Restless legs syndrome outside the blood-brain barrier--exacerbation by domperidone in Parkinson's disease.

INTRODUCTION: Models of dopaminergic function in restless legs focus on central dopaminergic neurons. Domperidone, a peripheral dopamine blocker that cannot cross the blood-brain barrier, is commonly used in Parkinson's disease. After encountering a case of restless legs syndrome that dramatically worsened with domperidone, we assessed whether Parkinson's patients may have exacerbation of restless legs with domperidone. METHODS: From two Parkinson's disease cohorts, we assessed restless legs prevalence according to standard criteria, in patients taking vs. not taking domperidone. Regression analysis was performed, adjusting for age, sex, disease duration, UPDRS, dopaminergic medications and other medications. RESULTS: One hundred eighty four patients were assessed, of whom 46 (25%) had restless legs. Thirteen out of twenty seven (48%) patients on domperidone had restless legs compared to 33/157 (21%) without (p = 0.010). Other medications were not associated with restless legs. CONCLUSION: This unexpected finding suggests that dopaminergic neurons outside of the blood-brain barrier may be important in restless legs syndrome pathophysiology.

[Demyelinating disease affecting both central and peripheral nervous system]. / Maladie démyélinisante du système nerveux central et périphérique.

INTRODUCTION: Demyelinating disease affecting both the central and the peripheral nervous systems has rarely been reported. CASE REPORT: A 30-year-old man, presented with ataxia and diffuse areflexia due to polyneuropathy fullfilling demyelination criteria. His medical history was notable for central nervous system demyelination compatible with multiple sclerosis. He improved transiently with intravenous immunoglobulin and then stabilized with methotrexate. CONCLUSION: This case report distinguishes a new kind of inflammatory disease affecting both central and peripheral nervous system. It seems to be different from multiple sclerosis and chronic immune demyelinating polyneuropathy, because of high hyperproteinorachia and absence of oligoclonal bands in the cerebrospinal fluid.

Strategy for anti-aquaporin-4 auto-antibody identification and quantification using a new cell-based assay.

NMO-IgG is a specific biomarker of neuromyelitis optica (NMO) that targets the aquaporin-4 (AQP4) water channel protein. The current gold standard for NMO-IgG identification is indirect immunofluorescence (IIF). Our aim in this study was to develop a new quantitative cell-based assay (CBA) and to propose a rational strategy for anti-AQP4 Ab identification and quantification. We observed an excellent correlation between the CBA and IIF for NMO-IgG/anti-AQP4 detection. The CBA appeared more sensitive than IIF but on the other hand, IIF allows the simultaneous detection of various auto-Abs, underlining the complementarity between both methods. In conclusion, we propose to use IIF for the screening of patients at diagnosis in order to identify auto-Abs targeting the central nervous system. A highly sensitive, AQP4 specific and quantitative assay such as our CBA could be used thereafter to specifically identify the target of the Ab and to monitor its serum concentration under treatment.

Hypocretinergic dysfunction in neuromyelitis optica with coma-like episodes.

Devic's neuromyelitis optica (NMO) is a severe demyelinating disease of the central nervous system, often misdiagnosed as multiple sclerosis, and involving mainly optic nerves and the spinal cord. We report on a peculiar case of relapsing NMO with severe recurrent dysautonomia and hypersomnia, in which we had the opportunity to observe a dramatic decrease in hypocretin/orexin cerebrospinal fluid level.

[Retinal atrophy using optical coherence tomography (OCT) in 15 patients with multiple sclerosis and comparison with healthy subjects]. / Etude de la perte axonale optique en tomographie en cohérence optique (OCT) chez 15 patients atteints de sclérose en plaques et comparaison avec une population de témoins appariés.

INTRODUCTION: Multiple sclerosis is a common disabling progressive neurological disorder. Axonal loss is thought to be a likely cause of persistent disability after a multiple sclerosis relapse. Retinal nerve fiber layer (RNFL) imaging by optical coherence tomography (OCT) seems to be a non-invasive way of detecting optical axonal loss following optic neuritis. OBJECTIVE: To determine whether multiple sclerosis affects retinal nerve fiber layer measurements obtained with optical coherence tomography (OCT3-Carl Zeiss Meditec, Dublin, California, USA). MATERIAL AND METHODS: Diagnosis of MS was based on the MacDonald criteria. The cohort was divided into two groups based on their clinical course (multiple sclerosis with [n=8; 16 eyes] or without [n=7; 14 eyes] optic neuritis antecedents). The disease-free controls were matched for age and gender (n=15; 30 eyes). Retinal nerve fiber layer thickness was measured using optical coherence tomography (OCT; fastRNFL and RNFL thickness software protocol). Visual acuity, visual field, color vision were also noted. RESULTS: There were highly significant reductions (p<0.001) of retinal nerve fiber layer thickness in affected patients (with or without optic neuritis antecedents) compared with control eyes (fastRNFL and RNFL procedures). Visual acuity, visual field and color vision were globally less altered than OCT. There were no significant relationships among RNFL thickness and visual acuity, visual field, or color vision. CONCLUSION: This study has demonstrated the anatomic changes of the retinal nerve fiber layer of patients with multiple sclerosis with optic neuritis antecedents. Thus axonal loss following optic neuritis can be detected with OCT. But the retinal nerve fiber layer of patients without optic neuritis is also thinner than disease-free controls so that chronic optic axonal loss can be frequent in multiple sclerosis. Additionally, OCT was more sensitive than the common ophthalmological explorations to detect optical nerve impairment during multiple sclerosis. Finally, we demonstrated that two procedures fastRNFL and RNFL could be used to detect optic nerve impairment.

[Recurrent inflammatory optic neuropathy]. / Neuropathies optiques inflammatoires récidivantes.

PURPOSE: To analyze clinical and paraclinical characteristics of recurrent isolated optic neuropathy. PATIENTS: and method: In three university hospitals (Montpellier, Nimes, and Strasbourg), between October 2005 and September 2006, the charts of patients with corticosensitive recurrent isolated optic neuropathy and normal cerebral magnetic resonance imaging included prospectively were reviewed. The following parameters were analyzed: date of the first relapse, age at onset, duration at the time of inclusion, recurrence after steroid withdrawal, unilateral or bilateral involvement, number of relapses, visual acuity, retinal nerve fiber layer thickness, diagnostic workup, and long-term treatment with immunosuppressive or immunomodulatory drugs. RESULTS: During the predefined period, 13 patients (11 women, 2 men; age, 17-54 years at onset) matched the inclusion criteria. Between two and six relapses of optic neuropathy were observed. The median duration was 4 years. In untreated patients (n=7), a significant (Spearman p=0.0156) inverse correlation was observed between visual acuity and duration of the disease; this correlation was not found in the group of patients (n=6) with long-term treatment (Spearman p=0.1032). CONCLUSION: The progressive loss of vision over time in this retrospective study of recurrent isolated optic neuropathy could be related to axonal loss. A prospective cohort study is necessary to confirm this hypothesis and to evaluate the benefit of long-term treatment on this progression.

[Chemotherapy treatment for anti-Hu paraneoplastic syndrome without active malignancy]. / Traitement par chimiothérapie d'un syndrome neurologique paranéoplasique anti-Hu sans cancer actif associé

INTRODUCTION: Anti-Hu associated paraneoplastic neurological syndromes are rare and characterized by poor prognosis. The research and treatment of a related cancer, a small-cell lung cancer most of the time, remains the best therapeutic strategy. CASE REPORT: We describe the clinical course of a paraneoplastic subacute sensory neuronopathy associated with anti-Hu antibodies in a male smoker treated by an early chemotherapy active against a small-cell lung cancer although no tumor could be found at repeated evaluations. In spite of this treatment, the neurological state deteriorated with the appearance of a cerebellar degeneration, and limbic encephalitis which resulted in a loss of autonomy. A small-cell lung cancer was found and treated 65 months after the onset of the neurological symptoms. The treatment of the underlying malignancy, when it can be found, is still considered as the optimal treatment for paraneoplastic neurological syndromes. Although no tumor could be found, we treated our patient with an empirical chemotherapy active against the most frequent malignancy associated to anti-Hu syndrome in a smoker man, without any improvement. CONCLUSION: Active and repeated research for a cancer related to an anti-Hu neurological syndrome and its treatment are undispensable. For our patient without any identified cancer empirical chemotherapy treatment was unable to stop neurological worsening. When no tumor can be identified by conventional imaging techniques, an early FDG-PET scan should be considered and then repeated if normal.

[Late onset forms of myasthenia gravis. Comparison with early-onset myasthenia gravis]. / Formes tardives de myasthénie. Etude comparative avec la myasthénie du sujet jeune.

INTRODUCTION: The incidence of myasthenia gravis appears to be increasing in elderly but few studies have been devoted to late onset myasthenia gravis. PATIENTS AND METHODS: We retrospectively compared myasthenic patients with an age at onset above or below 35 years which were observed in two departments of Neurology from 1980 to 2002. RESULTS: 81 cases were included, 28 of which were late onset myasthenia gravis. The two populations were similar in terms of sex-ratio, clinical symptoms, course of the disease and therapeutic response. There was a trend for older patients to present more frequently at onset with dysphagia and axial or proximal involvement, and to have extra-ocular symptoms more quickly. Antibodies against acetylcholine receptor and striated muscle were statistically more frequent in elder patients. CONCLUSIONS: A late onset is not a factor of poor prognosis in myasthenia gravis and older patients must be treated in the same way than younger ones.

Dissociation in circadian rhythms in a pseudohypersomnia form of fatal familial insomnia.

The authors present clinical, sleep, and neuroendocrine features of a patient with genetically confirmed fatal familial insomnia (D178N mutation with heterozygosity at codon 129 of the prion protein gene). The patient exhibited pseudohypersomnia behavior instead of insomnia. There was profound alteration in the sleep-wake cycle with a clear dissociation in the disappearance of circadian and neuroendocrine rhythms, findings unrelated to abnormalities in the hypocretinergic system.

CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions.

OBJECTIVE: To determine the role of CSF hypocretin-1 in narcolepsy with and without cataplexy, Kleine-Levin syndrome (KLS), idiopathic and other hypersomnias, and several neurological conditions. PATIENTS: 26 narcoleptic patients with cataplexy, 9 narcoleptic patients without cataplexy, 2 patients with abnormal REM-sleep-associated hypersomnia, 7 patients with idiopathic hypersomnia, 2 patients with post-traumatic hypersomnia, 4 patients with KLS, and 88 patients with other neurological disorders. RESULTS: 23 patients with narcolepsy-cataplexy had low CSF hypocretin-1 levels, while one patient had a normal hypocretin level (HLA-DQB1*0602 negative) and the other two had intermediate levels (familial forms). One narcoleptic patient without cataplexy had a low hypocretin level. One patient affected with post-traumatic hypersomnia had intermediate hypocretin levels. The KLS patients had normal hypocretin levels while asymptomatic, but one KLS patient (also affected with Prader-Willi syndrome) showed a twofold decrease in hypocretin levels during a symptomatic episode. Among the patients without hypersomnia, two patients with normal pressure hydrocephalus and one with unclear central vertigo had intermediate levels. CONCLUSION: Low CSF hypocretin-1 is highly specific (99.1%) and sensitive (88.5%) for narcolepsy with cataplexy. Hypocretin ligand deficiency appears not to be the major cause for other hypersomnias, with a possible continuum in the pathophysiology of narcolepsy without cataplexy and idiopathic hypersomnia. However, partial hypocretin lesions without low CSF hypocretin-1 consequences cannot be definitely excluded in those disorders. The existence of normal hypocretin levels in narcoleptic patients and intermediate levels in other rare aetiologies needs further investigation, especially for KLS, to establish the functional significance of hypocretin neurotransmission alterations.

Age at onset of narcolepsy in two large populations of patients in France and Quebec.

BACKGROUND: Narcolepsy usually starts around adolescence; however, there is great variability in the clinical presentation of narcolepsy. OBJECTIVE: To determine the age at onset in conjunction with severity of narcoleptic symptoms in two large populations of narcoleptic patients with a similar genetic background. METHODS: Information on age at onset and severity of the condition was obtained in 317 patients with well-defined narcolepsy-cataplexy from Montpellier (France) and in 202 from Montreal (Canada). RESULTS: The mean age at onset was 23.4 years in Montpellier and 24.4 in Montreal. The age at onset was bimodal in two independent patient populations: a first peak occurring at 14.7 years, and a second peak occurring at 35. Age at onset clearly differentiates patients with a positive family history of narcolepsy (early onset) from those without a family history. Other clinical and polygraphic findings may indicate that young age at onset is associated with increased severity of the condition (higher frequency of cataplexy and decreased mean sleep latency on the Multiple Sleep Latency Test). CONCLUSION: Bimodal distribution of age at onset of narcolepsy was found in two independent patient populations. Our data suggest that age at onset is genetically determined.

[Immunological aspects of narcolepsy]. / Aspects immunologiques de la narcolepsie.

Since the discovery of an almost 100 p. cent association of human narcolepsy with the HLA gene DQB1*0602, research has been focused on autoimmune mechanisms. Epidemiological data (age of onset, triggering factors, association with multiple sclerosis) would lend support to this hypothesis. However it has remained largely impossible to demonstrate immune abnormalities in blood or CSF by means of usual techniques. The canine form of the disease was supposed to be also immunologically mediated, since a linkage with a human immunoglobulin-related gene had been demonstrated. This was eventually demonstrated to be a pseudo-linkage, the real cause being a mutation in the closely related hypocretin receptor gene. This recently discovered neuropeptide is clearly involved in some aspects of sleep regulation. Soon thereafter, hypocretin deficiency was found in human narcoleptics, due to a severe neuronal loss in the hypothalamus; gliosis having been evidenced, it may be considered as the evidence of a prior inflammatory reaction, possibly due to an immune attack.

[Arousal of respiratory origin and upper airway resistance syndrome: pathophysiological and diagnostic aspects]. / Arousals de origen respiratorio y síndrome de aumento de resistencia de la vía aérea superior: aspectos fisiopatológicos y diagnósticos.

INTRODUCTION: The description of Upper Airway Resistance Syndrome (UARS) let us to recognize the importance of the pair 'respiratory effort-arousal' on sleep-disordered breathing pathophysiology. DEVELOPMENT: First part of this paper reviews knowledge about respiratory arousal pathophysiology. Arousal response is normally needed to end obstructive respiratory episodes, but it is also the cause of sleep fragmentation. Among respiratory stimuli able to provoke arousal (respiratory effort, hypoxemia and hypercapnia), respiratory effort is the most constant. Neurophysiological mechanisms involved in arousal, sleep and vegetative consequences, and the possible role of non visible arousals, are also discussed. In UARS, because of the absence of apnea/hypopnea and significative O2 desaturations, arousals are induced by the increased respiratory effort. Diagnosis needs the simultaneous recording of polysomnography and esophageal pressure. Some symptoms and signs of UARS are similar to those of Obstructive Sleep Apnea Syndrome. However, UARS shows any differences: a lower Body Mass Index, less constant snoring, males and females are similarly affected or higher frequency of craniofacial abnormalities. Diagnostic difficulties may be due to confusion between hypopneas and episodes of increased resistance of upper airway, or to the lack of definitive diagnostic criteria. Finally, differential diagnosis needs a broad knowledge of disorders of excessive daytime sleepiness.