Longitudinally Extensive Transverse Myelitis as a First Manifestation of Sarcoidosis.

Longitudinally extensive transverse myelitis (LETM) is a debilitating inflammatory spinal cord lesion involving several spinal segments. There are several possible etiologies, with spinal cord sarcoidosis being a rare cause of LETM. Spinal cord sarcoidosis is, in itself, a rare manifestation of sarcoidosis that can be difficult to diagnose, especially in patients with no prior history of systemic sarcoidosis, frequently leading to a delayed diagnosis. We report the case of a 53-year-old man who developed LETM as the first manifestation of sarcoidosis. The patient presented with progressive lower limb weakness, urinary retention, sensory disturbances, and muscle spasms. Imaging studies showed hyperintense lesions extending over multiple spinal segments. After the exclusion of other causes and a lymph node biopsy showing non-caseating granulomas, the diagnosis of LETM secondary to sarcoidosis was confirmed.

Ischaemic stroke as the initial manifestation of systemic amyloidosis.

A previously healthy 54-year-old woman was admitted to the stroke unit with an acute ischaemic stroke attributed to atrial fibrillation newly diagnosed at the emergency room. Nevertheless, preliminary investigation on stroke aetiology revealed incidental hypoalbuminaemia in the context of nephrotic syndrome, while clinically, the patient developed progressive signs of cardiac failure raising the suspicion of an underlying disorder. Systemic amyloidosis was histologically confirmed a few weeks after hospital admission. The rare presentation and non-specific symptom constellation contributed to delayed institution of the appropriated treatment regimen at a point where multiorganic involvement was irreversible leading to death only 2 months after the first manifestation. The presented case reminds us of the importance of always keeping in mind this rarer cause of ischaemic stroke since an early diagnosis remains the key to a more hopeful prognosis.

Increased risk of melanoma in C9ORF72 repeat expansion carriers: A case-control study.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are considered part of the same pathological spectrum. There is an increased risk of ALS in patients who have had melanoma. The risk of FTLD in melanoma (or cancer) patients is unknown. We aimed to study if C9ORF72 expansion is linked to a higher prevalence of melanoma. METHODS: We selected patients with a diagnosis in the ALS-FTLD spectrum who were tested for pathogenic mutations. Medical history was reviewed, to identify those with pathologically documented melanomas. RESULTS: We included 189 patients. Sixty-two had identified pathogenic mutations (39 C9ORF72). C9ORF72 carriers had a significantly higher risk of melanoma (odds ratio = 24.709; P < 0.007). There was no association with phenotype. CONCLUSIONS: These findings suggest that patients with a history of melanoma may have an increased probability of carrying a C9ORF72 repeat expansion. ALS or FTLD carriers of C9ORF72 should undergo surveillance for skin changes. Muscle Nerve 59:362-365, 2019.

Demyelinating disease of the central nervous system associated with Pembrolizumab treatment for metastatic melanoma.

Immune checkpoint inhibitors are used in metastatic melanoma with good efficacy and safety profile. We report the first case of an inflammatory demyelinating disease of the central nervous system during treatment with Pembrolizumab and discuss the evidence in the literature supporting its causative role. The patient had a good clinical recovery after intravenous steroids, plasma exchange and discontinuation of Pembrolizumab. Due to the expected increase in the importance of immune checkpoint inhibitors in cancer treatment, it is important to be aware of neurological adverse events, as early treatment usually leads to good clinical responses.

Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness.

Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK-CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742T > A; p.I581N found in homozygosis, and c.1634T > C; p.L545P found in compound heterozygosis with p.R166*. The reported patients had predominant limb girdle weakness with symptom onset at 12, 17, 18, and 30 years of age, and the majority exhibited a good clinical response to Salbutamol therapy, but not to esterase inhibitors. Meta-analysis including previously reported variants revealed an increased likelihood of a severe, respiratory phenotype with null alleles. Missense variants exclusively affecting the kinase domain, but not the catalytic site, are associated with late onset. These data refine the phenotype associated with MuSK-related CMS.

Disabling Central Paroxysmal Positioning Upbeat Nystagmus and Vertigo Associated With the Presence of Anti-Glutamic Acid Decarboxylase Antibodies.

An immune attack by anti-glutamic acid decarboxylase (GAD) antibodies is believed to cause a deficiency in gamma-aminobutyric acid-mediated neurotransmission in the cerebellum. This, in turn, leads to several eye movement disorders, including spontaneous downbeat (DBN) and periodic alternating nystagmus. We describe a 68-year-old diabetic woman with disabling paroxysmal positioning upbeat nystagmus (UBN) exclusively in the supine position, associated with asymptomatic spontaneous DBN, alternating skew deviation and hyperactive vestibulo-ocular reflex responses on head impulse testing, in whom high titers of anti-GAD antibodies were detected. After treatment with intravenous immunoglobulin, a complete resolution of positioning UBN and spontaneous DBN occurred, along with a decrease in anti-GAD antibody titers. Positioning UBN in this case may reflect a transient disinhibition of the central vestibular pathways carrying posterior semicircular canal signals, due to lack of normal inhibitory input from the cerebellar nodulus/uvula. Immunoglobulin restored cerebellar inhibitory output, possibly by improving gamma-aminobutyric acid neurotransmission.

Screening for Pompe disease in a Portuguese high risk population.

Pompe disease is a rare metabolic disorder with available enzymatic replacement therapy. Contrasting with the classic infantile form, the others subtypes have a heterogeneous presentation that makes an early and accurate diagnosis difficult. We conducted a prospective, multicenter, observational study to identify undiagnosed patients. During a one-year period, patients followed in Portuguese neuromuscular outpatient clinics with proximal muscle weakness affecting upper and/or lower limbs, hyperCKemia in two or more determinations or hypotonia and hyperCKemia, were screened for acid α-glucosidase deficiency by dried blood spots. Lysosomal acid-alpha-1,4-glucosidase activity was determined by tandem mass spectrometry and positive results were confirmed by molecular study. From the 99 patients screened, Pompe disease was confirmed in 4, with age of onset ranging from 2.5 to 48 years, all with limb girdle muscle weakness, corresponding to a frequency of 4% in our cohort and 4.9% of limb girdle muscle weakness. Screening for Pompe disease in high risk populations, using dried blood spots, was already performed in some European populations. Apart from two negative Scandinavian studies, positive cases were confirmed in 2.8-7.9% of patients presenting with limb girdle muscle weakness and in 0-2.5% with isolated hyperCKemia.

Charcot-Marie-Tooth 4B2 caused by a novel mutation in the MTMR13/SBF2 gene in two related Portuguese families.

INTRODUCTION: CMT4B2 is a rare subtype of CMT caused by pathogenic mutations in the myotubularin-related protein-13/set binding factor 2 (MTMR13/SBF2) gene. Nerve conduction velocities are markedly reduced and focally folded myelin sheaths are present on nerve biopsies. We presented two patients from two related Portuguese families with peripheral neuropathy caused by a novel mutation in the MTMR13/SBF2 gene. CASE REPORT: Family 1: Patient 1: A 30-year-old woman, with disease onset in early childhood presented pes cavus and hammertoes and walked with a steppage gait. Muscle weakness was present distally, myotactic reflexes were abolished and sensory examination revealed a stocking and glove pattern of hypoesthesia to all sensory modalities. Family 2: Patient 2: A 43-year-old man, second degree cousin of patient 1, born of a consanguineous marriage. At the age of 9 months, he was diagnosed with congenital glaucoma on the left eye, with progressive visual loss up to total blindness. He presented bilateral claw hand deformity, pes cavus and hammertoes and walked with a steppage gait. Myotactic reflexes were abolished and muscle weakness was severe distally in the upper and lower limbs. Sensory examination revealed a stocking and glove pattern of hypoesthesia to all modalities. In both patients electrodiagnostic studies evidenced an uniform and generalized sensorimotor demyelinating polyneuropathy and the molecular study found a frameshift/truncating homozygous novel mutation c.5073_5074del (p.Ser1692Tyrfs*42) in the MTMR13/SBF2 gene. CONCLUSIONS: We report a novel mutation in the MTMR13/SBF2 gene associated with a classical CMT phenotype. Congenital glaucoma associated with a frameshift/truncating mutation in CMT4B2 is reported for the first time.

[National Post Hospital Care Project and length of hospitalization of patients with stroke 2010-2011]. / Rede Nacional de Cuidados Continuados e Tempo de Internamento dos Doentes com Acidente Vascular Cerebral 2010-2011.

INTRODUCTION: The National Post Hospital Care Project was created to provide a continuity of care after hospitalization or to functionally dependent people. Currently there is a great difficulty in the integration of patients. The objective of this paper is to compare the impact of the referral to the Project versus being discharged home, in the length of stay of stroke patients between 2010 and 2011. MATERIAL AND METHODS: Retrospective study of patients admitted to the Neurology Infirmary A and Stroke Unit of Coimbra's University Hospital, in 2010 and 2011. The cases analyzed were 1 209, featuring demographic data, length of stay, Rankin Score (mRS) and destination after discharge. The data was analyzed comparing the two years concerning the length of stay of stroke patients referred to the Project and those discharged home, given the their Rankin Score. RESULTS: In 2011, the number patients referred to the National Post Hospital Care Project was higher, 23.5% compared to 21.4%. The length of stay for the same Rankin Score of the patients referred to National Post Hospital Care Project, remained higher than those discharged home: for a Rankin Score of 1: 11, versus 26 days for the Project; Rankin Score 2: 13, versus 29 days for the project; Rankin Score 3: 13, versus 23 days for the Project; Rankin Score 4: 17, to 33 days for the Project, Rankin Score 5: 27, versus 39 days to the Project. After comparison between the length of stay of patient discharged of and those referred to the National Post Hospital Care Project, it was estimated that the referral represented an hospitalization excess of 1 718 days in 2010 and 1 198 days in 2011. CONCLUSION: The National Post Hospital Care Project is unable to meet the actual needs although the waiting time has reduced, possibly due to the increased number of beds and the possibility of patients waiting at home.

Introdução: A Rede Nacional de Cuidados Continuados Integrados surgiu para proporcionar a continuação de cuidados após internamento ou para pessoas funcionalmente dependentes. Actualmente há uma grande dificuldade na integração dos doentes no domicílio ou em estruturas de retaguarda. Pretende-se comparar o impacto da referenciação para a Rede Nacional de Cuidados Continuados Integrados versus alta para domicílio, no tempo de internamento dos doentes com Acidente Vascular Cerebral, entre 2010 e 2011.Material e Métodos: Estudo retrospectivo envolvendo os doentes internados na Neurologia A e Unidade de Acidente Vascular Cerebral dos Hospitais da Universidade de Coimbra, naquele anos. Analisaram-se 1 209 processos, incluídos 819, caracterizados demograficamente, tempo de internamento, Score de Rankin modificado e destino pós-alta. Compararam-se os dados, relativamente ao tempo de internamento dos doentes com Acidente Vascular Cerebral, referenciados para a Rede Nacional de Cuidados Continuados Integrados e os com alta para domicílio, atendendo ao Score de Rankin final.Resultados: Em 2011, aumentaram os doentes referenciados para a Rede Nacional de Cuidados Continuados Integrados, 23,5% comparativamente 21,4%. Em 2011 o tempo de internamento, para um mesmo Score de Rankin, da população referenciada manteve-se superior: para um Rankin de 1: 11 dias para domicílio, 26 dias para os doentes referenciados; para um Rankin de 2: 13 dias para domicílio, 29 dias para a rede; para Rankin de 3: 13 dias para domicílio, 23 dias para referenciados; para um Rankin de 4: 17 dias para domicílio, 33 dias para Rede; e para um Rankin de 5: 27 dias para domicílio, 39 dias para Rede. Comparando com os tempos de internamento da população com alta para domicílio, estima-se que tenha representado mais 1 718 dias de internamento, em 2010 e1 198 dias, em 2011.Conclusão: A Rede Nacional de Cuidados Continuados Integrados é incapaz de responder às necessidades actuais, embora o tempo de espera tenha reduzido, devido ao aumento do número de camas e da possibilidade dos doentes aguardarem vaga no domicílio.

Private dysferlin exon skipping mutation (c.5492G>A) with a founder effect reveals further alternative splicing involving exons 49-51.

The allelic muscle disorders known as limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy and distal anterior compartment myopathy result from defects in dysferlin-a sarcolemma-associated protein involved in membrane repair. Mutation screening in the dysferlin gene (DYSF) enabled the identification of seven Portuguese patients presenting the variant c.5492G>A, which was observed to promote skipping of exon 49 (p.Gly1802ValfsX17). Several residually expressed products of alternative splicing also involving exons 50 and 51 were detected in the leukocytes and muscle of both patients and normal controls. Quantitative transcript analysis confirmed these results and revealed that Delta49/Delta50 transcripts were predominant in blood. Although the patients were apparently unrelated, the c.5492G>A mutation was found in linkage disequilibrium with a particularly rare haplotype in the population, corroborating the hypothesis of a common origin. Despite the presence of the same mutation on the same haplotype background, onset of the disease was heterogeneous, with either proximal or distal muscle involvement.