Melatonin in sleep disorders.

Melatonin is the main hormone involved in the control of the sleep-wake cycle. It is easily synthesisable and can be administered orally, which has led to interest in its use as a treatment for insomnia. Moreover, as production of the hormone decreases with age, in inverse correlation with the frequency of poor sleep quality, it has been suggested that melatonin deficit is at least partly responsible for sleep disorders. Treating this age-related deficit would therefore appear to be a natural way of restoring sleep quality, which is lost as patients age. However, despite the undeniable theoretical appeal of this approach to insomnia, little scientific evidence is available that supports any benefit of this substitutive therapy. Furthermore, the most suitable dose ranges and pharmaceutical preparations for melatonin administration are yet to be clearly defined. This review addresses the physiology of melatonin, the different pharmaceutical preparations, and data on its clinical usefulness.

Phenotypic correlations in a large single-center cohort of patients with BSCL2 nerve disorders: a clinical, neurophysiological and muscle magnetic resonance imaging study.

BACKGROUND AND PURPOSE: BSCL2 heterozygote mutations are a common cause of distal hereditary motor neuropathies (dHMNs). A series of BSCL2 patients is presented and clinical, neurophysiological and muscle magnetic resonance imaging (MRI) findings are correlated. METHODS: Twenty-six patients from five families carrying the p.N88S mutation were identified. Age of onset, clinical phenotype (dHMN, Charcot-Marie-Tooth, spastic paraplegia), physical examination, disability measured as a modified Rankin Scale score and neurophysiological findings were collected. A whole body muscle MRI had been performed in 18 patients. The pattern of muscle involvement on T1-weighted and short time inversion recovery sequences was analysed. Hierarchical analysis using heatmaps and an MRI Composite Score were generated. Statistical analysis was carried out with STATA SE v.15 (TX, USA). RESULTS: The mean age was 51.54 ± 19.94 years and 14 patients were men. dHMN was the most common phenotype (50%) and five patients (19.23%) showed no findings on examination. Disease onset was commonly in childhood and disability was low (modified Rankin Scale score 1.34 ± 1.13) although median time since onset of disease was 32 years (range 10-47). Charcot-Marie-Tooth-like patients were more disabled and disability correlated with age. On muscle MRI, thenar eminence, soleus and tibialis anterior were most frequently involved, irrespective of clinical phenotype. MRI Composite Score was strongly correlated with disability. CONCLUSION: Patients with the p.N88S BSCL2 gene mutation are phenotypically variable, although dHMN is most frequent and generally slowly progressive. Muscle MRI pattern is consistent regardless of phenotype and correlates with disease severity, probably serving as a reliable outcome measure for future clinical trials.

Melatonin in sleep disorders. / Melatonina en los trastornos de sueño.

Melatonin is the main hormone involved in the control of the sleep-wake cycle. It is easily synthesisable and can be administered orally, which has led to interest in its use as a treatment for insomnia. Moreover, as production of the hormone decreases with age, in inverse correlation with the frequency of poor sleep quality, it has been suggested that melatonin deficit is at least partly responsible for sleep disorders. Treating this age-related deficit would therefore appear to be a natural way of restoring sleep quality, which is lost as patients age. However, despite the undeniable theoretical appeal of this approach to insomnia, little scientific evidence is available that supports any benefit of this substitutive therapy. Furthermore, the most suitable dose ranges and pharmaceutical preparations for melatonin administration are yet to be clearly defined. This review addresses the physiology of melatonin, the different pharmaceutical preparations, and data on its clinical usefulness.

Familial amyloidosis with polyneuropathy type 1 caused by transthyretin mutation Val50Met (Val30Met): 4 cases in a non-endemic area. / Polineuropatía amiloidótica familiar I por mutación Val50Met (Val30Met) en el gen de la transtiretina.

INTRODUCTION: Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) typically arises as an autonomic neuropathy primarily affecting small fibres and it occurs in adult patients in their second or third decades of life. It progresses rapidly and can lead to death in approximately 10 years. Other phenotypes have been described in non-endemic areas. OBJECTIVES AND METHODS: We described 4 cases from the Spanish province of Guipuzcoa, a non-endemic area, to highlight the clinical variability of this disease. PATIENTS AND RESULTS: Three patients presented a late-onset form manifesting after the age of 50, featuring a predominantly motor polyneuropathy initially causing distal impairment of the lower limbs followed by the upper limbs. One patient suffered severe neuropathic pain. None showed signs of autonomic involvement. The fourth patient, of Portuguese descent, presented a typical form with onset in her thirties, neuropathic pain and dysautonomia. All patients carry the Val50Met mutation in the TTR gene. CONCLUSION: FAP is a pleomorphic disease even in patients carrying the same mutation. In non-endemic areas, its main form of presentation may resemble a predominantly motor polyneuropathy developing in the sixth decade of life with no signs of dysautonomia. Given this non-specific presentation and the widely available technical means of studying the TTR gene, we believe that the protocol for the aetiological diagnosis of any polyneuropathy should include genetic sequencing of TTR.

EARLY-ESLI study: Long-term experience with eslicarbazepine acetate after first monotherapy failure.

PURPOSE: Evaluate real-life experience with eslicarbazepine acetate (ESL) after first monotherapy failure in a large series of patients with focal epilepsy. METHOD: Multicentre, retrospective, 1-year, observational study in patients older than 18 years, with focal epilepsy, who had failed first antiepileptic drug monotherapy and who received ESL. Data from clinical records were analysed at baseline, 3, 6 and 12 months to assess effectiveness and tolerability. RESULTS: Eslicarbazepine acetate was initiated in 253 patients. The 1-year retention rate was 92.9%, and the final median dose of ESL was 800 mg. At 12 months, 62.3% of patients had been seizure free for 6 months; 37.3% had been seizure free for 1 year. During follow-up, 31.6% of the patients reported ESL-related adverse events (AEs), most commonly somnolence (8.7%) and dizziness (5.1%), and 3.6% discontinued due to AEs. Hyponatraemia was observed in seven patients (2.8%). After starting ESL, 137 patients (54.2%) withdrew the prior monotherapy and converted to ESL monotherapy; 75.9% were seizure free, 87.6% were responders, 4.4% worsened, and 23.4% reported ESL-related AEs. CONCLUSION: Use of ESL after first monotherapy failure was associated with an optimal seizure control and tolerability profile. Over half of patients were converted to ESL monotherapy during follow-up.

Safety, efficacy and outcome-related factors of perampanel over 12 months in a real-world setting: The FYDATA study.

BACKGROUND: Real-world data of current antiepileptic drugs (AEDs) used to treat focal seizures is of importance to understand the efficacy and safety outside of the clinical trial setting. Here we report real-world data from a large series of patients treated with perampanel for 1year. METHODS: FYDATA was a multicentre, retrospective, 1-year observational study assessing the efficacy and safety of adjuvant perampanel in patients ≥12 years of age with focal epilepsy in a real-world setting. At 12 months, the proportion of patients who were seizure free, median percentage seizure reduction, proportion of responders, retention rate and proportion of patients with adverse events (AEs) were assessed. Analyses were also performed to identify any patient-, medication- and disease-related factors associated with a large clinical response or carry a risk for AEs. RESULTS: A total of 464 patients were included in the study with a retention rate of 60.6% at 1year. The mean number of prior AEDs was 7.8. The median percentage reduction in overall seizures was 33.3% (75% for secondary generalised seizures) after 1year, with 7.2% of patients achieving seizure freedom. Furthermore, patients on non-enzyme-inducing AEDs were more likely to achieve seizure freedom, and logistic regression revealed that patients aged ≥65 years, those with epilepsy due to a vascular aetiology and those who had received fewer prior AEDs showed a better clinical response to perampanel. A total of 62.9% of the patients experienced AEs at 12 months; dizziness, somnolence and irritability were the most frequent AEs. Patients with prior psychiatric comorbidities (hyperactivity and personality disorder) were more likely to experience psychiatric AEs with perampanel, and slower titration schedules were associated with less AEs overall. CONCLUSION: Perampanel, for the treatment of focal epilepsy in a real-world setting in a refractory population, over 1year, demonstrates a similar efficacy and safety profile to that observed in clinical trials. Our results have implications for the optimisation of perampanel use in a clinical setting.

Cognitive/personality pattern and triplet expansion size in adult myotonic dystrophy type 1 (DM1): CTG repeats, cognition and personality in DM1.

BACKGROUND: Although central nervous system (CNS) involvement in adult myotonic dystrophy type 1 (DM1) was described long ago, the large number of variables affecting the cognitive and personality profile have made it difficult to determine the effect of DM1 on the brain. The aim of this study was to define the cognitive and personality patterns in adult DM1 patients, and to analyse the relationship between these clinical patterns and their association with the underlying molecular defect. METHOD: We examined 121 adult DM1 patients with confirmed molecular CTG repeat expansion and 54 control subjects using comprehensive neuropsychological tests and personality assessments with the Millon Clinical Multiaxial Inventory (MCMI)-II. We used a multiple linear regression model to assess the effect of each variable on cognition and personality adjusted to the remainders. RESULTS: Patients performed significantly worse than controls in tests measuring executive function (principally cognitive inflexibility) and visuoconstructive ability. In the personality profile, some paranoid and aggressive traits were predominant. Furthermore, there was a significant negative correlation between the CTG expansion size and many of the neuropsychological and personality measures. The molecular defect also correlated with patients' daytime somnolence. CONCLUSIONS: Besides muscular symptomatology, there is significant CTG-dependent involvement of the CNS in adult DM1 patients. Our data indicate that the cognitive impairment predominantly affects the fronto-parietal lobe.

Genetic analysis of the LGI/Epitempin gene family in sporadic and familial lateral temporal lobe epilepsy.

Mutations in the LGI1/Epitempin gene cause autosomal dominant lateral temporal lobe epilepsy (ADLTE), a partial epilepsy characterized by the presence of auditory seizures. However, not all the pedigrees with a phenotype consistent with ADLTE show mutations in LGI1/Epitempin, or evidence for linkage to the 10q24 locus. Other authors as well as ourselves have found an internal repeat (EPTP, pfam# PF03736) that allowed the identification of three other genes sharing a sequence and structural similarity with LGI1/Epitempin. In this work, we present the sequencing of these genes in a set of ADLTE families without mutations in both LGI1/Epitempin and sporadic cases. No analyzed polymorphisms modified susceptibility in either the familial or sporadic forms of this partial epilepsy.

[Total dream loss secondary to left temporo-occipital brain injury]. / Pérdida completa de ensoñaciones tras una lesión cerebral temporooccipital izquierda.

INTRODUCTION: Recently the case of a woman who reported cessation of dreaming after a bilateral PCA stroke but without REM sleep loss has been reported, suggesting that deep bilateral occipital lobe damage including the right inferior lingual gyrus may represent the "minimal lesion extension" necessary for dream loss. CASE REPORT: We report the case of a 24-year-old man who ceased dreaming after a unilateral left temporo- occipital hematoma. The polysomnographic characteristics in rapid eyes movements (REM) sleep were otherwise normal. CONCLUSION: Our patient demonstrates that a unilateral left temporo-occipital injury could be sufficient for losing dreams.

LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene.

We present here the clinical, molecular and biochemical findings from 238 limb-girdle muscular dystrophy type 2A (LGMD2A) patients, representing approximately 50% (238 out of 484) of the suspected calpainopathy cases referred for the molecular study of the calpain 3 (CAPN3) gene. The mean age at onset of LGMD2A patients was approximately 14 years, and the first symptoms occurred between 6 and 18 years of age in 71% of patients. The mean age at which the patients became wheelchair bound was 32.2 years, with 84% requiring the use of a wheelchair between the age of 21 and 40 years. There was no correlation between the age at onset and the time at which the patient became wheelchair bound, nor between the sex of the patient and the risk of becoming wheelchair bound. Of the cases where the CAPN3 gene was not affected, approximately 20% were diagnosed as LGMD2I muscular dystrophy, while facioscapulohumeral muscular dystrophy (FSHD) was uncommon in this sample. We identified 105 different mutations in the CAPN3 gene of which 50 have not been described previously. These were distributed throughout the coding region of the gene, although some exons remained free of mutations. The most frequent mutation was 2362AG-->TCATCT (exon 22), which was present in 30.7% of the chromosomes analysed (146 chromosomes). Other recurrent mutations described were N50S, 550DeltaA, G222R, IVS6-1G-->A, A483D, IVS17+1G-->T, 2069-2070DeltaAC, R748Q and R748X, each of which was found in >5 chromosomes. The type of mutation in the CAPN3 gene does not appear to be a risk factor for becoming dependent on a wheelchair at a determined age. However, in the cases with two null mutations, there were significantly fewer patients that were able to walk than in the group of patients with at least one missense mutation. Despite the fact that the results of phenotyping and western blot might be biased due to multiple referral centres, producing a diagnosis on the basis of the classical phenotype is neither sufficiently sensitive (86.7%) nor specific (69.3%), although western blot proved to be even less sensitive (52.5%) yet more specific (87.8%). In this case LGMD2I was a relevant cause of false-positive diagnoses. Considering both the clinical phenotype and the biochemical information together, the probability of correctly diagnosing a calpainopathy is very high (90.8%). However, if one of the analyses is lacking, the probability varies from 78.3 to 73.7% depending on the information available. When both tests are negative, the probability that the sample comes from a patient with LGMD2A was 12.2%.

[Comparison of mixed latency of ulnar and median nerve between wrist and elbow as diagnostic test of ulnar neuropathy in elbow]. / Comparación de la latencia mixta de muñeca a codo de nervios mediano y cubital como test diagnóstico de la neuropatía cubital en el codo.

INTRODUCTION: Conventional electrodiagnosis of ulnar neuropathy at the elbow is based on abnormalities in motor conduction across the elbow. However, sensory symptoms are predominant, and an accurate determination of the length of the nerve in this segment is difficult to obtain. OBJECTIVE: We present an electrodiagnostic technique which helps to avoid these difficulties. MATERIAL AND METHODS: We compared the mixed latency of ulnar and median nerve between wrist and above the elbow in 172 symptomatic and 407 asymptomatic ulnar nerves. RESULTS: We determined that a difference of the mixed latency of ulnar and median nerve between wrist and above the elbow equal or higher than 1 ms had a sensitivity of 87% to an specificity of 91% for the diagnosis of ulnar neuropathy at the elbow. Moreover, a difference between both arms equal to or higher than 0.3 ms had a sensitivity of 80% and specificity of 91 %. If both conditions are present, the test is very specific (98%). CONCLUSIONS: The measurement of the difference in mixed latency between ulnar and median nerves from wrist to above the elbow is a valuable tool for evaluating patients with suspected ulnar neuropathy at the elbow without motor involvement.

Prevalence of Parkinson's disease and other types of Parkinsonism. A door-to-door survey in Bidasoa, Spain.

OBJECTIVES: To assess the prevalence of Parkinson's disease and parkinsonism in two Spanish populations (Irun and Hondarribia, Bidasoa Region) and to compare the results with those of similar surveys. METHODS: The survey included 2000 participants aged 65 years or older in a door-to-door, three-phase design. In the screening phase we used the SNES (Sicilian Neuro-Epidemiologic Study) screening questionnaire, which has 100% sensitivity. In phases 2 and 3 we carried out a 3-year follow-up of all cases diagnosed with parkinsonism in phase 2. Progressively stricter diagnostic criteria were chosen in order to minimize the impact of false positives on the final results. RESULTS: The prevalence of Parkinson's disease (PD) was 1.5 % (95% confidence interval, 0.9 to 2.3) and the prevalence of other types of parkinsonism (OP) was 1.1 % (95% confidence interval 0.6 to 1.9). The overall prevalence by age group was 0.4 % (65-74 years), 4.7% (75-84 years), and 2.9% (> or =85 years) for Parkinson's disease and 0.7%, 2%, and 3.9 % for parkinsonism, respectively. The other parkinsonism prevalence was 1.3 % in men and 1.6 % in women. CONCLUSIONS: These prevalence rates are similar than those found in studies made in other European countries. The prevalence of both Parkinson's disease and other types of parkinsonism increased with age, with no significant differences between men and women.

PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome.

BACKGROUND: Mutations in KCNJ2, the gene encoding the inward-rectifying K+ channel Kir2.1, cause the cardiac, skeletal muscle, and developmental phenotypes of Andersen-Tawil syndrome (ATS; also known as Andersen syndrome). Although pathogenic mechanisms have been proposed for select mutations, a common mechanism has not been identified. METHODS: Seventeen probands presenting with symptoms characteristic of ATS were evaluated clinically and screened for mutations in KCNJ2. The results of mutation analysis were combined with those from previously studied subjects to assess the frequency with which KCNJ2 mutations cause ATS. RESULTS: Mutations in KCNJ2 were discovered in nine probands. These included six novel mutations (D71N, T75R, G146D, R189I, G300D, and R312C) as well as previously reported mutations R67W and R218W. Six probands possessed mutations of residues implicated in binding membrane-associated phosphatidylinositol 4,5-bisphosphate (PIP2). In total, mutations in PIP(2)-related residues accounted for disease in 18 of 29 (62%) reported KCNJ2 -based probands with ATS. Also reported is that mutation R67W causes the full clinical triad in two unrelated males. CONCLUSIONS: The novel mutations corresponding to residues involved in Kir2.1 channel-PIP2 interactions presented here as well as the overall frequency of mutations occurring in these residues indicate that defects in PIP2 binding constitute a major pathogenic mechanism of ATS. Furthermore, screening KCNJ2 in patients with the complex phenotypes of ATS was found to be invaluable in establishing or confirming a disease diagnosis as mutations in this gene can be identified in the majority of patients.

Identification and characterization of a novel human brain-specific gene, homologous to S. scrofa tmp83.5, in the chromosome 10q24 critical region for temporal lobe epilepsy and spastic paraplegia.

We describe the structure, genomic organization, and some transcription features of a human brain-specific gene previously localized to the genomic region involved in temporal lobe epilepsy and spastic paraplegia on chromosome 10q24. The gene, which consists of six exons disseminated over 16 kb of genomic DNA, is highly homologous to the porcine tmp83.5 gene and encodes a putative transmembrane protein of 141 amino acids. Unlike its porcine homolog, from which two mRNAs with different 5'-sequences are transcribed, the human gene apparently encodes three mRNA species with 3'-untranslated regions of different sizes. Mutation analysis of its coding sequence in families affected with temporal lobe epilepsy or spastic paraplegia linked to 10q24 do not support the involvement of this gene in either diseases.

The validity of Hodkinson's Abbreviated Mental Test for dementia screening in Guipuzcoa, Spain.

The objective of this research was to evaluate the validity of Hodkinson's Abbreviated Mental Test (AMT) in screening for dementia and to identify the optimum cut-off point to use in a prevalence survey. The study included two groups of persons: (i) a random sample of 183 individuals selected from census data, 96 of whom completed the study and (ii) another 36 persons with dementia were selected from a hospital outpatients department by sampling consecutive cases. The DSM-IV criteria were used as the "gold standard" to establish a diagnosis of dementia. The AMT was administered to the 132 participants who subsequently underwent independent clinical evaluation. In the community sample, 11 persons were diagnosed with dementia and 85 without. In the total sample, a score of 7 maximizes the efficacy of the test. The sensitivity for this cut-off point is 91.5% (78.7-97.2%) and the specificity is 82.4% (72.2-89.5%). A score of 9 gives 100% sensitivity, but the proportion of false positives rises to 66%. Our results are consistent with other studies and suggest that the AMT is a valid instrument for use in screening for dementia in populations similar to the one in this study.

Prevalence of essential tremor: a door-to-door survey in bidasoa, spain.

OBJECTIVES: To assess the prevalence of essential tremor (ET) in two Spanish populations (Irun and Hondarribia, Bidasoa region) and to compare the results with those of similar surveys. METHODS: The survey included 2,000 participants aged 65 years or older in a door-to-door, two-phase design. ET was defined as postural or kinetic tremor of the head or limbs. RESULTS: ET prevalence after age adjustment was 4.8% (95% confidence interval, 3.6-6.4). Prevalence increased significantly with age and there were no sex differences. CONCLUSIONS: The age-adjusted prevalence rate of ET in people 65 years old and older in Bidasoa, Spain, is close to those described in other studies using a similar design and suggest no geographical variation. ET prevalence increases with age and has a similar distribution in males and females.

[Epilepsy and genetics]. / Epilepsia y genética.

In the same way than in other areas of neurology, the development of genetics is revolutionizing our knowledge of epilepsies. In the last years, new epilepsy syndromes of genetic basis have been defined, and in some of them, the mechanism implicated in the origin of seizures has been determined. In the next years, we hope to determinate de innermost mechanisms by which epileptogenesis occurs, and to design new more rational strategies of prevention and treatment. The epilepsy syndromes in which a genetic basis has been established are presented.

[Sleep apnea syndrome and cerebral infarction]. / Síndrome de apnea del sueño e infarto cerebral.

OBJECTIVES: To analyze the relationship between snoring and sleep apnea with brain infarction. METHODS: We studied 79 consecutive patients of both sexes with cerebral infarction and 248 age and sex matched controls. We obtained data reflecting arterial hypertension, diabetes mellitus, hypercholesterolemia, smoking and drinking habits, coronary heart disease, cardiopathy, snoring, respiratory pauses during sleep and daytime sleepiness, by using a standard questionnaire to interview every subject and his/her spouse. RESULTS: 53% of patients and 46% of controls snored often or always (p = 0.27). Snoring was significantly more frequent in men. Thirty four percent of patients and 27% of controls were snorers and suffered apnea during sleep (p = 0.19). Nineteen per cent of patients and 11% of controls presented snoring, respiratory pauses during sleep and daytime sleepiness simultaneously, suggesting obstructive sleep apnea syndrome (OSAS) (p = 0.06). However, by separately analyzing people younger than 65 years, the frequency of OSAS was significantly higher in patients (29%) than in controls (7%) (p = 0.006). Finally, 10% of patients and 3% of controls presented snoring, respiratory pauses during sleep and moderate or severe daytime sleepiness simultaneously, suggesting moderate-severe OSAS (p = 0.01). A multiple logistic regression analysis confirmed the independent contribution of moderate-severe OSAS as a risk factor for ischemic stroke, with an adjusted odds ratio of 4.54. In people younger than 65 years, OSAS, regardless of its severity, was also an independent risk factor for ischemic stroke, with an adjusted odds ratio of 5.78. CONCLUSIONS: Clinically diagnosed obstructive sleep apnea syndrome is an independent risk factor for ischemic stroke, especially in people younger than 65 years.

[Andersen syndrome. Description of a case] . / Síndrome de Andersen. Descripción de un caso.

A 17 year-old man, with periodic muscular weakness since the age of 6 years, is presented. The episodes of periodic paralysis were of variable duration, from 1 to 3 days, and were induced by physical exercise or by stress. Weakness was generalised, although predominant in anterior compartment of the legs, with foot drop. Interictal neurological examination was absolutely normal. He showed dysmorphic features, with micrognatia. Cardiac examination revealed continuous arrhythmia. Basal EKG and 24 hours EKG-Holter confirmed the existence of abundant ventricular extrasystoles, with episodes of ventricular tachycardia, without clinical manifestations. Echocardiogram was normal. Ictal and interictal ENG-EMG, and muscle and nerve biopsies were normal. Serum potassium levels during the episodes ranged from 3 to 3.6 mEq/l (N: 3.5-4.5 mEq/l), being normal interictally (4-5 mEq/l). Oral administration of potassium did not prevent the development of episodic weakness. He had no familial history of similar symptoms. This association of periodic paralysis, cardiac arrhythmia and dysmorphic features correspond to a rare entity named Andersen's syndrome.