Stroke-related restless legs syndrome: Clinical and anatomo-functional characterization of an emerging entity.

BACKGROUND AND PURPOSE: Stroke-related restless legs syndrome (sRLS) secondary to ischemic lesions is an emerging entity and an interesting condition, but there are limited available data to help us further understand its underlying pathways. In this study, we characterized sRLS clinically, neuroanatomically and functionally. METHODS: Consecutive patients hospitalized in the Stroke Unit of the University Hospital of Strasbourg were assessed clinically and electrophysiologically for sRLS characteristics. They underwent brain magnetic resonance imaging for the neuroanatomical study of involved structures, and received functional evaluations with 18 F-FDG (2-deoxy-2-[fluorine-18]fluoro-D-glucose) positron emission tomography (PET) for glucose consumption, 123 I-FP-CIT ([123]I-2beta-carbometoxy-3beta-[4-iodophenyl]-N-[3-fluoropropyl]nortropane) single-photon emission computed tomography for dopamine reuptake and PET with 18 F-FDOPA ((3,4-dihydroxy-6-[18]F-fluoro-l-phenylalanine) for presynaptic dopaminergic synthesis. RESULTS: Sixteen patients with sRLS, eight women and eight men, aged 41-81 years, were included. The clinical characteristics of sRLS and idiopathic RLS were similar. Most patients presented with bilateral and symmetric de novo RLS. Eight patients had infarction in the lenticulostriate area (middle cerebral artery and internal carotid arteria). The body of the caudate nucleus was most commonly affected. Seven patients had sRLS secondary to ventral brainstem infarction (perforating branches of the basilar arteria) affecting the pons in six patients and the medulla oblongata in one patient. Both the corticospinal tract and the cortico-pontocerebellar fibres were lesioned in all patients with brainstem stroke. One patient had infarction in the left posterior cerebellar vermis and occipital area (posterior cerebral artery and superior cerebellar artery). Isotopic explorations showed a significantly increased dopaminergic tone in the striatum ipsilateral to lenticulostriate infarction. Dopamine fixation was normal in patients with stroke outside of the lenticulostriate area. CONCLUSIONS: Clinicians should be aware of the characteristics of sRLS for the appropriate diagnosis and treatment of this condition.

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.

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.

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.

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.

[RESTLESS LEGS SYNDROME--WILLIS-EKBOM DISEASE]. / Le syndrome des jambes sans repos: fréquent et handicapant.

Restless legs syndrome (RLS) is a sensorimotor disorder with a high prevalence (10% in Caucasian populations). It is a purely clinical diagnosis characterized by an urge to move the lower limbs usually accompanied or caused by unpleasant sensations in the legs with an improvement in symptoms with movement. These sensations occur during inactivity or at rest and worsen in the evening or at night. RLS may not only impact the quality of life for an individual, but may also increase mortality. Disease markers such as genetic predispositions have been identified, as well as reduced iron stores with altered intracerebral iron homeostasis and dopaminergic dysfunction. Medication is often necessary in severe forms, with low doses of dopaminergic agonists being the first-line of treatment. The use of α2δ ligands is an alternative. Finally benzodiazepines and opioid medications can be effective in refractory cases. In less severe forms of RLS, a non-pharmacological approach is usually sufficient with avoidance of stimulants and correction of contributing factors.

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.

Restless legs syndrome as a first manifestation of a cerebral infarct.

The onset of restless legs syndrome (RLS) is usually progressive and the neural substrates underlying its pathophysiology remain to be identified. Here we report on a patient presenting with acute-onset RLS that was symptomatic of a right anteromedial pontine infarction. This case is exceptional because RLS appeared several hours before the occurrence of a regressive dysarthria clumsy-hand syndrome. Additionally, millimetric MRI sections showed that the structures possibly involved in RLS pathogenesis were the corticospinal tract, the pontine nuclei, and the pontocerebellar fibers. Although this is uncommon, clinicians should be aware that RLS characterized by a sudden onset can be a clinical manifestation related to stroke.

PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine.

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.

[Indications for thrombolysis in ischemic stroke]. / 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.

Lessons from CADASIL.

Vascular dementia (VaD) includes several different vascular mechanisms and changes in the brain. Among VaD, CADASIL is an inherited angiopathy caused by mutations in the Notch3 gene. The pathological hallmark of CADASIL is a granular osmiophilic material deposit (GOM) that is not only found in the brain, but also in the peripheral vascular tree. Consequently, a window into the brain was opened from a strictly neurological disease with tremendous consequences thanks to a skin biopsy. The latter was and continues to be used as a diagnostic tool for CADASIL, despite an immunohistochemical test that is now available. The skin biopsy first used as a diagnostic tool revealed the existence of numerous other VaDs presenting systemic vascular changes. Later, skin biopsy became a research tool, and a morphological skin vessel change classification was proposed on 300 patients. Interestingly, similar skin vessel lesions appear to be related to the same biological modifications. In addition, an early destruction of the medial muscle cells was noticed in 74% of cases. Because vascular smooth muscle cells secrete a powerful endothelial permeability factor (VEGF), their destruction could lead to a decrease in vascular permeability. Cocultures of endothelial cells with vascular muscle cells showed that their presence doubled vascular permeability. Thus, alteration or the loss of vascular muscle cells likely results in hypopermeability, in addition to vessel wall hypotonia and a watershed hypoperfusion. The wealth of information brought forth by knowledge of CADASIL provided new tools for research and clues for understanding the consequences of vascular impairments in dementia.