Soňa Nevšímalová

CSF hypocretin/orexin levels in narcolepsy and other neurological conditions

Objective: To examine the specificity of low CSF hypocretin-1 levels in narcolepsy and explore the potential role of hypocretins in other neurologic disorders. Methods: A method to measure hypocretin-1 in 100 μL of crude CSF sample was established and validated. CSF hypocretin-1 was measured in 42 narcolepsy patients (ages 16–70 years), 48 healthy controls (ages 22–77 years,) and 235 patients with various other neurologic conditions (ages 0–85 years). Results: As previously reported, CSF hypocretin-1 levels were undetectably low (<100 pg/mL) in 37 of 42 narcolepsy subjects. Hypocretin-1 levels were detectable in all controls (224–653 pg/mL) and all neurologic patients (117–720 pg/mL), with the exception of three patients with Guillain–Barré syndrome (GBS). Hypocretin-1 was within the control range in most neurologic patients tested, including patients with AD, PD, and MS. Low but detectable levels (100–194 pg/mL) were found in a subset of patients with acute lymphocytic leukemia, intracranial tumors, craniocerebral trauma, CNS infections, and GBS. Conclusions: Undetectable CSF hypocretin-1 levels are highly specific to narcolepsy and rare cases of GBS. Measuring hypocretin-1 levels in the CSF of patients suspected of narcolepsy is a useful diagnostic procedure. Low hypocretin levels are also observed in a large range of neurologic conditions, most strikingly in subjects with head trauma. These alterations may reflect focal lesions in the hypothalamus, destruction of the blood brain barrier, or transient or chronic hypofunction of the hypothalamus. Future research in this area is needed to establish functional significance.

Common variants in P2RY11 are associated with narcolepsy

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10−10, odds ratio = 1.28, 95% CI 1.19–1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8+ T lymphocytes (72% reduced, P = 0.003) and natural killer (NK) cells (70% reduced, P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.

Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults

Alternating hemiplegia of childhood is a neurological disorder characterized by episodes of hemiplegia, various non-epileptic paroxysmal events and global neurological impairment. Characterization of the evolution and outcome into adulthood has not been sufficiently investigated. The goal of this study was to elucidate the natural history of alternating hemiplegia within a large cohort of 157 patients, as part of the European Network for Research on Alternating Hemiplegia project. A questionnaire was formulated to determine the severity of both paroxysmal and global neurological impairment and address progression of the disorder by allocating data to specific age epochs up to and over 24 years of age. Patients in early age groups were consistently present in subsequent later age groups and for each patient, data were collected for each corresponding age epoch. The study was based on predominantly retrospective and, for a period of 2 years, prospective data. At inclusion, patients were aged from 9 months to 52 years. The median age at diagnosis was 20 months. All patients experienced hemiplegic attacks; 86.5% reported episodes of bilateral weakness, 88% dystonic attacks, 53% epileptic seizures, 72% developed chorea and/or dystonia and 92% mental retardation. When data over the course of the illness were examined for the whole cohort, the severity of symptoms did not appear to change, with the exception of abnormal ocular movements and hypotonia that regressed, but did not disappear into adulthood (from 86 to 36% and 76 to 36%, respectively). No statistically significant correlation between a history of severe paroxysmal hemiplegic/dystonic episodes and a worse neurological outcome was identified. Seven patients died, some of whom experienced severe plegic attacks or epileptic seizures at the time of death. History of severe plegic/dystonic attacks was not found to be an aggravating factor for deceased patients. Our results provide evidence that the natural history of alternating hemiplegia is highly variable and unpredictable for individual patients. However, we did not find evidence to support a steadily progressive and degenerative course of the disorder when patients were analysed as a group. For a minority of patients, a risk of sudden death was associated with more severe neurological impairment. The European Network for Research on Alternating Hemiplegia Registry, validated by our study, includes all major neurological signs and symptoms of alternating hemiplegia and may thus be used as a precedent for the progressive inclusion and follow-up of patients as well as a reference for genetic studies and treatment trials.

Hypocretin deficiency in Prader–Willi syndrome

Four patients with clinically and genetically confirmed Prader–Willi syndrome (PWS) underwent nocturnal polysomnograpy (PSG), multiple sleep latency test (MSLT), human leukocyte antigens (HLA) typing and estimation of cerebrospinal fluid (CSF) hypocretin‐1 (Hcrt‐1) level to investigate if a role of hypothalamic dysfunction and sleep disturbance might be functionally connected through the hypocretin (orexin) system. In all four patients physical examination confirmed extreme obesity (increasing with age) with dysmorphogenetic features. Excessive daytime sleepiness (EDS) was manifested in only two subjects without any imperative feature. None of the patients under study suffered from cataplexy. Nocturnal PSG revealed fragmented sleep with low efficiency, the hypopnea and apnea indexes increasing from borderline up to very high values in direct proportion to the patients’ age. MSLT latency was shortened in two patients with clinically expressed EDS, only one sleep onset rapid eye movements (REM) period (SOREM) was found. HLA typing showed DQB1*0602 positivity in two patients; the further two were negative. Mean value of CSF Hcrt‐1 in the patients group was down to 164 ± 46.8 pg/ml (in comparison with 265.8 ± 48.8 pg/ml in 10 young healthy subjects, P = 0.02). The deficiency of CSF Hcrt‐1 level correlated in PWS patients with their EDS severity.

A role of autoimmunity in the etiopathogenesis of Landau-Kleffner syndrome?

Four children, 3 boys and 1 girl, with the syndrome of acquired aphasia Landau-Kleffner were followed up during the last 10 years. In 3 children an episodic form of the disease with a good response to corticosteroid treatment and with a favourable prognosis was observed. In the other 1 no improvement of speech function was observed and also epileptic fits were reduced only with difficulty. A positive autoimmune reaction to central (MOZAN) and peripheral (LISAN) myelin was observed repeatedly during the attacks of clinical worsening. On the contrary, during the periods of improvement of language disturbances during the treatment with corticosteroids this hypersensitivity to central as well as peripheral myelin disappeared. Possible changes in myelinization and the role of autoimmune reactions in the etiopathogenesis of the disease are discussed.

Sleep disorders in Wilson's disease.

Background:  Wilson’s disease (WD) is an autosomal recessive inherited disease with copper accumulation; neurodegeneration is associated with dopaminergic deficit. The aim of the study is to verify sleep co‐morbidity by questionnaire and objective sleep examinations (polysomnography, multiple sleep latency test).

Arousals in nocturnal groaning

BACKGROUND AND OBJECTIVE Nocturnal groaning (catathrenia) is a chronic sleep disorder classified as parasomnia with unclear effects on sleep and life quality. It is characterized by repeated episodes of monotonous vocalization in prolonged expiration (episodes of bradypnea) occurring mostly in REM sleep. We sought to assess its impact on sleep microstructure, i.e., the frequency of arousals relative to the groaning episodes. The frequency, duration and sleep-stage distribution of the groaning episodes were also studied. METHODS Eight patients with nocturnal groaning (5 male, 3 female, age range 11-32 years, mean age 23+/-7.1) were evaluated. All underwent standard neurologic examination and nocturnal videopolysomnography for two consecutive nights. The second night polysomnography data were used to evaluate sleep parameters. The groaning episodes (bradypneic events) were counted separately, not as clusters. RESULTS Sleep macrostructure revealed no specific changes. The number of groaning episodes/bradypneic events during the night varied from 40 to 182 (total number 725). The duration of bradypnea was from 2 to 46s (mean duration 12.5s). Groaning episodes prevailed in REM sleep (76.5%). The rate for NREM 2 was 21.5%, and only sporadic episodes were noted in delta sleep (1.9%); 63.3% of the events were associated with arousals, and in 94% of them an arousal occurred before or together with the onset of bradypnea. The arousal index was increased in 5 patients (mean 20.4). Bruxism was present in 4 cases, in 1 patient appearing in close association with groaning episodes. Ronchopathy was noted in 4 cases. CONCLUSION Almost two-thirds of the groaning episodes were connected with arousals. Hypothetically, nocturnal groaning may well be a source of sleep disruption (mainly REM) in some cases. Because an arousal mostly preceded or coincided with groaning we believe that arousal mechanisms may be involved in the pathogenesis of nocturnal groaning.

Diagnosing narcolepsy with cataplexy on history alone: challenging the International Classification of Sleep Disorders (ICSD-2) criteria

Background and purpose:  The second version of the International Classification of Sleep Disorders suggests narcolepsy with cataplexy can be diagnosed on history alone.

Narcolepsy with cataplexy in patients aged over 60 years: a case-control study

OBJECTIVE Narcolepsy with cataplexy (NC) is a chronic disabling disease; however, there are insufficient data on older NC subjects. METHODS A cross-sectional evaluation on health and social status, including intensity and progression of NC symptoms, was performed on 42 NC patients (age 71.9 years ± 7.5) and 46 age-and-sex-matched controls (age 72.2 years ± 7.0). RESULTS A greater proportion of patients than controls suffered from hypertension and type 2 diabetes. More controls had a history of treated depression; however, according to the Geriatric Depression Scale, more NC patients scored in the range of depression. There were no significant differences in Addenbrook Cognitive Examination scores. Average physical fitness assessed by the Short Physical Performance Battery was lower in the NC group. The frequency of meeting with family, friends, and participation in hobbies or sports did not differ between the two groups. CONCLUSIONS Symptoms of NC were present throughout life. Comorbidities and lower physical fitness, which are known to be present in young and middle-aged NC subjects, were also present in older patients. Although NC subjects were less professionally active during their lifetime, they did not differ from controls in important social parameters in older age.

Chapter 39 EEG changes and epilepsy in developmental dysphasia

Publisher Summary This chapter discusses the relationship between developmental dysphasia and electroencephalography (EEG) abnormalities and explains the relationship among the disorders of auditory perception, speech comprehension, and subclinical epileptic disturbances. Typical clinical picture of developmental dysphasia includes retarded speech development with specific disorders in all speech structures: the individual phonological system and the other linguistic levels—lexical, syntactic, grammatical, and semantic. The children have typical speech comprehension problems varying in intensity and have typical auditory decoding deficits, integration deficit, associative deficit, and output organization deficit of speech. Many children are not able to recognize acoustic contours or identify the keywords from a spoken message. The children with developmental dysphasia often behave as if peripheral hearing loss is present, despite normal hearing. Disorders of speech comprehension are typical for all patients with central auditory processing disorders. Developmentally dysphasic children exhibit a higher incidence of abnormal EEG than expected. Spontaneous verbal communication is limited and in the majority of cases, disappears completely. In most cases, epileptic seizures appear, sometimes even as a presenting symptom of the disease.