

Background and purpose: Mild action tremor is very common in the population. One fundamental question is whether this tremor is related to the neurological disease essential tremor (ET), which occurs in a much smaller segment of the population? ET is often genetic, and variable phenotypic expression is well‐documented in the literature. We determined whether normal controls who report a family history of ET have greater action tremor than normal controls who do not report such a history. Methods: Controls, enrolled in two epidemiological studies (New York and Turkey), were examined in detail and action tremor was rated using a valid and reliable clinical rating scale, resulting in a total tremor score (range 0–36). Results: In New York, the total tremor score was higher in 44/406 (10.8%) controls who reported a family history of ET than in 362/406 controls with no such history (4.25 ± 2.51 vs. 3.78 ± 2.93, P = 0.02). Controls who reported a first‐degree relative with ET had the highest total tremor scores. In Turkey, the total tremor score was higher in 7/89 (7.9%) controls with a family history than in 82/89 controls with no family history (3.43 ± 4.54 vs. 1.13 ± 2.54, P = 0.048). All affected relatives in Turkey were first‐degree. Conclusions: These data suggest that some of the normal tremor exhibited by people in the population is likely to be subclinical, partially expressed ET and that the sphere of ET is wider than is apparent from a consideration of clinically diagnosed cases.     

Faster rate of cognitive decline in essential tremor cases than controls: a prospective study

Background: Mild cognitive deficits have been reported in essential tremor (ET). However, these cognitive deficits have been assessed in cross‐sectional rather than longitudinal analyses. Objective: To determine whether decline in cognitive test scores occurs at a faster rate in ET cases than controls. Methods: In a population‐based study of older people (≥ 65 years) in central Spain (Neurological Disorders in Central Spain, NEDICES), non‐demented ET cases and controls were followed prospectively. Participants with baseline or incident Parkinson’s disease or dementia were excluded as were participants who developed incident ET. At baseline (1994–1995) and at follow‐up (1997–1998), a 37‐item version of the mini‐mental state examination (37‐MMSE) was administered. Results: A total of 2319 participants (72.4 ± 5.8 years) included 135 prevalent ET cases and 2184 controls. At baseline, the mean 37‐MMSE in cases was 28.8 ± 5.8 vs. 30.2 ± 4.8 in controls (P = 0.02). During the 3‐year follow‐up period, the 37‐MMSE declined by 0.70 ± 3.2 points in cases vs. 0.11 ± 3.8 points in controls (P = 0.03). In analyses that adjusted for age, education, and other potential confounders, the case–control difference remained robust. Discussion: In this population‐based, prospective study of non‐demented elders, baseline cognitive test scores were lower in ET cases than controls; moreover, during the 3‐year follow‐up period, these scores declined at a rate that was seven‐times faster in ET cases. This study provides evidence that cognitive deficits in ET are not static, and they appear to be progressing at a faster rate than in elders without this disease.     

Essential tremor centralized brain repository: diagnostic validity and clinical characteristics of a highly selected group of essential tremor cases.

We studied essential tremor (ET) cases enrolled in the Essential Tremor Centralized Brain Repository to (1) assess the validity of their diagnoses and (2) characterize the clinical features in a group of highly selected cases who might reflect a far end of the disease spectrum. Our over-arching goal was to provide a perspective of ET that complements that derived from population-based and clinic-based studies. Based on a history and videotaped examination, 94 of 100 ET cases had their diagnoses confirmed; most of the remainder had Parkinson's disease. When compared with ET cases ascertained through populations and clinics, a large proportion had been prescribed medication for tremor (87.2%), had a family history of tremor (88.3%), had rest tremor (33.0%), or had neck tremor (60.6%). One patient had facial tremor, which has not been reported previously. As has been reported once before, a large proportion wore hearing aids (26.9% of the 67 participants age>or=70). In summary, diagnostic validity was high. In terms of their clinical characteristics, the high proportion of cases with severe tremor and varied disease manifestations (neck tremor, rest tremor) make these cases a valuable resource in pathological studies; the high proportion with familial tremor would provide an enriched sample for genetic studies.     

Electroclinical and genetic findings in a family with cortical tremor, myoclonus, and epilepsy

We report a five-generation family showing cortical tremor, myoclonus, and epilepsy, originating from Naples, Italy. Eleven members, aged 24-56 years (mean: 39.2 years), suffered from hand tremor and myoclonus, whereas generalized seizures occurred in six. Electrophysiological study confirmed the presence of cortical reflex myoclonus in all affected members. In addition, giant somatosensory-evoked potential components and enhanced long loop reflex I were found also in three presymptomatic members who manifested hand tremor and myoclonus at upper limbs after 1.5 years of follow-up. Genetic study of the pedigree revealed a significant linkage on chromosome 2p (maximum lod score = 5.9). Further observations are needed to clarify the pathophysiology of this condition.     

Primary writing tremor: report of a case successfully treated with botulinum toxin A injections and discussion of underlying mechanism.

Primary writing tremor (PWT) is a rare motor disorder of unknown etiology, where tremor is elicited primarily or exclusively with writing. We describe a patient with PWT, present a video before and after successful treatment with botulinum toxin type A injections, and discuss a possible underlying dystonic mechanism.     

Isolated and combined genetic tremor syndromes: a critical appraisal based on the 2018 MDS criteria

The 2018 consensus statement on the classification of tremors proposes a two-axis categorization scheme based on clinical features and etiology. It also defines “isolated” and “combined” tremor syndromes depending on whether tremor is the sole clinical manifestation or is associated with other neurological or systemic signs. This syndromic approach provides a guide to investigate the underlying etiology of tremors, either genetic or acquired.Several genetic defects have been proven to cause tremor disorders, including autosomal dominant and recessive, X-linked, and mitochondrial diseases, as well as chromosomal abnormalities. Furthermore, some tremor syndromes are recognized in individuals with a positive family history, but their genetic confirmation is pending. Although most genetic tremor disorders show a combined clinical picture, there are some distinctive conditions in which tremor may precede the appearance of other neurological signs by years or remain the prominent manifestation throughout the disease course, previously leading to misdiagnosis as essential tremor (ET). Advances in the knowledge of genetically determined tremors may have been hampered by the inclusion of heterogeneous entities in previous studies on ET. The recent classification of tremors therefore aims to provide more consistent clinical data for deconstructing the genetic basis of tremor syndromes in the next-generation and long-read sequencing era.This review outlines the wide spectrum of tremor disorders with defined or presumed genetic etiology, both isolated and combined, unraveling diagnostic clues of these conditions and focusing mainly on ET-like phenotypes. Furthermore, we suggest a phenotype-to-genotype algorithm to support clinicians in identifying tremor syndromes and guiding genetic investigations.     

Episodic ataxia type 2 characterised by recurrent dizziness/vertigo: a report of four cases

Purpose: To report the clinical features and gene mutations in four episodic ataxia type 2 (EA2) patients whose main presentation was recurrent dizziness/vertigo.

Methods: Clinical data of four EA2 patients (three familial EA2 cases and one sporadic case) with recurrent dizziness/vertigo were collected to assess nystagmus and eye movement. Gene mutations were identified by whole exome sequencing.

Results: The three patients in family 1 experienced disease onset before 8 years of age, presented with a chief complaint of episodic dizziness, muscle weakness of the lower limbs and the inability to walk. These symptoms lasted a few hours and then subsided. The proband also had gaze-evoked nystagmus during attacks. Videonystagmography demonstrated that the saccade velocity was low, smooth pursuit was type III, and gain was abnormal at 0.1, 0.2 and 0.4?Hz. An optokinetic nystagmus test showed that the left eye optokinetic nystagmus disappeared, and the right eye optokinetic nystagmus weakened. A head-shaking test produced a left horizontal nystagmus. Gene analysis identified a novel c.1558?+?2T?>?G splice site mutation in the CACNA1A gene in the proband and his mother. The fourth patient was sporadic, with an onset age of 3 years. He mainly suffered from episodic vertigo, accompanied by severe anxiety and depression. He carried a CACNA1A mutation, c.4636C?>?T, which is a previously reported pathogenic mutation.

Conclusions: The onset of symptoms in these EA2 patients was early. The patients mainly presented recurrent dizziness/vertigo, with the absence of characteristic episodic ataxia. Detection of CACNA1A mutations facilitates the diagnosis of EA2.     

CACNA1A-related early-onset encephalopathy with myoclonic epilepsy: A case report

We report a one-year-old boy with early-onset myoclonic epilepsy, developmental arrest, and hyperekplexia during early infancy. He presented with refractory myoclonic/tonic seizures since birth. Electroencephalography revealed multifocal spikes, and rhythmic activities that occurred simultaneous with aggravation of myoclonus accompanied by tonic upper limb elevation. Brain magnetic resonance imaging revealed progressive cerebral atrophy with periventricular signal change and thin corpus callosum at one year of age. A de novo heterozygous missense mutation in the CACNA1A gene was confirmed. This patient was the most severe phenotype of CACNA1A-related early-onset encephalopathy among previous reports.     

Impaired motor imagery in patients with essential tremor: a case control study.

Motor imagery (MI), which refers to the process of mental representation of movements, has not been studied in patients with essential tremor (ET). We investigated the presence of impaired MI in ET patients compared with healthy controls. A group of drug-naive and nondemented ET patients and age-matched controls were studied using transcranial magnetic stimulation, while they were specifically instructed to try and imagine themselves performing two motor tasks. The various clinical and electrophysiological variables were evaluated and compared. Repeated measures ANOVA demonstrated a significant difference between ET patients and controls with respect to mean motor-evoked potential (MEP) amplitudes (F(1,38) = 31.92, P < 0.005) during MI. The process of MI effectively facilitated MEP amplitude in controls but not in ET patients, regardless of side of stimulation or motor tasks. We provide evidence to demonstrate impairment of MI in a group of ET patients compared with healthy controls. The basis for this novel finding is unclear, and further studies are warranted to determine whether it is related to cerebellar or motor cortical dysfunction.     

Dopa‐responsive dystonia presenting with prominent isolated bilateral resting leg tremor: Evidence for a role of parkin?

We report on a GTP cyclohydrolase 1 mutation‐confirmed case of dopa‐responsive dystonia who presented with an isolated parkinsonian rest tremor starting at the age of 15 years. There was no dystonia or other features of parkinsonism. Sequencing of the parkin gene demonstrated polymorphisms in a compound heterozygous state. The spectrum of unusual clinical presentations of dopa‐responsive dystonia is discussed. © 2003 Movement Disorder Society     

Thalamic DBS with a constant-current device in essential tremor: A controlled clinical trial

IntroductionThis study of thalamic deep brain stimulation (DBS) investigated whether a novel constant-current device improves tremor and activities of daily living (ADL) in patients with essential tremor (ET).MethodsA prospective, controlled, multicenter study was conducted at 12 academic centers. We investigated the safety and efficacy of unilateral and bilateral constant-current DBS of the ventralis intermedius (VIM) nucleus of the thalamus in patients with essential tremor whose tremor was inadequately controlled by medications. The primary outcome measure was a rater-blinded assessment of the change in the target limb tremor score in the stimulation-on versus stimulation-off state six months following surgery. Multiple secondary outcomes were assessed at one-year follow-up, including motor, mood, and quality-of-life measures.Results127 patients were implanted with VIM DBS. The blinded, primary outcome variable (n = 76) revealed a mean improvement of 1.25 ± 1.26 points in the target limb tremor rating scale (TRS) score in the arm contralateral to DBS (p < 0.001). Secondary outcome variables at one year revealed significant improvements (p ≤ 0.001) in quality of life, depression symptoms, and ADL scores. Forty-seven patients had a second contralateral VIM-DBS, and this group demonstrated reduction in second-sided tremor at 180 days (p < 0.001). Serious adverse events related to the surgery included infection (n = 3), intracranial hemorrhage (n = 3), and device explantation (n = 3).ConclusionUnilateral and bilateral constant-current VIM DBS significantly improves upper extremity tremor, ADL, quality of life, and depression in patients with severe ET.     

Frailty in elderly persons with essential tremor: a population‐based study (NEDICES)

Background and purpose: Essential tremor (ET), one of the most prevalent neurological diseases, has been associated with a variety of comorbidities and, in some studies, a modest increase in risk of mortality. The mechanisms underlying this possible increased mortality have yet to be explored, although one possibility is increased frailty. Frailty has not been studied in ET, and our objective was to address this gap in knowledge. We hypothesized that frailty would be greater in ET cases than in controls. Methods: A 20‐item frailty score assessed comorbid conditions, number of medications, and functional activity. The frailty score was compared in 237 non‐demented elderly ET cases and 3903 non‐demented age‐matched controls from a population‐based study in central Spain. Results: The frailty score was higher in ET cases than in controls (8.6 ± 5.2 vs. 6.8 ± 4.6, P < 0.001). Stratifying the frailty score into quartiles and tertiles similarly revealed case–control differences (both P < 0.001). The frailty score also increased with age (r = 0.25, P < 0.001), was higher in women than men (P = 0.02), was correlated with subjective rating of health status (r = 0.42, P < 0.001), and was inversely correlated with body weight (r = −0.06, P < 0.001) and hours/day that participants performed moderate or intensive physical activities (r = −0.16, P < 0.001). Conclusion: Essential tremor cases had increased frailty compared to their counterparts without this disease. Whether this increased frailty is a contributor to the increased risk of mortality that has been observed in some studies is a question that deserves further scrutiny.     

Cerebellar metabolic symmetry in essential tremor studied with 1H magnetic resonance spectroscopic imaging: implications for disease pathology.

The pathological basis for essential tremor (ET) is not known; however, metabolic changes in the cerebellum can be observed in positron emission tomography (PET) and (1)H magnetic resonance spectroscopic imaging (MRSI) studies. Tremor is relatively symmetric in ET, suggesting that underlying metabolic changes could be also symmetric. The degree of metabolic asymmetry in the cerebellum, however, has not yet been studied in ET, and knowledge about distribution and laterality of metabolic changes might shed some light on basic disease mechanisms. We measured brain metabolism (N-acetylaspartate[NAA]/creatine [tCR]) to obtain an asymmetry index for cerebellar cortical metabolism ET patients compared with that in controls. This index, a percentage, was calculated as [absolute value (value right - value left)]/(value right + value left) x 100. Multislice (1)H MRSI data were acquired for 20 patients and 11 controls. In ET patients, mean right and left cerebellar cortical NAA/tCR values were 1.61 +/- 0.42 and 1.55 +/- 0.38, respectively, compared with 1.81 +/- 0.62 and 1.87 +/- 0.49 in controls. The difference between right and left cerebellar cortical NAA/tCR was also calculated for each subject. In ET patients, the mean right-left difference was 0.14 +/- 0.11, compared with 0.32 +/- 0.27 in controls (P = 0.016). The mean cerebellar cortical asymmetry index was low in ET (8.8 +/- 6.1%), one-half of that in controls (17.0 +/- 13.7%, P = 0.027). These data suggest that pathological lesions in ET patients, which remain elusive, might be distributed similarly in each cerebellar cortex. Postmortem studies are needed to confirm these preliminary imaging results.