Pascal Grosse

Correlates of disability in multiple sclerosis detected by transcranial magnetic stimulation

Objective To study the usefulness of corticospinally mediated excitatory responses and transcallosal inhibition (TI) elicited by transcranial magnetic stimulation (TMS) as a surrogate marker of disability in patients with different courses of MS. Methods Focal TMS of the motor cortex was performed in 118 patients with MS (96 with relapsing-remitting, 19 with primary progressive, and three with secondary progressive disease) who had an Expanded Disability Status Scale (EDSS) score between 0 and 6.5 and in 35 normal subjects. Central motor latencies (CML) and TI (onset latency, duration) were investigated. The Spearman rank correlation was used for statistical analysis. Results TMS disclosed prolonged CML in 52.5% and abnormal TI in 61% of the patients. In all patients the EDSS correlated with the frequency of abnormal TI (r = 0.58, p < 0.01) and abnormal CML (r = 0.51, p < 0.01). In patients with primary progressive MS (EDSS 1.5 to 6.5) the frequency of TI abnormalities correlated with EDSS (r = 0.65, p < 0.01) whereas CML did not. Delayed corticospinal responses in hand muscles always led to abnormal TI. Conclusions The combination of central motor latencies and transcallosal inhibition evoked by transcranial magnetic stimulation yields objective data to estimate disease progression in MS as assessed by the EDSS.

Patterns of abnormal motor cortex excitability in atypical parkinsonian syndromes.

OBJECTIVE Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal-ganglionic degeneration (CBGD) are all clinically characterized by an akinetic-rigid syndrome together with a variety of additional signs. We hypothesised that these atypical parkinsonian syndromes (APS) will show distinctive patterns in their motor output upon transcranial magnetic stimulation (TMS) due to their different underlying anatomico-functional deficits. METHODS We performed single and paired-pulse TMS and assessed inhibitory and excitatory response parameters from the first dorsal interosseus muscles in 13 patients with MSA, 18 with PSP, 13 with CBGD, 15 patients with Parkinsons disease and 17 healthy subjects. RESULTS PSP and MSA patients had significantly enlarged response amplitudes at rest, reduced intracortical inhibition (ICI) and prolonged ipsi- and contralateral silent periods, whereas CBGD patients showed significantly increased motor thresholds, smaller response amplitudes at rest, shortened contralateral silent period, reduced transcallosal inhibition and a reduced ICI. In 22% of APS patients ipsilateral motor responses occurred in upper limb muscles irrespective of the underlying disease. CONCLUSIONS Our results indicate that motor cortex disinhibition is predominant in patients with PSP and MSA. In CBGD more severe neuronal cell loss in the motor cortex itself may lead to hypoexcitability of corticospinal and transcallosal pathways.

Patterns of EMG-EMG coherence in limb dystonia

Dystonia of the limbs may be due to a wide range of aetiologies and may cause major functional limitation. We investigated whether the previously described pathological 4 to 7 Hz drive to muscles in cervical dystonia is present in patients with aetiologically different types of dystonia of the upper and lower limbs. To this end, we studied 12 symptomatic and 4 asymptomatic carriers of the DYT1 gene, 6 patients with symptomatic dystonia due to focal basal ganglia lesions, and 11 patients with fixed dystonia, a condition assumed to be mostly psychogenic in aetiology. We evaluated EMG–EMG coherence in the tibialis anterior (TA) of these and 15 healthy control subjects. Ten of 12 (83%) of symptomatic DYT1 patients had an excessive 4 to 7 Hz common drive to TA, evident as an inflated coherence in this band. This drive also involved the gastrocnemius, leading to co‐contracting electromyographic bursts. In contrast, asymptomatic DYT1 carriers, patients with symptomatic dystonia, patients with fixed dystonia, and healthy subjects showed no evidence of such a drive or any other distinguishing electrophysiological feature. Moreover, the pathological 4 to 7 Hz drive in symptomatic DYT1 patients was much less common in the upper limb, where it was only present in 2 of 6 (33%) patients with clinical involvement of the arms. We conclude that the nature of the abnormal drive to dystonic muscles may vary according to the muscles under consideration and, particularly, with aetiology.

Corticospinal excitability in human sleep as assessed by transcranial magnetic stimulation

The excitability of the corticospinal system was studied in 23 healthy subjects in sleep stages NREM2, NREM4, REM, and wakefulness using transcranial magnetic stimulation. Assessment of motor thresholds, stimulus-response curves, and latencies of motor evoked potentials shows activation of the fast-conducting corticospinal fibers in all sleep stages and a neuronal recruitment pattern similar to wakefulness, however, at a lower level of excitability and with significant differences between sleep stages.

Inhibitory and excitatory intracortical circuits across the human sleep–wake cycle using paired-pulse transcranial magnetic stimulation

Studies using single‐pulse transcranial magnetic stimulation (TMS) have shown that excitability of the corticospinal system is systematically reduced in natural human sleep as compared to wakefulness with significant differences between sleep stages. However, the underlying excitatory and inhibitory interactions on the corticospinal system across the sleep–wake cycle are poorly understood. Here, we specifically asked whether in the motor cortex short intracortical inhibition (SICI) and facilitation (ICF) can be elicited at all in sleep using the paired‐pulse TMS protocol, and if so, how SICI and ICF vary across sleep stages. We studied 28 healthy subjects at interstimulus intervals of 3 ms (SICI) and 10 ms (ICF), respectively. Magnetic stimulation was performed over the hand area of the motor cortex using a focal coil and evoked motor potentials were recorded from the contralateral first dorsal interosseus muscle (1DI). Relevant data was obtained from 13 subjects (NREM 2: n= 7; NREM 3/4: n= 7; REM: n= 7). Results show that both SICI and ICF were present in NREM sleep. SICI was significantly enhanced in NREM 3/4 as compared to wakefulness and all other sleep stages whereas in NREM 2 neither SICI nor ICF differed from wakefulness. In REM sleep SICI was in the same range as in wakefulness, but ICF was entirely absent. These results in humans support the hypothesis derived from animal experiments which suggests that intracortical inhibitory mechanisms are involved in the control of neocortical pyramidal cells in NREM and REM sleep, but along different intraneuronal circuits. Further, our findings suggest that cortical mechanisms may additionally contribute to the inhibition of spinal motoneurones in REM sleep.

Evaluation of carisbamate, a novel antiepileptic drug, in photosensitive patients: an exploratory, placebo-controlled study.

PURPOSE Carisbamate, a novel neuromodulatory agent with antiepileptic properties, was evaluated in patients with photoparoxysmal responses to intermittent photic stimulation (IPS) in this multicenter, non-randomized, single-blind, placebo-controlled, proof-of-concept study. METHODS Eighteen Caucasian patients (14 females, 4 males) with a mean age of 30 years (range: 16-51 years) underwent standardized IPS under three eye conditions (during eye closure, eyes closed and eyes open) at hourly intervals for up to 8h after receiving placebo (Day 1), carisbamate (Day 2) and placebo (Day 3). Carisbamate was given at single doses of 250-1000 mg. All patients received one or two concomitant antiepileptic drugs, most commonly valproate. RESULTS Carisbamate produced a dose-dependent reduction in photosensitivity in the 13 evaluable patients, with abolishment of photoparoxysmal responses in 3 patients and clinically significant suppression of such responses in 7 additional patients. Photosensitivity was abolished or reduced in all five patients in the 1000-mg dose group. The onset of carisbamate occurred rapidly, with clinically significant suppression achieved before or near the time peak plasma drug levels were reached. The duration of action was dose-related and long-lasting, with clinically significant reductions of photosensitivity observed for up to 32 h after doses of 750 or 1000 mg. Carisbamate was generally well tolerated, with dizziness and nausea reported more frequently after active drug than placebo. CONCLUSION This study shows that carisbamate exhibits dose-related antiepileptic effects in the photosensitivity model. Randomized, controlled studies of carisbamate in epilepsy patients inadequately controlled by their existing AED therapy are warranted.

MRI study of human brain exposed to high-dose repetitive magnetic stimulation of visual cortex

Article abstract T1-, T2-, and diffusion-weighted MRI was used to determine whether repetitive transcranial magnetic stimulation (rTMS) affects the blood–brain barrier or induces localized brain edema. In 11 healthy individuals, 1,200 to 3,800 stimuli were applied over the visual cortex of one hemisphere in series of 5-, 10-, or 20-Hz stimulus trains. MRI performed 6 minutes to 6 hours after rTMS did not show pathologic changes in conventional MRI sequences, after application of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA), or by determining apparent diffusion coefficients.

Coherence analysis in the myoclonus of corticobasal degeneration

We investigated whether myoclonus in corticobasal degeneration (CBD) is cortical or subcortical in origin. Many authors have suggested that the myoclonus in CBD is a subtype of cortical myoclonus, despite the fact that back‐averaging fails to detect a cortical correlate to spontaneous or action induced jerks and giant sensory evoked potentials are seldom found. Electroencephalographic–electromyographic (EEG–EMG) and EMG–EMG frequency analysis may be more sensitive to cortical drives when EMG bursts occur at a high frequency and at low amplitudes as in CBD. We evaluated EEG–EMG and EMG–EMG coherence and phase in 5 patients with clinically probable CBD and unilateral, action‐induced and stimulus‐sensitive myoclonus. We found negligible corticomuscular coherence despite a dramatically exaggerated EMG–EMG coherence. We conclude that an inflated EMG–EMG coherence is found in some patients with CBD and that this is unlikely to be due to an exaggerated cortical drive.

ACOUSTIC SLEEP STARTS WITH SLEEP-ONSET INSOMNIA RELATED TO A BRAINSTEM LESION

Sensory sleep starts are variants of the more common motor sleep starts (hypnic jerks).1 Though sensory sleep starts may lead to repeated awakenings resulting in sleep-onset insomnia, their course is usually benign and no cerebral lesion has yet been described as being pathogenetically involved. Here we report a case of acoustic sleep starts (“exploding head syndrome”) which contests this latter assertion because their onset coincided with the occurrence of a brainstem lesion. ### Case report. A 64-year-old woman reported on problems initiating sleep related to the impression of a cracking sound of average loudness. Up to 15 times during the first hours after going to bed this sound occurred shortly after losing full consciousness, followed by an experience of jerking in all four limbs and a brief sensation of fear leading to full wakefulness. The patient, who had been healthy until then, noticed her sleep problem for the first time 12 years ago, coinciding with the diagnosis of pulmonary and extrapulmonary sarcoidosis. Corticosteroids were instituted under which no further progression of sarcoidosis occurred, even when steroids were tapered. Over this period the patient’s sleep problem was waxing and waning in intensity. Treatment with doxepin, citalopram, trimipramine, and amitriptyline led to no improvement. Only bromazepam (6 mg/day, 8 weeks) instantly led to unhampered sleep. Successive MRI scans of the brain (figure, A and B) revealed an unchanging, nonenhancing, singular, symmetric T2-hyperintense pontomesencephalic lesion around the periaquaductal gray reaching into the tegmentum. Figure MRI …

Paraneoplastic stiff-person syndrome: No tumor progression over 5 years

Stiff-person syndrome (SPS) is a rare disorder characterized by progressive stiffness of predominantly axial and proximal limb muscles, and painful spasms that are often precipitated by startle, emotional, and tactile stimuli.1 Evidence for an autoimmune pathogenesis has been derived from the detection of autoantibodies against glutamic acid decarboxylase in serum and CSF in up to 90% of SPS cases.2,3⇓ In occasional cases, SPS is considered to be of paraneoplastic origin, with amphiphysin being presumably the most common autoantigen.4,5⇓ Three years …