Clinical practice guidelines for the diagnosis and management of Charcot-Marie-Tooth disease.

INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is classified according to neurophysiological and histological findings, the inheritance pattern, and the underlying genetic defect. The objective of these guidelines is to offer recommendations for the diagnosis, prognosis, follow-up, and treatment of this disease in Spain. MATERIAL AND METHODS: These consensus guidelines were developed through collaboration by a multidisciplinary panel encompassing a broad group of experts on the subject, including neurologists, paediatric neurologists, geneticists, physiatrists, and orthopaedic surgeons. RECOMMENDATIONS: The diagnosis of CMT is clinical, with patients usually presenting a common or classical phenotype. Clinical assessment should be followed by an appropriate neurophysiological study; specific recommendations are established for the parameters that should be included. Genetic diagnosis should be approached sequentially; once PMP22 duplication has been ruled out, if appropriate, a next-generation sequencing study should be considered, taking into account the limitations of the available techniques. To date, no pharmacological disease-modifying treatment is available, but symptomatic management, guided by a multidiciplinary team, is important, as is proper rehabilitation and orthopaedic management. The latter should be initiated early to identify and improve the patient's functional deficits, and should include individualised exercise guidelines, orthotic adaptation, and assessment of conservative surgeries such as tendon transfer. The follow-up of patients with CMT is exclusively clinical, and ancillary testing is not necessary in routine clinical practice.

[Prognostic and monitoring biomarkers in chronic inflammatory demyelinating polyneuropathy]. / Biomarcadores pronósticos y de seguimiento en la polineuropatía desmielinizante inflamatoria crónica.

INTRODUCTION: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a clinical entity with significant phenotypic variability both in its onset and in its course. Therefore, it is important to have objective biomarkers with which to monitor its evolution. In this review we present clinical, neurophysiological, neuroimaging, blood and cerebrospinal fluid (CSF) biomarkers for the monitoring and prognosis of CIDP. DEVELOPMENT: Different clinical tools have been developed and validated to monitor CIDP by assessing strength and disability. However, the best parameter for monitoring gait remains to be determined. Monitoring by neurophysiological examination is also widespread and the amplitude of the compound muscle action potential is the most commonly used. More recently, the Motor Unit Number Index sum score has been developed, which is an accurate and reproducible technique. The role of nerve ultrasonography is under development and a correlation between clinical evolution and ultrasound findings has been described. Multiple biomarkers have been described in blood and CSF, including antinodal/paranodal antibodies, neurofilament light chain, serum immunoglobulin G levels and CSF sphingomyelin levels. Genetic variants and cytokines associated with prognosis and response to treatment have also been described. CONCLUSIONS: One of the most important challenges in the management of CIDP is the monitoring of clinical changes after treatment initiation. The combination of biomarkers that allow an accurate understanding of the disease is crucial for the optimal management of CIDP.

TITLE: Biomarcadores pronósticos y de seguimiento en la polineuropatía desmielinizante inflamatoria crónica.Introducción. La polineuropatía desmielinizante inflamatoria crónica (PDIC) es una entidad clínica con una variabilidad fenotípica muy importante tanto en el inicio como en la evolución. Por lo tanto, es importante disponer de biomarcadores objetivos para monitorizar la evolución. En esta revisión presentamos los biomarcadores clínicos, neurofisiológicos, de neuroimagen, y en la sangre y el líquido cefalorraquídeo (LCR) para el seguimiento y el pronóstico de la PDIC. Desarrollo. Se han desarrollado diferentes herramientas clínicas validadas para el seguimiento de la PDIC mediante la evaluación de la fuerza y la discapacidad. No obstante, falta determinar el mejor parámetro para monitorizar la marcha. El seguimiento mediante examen neurofisiológico también está ampliamente extendido, y la amplitud del compound muscle action potential es lo más utilizado. Más recientemente, se ha desarrollado la Motor Unit Number Index sum score, que es una técnica precisa y reproducible. El papel de la ecografía de nervio se encuentra en desarrollo, y se ha descrito correlación entre la evolución clínica y los hallazgos por ecografía. Se han descrito múltiples biomarcadores en sangre y el LCR, entre los que destacan los anticuerpos antinodales/paranodales, los neurofilamentos de cadena ligera, los niveles de inmunoglobulina G en el suero y los niveles de esfingomielina en el LCR. Asimismo, se han descrito variantes genéticas y citocinas relacionadas con el pronóstico y la respuesta a los tratamientos. Conclusiones. Uno de los retos más importante en el manejo de la PDIC es la monitorización de los cambios clínicos tras el inicio del tratamiento. La combinación de biomarcadores que permitan una comprensión exacta de la enfermedad es crucial para el manejo óptimo de la PDIC.

[Weakness as a complication of COVID-19 in critically ill patients: clinical features and prognostic factors in a case series]. / Debilidad como complicación del paciente crítico por COVID-19: características clínicas y factores pronósticos en una serie de casos.

INTRODUCTION: Weakness is a frequent complication in those critically ill due to COVID-19. This study describes its characteristics and the factors that can condition and predict it. PATIENTS AND METHODS: We conducted a prospective, descriptive, observational study of patients admitted to the intensive care unit (ICU) due to COVID-19 between April and May 2020 with muscle weakness. A motor balance equal to or lower than 3/5 according to the modified Medical Research Council muscle strength scale was considered to be severe clinical impairment. Altogether 25 analytical studies, 16 neurophysiological studies and one muscle biopsy were performed, with a telephone follow-up at one month, a comparative analysis between the groups with and without severe compromise, and determination of cut-off points for analytical parameters to predict severe involvement using ROC curves. RESULTS: The sample consisted of 25 patients with a mean age of 58 years (standard deviation ± 9). The median length of stay in the ICU was 27.5 days. All the electromyograms exhibited a myogenic pattern and 75% also showed neuropathy. The group with severe clinical involvement had higher levels of D-dimer (p = 0.08), lactate dehydrogenase (p = 0.03) and interleukin-6 (p = 0.10), and the combination of the alteration of any two of these three parameters predicted severe involvement with a sensitivity of 100% and a specificity of 76.9%. At one month of follow-up, 36% were unable to walk autonomously and 92% continued with muscle weakness. CONCLUSIONS: Weakness in severe COVID-19 patients has a major clinical impact. Its early detection and study by means of predictors of its development may allow for better management. The absence in some cases of classical risk factors for ICU-acquired weakness suggests a different pathophysiology.

TITLE: Debilidad como complicación del paciente crítico por COVID-19: características clínicas y factores pronósticos en una serie de casos.Introducción. La debilidad es una complicación frecuente en el enfermo crítico por COVID-19. Se describen sus características, y los factores que pueden condicionarla y predecirla. Pacientes y métodos. Estudio observacional descriptivo prospectivo con pacientes ingresados en la unidad de cuidados intensivos (UCI) por COVID-19 entre abril y mayo de 2020 con debilidad muscular. Se consideró una afectación clínica grave un equilibrio motor igual o inferior a 3/5 según la escala de fuerza muscular modificada del Medical Research Council. Se han realizado 25 estudios analíticos, 16 estudios neurofisiológicos y una biopsia muscular; seguimiento telefónico al mes; análisis comparativo entre los grupos con y sin afectación grave, y determinación de puntos de corte de parámetros analíticos para predecir afectación grave mediante curvas ROC. Resultados. Se incluyó a 25 pacientes con 58 años (desviación estándar ± 9) de edad media. La mediana de estancia en la UCI fue de 27,5 días. Todos los electromiogramas mostraban un patrón miógeno y el 75%, también una neuropatía. El grupo con afectación clínica grave tenía mayores niveles de dímero-D (p = 0,08), lactato deshidrogenasa (p = 0,03) e interleucina 6 (p = 0,10), y la combinación de la alteración de dos cualquiera de estos tres parámetros pronosticaba la afectación grave con una sensibilidad del 100% y una especificidad del 76,9%. Al mes de seguimiento, el 36% no podía deambular autónomamente y el 92% seguía con debilidad muscular. Conclusiones. La debilidad en el enfermo por COVID-19 grave tiene una repercusión clínica importante. Su detección y estudio precoces mediante predictores de su desarrollo pueden permitir un mejor manejo. La ausencia en algunos casos de los factores de riesgo clásicos para la debilidad adquirida en la UCI sugiere una fisiopatología diferente.

Novel CAPN3 variant associated with an autosomal dominant calpainopathy.

AIMS: The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies. METHODS: Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance. RESULTS: We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice. CONCLUSIONS: We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in-frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well-documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re-assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.

Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The prognostic value of serum neurofilament light chain (sNfL), a biomarker of neurodegeneration, compared to other prognostic factors of amyotrophic lateral sclerosis (ALS) at the time of diagnosis, remains unclear. METHODS: Sera from ALS patients were prospectively collected at the first diagnostic visit in our centre. sNfL levels were determined by single molecule array in 207 ALS patients and in 21 healthy controls. The prognostic value of sNfL was compared with that of other known clinical prognostic factors using a Cox regression model and multivariate analysis. RESULTS: Serum neurofilament light chain levels were higher in ALS patients than in controls (P < 0.0001). Seven parameters were predictive of death in ALS: older age, bulbar onset, higher ALS Functional Rating Scale revised (ALSFRS-R) score, greater weight loss, lower maximal inspiratory pressure, forced vital capacity and higher sNfL levels. A Cox regression model showed that sNfL (P < 0.0001), weight loss (P = 0.040) and site at onset (P = 0.048) were independent predictive factors of death. In a sub-cohort restricted to 139 patients with complete spirometry data, sNfL level (P < 0.005) and forced vital capacity (P = 0.022) were independent factors predictive of death. In a subgroup of 142 patients in whom ALSFRS-R score was available at several time points, sNfL levels positively correlated with ALSFRS-R rate of decline (r = 0.571, P < 10-12 ). CONCLUSIONS: Higher sNfL concentration is a strong and independent prognostic factor of death in ALS as early as the time of diagnosis.

Adult-onset spinal muscular atrophy: An update.

Spinal muscular atrophy (SMA) refers to a group of disorders affecting lower motor neurons. The age of onset of these disorders is variable, ranging from the neonatal period to adulthood. Over the last few years, there has been enormous progress in the description of new genes and phenotypes that throw new light on the molecular pathways involved in motor neuron degeneration. Advances in our understanding of the pathophysiology of the most frequent forms, SMA linked to SMN1 gene mutations and Kennedy disease, has led to the development of therapeutic strategies currently being tested in clinical trials. This report provides a general overview of the clinical features and pathophysiological mechanisms in adult-onset genetic SMA disorders in which the causative gene has been identified (SMN1-related SMA, Kennedy disease, CHCHD10, TRPV4, DYNC1H1 and BICD2). Sporadic lower motor neuron disease, also known as progressive muscular atrophy (PMA), is also discussed. The finding of TDP-43 aggregates in immunohistochemical studies of PMA strongly supports the idea that it is a phenotypic variant of amyotrophic lateral sclerosis (ALS).

[Neuralgic amyotrophy revealed by diaphragmatic palsy]. / Paralysie diaphragmatique révélant un syndrome de Parsonage Turner.

INTRODUCTION: Neuralgic amyotrophy is considered to be a form of mononeuropathy multiplex which generally involves the nerves of the upper limbs. OBSERVATIONS: We describe four cases of neuralgic amyotrophy revealed by dyspnea due to phrenic nerve involvement, with asymptomatic motor deficit in the upper part of the brachial plexus. CONCLUSION: Phrenic nerve involvement revealed by dyspnea is rare. Associated with neurologic signs, the diagnosis is evocative. In case of an isolated attack, the key to diagnosis is the electromyographic exam.

[Demyelinating disease affecting both central and peripheral nervous system]. / Maladie démyélinisante du système nerveux central et périphérique.

INTRODUCTION: Demyelinating disease affecting both the central and the peripheral nervous systems has rarely been reported. CASE REPORT: A 30-year-old man, presented with ataxia and diffuse areflexia due to polyneuropathy fullfilling demyelination criteria. His medical history was notable for central nervous system demyelination compatible with multiple sclerosis. He improved transiently with intravenous immunoglobulin and then stabilized with methotrexate. CONCLUSION: This case report distinguishes a new kind of inflammatory disease affecting both central and peripheral nervous system. It seems to be different from multiple sclerosis and chronic immune demyelinating polyneuropathy, because of high hyperproteinorachia and absence of oligoclonal bands in the cerebrospinal fluid.

[Isolated palsy of the hypoglossal nerve complicating infectious mononucleosis]. / Paralysie isolée du nerf hypoglosse compliquant une mononucléose infectieuse.

INTRODUCTION: Neurological complications of infectious mononucleosis are rare. Various disorders have been described: meningitis, encephalitis, peripheral neuropathy. Isolated cranial nerve palsy has rarely been reported. OBSERVATION: A 16-year-old man was admitted for isolated and unilateral hypoglossal nerve palsy, four weeks after infectious mononucleosis. Cerebral MRI, cerebrospinal fluid study and electromyography were normal. IgM anti-VCA were positive. Two months later, without treatment, the tongue had almost fully recovered. CONCLUSION: To the best of our knowledge, only seven cases of isolated palsy of the hypoglossal nerve complicating infectious mononucleosis have been previously reported.

[Recurrent Guillain-Barré syndrome after surgery]. / Syndrome de Guillain-Barré postopératoire récurrent.

INTRODUCTION: Recurrent Guillain-Barré syndrome is a very rare entity. Few cases have been reported. CASE REPORT: We report two patients who have developed a recurrent Guillain-Barré syndrome where one or even two episodes occurred after the same type of surgery, a hip prosthesis replacement. DISCUSSION: Occurrence of Guillain-Barré syndrome after surgery has mainly been reported in relation to epidural anesthesia and less frequently general anesthesia. Although underlying pathogenic mechanisms remain unknown, a molecular mimicry phenomenon has been proposed.

[Facial diplegia and acute inflammatory demyelinating neuropathy secondary to varicella]. / Diplégie faciale au cours d'une neuropathie démyélinisante inflammatoire aiguë secondaire à une varicelle.

INTRODUCTION: Primo-infection by varicella-zoster virus (VZV) may be associated with several neurologic complications. Bilateral facial palsy is a rather uncommon manifestation. CASE REPORT: We report the case of a 38-year-old woman who developed bilateral facial diplegia and paresthesia affecting all four limbs with subacute onset several days after varicella virus primoinfection. Ancillary tests showed hyperproteinorachia and signs of demyelinating polyneuropathy in nerve conduction tests. The diagnosis of Guillain-Barré syndrome was retained and a treatment with intravenous immunoglobulines was started, leading to progressive improvement. CONCLUSION: Immunotherapy is a possible therapeutic approach in the context of neurologic postinfectious complications after VZV infection where an underlying mechanism is probable.

[Fragile X premutation presenting as postural tremor and ataxia (FXTAS syndrome)]. / Tremblement postural et ataxie révélant une prémutation X fragile ou syndrome FXTAS.

We report a case of FXTAS in a 58-year-old man who presented with postural tremor, mild ataxia and dysexecutive cognitive signs. The syndrome had a slow progressive course. Brain imaging by MRI showed characteristic abnormalities with mild cerebellar atrophy, symmetric high signals in the middle cerebellar peduncles and in the subcortical white matter of cerebral hemispheres. The diagnosis was confirmed by molecular genetics showing by southern blot a 100-120 expansion repeat of the CGG trinucleotide. FXTAS is a recently described syndrome, still unknown by most neurologists and probably rather frequent in men older than 60. We emphasize the value of clinical evaluation and brain imaging by MRI in some patients presenting with non specific motor or cognitive symptoms. A diagnosis of FXTAS may have implications for genetic counselling of female relatives.

[Spinal epidural abscess in a patient with septicaemia]. / Absceso epidural vertebral en un paciente con septicemia.

INTRODUCTION: Spinal epidural abscess is a rare entity requiring early diagnosis and treatment. Sepsis is a factor with an unfavourable prognosis. CASE REPORT: We report the case of a 57 year old female with acute low back pain who was admitted to hospital suffering from a state of septic shock and multiple organ failure secondary to an infection disseminated by Staphylococcus aureus, which was treated early on with vancomycin. The probable source of infection was assumed to be necrotizing fasciitis of the left arm. Once the acute phase had been overcome, serious paraparesis became apparent and this led to magnetic resonance imaging of the spine being carried out, the results of which showed the existence of a lumbar spondylodiscitis with associated epidural abscess. CONCLUSION: In patients with sepsis and some previous symptom that arouses suspicion, it is important to consider this possible diagnosis, since treatment with antibiotics alone does not manage to prevent neurological complications in all cases.

[Gradenigo syndrome as the form of presentation of nasopharyngeal carcinoma]. / Síndrome de Gradenigo como forma de presentación de carcinoma nasofaríngeo.

INTRODUCTION: Nasopharyngeal carcinoma is a condition which usually has an insidious onset and non-specific features in the initial stages, so it is difficult to make an early diagnosis. The most usual presenting features are otological (serous otitis media) and involvement of adjacent cranial nerves. We report a case of Gradeningo's syndrome due to the tumour spreading towards the base of the skull. We review the literature on the aetiology of this syndrome. CLINICAL CASE: A 53 year old patient required neurological assessment for a clinical condition which was compatible with Gradenigo's syndrome that involved both right V and VI cranial nerves. This study permitted diagnosis of a nasopharyngeal carcinoma which had been undetected because of its non-specific features, until this complication occurred. Otorhinolaryngological assessment proved the presence of a neoplasm in the cavum. Biopsy of the lesion showed it to be a well-differentiated squamous cell carcinoma. Cranial magnetic resonance imaging showed extension of the tumour to the base of the skull, adjacent to the right sinus cavernosus. The cerebrospinal fluid was normal. Treatment by radiotherapy was indicated. CONCLUSIONS: Diagnosis of nasopharyngeal carcinoma requires a high index of suspicion in view of its initial, sparse, non-specific symptoms. Although ideally the disease should be detected in its early stages, we believe that it is useful to recommend that in cases of Gradenigo's syndrome a full systematic otorhinolaryngological exploration be made so as to effectively rule out this disorder.