Dysautonomia and related outcomes in Guillain-Barre syndrome.

BACKGROUND: Guillain-Barre syndrome (GBS) presents an annual incidence of 1.2-2.3 per 100,000. Sympathetic and parasympathetic nervous systems' peripheral control of visceral organs is affected by GBS aberrant immune response. Associated cardiovascular, gastrointestinal, sudomotor, pupillary, and other systems disturbances cause significant morbidity and mortality. This study aims to evaluate the dysautonomia spectrum in GBS patients, its relationship with patient outcomes, and compare it with those without autonomic disturbances. METHODS: We performed an ambispective review study of patients with GBS and dysautonomia admitted to the Institute of Neurology from 2017 to 2021. We recorded demographics, comorbidities, nerve conduction studies, clinical course, hospital complications, and functional outcomes. RESULTS: We included 214 patients, mean age 46.44 ± 16.49 years, 51 (31 %) presented dysautonomia, hypertension in most of the patients 39 (84.8 %), hypotension 35 (76.1 %), tachycardia 35 (76.1 %), enteric dysmotility 35 (76.1 %), and need for vasopressor 27 (58.7 %) were common characteristics. Twenty (39.2 %) with a demyelinating form and twenty (39.2 %) with an axonal motor form. The bivariate analysis report factors associated with dysautonomia, were lower cranial nerves (VII, IX, X) involvement (p = 0.002), need for mechanical ventilation (p = 0.0001) and intensive care (p = 0.0001), higher mEGOS (p = 0.05), EGRIS (p = 0.004), GBS disability score (p = 0.004), and delirium presence (p = 0.001). Kaplan-Meier survival analysis showed that dysautonomic patients needed more days for the independent walk (p = 0.004). There was no associated mortality. CONCLUSIONS: Autonomic dysfunction in GBS significantly affects the peripheral nervous system. With consequently worse functional results. Further investigation needs to clarify whether more aggressive treatment is beneficial in this category of GBS.

FUS as a cause of familial Amyotrophic lateral sclerosis, a case report in a pregnant patient.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. In 10% the disease is familial and rarely occurs in childbearing age women. A 28-year-old female pregnancy patient presented a two-month history of dropped head syndrome, dysphagia, muscle weakness, atrophy, and lingual wasting. Electromyography supported the diagnosis of ALS. Due to family history and background, we carried out molecular genetic testing. We identified a novel variant of uncertain significance: c. 1566 G > C (p.Arg522Ser) in exon 15 in FUS gene. Our findings provide the first case of ALS onset during pregnancy with a novel mutation in FUS gene reported in Mexico.

Classic and overlapping Miller-Fisher syndrome: clinical and electrophysiological features in Mexican adults.

Classic and overlapping Miller-Fisher syndrome (MFS) have divergent clinical courses. Few studies have addressed the electrophysiological evaluation of MFS patients, most of them carried out in Asia. This work describes and compares their clinical and neurophysiological characteristics. From a Guillain-Barré syndrome (GBS) patient cohort, we made a selection of twenty MFS cases. We defined classic and overlapping MFS, as stated by Wakerley et al. (Nat Rev Neurol 10(9):537-544, 2014). We describe and compare clinical, biochemical, and electrodiagnostic parameters between groups. Seventy-five percent were men, mean age was 42.2 ± 13.6 years, and 45% had a Hughes score ≥ 3. MFS/GBS was the most frequent clinical subtype with 50%. Almost one-third had unaltered electrophysiological studies. Comparative analysis between groups showed statistically significant differences in length of stay, dysautonomia presence, and treatment type. Kaplan-Meier survival analysis showed that 100% of the patients had an independent walk at 3 months. This study reports Mexican MFS patient's characteristics and represents the most extensive case series in Latin America. We observed a high proportion of overlapping syndromes, a good recovery profile, and no significant severe complications.

Intravenous cyclophosphamide monthly pulses in refractory myasthenia gravis.

INTRODUCTION: Refractory myasthenia gravis (MG) is defined as a failure to respond adequately to conventional therapies, the inability to reduce immunosuppressive therapy without clinical relapse or the need for ongoing rescue therapy, severe adverse effects from immunosuppressive therapy (treatment intolerant) or frequent myasthenic crisis even on therapy. Cyclophosphamide (CYC) is a DNA alkylating agent that causes important interference in transcription processes and DNA replication, it has been used in refractory MG with controversial results. We aim to determine the efficacy of CYC in refractory MG in the Mexican population. METHODS: In an observational, longitudinal retrospective study, we identified eight refractory MG patients treated with 30-50 mg/kg monthly CYC for at least 6 months. The efficacy was assessed by Osserman scale considering significant improvement a ≥ 1 point reduction and Myasthenia Gravis Composite Scale. The relapse-free and remission-free period were also calculated using the Kaplan-Meier statistic. RESULTS: Clinical improvement was achieved in 75% of the patients. According to the Kaplan-Meier analysis, the median progression-free survival (PFS) was 9 (6.2-11.5) months and the median time to progression (TTP) was 4 (1-8) months. Response was independent of patient's characteristics, except for the MG age of onset (p = 0.0025). CONCLUSIONS: CYC was effective in all patients with refractory MG for a mean of 9 months, with worsening thereafter, which could be associated with low cumulative dose. The symptomatic improvement with CYC was noted within the 1st month. We conclude that CYC is effective as an induction to remission therapy, although our data suggest it is not effective as a long-term therapy.

Novel Phenotypes and Cardiac Involvement Associated With DNA2 Genetic Variants.

Objectives: To report two novel DNA2 gene mutations causing early onset myopathy with cardiac involvement and late onset mitochondriopathy with rhabdomyolysis. Methods: We performed detailed clinical, muscle histopathology and molecular studies including mitochondrial gene NGS analysis in two patients (Patient 1 and 2), a mother and her son, belonging to a Mexican family, and a third sporadic French patient. Results: Patient 1 and 2 presented with an early onset myopathy associated with ptosis, velopharyngeal weakness, and cardiac involvement. Patient 3 presented rhabdomyolysis unmasking a mitochondrial disease characterized by a sensorineural hearing loss, ptosis, and lipomas. Muscle biopsies performed in all patients showed variable mitochondrial alterations. Patient 3 had multiple mtDNA deletion in his muscle. Genetic studies revealed a novel heterozygous frameshift mutation in DNA2 gene (c.2346delT p.Phe782Leufs*3) in P1 and P2, and a novel heterozygous missense mutation in DNA2 gene (c.578T>C p.Leu193Ser) in the P3. Conclusions: To date only few AD cases presenting either missense or truncating DNA2 variants have been reported. None of them presented with a cardiac involvement or rhabdomyolysis. Here we enlarge the genetic and phenotypic spectrum of DNA2-related mitochondrial disorders.

Catatonia in patients with anti-NMDA receptor encephalitis.

AIM: There is a lack of studies related to the frequency, phenomenology, and associated features of catatonic syndrome in patients with anti-NMDA receptor encephalitis (ANMDARE). This study aimed to measure the frequency of catatonia in this condition and to delineate its particular symptoms. METHODS: A prospective study was done with all inpatients who fulfilled the criteria of definite ANMDARE admitted to the National Institute of Neurology and Neurosurgery of Mexico from January 2014 to September 2018. The Bush-Francis Catatonia Rating Scale and Braünig Catatonia Rating Scale were administered at admission. RESULTS: Fifty-eight patients were included and catatonia was diagnosed in 41 of these patients (70.6%). Immobility, staring, mutism, and posturing were the most frequent catatonic signs. Catatonia was associated with delirium, hallucinations, psychomotor agitation, generalized electroencephalography dysfunction, and previous use of antipsychotics. Mortality was present in 10% of the total sample; it was associated with status epilepticus, and was less frequent in the catatonia group. After immunotherapy, all cases showed a complete recovery from catatonic signs. CONCLUSION: This systematic assessment of catatonic syndrome shows that it is a frequent feature in patients with ANMDARE as part of a clinical pattern that includes delirium, psychomotor agitation, and hallucinations. The lack of recognition of this pattern may be a source of diagnostic and therapeutic errors, as most physicians associate catatonia with schizophrenia and affective disorders.

Non-inflammatory cerebrospinal fluid delays the diagnosis and start of immunotherapy in anti-NMDAR encephalitis.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a form of autoimmune encephalopathy that presents with a wide variety of symptoms, including neuropsychiatric manifestations. The authors' aim for this study was to analyze the results of paraclinical studies of patients with a diagnosis of anti-NMDAR encephalitis and the association between symptom onset and diagnosis, and start of immunotherapy. Retrospective data of 29 patients with anti-NMDAR encephalitis were gathered and analyzed. Abnormal EEG was found in 27 patients (93.1%), whereas MRI was abnormal in 19 patients (65.5%). In contrast, an inflammatory pattern on CSF analysis was found in only 13 patients (44.8%). The absence of pleocytosis or increased proteins in the CSF was associated with a longer time from symptom onset to diagnosis and treatment (p = 0.003). The authors conclude that noninflammatory CSF may delay the correct diagnosis and start of immunotherapy in anti-NMDAR encephalitis. In the presence of suggestive clinical features, extensive studies including EEG are recommended.

Non-inflammatory cerebrospinal fluid delays the diagnosis and start of immunotherapy in anti-NMDAR encephalitis / La ausencia de hallazgos de inflamación en líquido cefalorraquídeo retrasa el inicio de inmunoterapia en la encefalitis anti-NMDAR

ABSTRACT Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a form of autoimmune encephalopathy that presents with a wide variety of symptoms, including neuropsychiatric manifestations. The authors' aim for this study was to analyze the results of paraclinical studies of patients with a diagnosis of anti-NMDAR encephalitis and the association between symptom onset and diagnosis, and start of immunotherapy. Retrospective data of 29 patients with anti-NMDAR encephalitis were gathered and analyzed. Abnormal EEG was found in 27 patients (93.1%), whereas MRI was abnormal in 19 patients (65.5%). In contrast, an inflammatory pattern on CSF analysis was found in only 13 patients (44.8%). The absence of pleocytosis or increased proteins in the CSF was associated with a longer time from symptom onset to diagnosis and treatment (p = 0.003). The authors conclude that noninflammatory CSF may delay the correct diagnosis and start of immunotherapy in anti-NMDAR encephalitis. In the presence of suggestive clinical features, extensive studies including EEG are recommended.

RESUMEN La encefalitis por receptor anti-N-metil-D-aspartato (anti-NMDAR) es una encefalopatía autoinmune con una amplia variedad de síntomas, incluyendo manifestaciones neuropsiquiátricas. Nuestro objetivo en este estudio fue analizar los resultados paraclínicos de pacientes diagnosticados con encefalitis anti-NMDAR y la asociación entre inicio de sintomatología, el diagnóstico y el inicio de inmunoterapia. Encontramos un EEG anormal en 27 pacientes (93.1%), así como IRM anormal en 19 de ellos (65.5%). En contraste, el análisis de LCR mostró un patrón inflamatorio en tan solo 13 pacientes (44.8%). La ausencia de pleocitosis o proteínas incrementadas en el LCR se asoció con un mayor tiempo desde el inicio de la sintomatología hasta el inicio del tratamiento (p=0.003). Concluimos que el LCR no inflamatorio puede retrasar el diagnóstico correcto y el inicio de tratamiento en encefalitis anti-NMDAR, por lo que se recomienda la realización de estudios exhaustivos, incluyendo EEG, ante la presencia de indicadores clínicos sugerentes del padecimiento.

Late onset Lafora disease and novel EPM2A mutations: breaking paradigms.

Lafora disease (LD) is an autosomal recessive progressive myoclonus epilepsy with classic adolescent onset of stimuli sensitive seizures. Patients typically deteriorate rapidly with dementia, ataxia, vegetative failure and death by 25 years of age. LD is caused by homozygous mutations in EPM2A or EPM2B genes. We found four novel mutations in EPM2A - three in exon 4 (Q247X, H265R G279C) and one in exon 1 (Y86D) - and a previously described mutation in exon 4 (R241X). These five EPM2A mutations were found in four index cases and affected relatives. Patient 1 with classic LD was doubly heterozygous for H265R and R241X in exon 4; while Patient 2, who also had classic LD, was homozygous for Q247X in exon 4. Patient 3 with classic LD was homozygous for Y86D in exon 1, but the same mutation in his affected brother manifested an atypical earlier childhood onset. For the first time, we describe a later onset and slower progression of EPM2A-deficient LD seen in Patient 4 and her three sisters who were doubly heterozygous for R241X and G279C in exon 4. In these sisters, seizures started later at 21 to 28 years of age and progressed slowly with patients living beyond 30 years of age. Our observations suggest that variations in phenotypes of EPM2A-deficient LD, like an earlier childhood or adolescent or later adult onset with a rapid or slower course, depend on a second modifying factor separate from pathogenicity or exon location of EPM2A mutations. A modifying gene amongst the patient's genetic background or environmental factors may condition age of onset and rapid or slow progression of LD.

Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis.

The aim of this study was to evaluate the ability of lithium carbonate and valproate cotreatment to modify the survival rate and functional score of patients with definite sporadic amyotrophic lateral sclerosis (ALS). The clinical response of 18 enrolled patients was compared to the evolution of 31 ALS out-patients, carefully paired by age, gender, evolution rate and time of the disease, who never received treatment with lithium and/or valproate. The ALS functional rating scale, revised version (ALSFRS-R), was applied at baseline, 1 month, and every 4 months until the outcome (death or an adverse event). Biochemical markers, such as Cu/Zn superoxide dismutase and glutathione peroxidase activity, and reduced glutathione were assayed in plasma samples obtained at the baseline visit and after 5 and 9 months of treatment. Our results showed that lithium and valproate cotreatment significantly increased survival (p=0.016), and this treatment also exerted neuroprotection in our patients because all three markers reached levels that were not significantly different from the matched samples of healthy donors. The trial stopped after 21 months, when the sample was reduced to under two-thirds, due to the late adverse events of the treatment. The results call for large randomized clinical trials with the dual association, but at low doses to avoid adverse events.

Immunodetection analysis of muscular dystrophies in Mexico.

INTRODUCTION: The muscular dystrophies (MDs) result from perturbations in the myofibers. These alterations are induced in part by mechanical stress due to membrane cell fragility, disturbances in mechanotransduction pathways, muscle cell physiology, and metabolism. METHODS: We analyzed 290 biopsies of patients with a clinical diagnosis of muscular dystrophy. Using immunofluorescence staining, we searched for primary and secondary deficiencies of 12 different proteins, including membrane, costamere, cytoskeletal, and nuclear proteins. In addition, we analyzed calpain-3 by immunoblot. RESULTS: We identified 212 patients with varying degrees of protein deficiencies, including dystrophin, sarcoglycans, dysferlin, caveolin-3, calpain-3, emerin, and merosin. Moreover, 78 biopsies showed normal expression of all investigated muscle proteins. The frequency rates of protein deficiencies were as follows: 52.36% dystrophinopathies; 18.40% dysferlinopathies; 14.15% sarcoglycanopathies; 11.32% calpainopathies; 1.89% merosinopathies; 1.42% caveolinopathies; and 0.47% emerinopathies. Deficiencies in lamin A/C and telethonin were not detected. CONCLUSION: We have described the frequency of common muscular dystrophies in Mexico.

[Two case studies of hypertrophic cardiomyopathy in Friedreich's ataxia]. / Cardiomiopatía hipertrófica en ataxia de Friedreich. Presentación de dos casos.

BACKGROUND: Friedreich's ataxia is the most common hereditary ataxia and its clinical spectrum includes cardiac disease, mainly hypertrophic cardiomyopathy. METHODS: We present two cases with molecular diagnosis of Friedreich's ataxia and cardiac disease shown on electrocardiogram and echocardiogram. RESULTS: Neurological symptoms which lead to the diagnosis are described together with cardiac comorbidities. CONCLUSIONS: The cases here described highlight the importance of early screening and identification of systemic complications, specifically cardiac disease, in patients with this neurological disease.

[Excessive daytime sleepiness in Mexico city]. / Somnolencia excesiva diurna en la ciudad de México.

OBJECTIVE: To determine the prevalence of excessive daytime somnolence (EDS) in a sample of residents from Mexico City. METHODS: A cross-sectional survey was done using a randomized telephone survey. A structured questionnaire (including demographic and clinical data) and Epworth Sleepiness Scale, a valid and reliable instrument for the detection of EDS, were administered. RESULTS: A total sample of 200 subjects was obtained, with a mean age of 37 +/- 16.24 years. EDS was found in 31.5% of the subjects; 12.5% considered that EDS interfered in a significant way with daily activities, and 9% with work related abilities. Subjects with EDS were older, came from lower socio-economic status, and had a significantly higher body mass index. DISCUSSION: Our results indicate that EDS is more frequent in Mexico City residents than in other populations. Notwithstanding, the association between EDS with advanced age, lower socio-economic status and high body mass index requires further investigation.

Somnolencia excesiva diurna en la ciudad de México / Excessive daytime sleepiness in Mexico city

Objetivo: Determinar la prevalencia de somnolencia excesiva diurna (SED) en una muestra de habitantes de la ciudad de México. Material y métodos: Se realizó un estudio transversal analítico mediante una encuesta telefónica al azar; la entrevista estructurada se aplicó con la finalidad de obtener datos demográficos y clínicos. Así mismo se utilizó la escala de Epworth, que es un instrumento confiable y válido para el diagnóstico de la SED. Resultados: Se estudiaron 200 habitantes de la ciudad de México, con una media de edad de 37±16 años. De ellos 31.5% cursaba con SED. En 12.5% de los sujetos la SED interfería de manera significativa con sus actividades cotidianas y 9% admitía que interfería con sus actividades laborales. Los sujetos con SED tenían mayor edad, pertenecían con mayor frecuencia al nivel socioeconómico bajo y presentaban un índice de masa corporal significativamente más alto. Discusión: Estos resultados indican que la SED es más frecuente en la ciudad de México que en otras poblaciones estudiadas. Se requieren estudios posteriores que permitan establecer la participación de la edad, nivel socioeconómico y el índice de masa corporal en el desarrollo de la SED.

OBJECTIVE: To determine the prevalence of excessive daytime somnolence (EDS) in a sample of residents from Mexico City. METHODS: A cross-sectional survey was done using a randomized telephone survey. A structured questionnaire (including demographic and clinical data) and Epworth Sleepiness Scale, a valid and reliable instrument for the detection of EDS, were administered. RESULTS: A total sample of 200 subjects was obtained, with a mean age of 37 +/- 16.24 years. EDS was found in 31.5% of the subjects; 12.5% considered that EDS interfered in a significant way with daily activities, and 9% with work related abilities. Subjects with EDS were older, came from lower socio-economic status, and had a significantly higher body mass index. DISCUSSION: Our results indicate that EDS is more frequent in Mexico City residents than in other populations. Notwithstanding, the association between EDS with advanced age, lower socio-economic status and high body mass index requires further investigation.