GABAA receptor and anti-titin antibody encephalitis in a patient with thymoma.

Autoimmune encephalitis (AE) associated to antibodies against GABA A R is a rare form of encephalitis. On the other hand, thymoma has been linked to antibodies against both muscular and neuronal epitopes, even if concurrent positivity for more than one antibody is exceptional, and their contribution to the clinical course and treatment decision is unclear. We report a case of a 73-year-old male with AE associated with thymoma secreting both anti-GABAaR and anti-titin antibodies. Clinical presentation included status epilepticus, behavioural changes and cognitive decline. While the status was stopped with lacosamide, AE treatment included first- and second-line immunomodulation, in addition to thymoma's removal. Nonetheless, the patient experienced a worsening in cognitive and behavioural status.

Sodium oxybate for idiopathic REM sleep behavior disorder: a report on two patients.

BACKGROUND: REM-sleep behavior disorder (RBD) therapy is based on small to medium-sized case series, as no large controlled clinical trials have been performed. The most used and widely recognized effective drugs are clonazepam and melatonin, with anecdotal reports on the potential benefit of other drug classes. METHODS: We report on two patients suffering from idiopathic RBD presenting with almost nightly complex and violent episodes, refractory to conventional drugs. Both patients, after informed consent, were treated off-label with sodium oxybate in add-on therapy. We followed up the patients in order to assess treatment efficacy by means of clinical interview, visual analog scales (VAS) for frequency and severity, Clinical Global Impression (CGI) improvement scale and efficacy index, video-polysomnography and at-home actigraphy. RESULTS: Sodium oxybate intake was well tolerated and effective in reducing the number and intensity of RBD episodes; patients reported no new traumatic episodes. Results were confirmed by bed-partner reports, VAS, CGI improvement scale and efficacy index, and at-home actigraphic monitoring, the latter showing a trend of improvement in nocturnal sleep quality and reduction in motor activity, compared to the baseline. Nevertheless, video-polysomnography did not show a clear beneficial effect on sleep-related electromyographic parameters. CONCLUSIONS: Our cases suggest that sodium oxybate can be an effective add-on option for the treatment of idiopathic RBD refractory to conventional therapies. The lack of improvement of polysomnographic parameters suggests caution in considering only polysomnographic data as endpoints in the assessment of the efficacy of therapies for RBD, and that long-term home-based assessment seems a promising tool.

Polysomnographic and neurometabolic features may mark preclinical autosomal dominant cerebellar ataxia, deafness, and narcolepsy due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1.

OBJECTIVE: We aimed to report the clinical picture of two asymptomatic daughters of a patient with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1. METHODS: Clinical assessment based on history, neurologic examination, sleep recordings, neurophysiologic neuroimaging, and genetic tests was performed. RESULTS: History and neurologic examination in both subjects were unremarkable. Genetic analysis disclosed in both the paternally-inherited heterozygous point mutation in the DNMT1 gene. Sleep recordings found sleep-onset rapid eye movement periods (SOREMPs) and proton magnetic resonance spectroscopy (MRS) revealed increased cerebellar myoinositol (mI) in both subjects. Auditory and ophthalmologic investigations as well as structural brain magnetic resonance imaging (MRI) scans revealed no abnormalities. CONCLUSIONS: The two asymptomatic carriers of the heterozygous DNMT1 mutation for ADCA-DN, a late-onset neurodegenerative disease, presented with SOREMPs associated with an increase of mI in the brain, a marker of glial cell activity and density characteristic of early stages of neurodegenerative diseases. Therefore, SOREMPs may precede the clinical picture of ADCA-DN as an early polysomnographic marker of central nervous system involvement detected by MRS.

Narcolepsy is a common phenotype in HSAN IE and ADCA-DN.

We report on the extensive phenotypic characterization of five Italian patients from four unrelated families carrying dominant heterozygous DNMT1 mutations linked to two distinct autosomal dominant diseases: hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE (HSAN IE) and autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Patients underwent genetic analysis of DNMT1 gene, neurophysiological tests investigating sleep, auditory functions and peripheral nervous system, ophthalmological studies including optical coherence tomography, lymphoscintigraphy, brain magnetic resonance and nuclear imaging, cerebrospinal fluid hypocretin-1, total tau, phosphorylated tau, amyloid-ß1-42 and 14-3-3 proteins measurement, skin, muscular and sural nerve biopsies. Exome and direct sequencing studies disclosed two different point mutations affecting exon 21 of DNMT1 gene in patients with ADCA-DN, a novel heterozygous point mutation in exon 20 in two affected HSAN IE siblings, and a trinucleotide deletion in exon 20 in the latter patient with HSAN IE. Phenotypic characterization pinpoints that ADCA-DN and HSAN IE represent two discrete clinical entities belonging to the same disease spectrum, with variable degree of overlap. Remarkably, narcolepsy with or without cataplexy with low/intermediate or normal cerebrospinal fluid hypocretin-1 is present in both diseases. The human leukocyte antigen DQB1*06:02 was absent in all patients. Other common symptoms and features observed in our cases, involving the central and peripheral nervous system, include deafness, optic neuropathy-previously not reported in HSAN IE-large and small fibres polyneuropathy and lower limbs oedema. Overall, the two syndromes share more characteristics than previously recognized and narcolepsy is common to both. HSAN IE and ADCA-DN are two extreme phenotypic manifestations of a DNMT1 methylopathy.

Narcolepsy with cataplexy mimicry: the strange case of two sisters.

We report on two sisters, 17 and 12 years of age, with clinical features suggesting narcolepsy with cataplexy (NC): daytime sleepiness, spontaneous and emotionally triggered sudden falls to the ground, and overweight/obesity. MSLT showed borderline sleep latency, with 1 and 0 sleep onset REM periods. HLA typing disclosed the DQB1*0602 allele. Video-polygraphy of the spells ruled out NC diagnosis by demonstrating their easy elicitation by suggestion, with wake EEG, electromyographic persistence of muscle tone, and stable presence of tendon reflexes (i.e., pseudo-cataplexy), together with normal cerebrospinal hypocretin-1 levels. Our cases emphasize the need of a clear depiction of cataplexy pattern at the different ages, the usefulness of examining ictal neurophysiology, and collecting all available disease markers in ambiguous cases.

Sleep disorders in patients with spinal cord injury.

Sleep disturbances are globally more frequent in patients with spinal cord injury (SCI) than in the able-bodied population, and could contribute to dysfunction and poor quality of life in these patients. Specific sleep disorders may also contribute to negative health outcomes enhancing cardiovascular risk in a condition that per se increases heart disease related mortality. This review focuses on prevalence, features and treatment of sleep disorders in SCI. Although data on these subjects have been produced, reports on pathophysiology, consequences and treatment of sleep disorders are scarce or contradictory and more studies are required.

The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns.

BACKGROUND: In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. METHODS: We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. RESULTS: Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. CONCLUSIONS: The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

Catathrenia under sodium oxybate in narcolepsy with cataplexy.

PURPOSE: This study aims to report on catathrenia occurring in narcolepsy with cataplexy (NC) patients under sodium oxybate (SO) treatment. Catathrenia is a parasomnia characterized by groaning and an abnormal respiratory pattern during sleep. METHODS: Fifty-one patients with NC and starting SO therapy underwent a baseline overnight polysomnography (PSG) to detect any sleep-related breathing disorders (SRBD). To avoid risks due to a possible central respiratory control depression by SO, all patients with concomitant obstructive sleep apnea (OSA) were treated with a nasal continuous positive airway pressure (nCPAP) device. After 2 months of treatment with SO, all patients underwent a follow-up overnight PSG to investigate possible newly occurring SRBD. They also underwent a semi-structured clinical interview to monitor other potential SO side effects. RESULTS: At baseline, four out of 51 patients showed simple snoring, and eight, mild to severe OSA. After a titration PSG night, patients with OSA received a nCPAP device. After 2 months of SO treatment, 28 patients (54.9%) showed SO-related side effects, including SRBD in 11 (21.6%). The follow-up PSG showed a respiratory pattern characteristic of catathrenia in seven patients (13.7%) as a newly observed and possibly benign SO side effect, and ruled out a worsening of OSA. CONCLUSIONS: Catathrenia should be considered a possible side effect in NC patients under SO treatment and should be accurately identified to prevent unnecessary SO withdrawal.

Narcolepsy with cataplexy associated with nocturnal compulsive behaviors: a case-control study.

STUDY OBJECTIVES: To assess the prevalence of sleep related-eating disorder (SRED) and nocturnal smoking (NS) in patients with narcolepsy with cataplexy (NC). DESIGN: Case-control study. SETTING: University hospital. PATIENTS OR PARTICIPANTS: 65 consecutive adult NC patients (33 men; mean age 43.9 ± 19.2 years) and 65 age-, sex-, and geographical origin-matched controls. INTERVENTIONS: Validated questionnaires were used to investigate SRED, NS, restless legs syndrome (RLS), and psychopathological traits (using Eating Disorder Inventory-2 [EDI-2]; Maudsley Obsessive-Compulsive Inventory [MOCI]; and Beck Depression Inventory [BDI]). MEASUREMENTS AND RESULTS: NC patients showed a higher prevalence of SRED (32% vs 3%, P=0.00001), NS (21% vs 0%, P=0.00006), and RLS (18% vs 5%, P=0.013) than controls. Moreover, NC patients presented more frequently with an eating-related pathological profile on the EDI-2 (80% vs 46%, P=0.00006) and had a higher prevalence of depressed mood on the BDI (41% vs 18%, P=0.004). In comparison to patients without SRED, NC patients with SRED were more frequently women (71% vs 39%, P=0.013), had higher "bulimic" (29% vs 2%, P=0.004) and "social insecurity" (48% vs 18%, P=0.013) traits on the EDI-2, had higher obsessive-compulsiveness on the MOCI (29% vs 4%, P = 0.009), and were more depressed on the BDI (67% vs 29%, P=0.005). NC patients with NS showed more frequent pathological profiles on the EDI-2 (100% vs 75%, P=0.035), including the "bulimic" (29% vs 6%, P=0.015), "perfectionism" (43% vs 14%, P=0.016), and "social insecurity" (50% vs 22, P=0.035) profiles. CONCLUSION: Our study shows a strong association of the compulsive nocturnal behaviors SRED and NS with adult NC.

Autonomic disturbances in narcolepsy.

Narcolepsy is a clinical condition characterized mainly by excessive sleepiness and cataplexy. Hypnagogic hallucinations and sleep paralysis complete the narcoleptic tetrad; disrupted night sleep, automatic behaviors and weight gain are also usual complaints. Different studies focus on autonomic changes or dysfunctions among narcoleptic patients, such as pupillary abnormalities, fainting spells, erectile dysfunction, night sweats, gastric problems, low body temperature, systemic hypotension, dry mouth, heart palpitations, headache and extremities dysthermia. Even if many studies lack sufficient standardization or their results have not been replicated, a non-secondary involvement of the autonomic nervous system in narcolepsy is strongly suggested, mainly by metabolic and cardiovascular findings. Furthermore, the recent discovery of a high risk for overweight and for metabolic syndrome in narcoleptic patients represents an important warning for clinicians in order to monitor and follow them up for their autonomic functions. We review here studies on autonomic functions and clinical disturbances in narcoleptic patients, trying to shed light on the possible contribute of alterations of the hypocretin system in autonomic pathophysiology.

Behavioural and neurophysiological correlates of human cataplexy: a video-polygraphic study.

OBJECTIVES: To investigate the behavioural and neurophysiological pattern of cataplexy. METHODS: Seven narcolepsy with cataplexy patients underwent daytime videopolygraphy using humorous movies or/and jokes to trigger cataplectic attacks. RESULTS: During segmental cataplectic attacks, EMG showed brief and irregular periods of silencing focally involving facial, neck, axial or limb muscles, sometimes coinciding with bursts of rapid eye movements. All patients enacted intentional movements in response to these segmental postural lapses. During global cataplectic attacks, EMG showed suppression of activity alternated with patterned enhancement, enhanced EMG activity in neck muscles preceding that of other cranial, axial and lower limb muscles. This waxing and waning EMG pattern ended with a complete body collapse and persistent muscle atonia. Breathing irregularities, heart rate (HR) instability and EEG desynchronization were observed during global cataplectic attacks without any appreciable blood pressure changes, but with HR deceleration and silencing of sympathetic skin response while in complete atonia. Patients subjectively perceived the involuntary postural lapses as startling and alarming. CONCLUSIONS: Cataplexy in our patients showed many of the features of tonic REM sleep. SIGNIFICANCE: Cataplexy can be construed as a "freezing-like" perturbation of the orienting response with transient impairment of posture and movements resulting in a "patchwork-compromise-behaviour".