A clinical and neurophysiological motor signature of Unverricht-Lundborg disease.

OBJECTIVES: Unverricht-Lundborg disease (ULD) is the most common form of progressive myoclonus epilepsy. Cerebellar dysfunction may appear over time, contributing along with myoclonus to motor disability. The purpose of the present work was to clarify the motor and neurophysiological characteristics of ULD patients. METHODS: Nine patients with genetically proven ULD were evaluated clinically (medical history collected from patient charts, the Scale for the Assessment and Rating of Ataxia and Unified Myoclonus Rating Scale). Neurophysiological investigations included EEG, surface polymyography, long-loop C-reflexes, somatosensory evoked potentials, EEG jerk-locked back-averaging (JLBA) and oculomotor recordings. All patients underwent brain MRI. Non-parametric Mann-Whitney tests were used to compare ULD patients' oculomotor parameters with those of a matched group of healthy volunteers (HV). RESULTS: Myoclonus was activated by action but was virtually absent at rest and poorly induced by stimuli. Positive myoclonus was multifocal, often rhythmic and of brief duration, with top-down pyramidal temporospatial propagation. Cortical neurophysiology revealed a transient wave preceding myoclonus on EEG JLBA (n=8), enlarged somatosensory evoked potentials (n=7) and positive long-loop C-reflexes at rest (n=5). Compared with HV, ULD patients demonstrated decreased saccadic gain, increased gain dispersion and a higher frequency of hypermetric saccades associated with decreased peak velocity. CONCLUSION: A homogeneous motor pattern was delineated that may represent a ULD clinical and neurophysiological signature. Clinical and neurophysiological findings confirmed the pure cortical origin of the permanent myoclonus. Also, oculomotor findings shed new light on ULD pathophysiology by evidencing combined midbrain and cerebellar dysfunction.

Switching between two targets with non-constant velocity profiles reveals shared internal model of target motion.

Several experiments have shown that smooth pursuit and saccades interact while tracking an object moving across the visual scene. It was proposed two decades ago that the amplitude of saccades triggered during smooth pursuit ('catch-up saccades') were corrected by a delayed sensory signal to account for the ongoing target displacement during catch-up saccades. However, recent studies used targets with non-constant velocity profiles and suggested that the correction of catch-up saccade amplitude must be done through an internal model of target motion. It is widely accepted that an internal model of target motion is also used by the central nervous system (CNS) to cancel inherent delays between visual input and smooth pursuit motor output, ensuring accurate tracking of moving targets. Our study proposes a new paradigm in which the target switches unexpectedly from one target with a non-constant periodic velocity profile to another with a non-constant aperiodic velocity profile. Our results confirm the hypothesis that the CNS uses an internal model of target motion to correct catch-up saccade amplitude. In addition, we reconcile the sensory delayed and the internal model of target motion hypotheses and show that a common internal model of target motion is shared within the CNS to control smooth pursuit and to correct catch-up saccade amplitude.

To jerk or not to jerk: A clinical pathophysiology of myoclonus.

Myoclonus is a sudden brief (20-250 ms) contraction (positive myoclonus), or a brief and sudden cessation of tonic muscle (negative myoclonus) inducing a simple jerky movement of body part. Myoclonus could have different origins in almost every part of the nervous system, from the cortex to the peripheral nerve, sharing a large panel of etiologies. It is regarded as the paradigmatic movement disorder causing jerks, although not the sole. This paper aims to depict the clinical and neurophysiological characteristics of myoclonus. It shows how neurophysiological investigations including surface polymyography and methods exploring cortical excitability, namely conventional EEG, EEG - jerk-locked back-averaging, somatosensory evoked potentials and C-reflex studies are required to define the generator of myoclonus in the central nervous system and clearly classify myoclonus as cortical, corticothalamic, subcortical - resulting from lesions or dysfunctions of basal ganglia/reticular system - or spinal. This paper also enlightens other movement disorders that may mimic myoclonus appearances, including psychogenic jerks, simple motor tics, spasms and startle syndromes. Finally, it raises few unresolved questions regarding the propriospinal myoclonus or peripheral myoclonus entities, the role of the cerebellum in myoclonic diseases and the relationship between cortical and epileptic myoclonus.

Clinical neurophysiology of psychogenic movement disorders: how to diagnose psychogenic tremor and myoclonus.

Tremor and myoclonus are very common manifestations of psychogenic movement disorders (PMD). In this context, recording of movement disorders aims to provide objective criteria for a positive diagnosis of PMD, independently of the psychological situation. Neurophysiological observations are therefore considered to have a huge impact both on diagnosis and on therapeutic approaches. A specific recording strategy should be employed whenever the medical history or clinical clues raise the eventuality of a PMD. Polymyography coupled to accelerometry is used to demonstrate the major electrophysiological criteria of psychogenic tremor, namely spontaneous variability of tremor frequency and frequency entrainment induced by contralateral rhythmic tasks. Other features, such as paradoxical increase of tremor amplitude with mass loading, co-activation preceding tremor onset and alteration of voluntary contralateral motor performances when tremor is present, are also of interest. The clinical presentation of psychogenic myoclonus is extremely rich and polymorphous and can mimic virtually all forms of cortical, subcortical or spinal myoclonus. Focal, multifocal, axial or generalized jerks can occur. Psychogenic jerks can be sporadic or repetitive, rhythmic or arrhythmic, spontaneous or stimulus-induced. All of these parameters are crucial to determine an individualized neurophysiological strategy. Polymyography is critical to identify a ballistic pattern or a discordant or non-reproducible temporo-spatial organisation of the jerks, but has usually to be completed by other potentially decisive approaches. Reflex psychogenic myoclonus for example displays stimulus-response delays that are too long and variable. Spontaneous psychogenic jerks may be also preceded by a pre-movement potential, detectable by jerk-locked-back-averaging methods.

Cerebellar rTMS stimulation may induce prolonged clinical benefits in essential tremor, and subjacent changes in functional connectivity: an open label trial.

BACKGROUND: Cerebello-thalamo-cortical (CTC) pathways dysfunction is involved in pathological oscillations causing tremor in essential tremor (ET). Low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of the cerebellum can effectively modulate the cerebellar output. OBJECTIVE: As one session of rTMS can induce a brief improvement, we hypothesized that repeated sessions might have a cumulative and potentially long-term therapeutic effect on ET. We assessed, in an open label trial, the efficacy of one-week rTMS treatment on tremor and on the motor-CTC dysfunction in ET patients. METHODS: Resting-state fMRI functional connectivity was used as an indicator of CTC network integrity in 11 ET patients and 11 healthy subjects. Resting-state fMRI connectivity was quantified at baseline in patients and control subjects between the cerebellum and the motor network, and between the cerebellum and the default brain network (DBN) taken as control. The fMRI study was repeated in patients after 5 days of bilateral 1 Hz rTMS applied to the posterior cerebellar cortex. Tremor was assessed clinically (Fahn-Tolosa-Marin scale) and quantified using electromyographic and accelerometric recordings at baseline (day 1, before the cerebellar stimulation) and after the end of the cerebellar stimulation period at day 5, day 12 and day 29. RESULTS: Repeated rTMS over the cerebellum significantly improved total and specific (tremor, drawing, functional disability) scores, and reduced tremor amplitude (P < 0.006). It also re-established the defective information processing in the CTC network (P(Δ|y) > 0.909), but not in the DBN. The effects persisted for 3 weeks after the last session. CONCLUSION: Cerebellar stimulation could be an effective treatment option for patients with severe essential tremor.

Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p.

BACKGROUND: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by autosomal dominant adult-onset cortical myoclonus (CM) and seizures in 40% of patients. Two loci, 8q23.3-q24.11 (FAME1/FCMTE1) and 2p11.1-q12.2 (FAME2/FCMTE2), were previously reported without an identified gene. Unlinked families argue for a third mutated gene. METHODS: A genome-wide scan was performed in a large FCMTE family using Linkage-12 microarrays (Illumina). Refinement of the locus on 5p was performed by genotyping 13 polymorphic microsatellite markers in the 45 available family members. RESULTS: This large French FCMTE family included 16 affected relatives. The first symptoms were CM in 5 patients (31.2%), seizures in 5 patients (31.2%), and both at the same time in 6 patients (37.5%). A total of 12.5% (2/16) had only CM without seizures. The genome-wide scan identified a single region on 5p15.31-p15, with a multipoint lod score of 3.66. Further genotyping of all family members confirmed that the region spans 9.31 Mb between D5S580 and D5S2096, 2-point lod scores reaching 6.3 at theta = 0 for D5S486. Sequencing of the SEMA5A and CTNND2 genes failed to detect mutations. CONCLUSIONS: We report the clinical and genetic characteristics of a large familial cortical myoclonic tremor with epilepsy family. The third gene maps to 5p15.31-p15. Identification of the mutated gene is ongoing.

Familial cortical myoclonic tremor with epilepsy (FCMTE): Clinical characteristics and exclusion of linkages to 8q and 2p in a large French family.

INTRODUCTION: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by an autosomal-dominant inheritance, adult onset of myoclonus of the extremities, infrequent epileptic seizures, a non-progressive course, polyspikes on electroencephalography (EEG), photosensitivity, giant somatosensory-evoked potentials (SEP), enhancement of C-reflex and a premyoclonus spike detected by jerk-locked EEG back-averaging. Two genes yet to be identified are mapped to 8q23.3-q24.1 and 2p11.1-q12.2. METHODS: The present study involved five generations of a French family presenting with FCMTE, including 76 family members. Clinical analyses were performed in 39 living subjects and electrophysiological studies in five patients. Altogether, 27 relatives (21 living and six deceased) had the clinical characteristics of FCMTE, 17 of whom were analyzed. Linkage analyses were performed with microsatellites encompassing the two known loci (8q 23.3-q24.1 and 2p11.1-q12.2). RESULTS: Mean age at onset in the 17 living patients was 28.8 years (range 24-41). All had myoclonus/cortical tremor, and 11/17 had generalized tonic-clonic seizures. Other clinical symptoms were photosensitivity (16 cases), partial seizures (five cases), sensitivity to starvation/exercise (six cases) and vibration (four cases), ophthalmic migraine (six cases) and gait disorders (10 cases). Electrophysiological studies confirmed the FCMTE diagnosis in the five studied patients. Of the remaining relatives, 14 were considered healthy (asymptomatic subjects aged more than 40years) and eight were of unknown status (asymptomatic aged lesser than 40years). The pattern of inheritance was consistent with autosomal-dominant inheritance, although the two loci responsible for FCMTE were excluded. CONCLUSION: This large family highlights some unusual clinical characteristics and suggests the presence of a third gene. Genetic research is ongoing to identify the mutated gene.

Propriospinal myoclonus revisited: Clinical, neurophysiologic, and neuroradiologic findings.

OBJECTIVE: The literature on propriospinal myoclonus (PSM) is poor and there are no systematic reviews of the subject. We sought to clarify the spectrum of PSM. METHODS: We first prospectively investigated all patients seen in our movement disorders clinic with a firm diagnosis of PSM between 2002 and 2007. All had a standardized interview, detailed clinical examination, laboratory investigations, comprehensive neurophysiologic examination, and spinal cord MRI, including diffusion tensor imaging with fiber tracking (DTI-FT). We also collected drug responses. Finally, we conducted a systematic review of the literature. RESULTS: We enrolled 10 patients meeting the strict criteria for PSM, and also analyzed data on 50 patients from 26 previous reports. PSM occurred predominantly in male and middle-aged patients. The typical clinical picture consisted of myoclonic jerks consistently involving abdominal wall muscles, which worsen in the lying position. A premonitory sensation preceding the jerks and wake-sleep transition phase worsening were frequent. Most patients had a myoclonic generator at the thoracic level, with a myoclonus duration between 200 msec and 2 s. An underlying cause was infrequently found. DTI-FT detected cord abnormalities all of our patients. CONCLUSION: The clinico-physiologic spectrum of propriospinal myoclonus (PSM) is homogenous. Involvement of the abdominal wall muscles, worsening in the lying position, premonitory sensation, and wake-sleep transition phase worsening are helpful clinical clues. Diffusion tensor imaging with fiber tracking appears more sensitive than conventional MRI for detecting associated microstructural abnormalities of the spinal cord. Symptomatic treatment of PSM is not straightforward, and clonazepam is reported to be the most effective drug. Zonisamide may be an interesting option.

Stromal-cell-derived factor 1alpha /CXCL12 modulates high-threshold calcium currents in rat substantia nigra.

Dopaminergic neurons of the substantia nigra constitutively express the CXCR4 receptor for the chemokine stromal-cell-derived factor 1alpha (CXCL12) but, to date, no direct effect of CXCR4 activation by CXCL12 on membrane conductance of dopaminergic neurons has been demonstrated. We tested the effects of CXCL12 on whole-cell currents of dopaminergic neurons recorded in patch clamp in substantia nigra slices and showed that CXCL12 (0.01-10 nm) increased the amplitude of total high-voltage-activated (HVA) Ca currents through CXCR4 activation. This effect was reversibly reduced by varpi-conotoxin-GVIA, suggesting that CXCL12 acted on N-type Ca currents, known to be involved in dopamine (DA) release. We therefore investigated the effects of CXCL12 on DA release from cultured dopaminergic neurons from the rat mesencephalon. In basal conditions, CXCL12 alone had no effect on DA release. When neurons were depolarized with KCl (20 mm), and thus when HVA Ca currents were activated, low CXCL12 concentrations (1-50 nm) increased DA release via CXCR4 stimulation. These data strongly suggest that the chemokine CXCL12 can act directly as a neuromodulator of dopaminergic neuronal electrical activity through the modulation of HVA currents.

[Dystonia, tremor and repetitive instrumental use]. / Dystonies et tremblements d'utilisation instrumentale répétitive.

Three characteristic observations are presented along with three tables presenting 24 patients with the following elements in common: excessively repeated use of an instrument such as a pen, a musical instrument or a tool. The appearance after that use of a central pathological phenomenon that includes a local dystonia of a hand or the mouth, a tremor, or the association of a tremor and a dystonia, all within the muscular domain corresponding to that of the use. The discussion, which is based exclusively on the clinical findings, deals with the following elements: the role of the use of the instrument rather than task itself, the predominant pathogenic factor which is the repetitive action, to which is added a genetic component in one incompletely penetrant case of DYT 1, and a probable genetic susceptibility in the others. The absence of improvement with rest distinguishes this central pathology from rheumatologic or orthopaedic problems involving repetitive activities. The evolution is slowly declining when the responsible action is continued. This occurs in three stages: a specific disorder involving only the use of the particular instrument, a more enlarged involvement affecting other activities and eventually a dystonia associated with a tremor or a postural tremor always located to the initial area. The therapeutic interventions suggested by the pathologic role of the repetitive movement is: (1) to advise a new training for the instrument that excludes the habitual movement; (2) to advise the patient to vary any newly acquired repetitive movements.

Myoclonus-dystonia: clinical and electrophysiologic pattern related to SGCE mutations.

OBJECTIVE: To clarify the clinical and neurophysiologic spectrum of myoclonus-dystonia patients with mutations of the SGCE gene. METHODS: We prospectively studied 41 consecutive patients from 22 families with documented mutations of the SGCE gene. The patients had a standardized interview, neurologic examination, and detailed neurophysiologic examination, including surface polymyography, long-loop C-reflex studies, and EEG jerk-locked back averaging. RESULTS: We noted a homogeneous electrophysiologic pattern of myoclonus of subcortical origin with short jerks (mean 95 msec, range 25 to 256 msec) at rest, during action, and during posture; there were no features of cortical hyperexcitability (specifically no abnormal C-reflex response and no short-latency premyoclonic potential on back-averaging studies). Myoclonus was either isolated or associated with mild to moderate dystonia, and predominated in the neck/trunk or proximal upper limbs in most cases. We found that 22% of the patients had a spontaneous improvement in their dystonia before reaching adulthood and that hypotonia can occasionally be a presenting symptom of the disorder. CONCLUSION: We describe the myoclonus in patients with mutations in the SGCE gene and characterize the electrophysiologic pattern of this myoclonus. This pattern may help to improve the sensitivity of molecular tests and to define homogeneous populations suitable for inclusion in therapeutic trials.

The chemokine stromal cell-derived factor-1/CXCL12 activates the nigrostriatal dopamine system.

We recently demonstrated that dopaminergic (DA) neurons of the rat substantia nigra constitutively expressed CXCR4, receptor for the chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 (SDF-1). To check the physiological relevance of such anatomical observation, in vitro and in vivo approaches were used. Patch clamp recording of DA neurons in rat substantia nigra slices revealed that SDF-1 (10 nmol/L) induced: (i) a depolarization and increased action potential frequency; and (ii) switched the firing pattern of depolarized DA neurons from a tonic to a burst firing mode. This suggests that SDF-1 could increase DA release from neurons. Consistent with this hypothesis, unilateral intranigral injection of SDF-1 (50 ng) in freely moving rat decreased DA content and increased extracellular concentrations of DA and metabolites in the ipsilateral dorsal striatum, as shown using microdialysis. Furthermore, intranigral SDF-1 injection induced a contralateral circling behavior. These effects of SDF-1 were mediated via CXCR4 as they were abrogated by administration of a selective CXCR4 antagonist. Altogether, these data demonstrate that SDF-1, via CXCR4, activates nigrostriatal DA transmission. They show that the central functions of chemokines are not restricted, as originally thought, to neuroinflammation, but extend to neuromodulatory actions on well-defined neuronal circuits in non-pathological conditions.

[Primary orthostatic tremor]. / Le tremblement orthostatique primaire.

INTRODUCTION: Tremor is frequent in neurologic practice but primary orthostatic tremor was first described in 1984. Its prevalence accounts for around 4% for tremors explored in neurophysiology; in contrast, essential and parkinsonian tremors represent respectively 28 and 22% of these cases. EXEGESIS: Orthostatic tremor is characterized by its appearance while standing. Walking, sitting, and lying down are unaffected. Clinical examination is normal except for unsteadiness disappearing when walking. Surface electromyography in the standing position is necessary for the diagnosis and shows a regular rapid tremor (frequency around 14 to 18 Hz). Its pathophysiology is unknown. CONCLUSION: Clonazepam is the first-line treatment for orthostatic tremor. In cases of resistance or side effects of this drug orthostatic tremor may be improved by primidone or, as in our case, gabapentin.

Fast orthostatic tremor in Parkinson's disease mimicking primary orthostatic tremor.

Leg tremor during standing is a rare feature in idiopathic Parkinson's disease (PD). Tremor during standing usually has a low frequency (range, 4-6 Hz), similar to PD rest tremor frequency, and is improved by levodopa. We describe three cases of fast orthostatic tremor (FoT) of legs and trunk mimicking primary orthostatic tremor (OT) in patients treated with levodopa for PD. Asymmetrical akinetorigid syndrome was accompanied by a rest tremor in two cases. We obtained electrophysiological parameters by electromyographic (EMG) polygraphic recording after 16 hours withdrawal of antiparkinsonian treatment and at the maximal effect of levodopa in order to investigate the effect of dopaminergic stimulation upon such cases of orthostatic tremor in PD. Electrophysiological parameters of orthostatic tremor, especially frequency (range 14-18 Hz), were similar to that seen in POT. Severity of tremor was independent of seriousness and duration of PD. Levodopa had no effect either on the handicap due to OT or on the amplitude and frequency of the EMG OT activity. In contrast, mild improvement of OT was obtained with benzodiazepines in two cases and parkinsonian syndrome was levodopa-sensitive. These findings suggest that FoT in PD would not be directly controlled by the dopaminergic system. However, increased rhythmicities in basal ganglia or in cerebello-thalamic loops at the rapid frequencies range seen in PD could favor the emergence of a primary orthostatic tremor-like tremor in PD patients.

Age-related changes in rhythmically bursting activity in the medial septum of rats.

The effects of aging on the firing of septohippocampal neurons were estimated in unanesthetized, restrained young, old and very old rats (respectively 3, 23 and 30 months). Extracellular recordings were obtained during various states of arousal. The mean spontaneous activity for the overall neuronal population was not modified by aging. In contrast, the percentage of rhythmically bursting neurons was significantly lower in aged rats. During wakefulness, decrease of bursting activity was observed in old and very old rats (P<0.01 and P<0.001) whereas during rapid eye movement sleep it appeared only in the oldest group (P<0.01). The frequency of the bursts decreased in 30-month-old rats during wakefulness while it remained unchanged in both aged groups during rapid eye movement sleep. In old rats, at a time when the cholinergic septal neurons already deteriorated, a third of neurons recorded during rapid eye movement sleep exhibited a pattern of activity composed of long duration bursts with higher intraburst frequency than in young or very old rats. Our study shows that rhythmically bursting septal activity is impaired in aged rats and that the amplitude of the changes depends on advancing age and on states of arousal. Our findings suggest that age-induced loss and atrophy of cholinergic septal neurons contribute to the disorganization of the rhythmic activity but that functional alterations, influenced by the states of arousal, may also be considered.

Loss of rhythmically bursting neurons in rat medial septum following selective lesion of septohippocampal cholinergic system.

The medial septum contains cholinergic and GABAergic neurons that project to the hippocampal formation. A significant proportion of the septohippocampal neurons (SHN) exhibit a rhythmically bursting (RB) activity that is involved in the generation of the hippocampal theta rhythm. The neurochemical nature of septal RB neurons is not firmly established. To address this question, the septal unit activity has been recorded in rats after selective destruction of the cholinergic septal neurons by the immunotoxin 192 IgG-saporin. Experiments have been performed in urethan-anesthetized and unanesthetized rats, 14-21 days after lesion. Acetylcholinesterase (AChE) histochemistry revealed a near-complete loss of cholinergic septal neurons and of cholinergic fibers in the hippocampus. The recorded neurons were located in the medial septum-diagonal band of Broca area. A number of these neurons were identified as projecting to the hippocampus (SHN) by their antidromic response to the electrical stimulation of the fimbria-fornix. In urethan-anesthetized lesioned rats, the percentage of RB neurons decreased significantly as compared with controls (17 vs. 41% for SHNs and 5 vs. 19% for unidentified septal neurons). The axonal conduction velocity and the burst frequency of the SHNs that retained a RB activity were higher in lesioned as compared with control rats. The number of spikes per burst was lower and the burst duration was shorter in lesioned rats as compared with controls. The urethan-resistant hippocampal theta was altered both in terms of frequency and amplitude. In unanesthetized lesioned rats, no RB septal neurons were found during arousal, as compared with 25% in controls. Their number was also markedly reduced during paradoxical sleep (9.7 vs. 38.5%). Histochemistry in 192 IgG-saporin-treated rats showed that RB neurons were found in areas devoid of AChE-positive neurons but containing parvalbumine-positive (presumably GABAergic) neurons. These data show that RB activity is considerably reduced after selective lesion of the cholinergic medial septal neurons. They suggested that the large majority of the RB septal neurons are cholinergic and that the few neurons that display RB activity in lesioned rats are GABAergic.

Immunolesion of the cholinergic basal forebrain: effects on functional properties of hippocampal and septal neurons.

Deficits in cholinergic function have been documented in a variety of brain disorders including Alzheimer's Disease and, to a lesser extent, in normal ageing. In the present article, we have reviewed our recent findings on the effects of the loss of basal forebrain cholinergic neurons on the functional properties of the septohippocampal pathway. In vivo and ex vivo investigations were performed in rats following basal forebrain cholinergic lesion with the specific immunotoxin 192 IgG-saporin. Our results suggest a significant contribution of cholinergic neurons in the rhythmically bursting activity recorded within the medial septum. In addition, they give evidence that acetylcholine may tonically decrease the glutamatergic synaptic responses in the hippocampus whereas the GABAergic mediated inhibitory potentials are not affected. The possible contribution of these cholinergic mechanisms in the age-related functional alterations of the septohippocampal activity is discussed.