Neuropathological changes in essential tremor: 33 cases compared with 21 controls

Louis, Elan D.; Faust, Phyllis L.; Vonsattel, Jean Paul; Honig, Lawrence S.; Rajput, Alex; Robinson, Christopher A.; Rajput, Ali H.; Pahwa, Rajesh; Lyons, Kelly E.; Ross, G. Webster; Borden, Sarah; Moskowitz, Carol; Lawton, Arlene; Hernández, Nora

doi:10.1093/brain/awm266

Cited by 521 publications

(718 citation statements)

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“…There is an ongoing debate on whether a cerebellar dysfunction in essential tremor is caused by disease progression and neurodegeneration (Louis et al, 2007) or a functional disruption of the cerebello-thalamo-cortical network through the interference of tremor-related neuronal oscillations with normal cerebellar timing function (Solomon et al, 1994;Elble, 1998;Deuschl et al, 2000;Blangero et al, 2009;Elble, 2009).…”

Section: Introductionmentioning

confidence: 99%

Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?

Reich¹,

Brumberg²,

Pozzi³

et al. 2016

Brain

123

117

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*These authors contributed equally to this work.Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.

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Section: Introductionmentioning

confidence: 99%

Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?

Reich¹,

Brumberg²,

Pozzi³

et al. 2016

Brain

123

117

View full text Add to dashboard Cite

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“…25,26 There is considerable evidence from clinical, neuroimaging and physiological studies, of cerebellar involvement, 27,28 and an emerging literature that documents a variety of changes, some of which are degenerative, in the Purkinje cell population. 29,30 There is also a related literature that indicates a possible change in brain gamma-amino butyric acid (GABA) tone in ET. 31,32 …”

Section: Introductionmentioning

confidence: 99%

Identification of candidate genes for familial early-onset essential tremor

et al. 2015

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Essential tremor (ET) is one of the most common causes of tremor in humans. Despite its high heritability and prevalence, few susceptibility genes for ET have been identified. To identify ET genes, whole-exome sequencing was performed in 37 early-onset ET families with an autosomal-dominant inheritance pattern. We identified candidate genes for follow-up functional studies in five ET families. In two independent families, we identified variants predicted to affect function in the nitric oxide (NO) synthase 3 gene (NOS3) that cosegregated with disease. NOS3 is highly expressed in the central nervous system (including cerebellum), neurons and endothelial cells, and is one of three enzymes that converts L-arginine to the neurotransmitter NO. In one family, a heterozygous variant, c.46G4A (p. (Gly16Ser)), in NOS3, was identified in three affected ET cases and was absent in an unaffected family member; and in a second family, a heterozygous variant, c.164C4T (p.(Pro55Leu)), was identified in three affected ET cases (dizygotic twins and their mother). Both variants result in amino-acid substitutions of highly conserved aminoacid residues that are predicted to be deleterious and damaging by in silico analysis. In three independent families, variants predicted to affect function were also identified in other genes, including KCNS2 (KV9.2), HAPLN4 (BRAL2) and USP46. These genes are highly expressed in the cerebellum and Purkinje cells, and influence function of the gamma-amino butyric acid (GABA)-ergic system. This is in concordance with recent evidence that the pathophysiological process in ET involves cerebellar dysfunction and possibly cerebellar degeneration with a reduction in Purkinje cells, and a decrease in GABA-ergic tone.

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“…OT has been suggested to arise from a central oscillator involving the brainstem or cerebellum [4][5][6][7]. Interestingly, neuropathological changes in essential tremor have also been found in brainstem and cerebellar structures [8]. An association between the severity of parkinsonian rest tremor and the reduction of serotonin receptor (5-HT 1A ) binding potential in the midbrain raphe has been shown in a positron emission tomography (PET) study which might indicate a role of the serotonergic system in the generation of tremor [9,10].…”

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confidence: 99%