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Objective: To describe the heterogeneity of electrodiagnostic (EDx) studies in Guillain-Barre syndrome (GBS) patients collected as part of the International GBS Outcome Study (IGOS). Methods: Prospectively collected clinical and EDx data were available in 957 IGOS patients from 115 centers. Only the first EDx study was included in the current analysis. Results: Median timing of the EDx study was 7 days (interquartile range 4-11) from symptom onset. Methodology varied between centers, countries and regions. Reference values from the responding 103 centers were derived locally in 49%, from publications in 37% and from a combination of these in the remaining 15%. Amplitude measurement in the EDx studies (baseline-to-peak or peak-to-peak) differed from the way this was done in the reference values, in 22% of motor and 39% of sensory conduction. There was marked variability in both motor and sensory reference values, although only a few outliers accounted for this. Conclusions: Our study showed extensive variation in the clinical practice of EDx in GBS patients among IGOS centers across the regions. Significance: Besides EDx variation in GBS patients participating in IGOS, this diversity is likely to be present in other neuromuscular disorders and centers. This underlines the need for standardization of EDx in future multinational GBS studies.(c) 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose of review: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). Recent findings: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. Summary: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.

SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. HSP is considered an upper motor neuron disorder characterized by progressive spasticity and weakness of the lower limbs caused by degeneration of the corticospinal tract. In other neurodegenerative motor disorders, the thalamus and basal ganglia are affected, with a considerable impact on disease progression. However, only a few works have studied these brain structures in HSP, mainly in complex forms of this disease. Our research aims to detect potential alterations in the volume and shape of the thalamus and various basal ganglia structures by comparing 12 patients with pure HSP and 18 healthy controls. We used two neuroimaging procedures: automated segmentation of the subcortical structures (thalamus, hippocampus, caudate nucleus, globus pallidus, and putamen) in native space and shape analysis of the structures. We found a significant reduction in thalamic volume bilaterally, as well as an inward deformation, mainly in the sensory-motor thalamic regions in patients with pure HSP and a mutation in SPG4. We also observed a significant negative correlation between the shape of the thalamus and clinical scores (the Spastic Paraplegia Rating Scale score and disease duration). Moreover, we found a ‘Group × Age’ interaction that was closely related to the severity of the disease. No differences in volume or in shape were found in the remaining subcortical structures studied. Our results suggest that changes in structure of the thalamus could be an imaging biomarker of disease progression in pHSP.

BackgroundMutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME.MethodsWe screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members.ResultsWe found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease.ConclusionMME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.

There are few reports on axonal CMT due to dominant GDAP1 mutations. We describe two unrelated Spanish families with a dominant axonal CMT. A novel in frame GAA deletion in exon 5 of the GDAP1 gene (c.677_679del; p.R226del) was identified in both families. Disease onset varied from early childhood to adulthood. Affected family members complained of distal lower limb weakness, cramps and foot deformities with variable CMTNS score in both families. Several individuals were asymptomatic or had paraesthesia only, however neurological examination and nerve conduction studies demonstrated neuropathic signs. Transfection of HeLa cells with the p.R226del mutation led to an increased mitochondrial aggregation. We report an AD-CMT2K with large phenotypic variability due to a novel dominant GDAP1 variant. This is the second founder GDAP1 pathogenic variant reported in Spain.

Background and purpose Myasthenia gravis (MG) may become life-threatening if patients have respiratory insufficiency or dysphagia. This study aimed to determine the incidence, demographic characteristics, risk factors, response to treatment and outcome of these life-threatening events (LTEs) in a recent, population-based sample of MG patients. Methods A retrospective analysis of MG patients who presented with an LTE between 2000 and 2013 was performed. Participants were identified from a neuromuscular diseases registry in Spain that includes 648 patients with MG (NMD-ES). Results Sixty-two (9.56%) patients had an LTE. Thirty-two were classified as class V according to the MG Foundation of America, and 30 as class IVB. Fifty per cent were previously diagnosed with MG and median duration of the disease before the LTE was 24 months (3–406). The most common related factor was infection (n = 18). All patients received intravenous human immunoglobulin; 11 had a second infusion and six had plasma exchange. Median time to feeding tube removal was 13 days (1–434). Median time to weaning from ventilation was 12 days (3–176), and it was significantly shorter in late onset MG (≥50 years) (P = 0.019). LTEs improved

Objective: To describe the frequency of antibodies against neurofascin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and the associated clinical features. Methods: Immunocytochemistry was used to identify antibodies to neurofascin 155 (NF155) and 186. Serum reactivity with paranodes and brain tissue was tested with immunohistochemistry of teased-nerve fibers and rat brain. Antibody titers and immunoglobulin (Ig) G isotypes were determined using ELISA. Clinical information was obtained retrospectively. Results: Two of 53 patients, but none of 204 controls, had antibodies to NF155 ( p = 0.041). The 2 patients with NF155 antibodies developed severe polyradiculoneuropathy with predominant distal weakness that was refractory to IVIg. Eight additional patients with IVIg-refractory CIDP were then identified from a national database; 2 of them with the same clinical features also had NF155 antibodies. Overall, 3 of the 4 patients with NF155 antibodies had a disabling and characteristic tremor (high amplitude, low frequency, postural, and intention). Patients9 antibodies reacted with the paranodes in teased-nerve fibers and with the neuropil of rat cerebellum, brain, and brainstem. Anti-NF155 antibodies were predominantly of the IgG4 isotype in all patients. Conclusion: Patients with CIDP positive for IgG4 NF155 antibodies constitute a specific subgroup with a severe phenotype, poor response to IVIg, and disabling tremor. Autoantibodies against paranodal structures associate with distinct clinical features in CIDP and their identification has diagnostic, prognostic, and therapeutic implications. Classification of evidence: This study provides Class IV evidence that autoantibodies to NF155 identify a CIDP subtype characterized by severe neuropathy, poor response to IVIg, and disabling tremor.

Neurology Department, Hospital Universitario “12 de Octubre”, Madrid, SpainAccepted 11 March 2013ABSTRACT: Introduction: The objective of this retrospectivestudy was to describe the short- and long-term patterns of IVIguse, safety, and response to treatment in patients with chronicinflammatory demyelinating polyneuropathy (CIDP). Methods:Response to therapy was defined as an improvement of 1point on the modified Rankin score at short- and mid-term vis-its. Patient status at long term was classified as remission, sta-bility, or non-responder. Results: Eighty-six patients wereincluded; 60.5% responded at short term and 54.6% at mid-term. At long term, 25.6% of patients were in remission, 65.1%were stable, and 9.3% were non-responders. The only variableassociated with remission was a better response during the first6 months of follow-up. Conclusions: A significant percentage ofpatients did not require any additional drugs in the long term.This suggests that treatment effect or disease outcome may bestable over time, and treatment regimens should therefore beindividualized to avoid overtreatment.

Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56 . Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ∼0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5–14 hexanucleotide repeats, expanded alleles range from ∼650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ∼1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia 36 is thus, so far, the most frequent dominant spinocerebellar ataxia in this region, which may have implications for American countries associated with traditional Spanish emigration. * Abbreviations : SCA : spinocerebellar ataxia SNP : single nucleotide polymorphism TP-PCR : triplet repeat primed polymerase chain reaction

Background and purpose: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by mutations in the CYP27A1 gene resulting in sterol-27-hydroxylase deficiency. Current information about CTX is based mainly on case reports, with only few large series reported. Although perceived as a potentially treatable condition, efficacy of chenodeoxycholic acid plus statin therapy remains unclear. To perform a nationwide survey of confirmed cases, with a thorough analysis of genotype-phenotype data and prognostic factors. Methods: Retrospective review of the clinical and epidemiological aspects and mutations of all the patients diagnosed since 1992 in the main reference centers for genetic testing of CTX in Spain. Results: Twenty-five patients from 19 families were identified. An average delay of 19years was observed between symptom onset and clinical diagnosis. Two main clinical subgroups were recognizable: a classic form (cerebellar and other supratentorial symptoms) and a spinal form (chronic myelopathy). Cholestanol levels did not correlate with clinical presentation, severity or response to therapy. Despite treatment, five patients died during follow-up, one to 4years after diagnosis. Thirteen different mutations were identified, with a higher frequency of p.R395C in Northwestern Spain and p.R405W in Southern Spain. None of the mutations could be associated with a particular clinical feature combination or prognosis. Conclusions: This is the first nationwide extensive series of CTX reported in Spain. The higher number of cases in some areas suggests a possible founder effect. Spinal forms had a less severe prognosis. A delayed diagnosis could contribute to the lack of significant response to treatment. Click for the corresponding questions to this CME article. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS.

Treatment of status epilepticus (SE) has not changed in the last few decades, benzodiazepines plus phenytoin being the most common first line treatment. Intravenous levetiracetam (ivLEV) is a new antiepileptic drug with interesting properties for SE. MATERIAL AND METHODS: Efficacy and effectiveness of ivLEV in SE were assessed in an observational, multicentric and retrospective study. Efficacy was defined as cessation of seizures in the 24h subsequent to starting ivLEV, with no need of any further antiepileptic drug. All patients were treated following the standard protocol (benzodiazepines plus phenytoin or valproate). ivLEV was used as add-on therapy, except in those cases with contraindication for the standard protocol, when it was administered earlier. RESULTS: 40 patients were included, 57% men, with a mean age of 63 years. The most common type of SE was partial convulsive (90%). ivLEV was effective in approximately half of the patients (57.5%), in a mean time of 14.4h. ivLEV was used as add-on treatment in 26 patients (after benzodiazepines plus phenytoin, valproate or both) with an efficacy of 46.1%, and as early treatment (pretreatment with benzodiazepines or nothing) in 14 patients with an efficacy of 78.5% (p 0.048). Adverse events were observed in 15% of patients. CONCLUSIONS: ivLEV was an effective antiepileptic drug for SE, but its efficacy depends on the timing of its administration, being more effective when used as early treatment, and less effective as add-on treatment.

The objective of this retrospective study was to describe the short- and long-term patterns of IVIg use, safety, and response to treatment in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).Response to therapy was defined as an improvement of ≥ 1 point on the modified Rankin score at short- and mid-term visits. Patient status at long term was classified as remission, stability, or non-responder.Eighty-six patients were included; 60.5% responded at short term and 54.6% at mid-term. At long term, 25.6% of patients were in remission, 65.1% were stable, and 9.3% were non-responders. The only variable associated with remission was a better response during the first 6 months of follow-up.A significant percentage of patients did not require any additional drugs in the long term. This suggests that treatment effect or disease outcome may be stable over time, and treatment regimens should therefore be individualized to avoid overtreatment.

Desminopathies represent a subtype of myofibrillar myopathy caused by mutations in the DES gene, which cause myofibril disruption and intracellular inclusions containing desmin and other protein components. Desminopathy mainly involves skeletal and cardiac muscle, separately or together. Both autosomal dominant and autosomal recessive inheritance have been reported. Here, we describe the second family identified to date with an L370P desmin mutation. The disease in this family shows autosomal dominant inheritance with a particular phenotype, where males suffer from sudden death of cardiac origin while females exhibit a more benign myopathy of distal onset and slower progression. Because the only family previously identified with this mutation was limited to one studied patient, the present kindred represents the largest clinical investigation of the phenotype associated with the L370P mutation.