Bertrand Carlander

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.

Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset

Hypocretin/orexin deficiency appears to be a consistent feature of narcolepsy with a putative autoimmune mechanism involved. We treated four hypocretin/orexin‐deficient narcolepsy patients with intravenous immunoglobulins and assessed the efficacy by repeated polysomnographies and questionnaires. Three patients received the treatment within a few months after acute onset of narcolepsy. A clear improvement in the frequency and severity of cataplexy was obtained with a benefic effect up to 7 months without any anticataplectics drugs at follow‐up. Our findings point to the importance of early diagnosis of narcolepsy, which once treated quickly may modify its long‐term outlook. Ann Neurol 2004;56:905–908

Use of modafinil in the treatment of narcolepsy: A long term follow-up study

One hundred and forty patients (104 male and 36 female) aged 42.26 +/- 19.19 (range = 8 to 79.5 years) with narcolepsy-cataplexy were given modafinil (200 to 400 mg) at the Montpellier sleep disorders center from 1984 onwards. The follow-up focused on the reduction of excessive daytime somnolence (EDS), side effects and duration of treatment. In order to determine if any clinical aspect of narcolepsy could be involved in modafinil discontinuation, patients were divided into two groups according to continued or interrupted treatment. When modafinil effect on EDS was evaluated according to a scale varying from 0 (no effect) to 3 (excellent effect), 64.1% of the subjects, scored good or excellent. The mean duration of treatment was 22.05 months +/- 24.9, ranging from 1 to 114 months. Dependency signs were never observed.

LETHAL MULTIPLE SCLEROSIS RELAPSE AFTER NATALIZUMAB WITHDRAWAL

Natalizumab dramatically reduces relapses in patients with active multiple sclerosis (MS), but it may induce progressive multifocal leukoencephalopathy (PML).1 A rebound of MS or an immune reconstitution inflammatory syndrome (IRIS) were described after natalizumab withdrawal, even in the absence of PML.2,3 Very few data concerning the potential severity and the neuropathology of this event are available. We report the case of a 50-year-old patient with MS who developed a fulminating relapse 3 months after stopping natalizumab, leading to death despite intensive care and immunosuppressive therapy. Radiologic and neuropathologic findings provide interesting data regarding the nature of the rebound.

A narcolepsy susceptibility locus maps to a 5Mb region of chromosome 21q

The genetic basis of human narcolepsy remains poorly understood. Multiplex families with full‐blown narcolepsy‐cataplexy are rare, whereas families with both narcolepsy‐cataplexy and excessive daytime sleepiness without cataplexy are more common. We performed a genomewide linkage analysis in a large French family with four members affected with narcolepsy‐cataplexy and 10 others with isolated recurrent naps or lapses into sleep. Only three regions showed logarithm of odds (LOD) scores greater than 1 in two‐point linkage analysis (D6S1960, D11S2359, and D21S228). Genotyping additional markers provided support for linkage to 9 markers on chromosome 21 (maximum two‐point LOD score, 3.36 at D21S1245). The multipoint linkage analysis using SimWalk2 provided further evidence for linkage to the same region (maximum parametric LOD score, 4.00 at 21GT26K). A single haplotype was shared by all affected individuals and informative crossovers indicated that the elusive gene that confers susceptibility to narcolepsy is likely to be located between markers D21S267 and ABCG1, in a 5.15Mb region of 21q. Ann Neurol 2004

A monozygotic twin pair discordant for narcolepsy and CSF hypocretin-1

A genetic basis for narcolepsy is evidenced by a strong association with the HLA DQB1*0602 and the occasional familial occurrence.1 A major discovery was recently made through the identification of orexin/hypocretin deficiency.2,3⇓ While a single mutation in the prepro-hypocretin gene was reported in one atypical patient,3 undetectable levels of CSF hypocretin-1 were reported in most sporadic narcoleptics2 and a dramatic decrease of hypocretin neurons in few postmortem brains.3 Among the 16 monozygotic twin pairs described,1 only 6 are considered to be concordant and most of them were not completely documented. One HLA-DQB1*0602 positive twin pair concordant for narcolepsy was recently reported with normal levels of CSF hypocretin-1 and without any mutation in the hypocretin genes system.4 We studied the CSF hypocretin-1 in a HLA DQB1*0602 positive monozygotic twin pair discordant for narcolepsy. The twin sisters (brought up together until age 18 years) were the second and third born among three siblings, born in 1976. …

Autoimmune hypothesis in narcolepsy

Since the discovery of an almost 100% association of HLA-DR2 with narcolepsy-cataplexy, many efforts have been made to demonstrate the intervention of immune factors in the pathogeny of the disease. Some epidemiological features could support this hypothesis: age of onset around 25, triggering factors, association with multiple sclerosis. Molecular studies at the DNA level have, up to now, failed to uncover an abnormal gene in the HLA system, which would imply that the DR2 antigen acts through its role in the immune response. However, results have been largely inconclusive as far as classical features of autoimmunity in blood and CSF are concerned. In canine narcolepsy, a linkage with a human immunoglobulin-related gene has recently been shown, and may constitute a counterpart of the HLA association in man. Thus, the hypothesis of a transient and discrete autoimmune aggression may be ruled out.

A brain PET study in patients with narcolepsy–cataplexy

Objective To investigate brain changes in both basal and cataplectic conditions in awake patients with narcolepsy–cataplexy. Background Recent insights in pathophysiology have demonstrated that narcolepsy–cataplexy is caused by early loss of hypothalamus hypocretin neurons. However, the neurophysiological mechanisms underlying sleepiness and the dramatic cataplexy reaction to positive emotion remain unclear. Methods Twenty-one patients with narcolepsy–cataplexy and 21 age- and sex-matched controls were included. Diagnosis of narcolepsy was fully confirmed by polysomnography, HLA DQB1*0602 and CSF hypocretin levels (n=9). Seven patients were free of all drugs, and 14 were treated with psychostimulant and/or anticataplectic drugs. 18-F-fluorodeoxy glucose positron emission tomography procedures were performed at baseline in all subjects and during cataplexy attacks (n=2). Results The authors found significant hypermetabolism in narcolepsy–cataplexy in fully awake condition in the limbic cortex specifically in the anterior and mid cingulate cortex, in the right cuneus and lingual gyrus. In contrast, no hypometabolism was found. Hypermetabolism was detected in the cerebellum and pre–postcentral gyri in treated compared with untreated patients. During cataplectic attacks, cerebral metabolism significantly increased in the bilateral pre–postcentral gyri, primary somatosensory cortex, with a marked decrease in the hypothalamus. Conclusion Hypermetabolism was found in the executive network in narcolepsy at baseline in fully awake condition. Wake state assessment during scanning appears critical to avoid results showing altered functional neurocircuitry secondary to sleepiness and not to the underlying neurological disorder per se. Finally, cataplexy attacks were characterised by a hypometabolism in the hypothalamus associated with wide bilateral brain area hypermetabolisms.

Decision making in restless legs syndrome

The dopamine system is implicated in reward‐based decision making with explicit information (decision making under risk) and implicit probabilities (decision making under ambiguity). Although the pathophysiology of restless legs syndrome (RLS) is not yet fully understood, the genetic factors, iron status, and dopaminergic system are thought to play a role. RLS provides an opportunity to test the dopaminergic hypothesis in a drug‐free population and to characterize reward processing using decision‐making paradigms. We investigated impulsivity, impulse control disorders, and decision making in 50 untreated patients with primary RLS compared with 60 sex‐ and age‐matched normal controls using one night of polysomnography recording, a structured psychiatric interview, and questionnaires (RLS Severity Scale, Beck Depression Inventory, and Urgency Premeditation Perseverance Impulsive Behavior Scale). Subjects performed the Iowa Gambling Task to assess decision making under ambiguity and the Game of Dice Task to assess decision making under risk. Patients with RLS showed selective changes in decision making on the Iowa Gambling Task and normal decision making on the Game of Dice Task compared with controls. Patients with RLS had greater depressive symptoms than controls, but no difference was found in impulsivity, impulse control disorders, or addictive behaviors. Clinical and polysomnographic variables were unrelated to decision‐making performance. Results indicate reduced decision‐making performance under ambiguity in drug‐free patients with RLS. From a clinical perspective, when using dopaminergic medication to treat RLS, patients with abnormal baseline behaviors should be closely monitored.

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.