Narcolepsy with intermediate cerebrospinal level of hypocretin-1.

STUDY OBJECTIVES: To describe the phenotype of narcolepsy with intermediate cerebrospinal fluid hypocretin-1 levels (CSF hcrt-1). METHODS: From 1600 consecutive patients with narcolepsy from Bologna and Montpellier sleep centers, we selected patients with intermediate CSF hcrt-1 levels (110-200 pg/mL). Clinical, neurophysiological, and biological data were contrasted for the presence of cataplexy, human leukocyte haplotype (HLA)-DQB1*06:02, and median CSF hcrt-1 levels (149.34 pg/mL). RESULTS: Forty-five (55% males, aged 35 ± 17 years) patients (2.8% of all cases) were included. Thirty-three (73%) were HLA-DQB1*06:02, 29 (64%) reported cataplexy (21, 72.4% with typical features), and 5 (11%) had presumed secondary etiology. Cataplexy was associated with other core narcolepsy symptoms, increased sleep onset rapid eye movement periods, and nocturnal sleep disruption. Cataplexy and irrepressible daytime sleep were more frequent in HLA-DQB1*06:02 positive patients. Lower CSF hcrt-1 levels were associated with hallucinations. CONCLUSIONS: Narcolepsy with intermediate CSF hcrt-1 level is a rare condition with heterogeneous phenotype. HLA-DQB1*06:02 and lower CSF hcrt-1 were associated with typical narcolepsy features, calling for future research to distinguish incomplete from secondary narcolepsy forms.

Impact of COVID-19 pandemic lockdown on narcolepsy type 1 management.

STUDY OBJECTIVES: Narcolepsy type 1 (NT1) is a chronic rare hypersomnia of central origin requiring a combination of behavioral and pharmacological treatments. During the coronavirus disease 2019 (COVID-19) pandemic, in Italy the population was forced into a lockdown. With this study, we aimed to describe the lockdown impact on NT1 symptom management, according to different patients' working schedule. METHODS: In the period between 10 April and 15 May 2020, we performed routine follow-up visits by telephone (as recommended during the COVID-19 emergency) to 50 patients >18 years old (40% males) under stable long-term treatment. We divided patients into three groups: unchanged working schedule, forced working/studying at home, and those who lost their job ("lost occupation"). Current sleep-wake habit and symptom severity were compared with prelockdown assessment (six months before) in the three patient groups. RESULTS: At assessment, 20, 22, and eight patients belonged to the unchanged, working/studying at home, and lost occupation groups, respectively. While in the lost occupation group, there were no significant differences compared with prepandemic assessment, the patients with unchanged schedules reported more nocturnal awakenings, and NT1 patients working/studying at home showed an extension of nocturnal sleep time, more frequent daytime napping, improvement of daytime sleepiness, and a significant increase in their body mass index. Sleep-related paralysis/hallucinations, automatic behaviors, cataplexy, and disturbed nocturnal sleep did not differ. CONCLUSIONS: Narcolepsy type 1 patients working/studying at home intensified behavioral interventions (increased nocturnal sleep time and daytime napping) and ameliorated daytime sleepiness despite presenting with a slight, but significant, increase of weight.

Cataplexy and ataxia: red flags for the diagnosis of DNA methyltransferase 1 mutation.

None: Mutations in exons 21 and 20 of the DMNT1 gene have been associated with two multisystem neurodegenerative diseases that involve central and peripheral nervous system ADCADN (Autosomal Dominant Cerebellar Ataxia with Deafness and Narcolepsy) and HSAN 1E (Hereditary Sensory and Autonomic Neuropathy IE). We describe a new case of ADCADN that was referred to us in the suspicion of secondary narcolepsy. A 44-year-old female with personal and familiar longstanding history of progressive bilateral sensorineural deafness, and sensitive cerebellar ataxia, presenting with brief episodes of falls while laughing and excessive diurnal somnolence. Clinical and neurophysiological evaluations reveled signs of cerebellar, pyramidal, peripheral, cognitive involvement, and optical atrophy. A 48-hour continuous polysomnography (PSG) and Multiple Sleep Latency Test at first evaluation revealed a normal sleep structure with frequent diurnal sleep episodes and a pathological sleep latency without sleep onset REM periods (SOREMPs). Normal level of cerebrospinal fluid (CSF) hypocretine 1 was detected. Given the reminiscence with DNMT 1 spectrum a direct sequencing of exons 20 and 21 of the DNMT1 gene was performed revealing the p.Glu575Lys mutation in exon 21 in the proband and her mother. During the 4 years of follow-up her walking ability declined, she became more somnolent and repeated PSG documented REM sleep latency shortening, and finally the evidence of de novo spontaneous SOREMPs, although normal CSF hrct-1 at second revaluation. This case highlights the progressive course of disease although a full-blown picture of classical narcolepsy type 1 was never reached.

Segmental Hair Testing of Triazolam to Unmask a Suspected Case of Idiopathic Recurrent Stupor.

ABSTRACT: Stupor is a diagnostic challenge at emergency department. Differential diagnosis includes idiopathic recurrent stupor, formerly attributed to "endozepine-4" accumulation. This condition has been recently questioned because many suspected cases resulted in exogenous benzodiazepine intake that eludes the conventional toxicological assay. In case of unexplained recurrent stupor, to extend the benzodiazepine search in nonconventional matrices can allow unmasking of hidden toxic behavior.

The clinical spectrum of childhood narcolepsy.

Narcolepsy type 1 is a life-long, severe, multifaceted disease often arising in childhood or adolescence. Beyond the classical symptoms (excessive daytime sleepiness, cataplexy, hallucinations, sleep paralysis and nocturnal fragmented sleep), metabolic, endocrinological, psychiatric and psychosocial aspects must be considered. Despite the increased awareness after H1N1 pandemic influenza and vaccination, narcolepsy is still misdiagnosed and unrecognized. The peculiar presentation of symptoms in narcoleptic children could in part explain the misdiagnoses. Excessive daytime sleepiness presenting as chronic drowsiness or irritability could be stigmatized as laziness or misinterpreted as behavior or inattention disorder. The persistent hypotonia and the complex hyperkinetic movements that characterize cataplexy close to the onset, could be misdiagnosed as a movement disorder or as other neurologic conditions. The consequent therapeutic delay could turn into dramatic consequences. The narcolepsy onset, indeed, is associated with abrupt weight gain and sometimes with precocious puberty that require a prompt recognition and treatment to avoid auxological and metabolic complications. Moreover, narcoleptic children could have behavioral and psychiatric disorders ranging from mood to psychotic ones that need ad hoc management. Accordingly, spreading the awareness outside the sleep specialist community is necessary in order to reduce the diagnostic delay and to obtain prompt and multidisciplinary management.

Lack of correlation between extracranial venous abnormalities and multiple sclerosis: a quantitative MRI study.

OBJECTIVE:: We aimed to evaluate the presence of venous stenosis and blood flow abnormalities in the neck vessels of patients with multiple sclerosis (MS), in respect to a group of age- and sex-matched healthy controls (HC), and their possible relations with clinical variables using a semi-automated quantitative MRI method. METHODS:: 45 patients with relapsing remitting MS and 40 HC were enrolled in this study. Flow rates and cross-sectional areas of arterial and venous neck vessels were assessed by phase-contrast MRI at two different neck levels (C2-C3 and C6-C7), and differences between groups were evaluated with an unpaired t-test. Correlation between blood flow variables and clinical parameters was analyzed with Spearman's test. RESULTS:: A significant internal jugular vein (IJV) stenosis was found in 23/45 (51.1%) patients with MS and 18/40 (45.0%) HC. No differences were observed between patients with MS and HC for any of the flow measures obtained. No correlations were found between MRI measures and any of the tested clinical variables. CONCLUSION:: No differences in the IJV area emerged at quantitative MRI evaluation, suggesting that stenosis of the extracranial veins is unrelated to MS. Furthermore, no flow differences in the neck vessels were found between patients with MS and HC in any of the tested flow measures, with no correlation with clinical variables. Our results confirm that the hypothesis of the presence of extracranial venous abnormalities in MS, both in terms of stenosis or flow measures, is not suitable. ADVANCES IN KNOWLEDGE:: Neck venous drainage abnormalities have been claimed to be associated with MS. Conversely, our quantitative MRI analysis seems to exclude that extracranial venous alterations are related to the disease.

In vivo dentate nucleus MRI relaxometry correlates with previous administration of Gadolinium-based contrast agents.

OBJECTIVES: To evaluate changes in T1 and T2* relaxometry of dentate nuclei (DN) with respect to the number of previous administrations of Gadolinium-based contrast agents (GBCA). METHODS: In 74 relapsing-remitting multiple sclerosis (RR-MS) patients with variable disease duration (9.8±6.8 years) and severity (Expanded Disability Status Scale scores:3.1±0.9), the DN R1 (1/T1) and R2* (1/T2*) relaxation rates were measured using two unenhanced 3D Dual-Echo spoiled Gradient-Echo sequences with different flip angles. Correlations of the number of previous GBCA administrations with DN R1 and R2* relaxation rates were tested, including gender and age effect, in a multivariate regression analysis. RESULTS: The DN R1 (normalized by brainstem) significantly correlated with the number of GBCA administrations (p<0.001), maintaining the same significance even when including MS-related factors. Instead, the DN R2* values correlated only with age (p=0.003), and not with GBCA administrations (p=0.67). In a subgroup of 35 patients for whom the administered GBCA subtype was known, the effect of GBCA on DN R1 appeared mainly related to linear GBCA. CONCLUSIONS: In RR-MS patients, the number of previous GBCA administrations correlates with R1 relaxation rates of DN, while R2* values remain unaffected, suggesting that T1-shortening in these patients is related to the amount of Gadolinium given. KEY POINTS: • In multiple sclerosis, previous Gadolinium administrations correlate with dentate nuclei T1 relaxometry. • Such correlation is linked to linear Gadolinium chelates and unrelated to disease duration or severity. • Dentate nuclei T2* relaxometry is age-related and independent of previous Gadolinium administrations. • Changes in dentate nuclei T1 relaxometry are not determined by iron accumulation. • MR relaxometry can quantitatively assess Gadolinium accumulation in dentate nuclei.

Uric acid in relapsing-remitting multiple sclerosis: a 2-year longitudinal study.

Uric acid (UA) is reduced in multiple sclerosis (MS), and possibly relates to MS outcomes, with lower UA levels in subjects experiencing a relapse or presenting higher disability scores. The present retrospective longitudinal study evaluated UA variations in MS, in relation to clinical relapses, disability progression, and cognitive functions. We included 141 subjects with relapsing-remitting MS (RRMS) and performed expanded disability status scale (EDSS), symbol digit modalities test (SDMT) and UA evaluation at baseline visit and after 2-year follow-up. Paired t test showed significantly lower UA levels after 2-year follow-up than at baseline (3.987 ± 1.135 and 4.167 ± 1.207 mg/dL, respectively) (p = 0.001). The difference in UA levels between 2-year follow-up and baseline related to EDSS sustained progression (p < 0.001; OR = 0.099), and presented a trend for clinical relapses at logistic regression (p = 0.211; OR = 0.711) and for the time to relapse at Cox regression (p = 0.236; HR = 0.792). Analysis of variance showed reduced baseline UA levels in subjects with impaired SDMT at baseline (p = 0.045; adjusted R(2) = 0.473) and after 2-year follow-up (p = 0.034; adjusted R(2) = 0.470). This is the first study showing a progressive reduction of UA levels during the course of RRMS, suggesting a progressive decrease of antioxidant reserves, in relation to relapse risk, disability progression and cognitive function.