Intention Tremor Research Articles

Thermoelectric Cooling Device Integrated with PCM Heat Storage for MS Patients

Most Multiple Sclerosis (MS) patients are sensitive to temperature resulting in wide range of symptoms including fatigue and intention tremor. Published work showed that cooling the upper limbs can reduce the severity of these symptoms thus improving the quality of lives of MS patients. Currently available cooling devices are large, heavy and power intensive. This work aims to develop a compact light weight wearable upper limb cooling device that can be used to reduce the skin temperature to 10oC and for duration of 20 minutes. This work combines the heat pumping ability of thermoelectric devices together with the heat storage capability of PCM materials. Experimental work was carried out to investigate the performance of three different PCM materials. Results showed that PCM-OM37 with power input of 3W can deliver the required temperature of 10oC for duration of 20 minutes highlighting the potential of this proposed technology.

Effect of ultrasonography-guided botulinum toxin type a injection in holmes' tremor secondary to pontine hemorrhage: case report.

Holmes' tremor is a low-frequency rest and intentional tremor secondary to various insults, including cerebral ischemia, hemorrhage, trauma, or neoplasm. Pharmacologic treatment is usually unsuccessful, and some cases require surgical intervention. We report a rare case of Holmes' tremor secondary to left pontine hemorrhage in a 29-year-old Asian male patient who developed 1.6-Hz postural and rest tremor of the right hand. He responded markedly to ultrasonography-guided botulinum toxin type A injection. To our knowledge, this is the first report of Homes' tremor treated with ultrasonography-guided botulinum toxin type A injection with favorable results.

Quantitative assessment of upper limb motor function in Multiple Sclerosis using an instrumented Action Research Arm Test.

BackgroundArm impairment in Multiple Sclerosis (MS) is commonly assessed with clinical scales, such as Action Research Arm Test (ARAT) which evaluates the ability to handle and transport smaller and larger objects. ARAT provides a complete upper limb assessment, as it considers both proximal arm and hand, but suffers from subjectivity and poor sensitivity to mild impairment. In this study an instrumented ARAT is proposed to overcome these limitations and supplement the assessment of arm function in MS.MethodsARAT was executed by 12 healthy volunteers and 21 MS subjects wearing a single inertial sensor on the wrist. Accelerometers and gyroscopes signals were used to calculate the duration of each task and its sub-phases (reaching, manipulation, transport, release and return). A jerk index was computed to quantify movement smoothness. For each parameter, z-scores were calculated to analyze the deviation from normative data. MS subjects were clinically assessed with ARAT score, Nine-Hole Peg test (9HPT) and Fahn Tremor Rating Scale (FTRS).ResultsARAT tasks executed by MS patients were significantly slower (duration increase: 70%) and less smooth (jerk increase: 16%) with respect to controls. These anomalies were mainly related to manipulation, transport and release sub-movements, with the former showing the greatest alterations. A statistically significant decrease in movement velocity and smoothness was also noticed in patients with normal ARAT score. Z-scores related to duration and jerk were strongly correlated with ARAT rating (r < -0.80, p < 0.001) and 9HPT (r < -0.75, p < 0.001) and were significantly different among MS sub-groups with different levels of arm impairments (p < 0.001). Moreover, Z-score related to manipulation-phase jerk was significantly correlated with the FTRS rating of intention tremor (r = 0.84, p < 0.001).ConclusionsThe present study showed that the proposed method is able to discriminate between control and MS groups and to reveal subtle arm alterations not detectable from ARAT score. Validity was shown by high correlations between instrumental variables and clinical ratings. These results suggested that instrumented ARAT could be a valid quick and easy-to-use method for a sensitive quantification of arm function in MS. Inclusion of finger-mounted sensors could complement present findings and provide further indications about hand function in MS.

Memantine for Fragile X–Associated Tremor/Ataxia Syndrome

Memantine, an uncompetitive N-methyl-d-aspartate receptor antagonist, is currently approved by the US Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. Anecdotal reports have suggested that memantine may improve neurologic and cognitive symptoms of individuals with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial. Individuals with FXTAS aged 34-80 years were enrolled in a randomized, double-blind, placebo-controlled, 1-year trial between September 2007 and August 2012. Inclusion required definite, probable, or possible FXTAS in clinical stages 1-5 according to previously published criteria. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity. Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started treatment with memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants receiving memantine and 36 receiving placebo completed the 1-year endpoint assessment (n = 70). Intention-to-treat analysis showed no improvement with respect to intention tremor severity (mean [SD] values with memantine vs placebo: 1.05 [0.73] vs 1.89 [2.19], P = .047) or BDS score (16.12 [5.43] vs 15.72 [3.93], P = .727) at follow-up. Post hoc analyses of participants with early FXTAS (stage ≤ 3), those with late FXTAS (stage > 3), and those in different age groups (≤ 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events were observed in the placebo group, while more frequent moderate adverse events occurred in the memantine group (P = .007). This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit compared to placebo with respect to the selected outcome measures. ClinicalTrials.gov identifier: NCT00584948.

A clinical study of non-parkinsonian tremor in Moroccan patients

ObjectiveTo report the characteristics of the most frequent tremors in a population of Moroccan patients. BackgroundTremor is the most common movement disorder. It implies a wide variety of disorders with Parkinson's disease and essential tremor being the most frequent. MethodsA retrospective study of 148 patients with tremor referred to our movement disorders outpatient clinic was performed. Clinical features and treatment regimens were analyzed. Patients with parkinsonian tremor were excluded. ResultsWe included 62 patients with non-parkinsonian tremor. The etiologies were as follows: essential tremor (54.8%), dystonic tremor (19.4%), tremor associated with dystonia (14.5%), enhanced physiological tremor (3.2%), cerebellar tremor (3.2%), psychogenic tremor (3.2%) and Holmes’ tremor (1.6%). The characteristics of essential tremor patients were analyzed. Female patients accounted for 67.6% of patients. Mean age at the onset of tremor was 52.2±16.4 years. Family history of tremor was reported in 17.6% of cases. Tremor affected the arms (94.1%), head (52.9%), voice (35.3%) and legs (8.8%). Tremor was bilateral in 87.5% but was asymmetrical in 50% of patients. Patients had postural tremor (76.5%), kinetic tremor (79.4%) and rest tremor (associated in 11.8%). Treatment relied on propranolol (88.3%), primidone (14.7%), gabapentin (14.7%), clonazepam (14.7%), alprazolam (11.8%), topiramate (5.9%) and, in one patient, radiosurgery. ConclusionsEssential tremor was the predominant diagnosis, confirming its high prevalence. There was a predominance of female patients and a peak of age at onset in the fifth and sixth decades. Asymmetry of the disease was noted in half of patients.

Physiological and anatomical decomposition of subthalamic neurostimulation effects in essential tremor

Postural tremor is the leading symptom in essential tremor, but in some cases intention tremor and limb ataxia emerge and can become highly disabling features. Deep brain stimulation of the thalamus or subthalamic white matter improve tremor and ataxia; however, the underlying network mechanisms are enigmatic. To elucidate the mechanisms of deep brain stimulation in essential tremor, we pursued a multimodal approach combining kinematic measures of reach-to-grasp movements, clinical assessments, physiological measures of neuronal excitability and probabilistic tractography from diffusion tensor imaging. Seven patients with essential tremor (age 62.9 ± 10.3 years, two females) received thalamic deep brain stimulation and a clinical examination of severity of limb tremor and ataxia at off stimulation, using therapeutic and supratherapeutic stimulation parameters. A reach-to-grasp task based on acoustic cues was also performed. To examine the electrical properties of target structures, we determined the chronaxie of neural elements modulated. A control group of 13 healthy subjects (age 56 ± 7.6 years, five females) underwent whole-brain diffusion tensor imaging at 3 T. Probabilistic tractography was applied in healthy subjects from seeds in cerebellum and midbrain to reconstruct the connectivity pattern of the subthalamic area. The positions of stimulation electrodes in patients were transferred into probability maps and connectivity values were correlated to clinical outcome measures. Therapeutic stimulation improved ataxia and tremor mainly during the target period of the reaching paradigm (63% reduction compared with off stimulation). Notably the acceleration (29%) and deceleration periods (41%) were improved. By contrast, supratherapeutic stimulation worsened ataxia during the deceleration period with a 55% increase of spatial variability, while maintaining near complete suppression of tremor. Chronaxie measures were in the range of rapidly-conducting myelinated fibres with significantly different values for the anti-tremor effect of therapeutic stimulation (27 s) and the pro-ataxic effect of supratherapeutic stimulation (52 s). The degree of connectivity to the dentato-thalamic tract at the stimulating electrode correlated significantly with the reduction of tremor in the therapeutic condition. Our data suggest that stimulation induced tremor reduction and induction of ataxia by supratherapeutic stimulation are mediated by different fibre systems. Probalistic tractography identified the dentato-thalamic tract as a likely target of tremor suppression. Stimulation-induced ataxia may be caused by additional recruitment of adjacent fibre systems at higher amplitudes. Stimulation with short pulse duration may help to increase the therapeutic window and focus on the anti-tremor effect.

Heterogeneity and frequency of movement disorders in juvenile and adult-onset Niemann-Pick C disease

Niemann-Pick type C disease (NPC) is a recessive neurolipidosis. We report five adolescent and adult NPC cases to underscore the frequency and heterogeneity of movement disorders in NPC. Clinical, morphologic, biochemical and genetic study was performed in the five patients. Disease onset was between 8 and 50 years. Movement disorders were present in all cases, were heterogeneous and often combined [cerebellar ataxia (5/5), myoclonus (3/5), dystonia (2/5), chorea (1/5) and tremor (1/5)] and were the first sign in 4/5. Two patients were reported to have no vertical supranuclear gaze palsy (VSGP) at the first examination. Two patients experienced acute neuropsychiatric signs leading to death in one case due to myoclonic storm. Filipin staining was always positive. Two NPC1 mutations were identified in three patients, only one in two siblings. NPC should be considered in case of unexplained movement disorders, even when VSGP or cataplexy are not reported. Filipin staining remains a strong support for the diagnosis. Treatment with miglustat should be considered which is currently the only approved disease-specific treatment of NPC in children and adults.

A LATE ONSET ATAXIA WITH TELANGIECTASIA

Ataxia telangiectasia (AT) is a multisystem autosomal recessive disorder caused by mutations in the ATM gene found on the large arm of chromosome 11 (11q 22–23). The ATM gene encodes...

HEAVY METAL TOXICITY: LESSONS FROM A CASE OF SIMULTANEOUS OCCUPATIONAL EXPOSURE TO MANGANESE AND MERCURY

Heavy metal toxicity represents a heterogenous group of rare diseases that are associated with a wide variety of neurological syndromes. Manganese and mercury are two heavy metals that are neurotoxic...

Lissencephaly and cerebellar hypoplasia in a goat

A case of lissencephaly and cerebellar hypoplasia was observed in a 30-day-old goat. The goat presented with sternal recumbence, absence of a menace response, intention tremors, ataxia, and nystagmus. The goat was euthanized and necropsied after having been hospitalised for eleven days. At necropsy, the surface of the brain was found to be smooth, the cerebral sulci and gyri were absent, and the cerebellum was reduced in size. Histologically, the grey matter and white matter were thicker and thinner than normal in cortices, respectively. The neurons were randomly arranged in the grey matter. In the cerebellum, the layers were disorganised, and cells were heterotopics. The histologic and gross lesions observed in this animal are characteristic of lissencephaly associated with cerebellar hypoplasia. The presence of a single goat affected suggests that the malformation was not of infectious origin and because lissencephaly is a malformation not previously described in goats, it is unlikely this case was inherited.

A Chinese boy with episodic ataxia and low CSF glucose

A 3-year-8-month-old Chinese boy presented with acute exacerbation of ataxia precipitated by a viral illness. Past health revealed a clumsy boy with unsteady gait all along associated with moderate language and gross and fine motor delay but relatively preserved cognitive function. He was born normally at full term to non-consanguinous parents. There was no history of perinatal asphyxia or convulsion. The movement problem was paroxysmal, worse in early morning and during sick days. No history of any drugs was taken. Examination revealed a conscious boy with normal growth and head size. He had cerebellar ataxia with wide-based unsteady gait, truncal ataxia, intentional tremor and horizontal nystagmus. Cranial nerves, muscle tone, power and reflexes were normal. Gross sensation and hearing were normal. No skin rash, telangiectasia or neurocutaneous stigmata was noted. MRI was normal. CSF showed a lowish glucose of 1.9 mmol/l at a blood glucose of 4.8 mmol/l (CSF/blood glucose ratio 0.4), lactate and other biochemistries were normal, viral and bacterial cultures were negative. In view of the episodic nature with acute exacerbation during viral illnesses, congenital metabolic disease was highly suspected. Metabolic screening including plasma and urine amino acids, urine organic acids, plasma carnitine /acylcarnitine, ammonia, very-long-chain-fatty-acid, lyzosomal enzymes, transferrin, copper, ceruloplasmin and pre and post meal lactate, pyruvate, betahydroxybutyrate, acetoacete and glucose were all normal. Glucose transporter defect was suspected. However, common mutation SLC2A1 gene (1p35-31.3) for glucose transport protein (GLUT1) deficiency was not detected. Erythrocyte uptake test showed decreased glucose uptake. The clinical features together with low CSF glucose and decreased erythrocyte uptake were compatible with GLUT1 deficiency. Ketogenic diet with modified Atkins diet was started. Ataxia showed marked improvement. The diet was well-tolerated. No adverse effect was noted. GLUT1 deficiency commonly presents with infantile epileptic encephalopathy, movement disorder, progressive microcephaly and psychomotor retardation. It is inherited as an autosomal recessive disorder, 70-80% associated with SLC2A1 gene (1p35-31.3) mutation. The prognosis is good with early diagnosis and treatment with ketogenic diet (KD). Recent research reported similar efficacy to classical KD with lower ketogenic ratios (2:1 or 1:1), such as medium-chain-triglyceride oil diet, modified Atkins diet, and low-glycemic-index treatment. These allow better tolerability and less adverse effects. Further research makes KD more widely available, effective and safer.

The many roads to tremor

Tremor represents one of the most prominent examples of aberrant synchronisation within the human motor system, and Essential Tremor (ET) is by far the most common tremor disorder. Yet, even within ET there is considerable variation, and patients may have contrasting amounts of postural and intention tremor. Recently, Pedrosa et al. (2013) challenged tremor circuits in a cohort of patients presenting with ET, by applying low-frequency deep brain stimulation within thalamus. This interventional approach provided strong evidence that distinct (yet possibly overlapping) neural substrates are responsible for postural and intention tremor in ET. Intention tremor, and not postural tremor, was exacerbated by low frequency stimulation, and the effect was localised in the region of the ventrolateral thalamus in such a way as to implicate cerebello-thalamic pathways.These results, taken in conjunction with the contemporary literature, reveal that pathological changes exaggerate oscillatory synchrony in selective components of an extensive and distributed motor network, and that synchronisation within these networks is further regulated according to motor state. Through a combination of pathological and more dynamic physiological factors, activity then spills out into the periphery in the form of tremor. The findings of Pedrosa et al. (2013) are timely as they coincide with an emerging notion that tremor may result through selective dysregulation within a broader tremorgenic network.

Movement disorders in demyelinating diseases

Background: In multiple sclerosis (MS), movement disorders other than cerebellar tremors are rare.

Spinocerebellar Ataxia Type 10: From Amerindians to Latin Americans

Autosomal dominant cerebellar ataxias, currently denominated spinocerebellar ataxias (SCAs), constitute a large, complex group of heterogeneous autosomal dominant degenerative diseases characterized by progressive degeneration of the cerebellum and its afferent and efferent connections [1, 2]. Other nervous system structures are usually affected, including the basal ganglia, brainstem nuclei, pyramidal tracts, and posterior column and anterior horn of the spinal cord, as well as the peripheral nerves. SCAs are clinically characterized by the presence of cerebellar gait, limb ataxia (with dysmetria, dysdiadochokinesia, intention tremor), scanning dysarthria, dysphagia, nystagmus, and ocular motility abnormalities, which may be accompanied by extracerebellar signs such as ophthalmoplegia, pyramidal signs, movement disorders (including parkinsonism, dystonia, myoclonus, and chorea), dementia, epilepsy, visual disorders (including pigmentary retinopathy), lower motor neuron disease, and peripheral neuropathy [1–4]. Magnetic resonance imaging has been useful to demonstrate cerebellar atrophy with or without brainstem and occasionally whole brain atrophy depending on the form of the SCA. The prevalence of SCAs differs widely, mainly according to the ethnic distribution in most areas of the world where it has been studied [1–4]. One epidemiological study from the Netherlands [5] erichsuggested that the prevalence of SCAs is 3/100,000 and another from Norway suggested it is 4.2/100,000 [6]. Approximately 36 distinct loci of SCAs have been recognized. Among them, SCA type 3 (or Machado–Joseph disease) is the commonest subtype of SCA in the world. SCA type 10 (SCA10) is a rare form of SCA, but it is the commonest SCA after SCA type 2 in Mexico and SCA type 3 in Brazil [1, 2].

Tremor in Multiple System Atrophy – a review

<strong>Background:</strong> Multiple system atrophy (MSA) is a rare neurodegenerative movement disorder characterized by a rapidly progressive course. The clinical presentation can include autonomic failure, parkinsonism, and cerebellar signs. Differentiation from Parkinson’s disease (PD) is difficult if there is levodoparesponsive parkinsonism, rest tremor, lack of cerebellar ataxia, or mild/delayed autonomic failure. Little is known about tremor prevalence and features in MSA. <strong>Methods:</strong> We performed a PubMed search to collect the literature on tremor in MSA and considered reports published between 1900 and 2013. <strong>Results:</strong> Tremor is a common feature among MSA patients. Up to 80% of MSA patients show tremor, and patients with the parkinsonian variant of MSA are more commonly affected. Postural tremor has been documented in about half of the MSA population and is frequently referred to as jerky postural tremor with evidence of minipolymyoclonus on neurophysiological examination. Resting tremor has been reported in about one-third of patients but, in contrast to PD, only 10% show typical parkinsonian ‘‘pill-rolling’’ rest tremor. Some patients exhibit intention tremor associated with cerebellar dysmetria. In general, MSA patients can have more than one tremor type owing to a complex neuropathology that includes both the basal ganglia and pontocerebellar circuits. <strong>Discussion:</strong> Tremor is not rare in MSA and might be underrecognized. Rest, postural, action and intention tremor can all be present, with jerky tremulous movements of the outstretched hands being the most characteristic. However, reviewing the data on tremor in MSA suggests that not every shaky movement satisfies tremor criteria; therefore, further studies are needed.

Tremor in Multiple System Atrophy - a review.

Multiple system atrophy (MSA) is a rare neurodegenerative movement disorder characterized by a rapidly progressive course. The clinical presentation can include autonomic failure, parkinsonism, and cerebellar signs. Differentiation from Parkinson's disease (PD) is difficult if there is levodopa-responsive parkinsonism, rest tremor, lack of cerebellar ataxia, or mild/delayed autonomic failure. Little is known about tremor prevalence and features in MSA. We performed a PubMed search to collect the literature on tremor in MSA and considered reports published between 1900 and 2013. Tremor is a common feature among MSA patients. Up to 80% of MSA patients show tremor, and patients with the parkinsonian variant of MSA are more commonly affected. Postural tremor has been documented in about half of the MSA population and is frequently referred to as jerky postural tremor with evidence of minipolymyoclonus on neurophysiological examination. Resting tremor has been reported in about one-third of patients but, in contrast to PD, only 10% show typical parkinsonian "pill-rolling" rest tremor. Some patients exhibit intention tremor associated with cerebellar dysmetria. In general, MSA patients can have more than one tremor type owing to a complex neuropathology that includes both the basal ganglia and pontocerebellar circuits. Tremor is not rare in MSA and might be underrecognized. Rest, postural, action and intention tremor can all be present, with jerky tremulous movements of the outstretched hands being the most characteristic. However, reviewing the data on tremor in MSA suggests that not every shaky movement satisfies tremor criteria; therefore, further studies are needed.

P 117. Can cerebellar theta burst stimulation improve recovery of cerebellar stroke patients?

Ischemic cerebellar infarctions produce distinct clinical patterns including motor disturbances such as limb dysmetria, intention tremor, axial lateropulsion, and dysarthria. Repetitive transcranial magnetic stimulation (rTMS) might serve as an innovative tool to support functional recovery in stroke patients but has never been tested in patients with cerebellar stroke. The aim of the present study was to determine if excitatory repetitive transcranial magnetic stimulation protocol the “intermittent theta burst stimulation” (iTBS) applied over the lateral cerebellum on patients affected by cerebellar stroke could influence the plasticity of the cerebello-thalamo-cortical-circuits. Six chronic cerebellar stroke patients were submitted to two weeks of iTBS applied bilaterally over the cerebellum. All patients underwent magnetic resonance imaging (MRI) at 3T including T1-weighted volumes to reconstruct for each patient the damaged area. Before and after the iTBS treatment all patient were evaluated by the Modified International Cooperative Ataxia Rating Scale (MICARS), an useful tool for assessing and monitoring cerebellar motor function. Moreover, we explored the functional connectivity between the cerebellar hemisphere and the contralateral motor cortex (CBI), the intra-cortical inhibition (SICI) and intra-cortical facilitation (ICF) by means of paired-pulse TMS. We found that after two weeks of cerebellar iTBS was a decreased CBI at ISI = 5 ms and induced an increase of ICF at ISI = 15 ms. These neurophysiological changes were paralleled by clinical improvement as assessed by the MICARS scale. Among the sub-scales of the MICARS patients reported a clinical improvement ( p = 0.02 at t -test) of the posture and gait items, but not in the kinetic functions, speech disorders or oculomotor items. These preliminary results provide novel evidence that cerebellar TBS can be used to promote functional recovery of patients with cerebellar stroke. These clinical improvement could be related to long-lasting changes in the excitability of cerebello-thalamo-cortical pathways.

Pure psychiatric presentation of Fragile X‐associated tremor/ataxia syndrome

Fragile X syndrome is a leading cause of intellectual disability in childhood related to the presence of more than 200 repeats of CGG triplets in the FMR1 gene [1]. By contrast, premutation carriers (number of CGG triplets between 55 and 200) have normal development but are at high risk of developing in their late adulthood the so-called Fragile Xassociated tremor/ataxia syndrome (FXTAS) [2]. This syndrome is characterized by late-onset cerebellar ataxia and intention tremor often associated with executive dysfunction. Other frequent clinical manifestations are parkinsonism, psychiatric symptoms, peripheral neuropathy and lower limb weakness [2–4]. The case of a patient affected by FXTAS whose presentation was psychiatric, without tremor and without ataxia, is reported. A 66-year-old right-handed man was referred for behavioural disturbances. He had been in good health until 10 years ago when he presented a first major depressive episode that lasted several months under antidepressant drugs. Three years before admission, his wife began complaining of short lasting episodes of sudden irritability and aggressive behaviour. He was treated by tianeptin and bromazepam for ‘atypical’ depression, but the symptoms kept worsening. His wife became frightened to stay alone with him. Antipsychotic drugs were prescribed with partial efficacy. A few weeks before admission, the patient saw an ear, nose and throat specialist for brief episodes of vertigo. A benign paroxysmal positional vertigo was diagnosed and a brain MRI was systematically prescribed, which revealed symmetrical abnormalities in the cerebellum. The patient was referred to our neurological department. He was kind and alert. His speech was adapted and coherent. He had no particular complaint but admitted having difficulties controlling himself on some occasions. On examination, motor and sensory testing was unremarkable. He had no rest, postural or intention tremor in either hand. He had no truncal or segmental ataxia but a slightly wide-based gait. Tandem walking was possible. Muscle tone and oculomotor movements were normal. There was no dysarthria, sphincter disturbances or orthostatic hypotension. Mini-mental state examination score was 28/30. He performed the clock drawing test well but otherwise showed mild dysexecutive symptoms and reduction of speed processing. Evaluation by a psychiatrist revealed no personality disorder but some elements of delusional jealousy, without depressed mood. The aspect of brain MRI was that of global brain atrophy with large ventricles and typical hyperintense signal in both middle cerebellar peduncles (Fig. 1). The diagnosis of FXTAS was considered. Data about the patient’s family were scarce as they were living in Algeria. He was an only child, but his mother had two daughters and two sons from another marriage. One of his half-brothers had three daughters, one of whom had two sons with severe behavioural disturbances in childhood. The other one had two daughters, one of whom had a son with severe intellectual disability. Genetic testing with both PCR and southern blot methods confirmed a premutation in the FMR1 gene with 95 repeats of the CGG triplet. The potential links between FMR1 premutation and psychiatric comorbidities are under debate [5]. Here, the appearance after the age of 50 of atypical psychiatric symptoms strongly suggests a causal link with the presence of the premutation. More generally, physicians must pay attention to familial history of both psychiatric and neurological symptoms when facing late-onset atypical psychiatric symptoms. Because the prevalence of the Fragile X premutation is high in the general population (estimated around one in 813 in males and one in 259 in females [2]), general neurologists should be aware of this diagnosis. Genetic counselling does not only involve the patient but also his whole family, as his daughters are obligate carriers. This was particularly true in the present case, as two of his daughters were actively considering pregnancy.

Downbeat nystagmus as the initial manifestation of anti-NMDAR encephalitis

Downbeat nystagmus (DBN) is a rare neurological disorder characterized by slow upward drifts and fast downward phases [1]. In most cases no anatomical lesion is identified, whereas Arnold-Chiari malformation or spinocerebellar degeneration may underlie this condition [1]. AntiNMDAR (N-methyl-D-aspartate receptor) encephalitis rarely causes DBN [2]. Recently, we observed a young lady showing DBN as the sole initial manifestation. A 21-year-old lady presented with the 5-day history of dizziness that worsened gradually. On examination she had spontaneous DBN, which was occasionally overlapped with ocular flutter-like movement. Smooth pursuit was slightly saccadic, and during horizontal gaze horizontal nystagmus overlapped DBN. Eye movements were otherwise intact. She had no intentional tremor or dysmetria on finger-to-nose and heel-to-shin testing. However, her gait was wide-based and mildly unsteady. The remainder of her examination was normal. However, 4 days later, emotional lability and delirium manifested, gradually followed by involuntary movement (crawl swimming-like, myoclonic), mutism, and hyperpnea/apnea that eventually required mechanical ventilation (Fig. 1). Brain magnetic resonance imaging (MRI) on the admission day showed normal findings throughout the course of disease. Single-photon emission computed tomography (SPECT) on the third day showed decrease cerebral perfusion in the medial frontal cortex. An electroencephalography (EEG) was normal. Routine blood studies showed no abnormalities. Cerebrospinal fluid (CSF) analysis showed mildly increased cell count of 35/mm (mononuclear:polymorphonuclear = 32:3) and normal total protein. Viral antigens were all negative. Although survey for malignancies including ovary and paraneoplastic antibodies including anti-Hu, anti-Yo and anti-GAD was negative, she was suspected to have autoimmune encephalitis. Steroid pulse and high-dose intravenous immunoglobulin (IVIG) therapy was of limited benefit. However, anti-NMDAR antibodies in CSF appeared to be increased significantly. From the 37th day she underwent plasmapheresis, which ameliorated significantly her involuntary movement and mildly her level of consciousness. Repeated CT scans of the pelvis showed a 1.5 cm ovarian mass. On the 69th day she underwent tumor resection, which revealed a 14 mm * 13 mm mature teratoma. This surgery brought her to normal consciousness. Previously, DBN has been seldom reported in paraneoplastic encephalitis except for anti-Ma2 antibody encephalitis (one case) [3], anti-glutamate acid decarboxilase (GAD) antibody encephalitis (one case) [4], and anti-NMDAR encephalitis (one case) with upbeat nystagmus at the plateau stage under mechanical ventilation [2]. Our patient was unique in that she presented with DBN and dizziness as the sole initial manifestation. Experimental and functional neuroimaging studies indicated that DBN is caused by dysfunction of the vestibulocerebellum (flocculus, nodulus of cerebellar vermis) and, rarely, bilateral paramedian brainstem [1]. Although brainstem and cerebellum are not commonly Y. Tsuyusaki R. Sakakibara (&) M. Kishi F. Tateno Neurology, Internal Medicine, Sakura Medical Center, Toho University, 564-1 Shimoshizu, Sakura 285-8741, Japan e-mail: sakakibara@sakura.med.toho-u.ac.jp

Thalamic physiology of intentional essential tremor is more like cerebellar tremor than postural essential tremor

The neuronal physiological correlates of clinical heterogeneity in human essential tremor are unknown. We now test the hypothesis that thalamic neuronal and EMG activities during intention essential tremor are similar to those of the intention tremor which is characteristic of cerebellar lesions. Thalamic neuronal firing was studied in a cerebellar relay nucleus (ventral intermediate, Vim) and in a pallidal relay nucleus (ventral oral posterior, Vop) during stereotactic surgery for the treatment of tremor. Nine patients with essential tremor were divided clinically into two categories: one with a substantial component of tremor with intention (termed intention ET) and the other without (postural ET). These types of essential tremor were compared with patients having intention tremor plus other clinical signs of cerebellar disease (cerebellar tremor). Neurons in patients with either intention ET or cerebellar tremor had lower firing rates and lower spike×EMG coherence than those in patients with postural ET. Patients with intention ET had a lower spike×EMG phase lead than those with postural ET. Overall, thalamic activity measures of intention ET were different from postural ET but not apparently different from those of cerebellar tremor. One patient with the intention ET (number 4) had a good response to a left thalamotomy and then suffered a right cerebellar hemispheric infarct five years later. After the stroke the intention ET recurred, which is consistent with our hypothesis that intention ET is similar to that of the intention tremor which is characteristic of cerebellar lesions.