Cerebellar Atrophy in Cortical Myoclonic Tremor and Not in Hereditary Essential Tremor—a Voxel-Based Morphometry Study

Essential tremor (ET) presumably has a cerebellar origin. Imaging studies showed various cerebellar and also cortical structural changes. A number of pathology studies indicated cerebellar Purkinje cell pathology. ET is a heterogeneous disorder, possibly indicating different underlying disease mechanisms. Familial cortical myoclonic tremor with epilepsy (FCMTE), with evident Purkinje cell degeneration, can be an ET mimic. Here, we investigate whole brain and, more specifically, cerebellar morphological changes in hereditary ET, FCMTE, and healthy controls. Anatomical magnetic resonance images were preprocessed using voxel-based morphometry. Study 1 included voxel-wise comparisons of 36 familial, propranolol-sensitive ET patients, with subgroup analysis on age at onset and head tremor, and 30 healthy controls. Study 2 included voxel-wise comparisons in another nine ET patients, eight FCMTE patients, and nine healthy controls. Study 3 compared total cerebellar volume between 45 ET patients, 8 FCTME patients, and 39 controls. In our large sample of selected hereditary ET patients and ET subgroups, no local atrophy was observed compared to healthy controls or FCMTE. In ET patients with head tremor, a volume increase in cortical motor regions was observed. In FCMTE, a decrease in total cerebellar volume and in local cerebellar gray matter was observed compared to healthy controls and ET patients. The current study did not find local atrophy, specifically not in the cerebellum in hereditary ET, contrary to FCMTE. Volume increase of cortical motor areas in ET patients with head tremor might suggest cortical plasticity changes due to continuous involuntary head movements.     

Über eine erbliche Altershalluzinose mit Tremor

Zusammenfassung Drei Geschwister sind im höheren Lebensalter seelisch erkrankt. Obwohl nur der Vater in unbestimmter Weise psychisch auffällig war, muß die Krankheit wegen der gleichsinnigen Erkrankung der Geschwister doch als erblich angesprochen werden.Das Leiden ist in verschiedener Intensität bei den Geschwistern ausgeprägt, aber verläuft in der gleichen Bahn.Ein paranoisches Stadium lief der eigentlichen Psychose zum Teil um Jahre voraus. Die Wahnideen, persekutorisch, expansiv und phantastisch, sind systematisiert. Sie hängen ab von einer zunächst angstvollen, später ekstatischen Verschiebung des Affektes und werden unterstützt durch Halluzinationen aller Sinnesgebiete.Die elementaren ungeformten Sinnesreize weisen im Verein mit den Halluzinationen von hoher sinnlicher Deutlichkeit auf eine organische Genese hin. Das wird durch die übrigen organischen Kriterien gefestigt, wie Merkschwäche, Kombinationsschwäche, vegetative Reizerscheinungen, Schlaflosigkeit, Ruhe- und Intentionstremor und endlich eine zum Teil beträchtliche Hirnatrophie.Von einer Schizophrenie unterscheidet sich das psychische Krankheitsbild allein, neben den elementaren ungeformten Sinnesreizen und den sehr plastischen Trugwahrnehmungen auf allen Sinnesgebieten, durch die Systematisierung der Wahnideen und die gut erhaltene affektive Zuwendung mit der arglosen Aufgeschlossenheit.Lokalisatorisch sprechen die vielfältigen Symptome für einen ausgedehnten Hirnprozeß.Ein gewöhnlicher seniler Abbauprozeß liegt wegen der präzis differenzierten Symptome ohne regellosen Wechsel und dem Fehlen gröberer intellektueller Einbußen nicht vor. Nähere Beziehungen ergeben sich dagegen zur Involutionsparanoia Kleists. Vieles deutet auf eine spät ausgebrochene degenerative Erkrankung einzelner Systeme hin, doch ließen sich aus dem Kreis der Heredodegenerationen nur Ähnlichkeiten aufzeigen zur Chorea Huntington und zum hereditären Tremor, aber keine sichere Verwandtschaft.     

Über den Tremor bei schweren chronischen Lebererkrankungen

Zusammenfassung Bei schweren chronischen Lebererkrankungen findet sich häufig ein typischer Tremor. Es handelt sich um einen ausgesprochenen Haltetremor langsamer Frequenz, in Ruhe fehlt er stets. Am häufigsten ist er an den ausgestreckten Händen und gelegentlich in der Umgebung des Mundes und an der Zunge zu beobachten. Außer als Bestandteil des Syndroms des drohenden hepatischen Komas kann dieser charakteristische Tremor in wechselnder Stärke auch bei fehlenden oder nur geringen psychischen Veränderungen nachweisbar sein. Im Verlauf zum Coma hepaticum geht er nicht immer den psychischen Erscheinungen parallel und kann in seltenen Fällen fehlen. Die Untersuchungen zeigen, daß sowohl die Schwere der Leberfunktionsstörung als auch der portocavale Kollateralkreislauf für das Auftreten des Tremors von Bedeutung sind. An Hand von Beispielen wird außerdem auf die Wichtigkeit von Vorschädigungen oder Zweitschädigungen des Gehirns, seien sie toxischer oder hypoxämischer Art, als dritten Faktor hingewiesen, die das Auftreten des charakteristischen Tremors begünstigen können. Vereinzelte Beobachtungen des beschriebenen Tremors auch bei Patienten ohne Lebererkrankung zeigen, daß dieser zwar für Lebererkrankungen weitgehend charakteristisch, jedoch nicht spezifisch ist. Ergebnisse der für die Entstehung neurologischpsychiatrischer Symptome bei schweren Lebererkrankungen wichtigen Stoffwechseluntersuchungen werden abschließend referiert und diskutiert. Die therapeutische Konsequenz liegt in einer weitgehenden Eiweißbeschränkung der Nahrung, durch die oft erstaunliche therapeutische Erfolge zu erzielen sind.     

Linking Essential Tremor to the Cerebellum—Neuroimaging Evidence

Essential tremor (ET) is the most common pathological tremor disorder in the world, and post-mortem evidence has shown that the cerebellum is the most consistent area of pathology in ET. In the last few years, advanced neuroimaging has tried to confirm this evidence. The aim of the present review is to discuss to what extent the evidence provided by this field of study may be generalised. We performed a systematic literature search combining the terms ET with the following keywords: MRI, VBM, MRS, DTI, fMRI, PET and SPECT. We summarised and discussed each study and placed the results in the context of existing knowledge regarding the cerebellar involvement in ET. A total of 51 neuroimaging studies met our search criteria, roughly divided into 19 structural and 32 functional studies. Despite clinical and methodological differences, both functional and structural imaging studies showed similar findings but without defining a clear topography of neurodegeneration. Indeed, the vast majority of studies found functional and structural abnormalities in several parts of the anterior and posterior cerebellar lobules, but it remains to be established to what degree these neural changes contribute to clinical symptoms of ET. Currently, advanced neuroimaging has confirmed the involvement of the cerebellum in pathophysiological processes of ET, although a high variability in results persists. For this reason, the translation of this knowledge into daily clinical practice is again partially limited, although new advanced multivariate neuroimaging approaches (machine-learning) are proving interesting changes of perspective.     

Tremor in Klinefelter’s syndrome improved by testosterone administration

Tremor in Klinefelter’s syndrome is believed to be essential tremor since the publication of “Klinefelter’s syndrome and essential tremor” in 1969. However, the author also stated that tremor in Klinefelter’s syndrome might differ from essential tremor. A 71-year-old man with Klinefelter’s syndrome who suffers from postural hand tremor is described. The electromyogram indicated lower motor neuron disturbance and chronic neurogenic change. The muscle biopsy indicated neurogenic muscle atrophy. Upon testosterone administration, the amplitude of tremor was reduced and a gradual improvement in handwriting was observed. The tremor in this patient was different from essential tremor. The foresight by Baughman in 1969 proved to be true in this patient. This case report provides new insights into the pathogenesis and treatment of tremor in Klinefelter’s syndrome, which would benefit patients who suffer from the tremor.     

Linking Essential Tremor to the Cerebellum—Animal Model Evidence

In this review, we hope to stimulate interest in animal models as opportunities to understand tremor mechanisms within the cerebellar system. We begin by considering the harmaline model of essential tremor (ET), which has ET-like anatomy and pharmacology. Harmaline induces the inferior olive (IO) to burst fire rhythmically, recruiting rhythmic activity in Purkinje cells (PCs) and deep cerebellar nuclei (DCN). This model has fostered the IO hypothesis of ET, which postulates that factors that promote excess IO, and hence PC complex spike synchrony, also promote tremor. In contrast, the PC hypothesis postulates that partial PC cell loss underlies tremor of ET. We describe models in which chronic partial PC loss is associated with tremor, such as the Weaver mouse, and others with PC loss that do not show tremor, such as the Purkinje cell degeneration mouse. We postulate that partial PC loss with tremor is associated with terminal axonal sprouting. We then discuss tremor that occurs with large lesions of the cerebellum in primates. This tremor has variable frequency and is an ataxic tremor not related to ET. Another tremor type that is not likely related to ET is tremor in mice with mutations that cause prolonged synaptic GABA action. This tremor is probably due to mistiming within cerebellar circuitry. In the final section, we catalog tremor models involving neurotransmitter and ion channel perturbations. Some appear to be related to the IO hypothesis of ET, while in others tremor may be ataxic or due to mistiming. In summary, we offer a tentative framework for classifying animal action tremor, such that various models may be considered potentially relevant to ET, subscribing to IO or PC hypotheses, or not likely relevant, as with mistiming or ataxic tremor. Considerable further research is needed to elucidate the mechanisms of tremor in animal models.     

Geschmacksstörung unter tiefer Hirnstimulation des Thalamus bei essenziellem Tremor

Deep brain stimulation of ventral intermediate nucleus (VIM-DBS) has become an established therapy for severe essential tremor (ET). The technique is however limited in some ET patients by relevant side effects such as paresthesia, dysarthria, and gait disturbances. To our knowledge, this is the first report of VIM-DBS-induced reversible hypogeusia along with retroinsular cortical deactivation under effective VIM stimulation measured with 18-fluorodexoglucose positron emission tomography. This case demonstrates that gustatory dysfunction should be considered in the pre- and postsurgical management of patients with VIM-DBS. Moreover it provides direct evidence that the thalamus acts as an important relay station in the human cerebral gustatory pathway.     

Cannabinoids and Tremor Induced by Motor-related Disorders: Friend or Foe?

Tremor arises from an involuntary, rhythmic muscle contraction/relaxation cycle and is a common disabling symptom of many motor-related diseases such as Parkinson disease, multiple sclerosis, Huntington disease, and forms of ataxia. In the wake of anecdotal, largely uncontrolled, observations claiming the amelioration of some symptoms among cannabis smokers, and the high density of cannabinoid receptors in the areas responsible for motor function, including basal ganglia and cerebellum, many researchers have pursued the question of whether cannabinoid-based compounds could be used therapeutically to alleviate tremor associated with central nervous system diseases. In this review, we focus on possible effects of cannabinoid-based medicines, in particular on Parkinsonian and multiple sclerosis-related tremors and the common probable molecular mechanisms. While, at present, inconclusive results have been obtained, future investigations should extend preclinical studies with different cannabinoids to controlled clinical trials to determine potential benefits in tremor.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0367-5) contains supplementary material, which is available to authorized users.     

Tremor analysis separates Parkinson’s disease and dopamine receptor blockers induced parkinsonism

Parkinson’s disease, the most common cause of parkinsonism is often difficult to distinguish from its second most common etiology due to exposure to dopamine receptor blocking agents such as antiemetics and neuroleptics. Dual axis accelerometry was used to quantify tremor in 158 patients with parkinsonism; 62 had Parkinson’s disease and 96 were clinically diagnosed with dopamine receptor blocking agent-induced parkinsonism. Tremor was measured while subjects rested arms (resting tremor), outstretched arms in front (postural tremor), and reached a target (kinetic tremor). Cycle-by-cycle analysis was performed to measure cycle duration, oscillation amplitude, and inter-cycle variations in the frequency. Patients with dopamine receptor blocker induced parkinsonism had lower resting and postural tremor amplitude. There was a substantial increase of kinetic tremor amplitude in both disorders. Postural and resting tremor in subjects with dopamine receptor blocking agent-induced parkinsonism was prominent in the abduction–adduction plane. In contrast, the Parkinson’s disease tremor had equal amplitude in all three planes of motion. Tremor frequency was comparable in both groups. Remarkable variability in the width of the oscillatory cycles suggested irregularity in the oscillatory waveforms in both subtypes of parkinsonism. Quantitative tremor analysis can distinguish Parkinson’s disease from dopamine receptor blocking agent-induced parkinsonism.     

Tremor reduction by subthalamic nucleus stimulation and medication in advanced Parkinson’s disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has proved to be effective for tremor in Parkinson’s disease (PD). Most of the recent studies used only clinical data to analyse tremor reduction. The objective of our study was to quantify tremor reduction by STN DBS and antiparkinsonian medication in elderly PD patients using an objective measuring system. Amplitude and frequency of resting tremor and re-emergent resting tremor during postural tasks were analysed using an ultrasound-based measuring system and surface electromyography. In a prospective study design nine patients with advanced PD were examined preoperatively off and on medication, and twice postoperatively during four treatment conditions: off treatment, on STN DBS, on medication, and on STN DBS plus medication. While both STN DBS and medication reduced tremor amplitude, STN DBS alone and the combination of medication and STN DBS were significantly superior to pre- and postoperative medication. STN DBS but not medication increased tremor frequency, and off treatment tremor frequency was significantly reduced postoperatively compared to baseline. These findings demonstrate that STN DBS is highly effective in elderly patients with advanced PD and moderate preoperative tremor reduction by medication. Thus, with regard to the advanced impact on the other parkinsonian symptoms, STN DBS can replace thalamic stimulation in this cohort of patients. Nevertheless, medication was still effective postoperatively and may act synergistically. The significantly superior efficacy of STN DBS on tremor amplitude and its impact on tremor frequency in contrast to medication might be explained by the influence of STN DBS on additional neural circuits independent from dopaminergic neurotransmission. Received in revised form: 27 April 2006     

Tremor associated with Klinefelter syndrome – A case series and review of the literature

BackgroundPrevious case series suggested a link between Klinefelter syndrome (KS) and essential tremor (ET) or an ET-like syndrome.MethodsWe investigated three KS-patients with tremor including tremor-analyzes and discuss our data in context to findings from a literature review. The clinical outcome after deep brain stimulation (DBS) is also reviewed.ResultsTremor in KS is predominantly a postural and kinetic tremor that resembles ET. Our patients were further characterized by absent family history for tremor in first degree relatives, lack of subjective alcohol responsiveness inquired by history, and tremor onset in childhood. One of our patients and two cases from literature improved after DBS of the ventral intermediate nucleus (VIM) of the thalamus.ConclusionsTremor in KS shares several features with ET. If other characteristics such as family history, alcohol responsiveness, and age at tremor onset may serve as discriminating factors from ET, needs to be further investigated. First observations suggest that VIM-DBS may be efficacious.     

Memory Similarities Between Essential Tremor and Parkinson’s Disease: A Final Common Pathway?

Objective: A growing body of literature supports the view that essential tremor (ET) involves alteration of cerebellar–thalamo–cortical networks which can result in working memory and executive deficits. In this study, we tested the hypothesis that individuals with ET would exhibit worse performance on memory tasks requiring more intrinsic organization and structuring (i.e., word lists) relative to those with fewer ‘executive’ demands (i.e., stories), similar to that previously observed in individuals with Parkinson’s disease (PD). Method: Participants included a convenience sample of 68 ET patients and 68 idiopathic PD patients, retrospectively matched based on age, education, and sex. All patients underwent routine neuropsychological evaluation assessing recent memory, auditory attention/working memory, language, and executive function. Memory measures included the Hopkins Verbal Learning Test-R and WMS-III Logical Memory. Results: Both ET and PD patients performed significantly worse on word list than story memory recall tasks. The magnitude of the difference between these two memory tasks was similar for ET and PD patients. In both patient groups, performance on measures of executive function and auditory attention/working memory was not distinctly correlated with word list vs. story recall. Conclusions: These findings suggest that frontal-executive dysfunction in both ET and PD may negatively influence performance on memory tests that are not inherently organized. Although the pathophysiology of these two ‘movement disorders’ are quite distinct, both have downstream effects on thalamo–frontal circuitry which may provide a common pathway for a similar memory phenotype. Findings are discussed in terms of neuroimaging evidence, conceptual models, and best practice.     

Tremor in Parkinson’s disease is not associated with the DRD3 Ser9Gly polymorphism

A common subset of genetic risk factors for Parkinson’s disease (PD) and essential tremor (ET) has been postulated. Recently, an association between the dopamine D₃ receptor (DRD3) Ser9Gly polymorphism and ET has been reported. We studied whether PD tremor is influenced by Ser9Gly in a genetic association study based on the gene bank of the German Competence Network on Parkinson’s disease. The study included analyses of motor predominance (mixed, hypokinetic, and tremor), and tremor type (resting, postural, and action). We did not identify any effect of DRD3 Ser9Gly on tremor in PD, even when regarding various symptom combinations to avoid missing a weak effect on the phenotype. Additional studies incorporating symptoms at disease onset, and grading of tremor response to dopaminergic therapy, are warranted.     

Which Approach is Better: Bilateral Versus Unilateral Thalamic Deep Brain Stimulation in Patients with Fragile X–Associated Tremor Ataxia Syndrome

Fragile X–associated tremor ataxia syndrome (FXTAS) is a relatively recently described condition that is frequently misdiagnosed as essential tremor and then occasionally treated as such with deep brain stimulation (DBS) to the nucleus ventralis intermedius of the thalamus (Vim). Reports of ataxia worsening after bilateral Vim DBS in FXTAS patients are conflicting, and only five FXTAS patients treated with Vim DBS for intractable tremor have been reported in the literature, three of whom having undergone a bilateral procedure. We report a patient who underwent a staged Vim DBS procedure, with excellent contralateral hand tremor control and no worsening of ataxia after the first procedure, but immediate worsening of his ataxia after the second one, arguing in favor of a unilateral surgical approach for intractable tremor in FXTAS.     

The Neuropsychological Assessment Battery Categories Test as a Measure of Executive Dysfunction in Patients With Parkinson’s Disease and Essential Tremor: An Exploratory Study

Patients with Parkinson’s disease (PD) and essential tremor (ET) can experience deficits in executive functioning (EF) secondary to abnormalities in fronto-striatal and cerebellar-frontal pathways respectively. The assessment of EF can be confounded in these patients due to motor difficulties and slowed processing speed. Thus, instruments which do not require speeded motor responses are potentially attractive in this population. The Neuropsychological Assessment Battery-Categories Test (NABCAT) is one such instrument. This study evaluated the convergent and divergent validity of this measure as well as its diagnostic accuracy in comparison to other commonly administered tests. Records for 28 patients with PD and/or ET who presented for evaluation pre-deep brain stimulation surgery were analyzed. The NABCAT had modest correlations with other measures of EF, as well as memory. However, it demonstrated relatively poor sensitivity and modest specificity to executive dysfunction. The NABCAT did not demonstrate adequate psychometric properties to replace traditional measures of EF in this population; however, it may have utility as a screening instrument for more significant dysfunction.     

<Emphasis Type="Italic">De Sedibus et Causis Morborum</Emphasis>: is Essential Tremor a Primary Disease of the Cerebellum?

Morgagni’s 1761 publication of De sedibus et causis morborum (i.e., of the Seats and Causes of Diseases) represented a paradigmatic moment in the history of medicine. The book ushered in a new way of conceptualizing human disease, shattering old dogma, and linking constellations of symptoms and signs (i.e., clinical disease) with anatomic pathology in specific organs (i.e., organ disease). This was the anatomical-clinical method, and it attempted to unveil “the seat” of each disease in a specific organ. Essential tremor (ET) is among the most common neurological diseases. There is little debate that the origin of ET lies in the brain, but if one tries to delve more deeply than this, things become murky. The dogma for the past 40 years has been that the seat of ET is the inferior olivary nucleus. Closer scrutiny of this model, however, has revealed its many flaws, and the model, based on little if any empiric evidence, has increasingly lost favor. Arising from a wealth of research in recent years is a growing body of knowledge that links ET to a disarrangement of the cerebellum. Data from a variety of sources reviewed in this issue (clinical, neuroimaging, neurochemical, animal model, physiological, and pathological) link ET to the cerebellum. That the cerebellum is involved in an abnormal brain loop that is responsible for ET is not debated. The tantalizing question is whether an abnormality in the cerebellum is the prime mover, and whether the cerebellum is the seat of this particular disease.