The Impact Of Thymectomy In Thymomatous And Nonthymomatous Myasthenia Gravis - The Experience Of A Tertiary Center.

INTRODUCTION: Thymectomy remains a mainstay of treatment in Thymomatous (T) and Nonthymomatous (nT) Myasthenia Gravis (MG), with improved clinical outcomes and reduced need for medical treatment, however, there is little research regarding long-term follow-up. We aim to assess the impact of surgery on the long-term outcome of patients with MG at our center. METHODS: Retrospective analyses of MG patients submitted to thymectomy between 2007 and 2017 at the thoracic surgery department of CHUC. Clinical assessment was performed according to the MG Foundation of America (MGFA) Clinical Classification (cMGFA). The follow-up was categorized according to the MGFA Post-intervention Status (MGFA-PIS) and cMGFA. Statistical analysis was performed with SPSS, to a significance level of 5%. RESULTS: Thirty-seven patients underwent extended thymectomy and 67.6% were female. Median age at diagnosis was 46.68±19.2 years. Most patients (83.8%) had anti-acetylcholine receptor antibodies and 81.1% had generalized forms of MG. Many patients (67.6%) had surgery less than 12 months after the clinical diagnosis. TMG was present in 19 (51.4%) patients. Compared to nTMG, these patients were older (54.06±17.9 vs 40.17±19.4 years) and most were men (52.9% vs 16.7%). We obtained a good outcome in most patients in the first (81.1%), second (86.1%), and fifth (84.8%) year of follow-up. There was a shift towards better prognosis categories in the good outcome group: 9.1% CSR, 3.0% PR, and 66,7% MM in the fifth year. Preoperative medical treatment did not influence the long-term follow-up outcome. A shorter time to surgery (< 12 months) correlated with better outcomes at year 5 (p=0.016). CONCLUSION: Thymectomy led to a sustained clinical improvement in our cohort, allowing for a reduced need for medication. A shorter time to surgery seems to have a positive influence on long-term prognosis. We expect that an extended follow-up would improve our results.

Single-phase CT angiography predicts ASPECTS decay and may help determine when to repeat CT before thrombectomy.

OBJETIVES: Time is relative in large-vessel occlusion acute ischemic stroke (LVO-AIS). We aimed to evaluate the rate of inter-hospital ASPECTS decay in patients transferred from a primary (PSC) to a comprehensive stroke center (CSC); and to identify patients that should repeat computed tomography (CT) before thrombectomy. MATERIALS AND METHODS: This was a retrospective cohort study of consecutive anterior circulation LVO-AIS transferred patients. The rate of ASPECTS decay was defined as (PSC-ASPECTS - CSC-ASPECTS)/hours elapsed between scans. Single-phase CT angiography (CTA) at the PSC was used to classify the collateral score. We compared patients with futile versus useful CT scan re-evaluation. RESULTS: We included 663 patients, of whom 245 (37.0%) repeated CT at a CSC. The median rate of ASPECTS decay was 0.4/h (0.0-0.9). Patients excluded from thrombectomy after a CT scan repeat (n=64) had a median ASPECTS decay rate of 1.18/h (0.83-1.61). Patients with absent collateral circulation had a median rate of 1.51(0.65-2.19). The collateral score was an independent predictor of the ASPECTS decay rate (aß = -0.35; 95%CI -0.45 - -0.19, p<0.001). Age (aOR: 1.04 95% CI 1.02-1.07, p<0.001), NIHSS (aOR: 1.11 95% CI 1.06-1.15, p<0.001), PSC ASPECTS (aOR: 0.74 95% CI 0.60-0.91, p=0.006) and the CTA collateral score (aOR: 0.14 95% CI 0.08-0.22, p<0.001) were independent predictors of the usefulness of a CT scan repeat. CONCLUSIONS: The rate of ASPECTS decay can be predicted by the CTA collateral score, helping in the selection of patients that would benefit from repeating a CT assessment on arrival at the CSC.

Vasculitic peripheral neuropathy in deficiency of adenosine deaminase 2.

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory vasculopathy characterized by systemic vasculitis, early-onset stroke and livedo racemosa. We report a family cohort of 3 patients with ADA2 compound heterozygous mutation p.[Thr360Ala] and [Gly383Ser]. Two of them had progressive involvement of the peripheral nervous system in the fourth decade, both after stroke. In one patient, clinical and neurophysiological studies showed progression of mononeuritis multiplex to chronic axonal sensorimotor polyneuropathy, nerve biopsy had features of small vessel vasculitic neuropathy, and muscle biopsy disclosed neurogenic atrophy with reinnervation. The second patient presented with progressive sensory symptoms of the lower limbs and chronic axonal sensorimotor polyneuropathy in nerve conduction studies. These two patients had absent plasma ADA2 activity. The third patient had no neurological affection despite low, but not absent, plasma ADA2 activity. Patients were started on a tumor necrosis factor (TNF) inhibitor, which has presumed benefits for the vasculitic phenotype of DADA2.

Phospholipase A2 and Ischemic Stroke Etiology.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2), which is involved in the inflammatory atherosclerotic process, has emerged as an independent risk factor for atheromatous vascular events. Its impact on coronary disease has already been demonstrated, however, its influence in cerebrovascular etiology is still unknown. We aimed to observe and describe the potential association between Lp-PLA2 levels and the etiologic subtype of ischemic stroke. METHODS: Unicentric, observational, and prospective cohort study of consecutive patients with acute ischemic stroke, admitted in a comprehensive stroke center. Patients with incomplete investigation or coexisting causes were excluded. Lp-PLA2 was dosed in peripheral blood between day 3 and 14 postevent with "Lp-PLA2-SNIBE" kit. Statistical significance was set for P<0.05. RESULTS: A total of 96 patients were enrolled, with mean age of 75.31±11.88 years, 41 males (42.7%); 12.5% with lacunar stroke, 16.7% atherothrombotic, 46.9% cardioembolic, and 24% embolic stroke of undetermined source (ESUS). The level of Lp-PLA2 was different between etiologies (F=2.982, P=0.035), being lower in ESUS (143.3±42.8 ng/mL). There were no significant associations with previous vascular risk factors, history of ischemic stroke and modified-Rankin scale (mRS) score 3 months postevent. In ESUS patients, Lp-PLA2 was not associated with cervical ultrasound findings or frequent supraventricular extrasystoles. CONCLUSIONS: Lp-PLA2 levels are different between etiologic subtypes of ischemic stroke, being lower in ESUS patients. The results of this study reinforce the existence of distinct pathophysiological mechanisms in patients with ESUS. Multicenter clinical trials with larger sample sizes are needed to clarify the role Lp-PLA2 on the etiology of stroke.

Pathophysiology of Blood-Brain Barrier Permeability Throughout the Different Stages of Ischemic Stroke and Its Implication on Hemorrhagic Transformation and Recovery.

The blood-brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting the brain from unwanted compounds, but its impairment is involved in a vast number of pathological conditions. Disruption of the BBB and increase in its permeability are key in the development of several neurological diseases and have been extensively studied in stroke. Ischemic stroke is the most prevalent type of stroke and is characterized by a myriad of pathological events triggered by an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). BBB permeability seems to follow a multiphasic pattern throughout the different stroke stages that have been associated with distinct biological substrates. In the hyperacute stage, sudden hypoxia damages the BBB, leading to cytotoxic edema and increased permeability; in the acute stage, the neuroinflammatory response aggravates the BBB injury, leading to higher permeability and a consequent risk of HT that can be motivated by reperfusion therapy; in the subacute stage (1-3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky BBB, but this permeability has been associated with improved clinical recovery. In the chronic stage (>6 weeks), an increase of BBB restoration factors leads the barrier to start decreasing its permeability. Nonetheless, permeability will persist to some degree several weeks after injury. Understanding the mechanisms behind BBB dysregulation and HT pathophysiology could potentially help guide acute stroke care decisions and the development of new therapeutic targets; however, effective translation into clinical practice is still lacking. In this review, we will address the different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery.

Ischemic Stroke Incidence in Patients With Microvascular Ocular Motor Palsy Versus Patients With Lacunar Ischemic Stroke.

OBJECTIVE: Presumed microvascular ischemia is the most frequent cause of ocular motor palsy (OMP). Ischemic stroke incidence after an episode of microvascular OMP (mOMP) is not established, contrasting with other common vascular conditions, such as lacunar ischemic stroke (LS). We sought to compare the incidence of subsequent ischemic stroke between mOMP and LS populations. METHODS: A retrospective observational analysis was conducted on acute patients presenting with either mOMP or LS. A propensity score match was applied to ensure a balance between groups. We compared the incidence of subsequent ischemic stroke during an 80-month follow-up. RESULTS: A total of 110 patients were included in the study (57, mOMPs; 53, LS). During follow-up, the annual occurrence rate of ischemic stroke was 2.1% per year in mOMP group and 0.6% per year in the LS group. After performing Cox regression, we found no statistical significance difference between groups in the incidence of subsequent ischemic stroke (P=0.801). CONCLUSIONS: Patients with presumed mOCP seem to share similar incidence of subsequent ischemic stroke with patients with LS. Presumed mOCP may be an underrecognized independent risk factor for ischemic stroke.

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.

SIGMAR1 gene mutation causing Distal Hereditary Motor Neuropathy in a Portuguese family.

SIGMAR1 gene encodes a non-opioid endoplasmic reticulum (ER) protein which is involved in a large diversity of cell functions and is expressed ubiquitously in both central and peripheral nervous systems. Alterations of its normal function may contribute to two different phenotypes: juvenile amyotrophic lateral sclerosis (ALS 16) and distal hereditary motor neuropathies (dHMN). We present the case of a female patient, of 37-years-old, with distal muscle weakness and atrophy beginning in childhood and slowly progressive in the first two decades of life. Neurological examination revealed a symmetrical severe muscle wasting and weakness in distal lower and upper limbs, with claw hands, footdrop with equinovarus deformity and hammer toes, generalized areflexia and normal sensory examination. The electrodiagnostic study revealed a pure chronic motor peripheral nerve involvement without signs of demyelination. The molecular study found the deletion c.561_576del on exon 4 and a deletion of all exon 4, in the SIGMAR1 gene.

LAMA2 gene mutation update: Toward a more comprehensive picture of the laminin-α2 variome and its related phenotypes.

Congenital muscular dystrophy type 1A (MDC1A) is one of the main subtypes of early-onset muscle disease, caused by disease-associated variants in the laminin-α2 (LAMA2) gene. MDC1A usually presents as a severe neonatal hypotonia and failure to thrive. Muscle weakness compromises normal motor development, leading to the inability to sit unsupported or to walk independently. The phenotype associated with LAMA2 defects has been expanded to include milder and atypical cases, being now collectively known as LAMA2-related muscular dystrophies (LAMA2-MD). Through an international multicenter collaborative effort, 61 new LAMA2 disease-associated variants were identified in 86 patients, representing the largest number of patients and new disease-causing variants in a single report. The collaborative variant collection was supported by the LOVD-powered LAMA2 gene variant database (https://www.LOVD.nl/LAMA2), updated as part of this work. As of December 2017, the database contains 486 unique LAMA2 variants (309 disease-associated), obtained from direct submissions and literature reports. Database content was systematically reviewed and further insights concerning LAMA2-MD are presented. We focus on the impact of missense changes, especially the c.2461A > C (p.Thr821Pro) variant and its association with late-onset LAMA2-MD. Finally, we report diagnostically challenging cases, highlighting the relevance of modern genetic analysis in the characterization of clinically heterogeneous muscle diseases.

Tremor Frequency Assessment by iPhone® Applications: Correlation with EMG Analysis.

Tremor frequency analysis is usually performed by EMG studies but accelerometers are progressively being more used. The iPhone® contains an accelerometer and many applications claim to be capable of measuring tremor frequency. We tested three applications in twenty-two patients with a diagnosis of PD, ET and Holmes' tremor. EMG needle assessment as well as accelerometry was performed at the same time. There was very strong correlation (Pearson >0.8, p < 0.001) between the three applications, the EMG needle and the accelerometry. Our data suggests the apps LiftPulse®, iSeismometer® and Studymytremor® are a reliable alternative to the EMG for tremor frequency assessment.

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.