Mahmoud Charif

Lack of confirmation of anti-inward rectifying potassium channel 4.1 antibodies as reliable markers of multiple sclerosis.

Background: auto-antibodies against the potassium channel inward rectifying potassium channel 4.1 (Kir4.1) have previously been identified in 46% of patients with multiple sclerosis (MS). Objectives: to confirm these findings. Methods: we evaluated the presence of anti-Kir4.1 antibodies by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence in 268 MS patients, 46 patients with other neurological diseases (OND) and 45 healthy controls. Results: anti-Kir4.1 antibodies were found in 7.5% of MS patients, 4.3% of OND patients and 4.4% of healthy controls. Immunofluorescence analysis did not identify any specific staining. Conclusions: we confirmed the presence of anti-Kir4.1 antibodies in MS patients, but at a much lower prevalence than previously reported.

Daytime sleepiness in Parkinson's disease: a reappraisal.

Background Excessive daytime sleepiness is a frequent complaint in Parkinson’s disease (PD); however the frequency and risk factors for objective sleepiness remain mostly unknown. We investigated both the frequency and determinants of self-reported and objective daytime sleepiness in patients with Parkinson’s disease (PD) using a wide range of potential predictors. Methods One hundred and thirty four consecutive patients with PD, without selection bias for sleep complaint, underwent a semi-structured clinical interview and a one night polysomnography followed by a multiple sleep latency test (MSLT). Demographic characteristics, medical history, PD course and severity, daytime sleepiness, depressive and insomnia symptoms, treatment intake, pain, restless legs syndrome, REM sleep behaviour disorder, and nighttime sleep measures were collected. Self-reported daytime sleepiness was defined by an Epworth Sleepiness Scale (ESS) score above 10. A mean sleep latency on MSLT below 8 minutes defined objective daytime sleepiness. Results Of 134 patients with PD, 46.3% had subjective and only 13.4% had objective sleepiness with a weak negative correlation between ESS and MSLT latency. A high body mass index (BMI) was associated with both ESS and MSLT, a pain complaint with ESS, and a higher apnea/hypopnea index with MSLT. However, no associations were found between both objective and subjective sleepiness, and measures of motor disability, disease onset, medication (type and dose), depression, insomnia, restless legs syndrome, REM sleep behaviour disorder and nighttime sleep evaluation. Conclusion We found a high frequency of self-reported EDS in PD, a finding which is however not confirmed by the gold standard neurophysiological evaluation. Current treatment options for EDS in PD are very limited; it thus remains to be determined whether decreasing pain and BMI in association with the treatment of sleep apnea syndrome would decrease significantly daytime sleepiness in PD.

Susac's syndrome, a rare, potentially severe or lethal neurological disease

Susacs syndrome (SS) is a rare, immune-mediated endotheliopathy affecting the microvasculature of the brain, the inner ear and the retina. Clinical presentation is characterised by a triad: encephalopathy, hearing loss and branch retinal artery occlusion (BRAO). Given the rarity of this disease, its natural history still remains partially unknown, but lethal cases appear to be extremely rare since there has never been, to our knowledge, a report of SS leading to death. We report 2 cases of SS illustrating the multiplicity of neurological symptomatology and its unpredictable course. One case is particularly unusual due to its severe neurological evolution, leading to death despite treatments. This report presents clinical and paraclinical findings contributory to SS diagnosis and offers an innovative perspective on disease management. These cases represent the potential severity of this disease. Early, aggressive treatment strategies may be warranted for SS in order to avoid neurological deterioration and lethal evolution.

Supine sleep and obstructive sleep apnea syndrome in Parkinson's disease.

OBJECTIVE Supine sleep is associated with increased obstructive sleep apnea. People with Parkinsons disease (PD) complain about difficulties turning around in bed. The relationship between supine sleep and sleep-disordered breathing has never been explored in people with Parkinsons disease. METHODS Fifteen consecutive people with PD with severe Obstructive Sleep Apnea Syndrome (OSAS) were compared to: (1) 15 age-matched, gender-matched, body mass index-matched and Unified Parkinsons Disease Rating Scale-III score-matched people with PD without sleep-disordered breathing; (2) 11 age-matched and gender-matched people with severe obstructive sleep apnea syndrome (OSAS) alone; and (3) 11 age-matched and gender-matched healthy controls. Outcomes were: number of position changes during the night and per hour of sleep, and the percentage of sleep time spent in supine. RESULTS People with PD and severe OSAS spent most of their sleep time in the supine position (93 ± 11%); while people with PD without OSAS (61 ± 24%, p <0.001), people with isolated, severe OSAS (50 ± 28%, p <0.001), and the controls (40 ± 21, p <0.001) spent significantly less time on their back. People with PD and severe OSAS changed their position in bed per hour of sleep (0.4 ± 0.5) less frequently than those with PD without OSAS (1.1 ± 0.8, p = 0.002), those with isolated OSAS (1.2 ± 1.0, p = 0.006) and the controls (1.5 ± 0.5, p <0.001). CONCLUSION PD and severe OSAS are associated with a major reduction in the number of position changes and an increased supine sleep position during the night. For people with PD, alleviating the difficulties of turning around in bed might reduce the supine sleep position and improve sleep-disordered breathing.

Hemolytic uremic syndrome: an unusual complication of interferon-β treatment in a MS patient

Interferon-b therapy is one of the most frequently used treatments in multiple sclerosis (MS), and is considered as safe. We report a patient with hemolytic uremic syndrome (HUS) related to recent prescription of interferon-b. A 38-year-old woman, without medical history, had a diagnosis of relapsing–remitting (RR) MS [1] (Fig. 1a). Subcutaneous interferon-b-1a (22 lg thrice weekly) was started THREE months later. Biological parameters including renal function were normal before interferon-b1a prescription. Seven months later, she presented asthenia, lower limb edema, and weight gain. She had no recent history of viral infection, transfusion, or additional drug intake. A few days later, she became oliguric. Physical examination showed high systolic and diastolic blood pressure (190/110 mmHg) and anasarca. Neurological examination was normal (EDSS score: 0). Biological parameters were the following: serum creatinine level 1,221 lmol/l (\90), urea level 31.8 mmol/l (\9), hemoglobin 4.6 g/dl (12–15). Initial platelet count was normal, followed by thrombocytopenia at 116,000/mm (250,000– 400,000). Occurrence of high LDH levels, immeasurable haptoglobin, and presence of 4 % of schistocytes, led to a diagnosis of hemolytic anemia. All autoimmune antibodies, including Coomb’s test, complement C3 and C4 levels, bacterial infection research, were normal or negative. The ADAMTS 13 activity was normal, without any ADAMTS 13 antibody and H or I factors deficit. Daily ultrafiltration and oral antihypertensive drugs were started, followed by plasma exchange and corticosteroid therapy (1 mg/kg/day). Renal biopsy confirmed acute thrombotic microangiopathy (TMA) (Fig. 1b). Absence of other causes and temporal relation between interferon-b and HUS led to a diagnosis of interferon-binduced HUS. Interferon-b-1a was withdrawn. The evolution was characterized by: (1) Three months of corticosteroids, hemodialysis, plasmapheresis, (2) occurrence of a typical posterior reversible encephalopathy syndrome (PRES) (Fig. 1c, d), secondary to the blood pressure imbalance, (3) definitive hemodialysis because of persistent anuria, (4) normalization of all hematological parameters. HUS is a type of thrombotic microangiopathy (TMA), as well as thrombotic thrombocytopenic purpura (TTP) [1–4]. HUS diagnosis is based on occurrence of mechanical hemolytic anemia, thrombocytopenia, and renal failure. High levels of LDH and reticulocytes, low haptoglobin levels, presence of schistocytes, and negative Coombs test, define the mechanical origin. Most cases are secondary to infection with Escherichia coli serotypes O157:H7, O111:H8, O103:H2, O123, O26, or other bacteria, such as E. Nerrant M. Charif P. Labauge (&) Department of Neurology, Montpellier University Hospital, 34295 Montpellier, France e-mail: labauge@yahoo.fr

Suggested Immobilization Test for Diagnosis of Restless Legs Syndrome in Parkinson's Disease

Diagnosis of restless leg syndrome (RLS) in Parkinsons disease (PD) is difficult because of clinical confounds. The suggested immobilization test (SIT) is validated for diagnosis of primary RLS. This study evaluated the usefulness of the SIT for diagnosis of RLS in PD. We compared SIT scores, as well as polysomnography measures in 50 patients with PD (25 with RLS, 25 without), 25 patients with primary RLS, and 25 age/sex matched controls. Mean leg discomfort score was increased in patients with PD and RLS compared to PD without RLS, and also in patients with primary RLS compared to controls. Leg discomfort was significantly higher at the end of the test in patients with RLS compared to patients without RLS. Intensity of leg discomfort was similar between patients with RLS, with or without PD. Using a mean leg discomfort cutoff of 11, we showed sensitivity of 91% and specificity of 72% for RLS diagnosis in PD during symptomatic time intervals. Periodic leg movements index during the SIT did not differ between groups. Periodic leg movements index during sleep and wakefulness was increased in patients with primary RLS compared to controls, but did not differ between patients with PD, with and without RLS. The sensory SIT is a simple test that may help diagnose RLS in patients with PD.

Traitement par chimiothérapie d’un syndrome neurologique paranéoplasique anti-Hu sans cancer actif associé

Resume Introduction Les syndromes neurologiques paraneoplasiques associes aux anticorps anti-Hu sont rares et de pronostic severe. La recherche et le traitement d’un cancer associe, un carcinome pulmonaire a petites cellules le plus souvent, demeure la meilleure approche therapeutique. Observation Les auteurs decrivent l’evolution clinique d’un patient atteint d’une neuronopathie sensitive subaigue associee aux anticorps anti-Hu chez un fumeur actif traite par une chimiotherapie precoce active contre un carcinome pulmonaire a petites cellules bien qu’aucune tumeur n’ait pu etre identifiee lors de bilans repetes. En depit de ce traitement, l’etat neurologique s’est aggrave avec l’apparition d’une degenerescence cerebelleuse et d’une encephalite limbique responsables d’une perte d’autonomie et definissant une encephalomyelite. Un carcinome pulmonaire a petites cellules fut identifie et traite 65 mois apres le debut des symptomes neurologiques. Le traitement du cancer associe, lorsqu’il est identifie, reste le traitement optimal des syndromes neurologiques paraneoplasiques. Malgre l’absence de cancer identifie initialement, nous avons traite notre patient par une chimiotherapie probabiliste, active contre le cancer le plus frequemment associe aux syndromes des anti-Hu chez un fumeur, sans obtenir de benefices. Conclusion La recherche active et repetee d’un cancer associe a un syndrome neurologique anti-Hu et son traitement sont indispensables. Le traitement probabiliste d’un cancer suppose n’ayant pas fait sa preuve n’a pas empeche l’aggravation neurologique chez ce patient. En l’absence de cancer identifie par les techniques d’imagerie de premiere intention, un FDG-PET scanner precoce puis regulier en cas de normalite initiale devrait donc etre propose.

REVERSAL OF SYMPTOMATIC TUMORAL NARCOLEPSY, WITH NORMALIZATION OF CSF HYPOCRETIN LEVEL

Narcolepsy is primarily characterized by excessive daytime sleepiness (EDS) and cataplexy.1 Most patients with sporadic narcolepsy with cataplexy and HLA DQB1*0602 have low CSF hypocretin-1 level in relation to a loss of hypocretin neurons.1–3 The origin of hypocretin neurons deficiency remains uncertain, but an autoimmune process is the most probable.1–3 Symptomatic narcolepsies associated with tumors located in the hypothalamic or the brainstem regions have been previously reported, half of them with cataplexy.4 The nature of the link among clinical symptoms, sleep onset REM periods, HLA, and CSF hypocretin remains unclear, especially in symptomatic narcolepsy. However, due to widespread excitatory projections to monoaminergic and cholinergic neurons, hypocretin neurons are supposed to be involved in maintaining wakefulness. Undetectable CSF hypocretin levels that correspond to a major functional impairment of the hypocretin region predispose to hypersomnia.1–3 We report a patient with severe symptomatic narcolepsy caused by a primary CNS lymphoma with undetectable CSF hypocretin-1 level whose symptoms reversed after chemotherapy. ### Case report. A 46-year-old man was referred to our …

Cerebrospinal Fluid Alzheimer’s Disease Biomarkers in Cerebral Amyloid Angiopathy-Related Inflammation

BACKGROUND Decreased cerebrospinal fluid (CSF) amyloid-β 1-40 (Aβ40) and amyloid-β 1-42 (Aβ42) and increased total and phosphorylated tau (t-tau, p-tau) concentrations have been described in cerebral amyloid angiopathy (CAA). OBJECTIVE Our aim was to analyze these biomarkers in patients with CAA-related inflammation (CAA-I). METHODS We prospectively recruited nine patients with acute phase CAA-I fulfilling Chung criteria. CSF was analyzed for t-tau, p-tau, Aβ42, and Aβ40. Data were compared to controls (n = 14), patients with Alzheimers disease (AD, n = 42), CAA (n = 10), and primary angiitis of the central nervous system (PACNS, n = 3). RESULTS For the CAA-I group, statistically significant differences were: lower Aβ42 (p = 0.00053) compared to the control group; lower t-tau (p = 0.018), p-tau (p <  0.001), and Aβ40 (p <  0.001) compared to AD; lower Aβ42 (p = 0.027) compared to CAA; lower Aβ42 (p = 0.012) compared to PACNS. Nearly significantly lower Aβ40 (p = 0.051) and higher t-tau (p = 0.051) were seen in CAA-I compared to controls. CONCLUSION CSF biomarkers profile similar to that of CAA was observed in CAA-I (with even lower levels of Aβ42 compared to CAA). Based on our findings, high p-tau seems more specific for AD, whereas low Aβ42 differentiates CAA-I from CAA, PACNS, and controls, and low Aβ40 differentiates CAA-I from AD.

Diffusion tensor imaging differentiates vascular parkinsonism from parkinsonian syndromes of degenerative origin in elderly subjects

BACKGROUND AND PURPOSE The etiologic diagnosis of parkinsonian syndromes is of particular importance when considering syndromes of vascular or degenerative origin. The purpose of this study is to find differences in the white-matter architecture between those two groups in elderly patients. MATERIALS AND METHODS Thirty-five patients were prospectively included (multiple-system atrophy, n=5; Parkinsons disease, n=15; progressive supranuclear palsy, n=9; vascular parkinsonism, n=6), with a mean age of 76 years. Patients with multiple-system atrophy, progressive supranuclear palsy and Parkinsons disease were grouped as having parkinsonian syndromes of degenerative origin. Brain MRIs included diffusion tensor imaging. Fractional anisotropy and mean-diffusivity maps were spatially normalized, and group analyses between parkinsonian syndromes of degenerative origin and vascular parkinsonism were performed using a voxel-based approach. RESULTS Statistical parametric-mapping analysis of diffusion tensor imaging data showed decreased fractional anisotropy value in internal capsules bilaterally in patients with vascular parkinsonism compared to parkinsonian syndromes of degenerative origin (p=0.001) and showed a lower mean diffusivity in the white matter of the left superior parietal lobule (p=0.01). Fractional anisotropy values were found decreased in the middle cerebellar peduncles in multiple-system atrophy compared to Parkinsons disease and progressive supranuclear palsy. The mean diffusivity was increased in those regions for these subgroups. CONCLUSION Clinically defined vascular parkinsonism was associated with decreased fractional anisotropy in the deep white matter (internal capsules) compared to parkinsonian syndromes of degenerative origin. These findings are consistent with previously published neuropathological data.