Marc Bataillard

PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine

ABSTRACT Objective: Whole genome sequencing and the screening of 103 families recently led us to identify PRRT2 (proline-rich-transmembrane protein) as the gene causing infantile convulsions (IC) with paroxysmal kinesigenic dyskinesia (PKD) (PKD/IC syndrome, formerly ICCA). There is interfamilial and intrafamilial variability and the patients may have IC or PKD. Association of IC with hemiplegic migraine (HM) has also been reported. In order to explore the mutational and clinical spectra, we analyzed 34 additional families with either typical PKD/IC or PKD/IC with migraine. Methods: We performed Sanger sequencing of all PRRT2 coding exons and of exon-intron boundaries in the probands and in their relatives whenever appropriate. Results: Two known and 2 novel PRRT2 mutations were detected in 18 families. The p.R217Pfs*8 recurrent mutation was found in ≈50% of typical PKD/IC, and the unreported p.R145Gfs*31 in one more typical family. PRRT2 mutations were also found in PKD/IC with migraine: p.R217Pfs*8 cosegregated with PKD associated with HM in one family, and was also detected in one IC patient having migraine with aura, in related PKD/IC familial patients having migraine without aura, and in one sporadic migraineur with abnormal MRI. Previously reported p.R240X was found in one patient with PKD with migraine without aura. The novel frameshift p.S248Afs*65 was identified in a PKD/IC family member with IC and migraine with aura. Conclusions: We extend the spectrum of PRRT2 mutations and phenotypes to HM and to other types of migraine in the context of PKD/IC, and emphasize the phenotypic pleiotropy seen in patients with PRRT2 mutations.

Cannabis-related Stroke Myth or Reality?

Cannabis, which is the most widely used recreational substance in the world, is considered by many consumers as safe with few negative side effects.1 This opinion is somehow strengthened by the fact that cannabis was also shown to have therapeutic applications.2 Cannabis is obtained from the plant Cannabis sativa and its varieties Cannabis indica and Cannabis americana .3 The 2 main preparations derived from cannabis are marijuana and hashish.2 The principal psychoactive cannabinoid in cannabis is delta 9 tetrahydrocannabinol4, and the potency of different preparations of cannabis that relates to tetrahydrocannabinol content is extremely variable.3 The plasma half-life of tetrahydrocannabinol isμ56 hours in occasional users and 28 hours in chronic users.5 Psychopharmacological acute effects associated with cannabis use are euphoria, increased self-confidence, relaxation, and a general sense of well being.3 Except for nausea associated with cancer chemotherapy, most of the potential beneficial effects are not approved by many administrations around the world. Indeed, the more common effects described as beneficial are glaucoma, analgesia, appetite in AIDS patients, tremor, Parkinson disease, spasticity in multiple sclerosis, epilepsia, anxiolytic, or antidepressive actions.1,3 However, several important negative side effects associated with cannabis are also observed. Indeed, in selected patients, acute psychiatric and behavioral abnormalities, such as anxiety, panic, and attentional abnormalities, have been reported.3,6 Risk of psychotic disorders or symptoms is higher in regular users of cannabis.6 Furthermore, psychological and physical dependence are described as chronic effects of cannabis use.6 As for other drugs, cannabis withdrawal syndrome, including anxiety, depressed mood, and sleep difficulties, may occur in heavy users on cessation.6,7 Also, somatic negative effects, such as cardiovascular complications (myocardial infarction, ventricular tachycardia, and sudden death), peripheral events (peripheral arteritis and kidney infarction), and …

Stroke Mimics in a Stroke Care Pathway Based on MRI Screening.

Background: Since the use of tissue plasminogen activator for acute ischemic stroke (IS), stroke care pathways have been developed for patients with suspicion of acute stroke. The aim of this prospective observational study was to analyze the stroke mimic (SM) characteristics in patients who were part of our stroke care pathway. Methods: All consecutive patients admitted in the code stroke within a 1-year period were prospectively enrolled in this study. Patients with a sudden onset of neurological focal deficit in a time window less than 4H30 as indicated for intravenous thrombolysis, had been accepted in the pathway by a neurologist who was directly contactable by the prehospital emergency medical service 24 h per day. Patients arrived directly on the MRI site without passing by the emergency department. A clinical neurological evaluation and a brain MRI with tri-dimensional time-of-flight magnetic resonance angiography were performed. The FAST score was calculated a posteriori. The final discharge diagnosis was concluded either immediately after both neurological examination and cerebrovascular neuroimaging or after other relevant investigations. We classified the discharge diagnosis into neurovascular diseases (NVDs) and into SM. Results: There were 1,361 consecutive patients admitted for suspicion of acute stroke. Sixty-two percent (n = 840) had an NVD including IS (n = 529), transient ischemic attacks (n = 236), intracranial hemorrhages (n = 68), cerebral venous thrombosis (n = 3) and neurovascular medullar pathologies (n = 4). SM represented 38% of cases (n = 521) and the most frequent discharge diagnosis was defined as headaches (18.6%), psychological disorders (16.7%), peripheral vertigo (11.9%) and epilepsy (10.6%). The comparison between the characteristics of the NVD and those of the SM groups showed some significant differences: in the SM group, women were more represented, patients were younger and the NIHSS was lower than in the NVD group. All cardiovascular risk factors were more represented in the NVD group. Concerning the symptoms, motor deficit, speech disturbances, homonymous lateral hemianopia and head and gaze deviation were more represented in the NVD group, whereas vertigo, non-systematized visual trouble, headache, confusion, weakness, neuropsychological symptoms, seizure and chest pain were significantly more frequent in the SM group. The negative predictive value of the FAST score was 64% and the positive predictive value was 76%. Conclusions: A rate of SM up to 38% of the code stroke system confirms the difficulty to distinguish clinically a stroke from another diagnosis. In this study, using cerebral MRI in first intention was of special interest in patients with acute neurological symptoms to differentiate an NVD from an SM.

Pompe disease presenting as an isolated generalized dilative arteriopathy with repeated brain and kidney infarcts

Pompe disease is a rare metabolic affection caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase encoded by the GAA gene and responsible for the degradation of lysosomal glycogen [1]. Late-onset Pompe disease (LOPD) develops in adults and is usually limited to myopathy [1]. Cardio-cerebrovascular manifestations have been described in addition to myopathy in LOPD, including heart rythm alterations, left ventricular hypertrophy, and cerebral and aortic dilated arteriopathy [2–4]. Here, we describe for the first time a patient with Pompe disease who presented with a pure vascular phenotype of the disease. A 52-year-old male caucasian patient with no past medical or family history presented with an episode of acute left abdominal pain in 2008. Abdominal magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) demonstrated a left kidney infarct, and bilateral dilative renal and iliac arteriopathy without aortic involvement (Fig. 1). Electrocardiography (EKG) and echocardiography were normal, and treatment with aspirin 160 mg/day was introduced. In 2011, he presented with another episode of acute left abdominal pain, and abdominal MRI demonstrated an enlargement of the previously known left kidney infarct. EKG and echocardiography were normal, and aspirin treatment was replaced with an oral anticoagulant, i.e. fluindione. In 2012, the patient presented with an episode of transitory aphasia. Brain MRI revealed an acute ischemic stroke in the territory of the left middle cerebral artery, and neck MRA showed bilateral dilative carotid and vertebral arteriopathy (Fig. 1). EKG and echocardiography were normal, and treatment with fluindione was maintained. Marfan syndrome, Ehlers– Danlos syndrome and Fabry disease were excluded, and Pompe disease was considered despite the patient presenting with no sign of myopathy, i.e. normal motor examination and normal creatine kinase (CK) levels, echocardiography, pulmonary function tests, and muscle biopsy. Muscle biopsy was processed with standard methods for histology, histochemistry, and electron microscopy, including periodic acid-Schiff (PAS) staining. Motor examination included manual muscle testing, timed tests (time to climb 4 steps, to rise from a chair, and to walk 10 m), motor function measurement (MFM scale), and the 6-min walking test. Acid alpha-glucosidase deficiency was found in blood lymphocytes, cultured skin fibroblasts and skeletal muscle, and the patient was a compound heterozygote for 1 previously reported pathogenic variation in intron 1 of the GAA gene (c.-32-13T[G), and 1 newly described pathogenic variation in exon 6 of the GAA gene (p.V350M, c.1048G[A) (Table 1). Two years follow-up showed no additional cerebral or kidney infarcts with oral anticoagulation. As the patient presented with no myopathy, cardiomyopathy and respiratory insufficiency, enzyme replacement therapy was not considered [5]. This is the first description of a patient with Pompe disease presenting with a generalized dilative arteriopathy V. Quenardelle (&) M. Bataillard V. Wolff A. Echaniz-Laguna Departement de Neurologie, Hopitaux Universitaires de Strasbourg, Hopital de Hautepierre, 67098 Strasbourg, France e-mail: veronique.quenardelle@chru-strasbourg.fr

Brainstem stroke-related restless legs syndrome: frequency and anatomical considerations.

Background: Given the discordant results of studies that have reported cases of RLS associated with brainstem stroke and the absence of RLS in large series describing the clinical spectrum of brainstem infarctions, we decided to assess RLS in all patients admitted for brainstem stroke. Methods: All patients who were consecutively referred to the Strasbourg stroke unit for brainstem infarction were prospectively evaluated for RLS. The different parameters analyzed were the topography of the ischemic lesions (magnetic resonance imaging), the different symptoms (sensory, motor, cerebellar, cranial nerves and dysarthria) and the NIH stroke scale. Statistical analyses used the Bayesian paradigm. Results: Thirty patients have been included, and RLS was observed in three patients (10%). Two patients suffered from an exacerbation of symptoms anterior to the stroke, and the other patient a de novo, but transient, RLS. Patients with stroke-induced sensory symptoms have a higher risk to develop brainstem stroke-related RLS as compared to patients without sensory symptoms. Conclusion: The results suggest that RLS should be systematically screened in patients affected with brainstem stroke, especially in the case of stroke-induced sensory symptoms. Clinicians should be aware of this association, especially as efficient treatments are available and allow improving the management of patients affected with stroke. i 2014 S. Karger AG, Basel

Hyperdopaminergism in lenticulostriate stroke-related restless legs syndrome: an imaging study

OBJECTIVE The pathophysiology of restless legs syndrome (RLS) involves a dopaminergic dysregulation that remains poorly understood, with controversial data from the literature. Stroke-related RLS is a rare condition that involves primarily the basal ganglia, the paramedian pons, and the thalamus. Given these elements, we studied dopaminergic metabolism in patients with RLS secondary to lenticulostriate infarction using structural and nuclear imaging in the striatum ipsilateral to the infarction area, as compared to the contralateral side. We hypothesized that dopaminergic metabolism would be impaired in the striatum ipsilateral to stroke. METHODS In this observational case-control study, we aimed to prospectively include patients with RLS secondary to lenticulo-striate infarction, for analyses of dopamine dysfunction ipsilateral to stroke as compared to the contralateral striatum and to a control population. Four patients fulfilled inclusion criteria with either de novo RLS or major exacerbation of RLS existing prior to stroke, and all four patients were included. Structural imaging was performed using brain magnetic resonance imaging, and the stroke-induced metabolic modifications were assessed by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). Dopamine reuptake via DAT was explored using 123I-FP-CIT SPECT. PET with 18F-FDOPA was used to evaluate the functional integrity of the presynaptic dopaminergic synthesis. RESULTS The only structure damaged in all patients was the body of the caudate nucleus, right-sided for three and left-sided for one, as illustrated by magnetic resonance imaging. 18F-FDG PET showed a hypometabolism in the infarcted area, the ipsilateral thalamus, and the contralateral cerebellum. All patients displayed, in the ipsilateral putamen, increased dopaminergic tone. CONCLUSION The present findings suggest that increased dopaminergic tone in the striatum may participate in the pathogenesis of RLS. These observations should encourage further research on RLS symptomatic with well-defined lesions as a promising way to further improve our understanding of its pathophysiology.

Indications de la thrombolyse des infarctus cérébraux

Cerebral MRI with angio-MR are more effective than CT scan for selecting patients with ischemic stroke for thrombolysis. The use of cerebral MRI has to be available 24h a day and everyday as a standardized emergency procedure. Off-label criteria for thrombolysis after acute ischemic stroke are too restritive and have to be revised. In acute ischemic stroke, imaging that shows the collateral circulation within the hypoperfusion area has to be used to estimate the potential of therapeutic revascularization. When there are contraindications for intravenous thrombolysis, the endovascular approach must be argued individually by neurologists and neurointerventionalists together.

Restless legs syndrome related to hemorrhage of a thoracic spinal cord cavernoma

Context: Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the lower limbs often accompanied by unpleasant sensations in the legs, worsened at rest and in the evening. Symptoms are improved by movement. Its pathophysiology remains poorly understood. Lesion-related RLS has been reported, mainly in cases of stroke-related RLS involving the brainstem and lenticulostriate nuclei. Only few data of RLS in a context of spinal cord injury have been reported. Findings: We report the case of a woman with secondary RLS due to hemorrhage of a spinal cord cavernoma located at T9-T10. Following recovery from the acute phase of the hemorrhage, the patient began to complain about restlessness in her legs causing impaired sleep and daytime somnolence. Polysomnographic investigations found a high index of periodic leg movements during sleep (71/hour), but no sleep disordered breathing. Iron stores were normal. Relief of symptom’s severity was obtained with gabapentin 600mg in the evening. Conclusion/Clinical Relevance: We hypothesize a possible involvement of the diencephalospinal pathway in the patient’s RLS pathophysiology. A systematic study of focal lesions associated with RLS may contribute to improving our understanding of the pathophysiological mechanisms underlying this condition. The frequency of RLS associated with lesions of the spinal cord might be underestimated. Clinicians should be aware of spinal cord lesion-related RLS, especially as efficient treatments are available.

Intravenous Immunoglobulin Therapy Administered Early after Narcolepsy Type 1 Onset in Three Patients Evaluated by Clinical and Polysomnographic Follow-Up

Narcolepsy type 1 is a rare disabling sleep disorder mainly characterized by excessive daytime sleepiness and cataplexy, an emotion-triggered sudden loss of muscle tone. Patients have a selective degeneration of hypocretin-producing neurons in the dorsolateral posterior hypothalamus with growing evidence supporting the hypothesis of an autoimmune mechanism. Few case studies that reported intravenous immunoglobulin therapy (IVIg) suggest the efficacy of IVIg when administered early after disease onset, but the results are controversial. In these retrospective case observations, IVIg cycles were initiated within one to four months after cataplexy onset in a twenty-seven-year-old man, a ten-year-old girl, and a seven-year-old boy, all three with early onset typical narcolepsy type 1. Efficacy of treatment (three IVIg cycles of 1 g/kg administered at four-week intervals) was evaluated based on clinical, polysomnographic, and multiple sleep latency test (mean latency and SOREM) follow-up. Two patients reported decreased cataplexy frequency and ameliorated daytime sleepiness, but no significant amelioration of polysomnographic parameters was observed. Given the possibility of spontaneous improvement of cataplexy frequency with self-behavioral adjustments, these observations would need to be confirmed by larger controlled studies. Based on the present study and current literature, proof of concept is still missing thus prohibiting the consideration of IVIg as an efficient treatment option.

Bedtime-related jerks in the upper limbs associated with restless arms syndrome

A 73-year-old man complained at bedtime of “electric shock” sensations, corresponding to myoclonic-like jerks, observed solely in both arms, causing severe insomnia. These involuntary movements appeared at rest and were accompanied by an urge to move that relieved symptoms (video on the Neurology® Web site at Neurology.org). To date, few observations have been reported on arm restlessness and periodic movements of the upper limbs.1,2 This variant shares common features with restless legs syndrome and periodic limb movement disorder, such as therapeutic response to dopaminergic agonists. Clinicians should be aware of restlessness of the upper limbs, which likely remains underdiagnosed and requires appropriate therapeutic management.