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Introduction Laryngospasm is an involuntary sustained closure of sphincter musculature that leads to an unpleasant subjective experience of dyspnea and choking. It is an underreported symptom in amyotrophic lateral sclerosis (ALS). This study aimed to better characterize the prevalence and clinical characteristics of laryngospasm in ALS patients. Methods The medical records of 571 patients with ALS followed between 2008-2018 were searched for evidence of laryngospasm. A total of 23 patients with laryngospasm were identified and data related to patient and laryngospasm characteristics were extracted. Results Laryngospasm was reported in 4% of ALS patients. Females comprised 57% of patients and mean age was 63.4 years. Laryngospasm frequently manifested in patients with moderate bulbar dysfunction and seemed independent of respiratory function. Among laryngospasm patients, 26% were cigarette smokers and 13% had a history of gastroesophageal reflux. The most common reported trigger was excessive saliva irritating the vocal cords (35%) followed by eating a meal (17%). There was significant variation in laryngospasm frequency (up to 5 per hour) and duration (seconds to minutes). Most patients could not identify an effective coping mechanism, although 13% reported that drinking water was effective. Discussion Despite its low prevalence in ALS, laryngospasm should be included in the symptom enquiry. This study may improve patient care through increased recognition of the clinical features of laryngospasm in ALS patients, identifying a link between laryngospasm and moderate bulbar dysfunction, and highlighting trigger avoidance as a management strategy. Additional research is required to understand the pathophysiology and optimal treatment.

We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods, including analysis of novel candidate genes, identified candidates in 21% (61/287). Of these, 24 families have additional evidence through data sharing to support likely diagnoses (8% of cohort). This study indicates few diagnoses are missed by clinical laboratories, the incremental gain from reanalysis of clinically-relevant genes is modest, and the highest yield comes from validation of novel disease-gene associations. Future implementation of translational research methods, including continued reporting of compelling genes of uncertain significance by clinical laboratories, should be considered to maximize diagnoses.

Background and Purpose: Elevation of total protein level in cerebrospinal fluid (CSF-TP) in diabetic patients is often disregarded by clinicians. However, existing studies on the topic have significant limitations, and therefore we aimed to explore the relationship between diabetes and CSF-TP in a large database of CSF samples. Methods: Retrospective review of all diagnostic lumbar punctures at the Ottawa Hospital between 1996-2016. Patients were excluded if they had elevated CSF cell counts, or a condition known to elevate CSF-TP. Multivariate linear regression modeling considered the effects of age, sex, and diabetes. Results: Among 6124 patients (746 with diabetes, 5378 without), mean CSF-TP did not differ significantly between groups (0.39 and 0.35 mmol/L, p = 0.2). When controlled for age and sex, there was no significant effect of diabetes on CSF-TP and no significant correlation between mean serum glucose and CSF-TP (R2 = 0.12). Conclusions: CSF-TP did not differ significantly between diabetic and non-diabetic groups, once the influence of age and sex was controlled. Elevated CSF-TP should be regarded as pathologic, even in the setting of diabetes.

Background: Spinal Muscular Atrophy (SMA) is a rare disease that affects 1 in 11 000 live births. Recent developments in SMA treatments have included new disease-modifying therapies that require high quality data to inform decisions around initiation and continuation of therapy. In Canada, there are no nationally agreed upon outcome measures (OM) used in adult SMA. Standardization of OM is essential to obtain high quality data that is comparable among neuromuscular clinics. Objective: To develop a recommended toolkit and timing of OM for assessment of adults with SMA. Methods: A modified delphi method consisting of 2 virtual voting rounds followed by a virtual conference was utilized with a panel of expert clinicians treating adult SMA across Canada. Results: A consensus-derived toolkit of 8 OM was developed across three domains of function, with an additional 3 optional measures. Optimal assessment frequency is 12 months for most patients regardless of therapeutic access, while patients in their first year of receiving disease-modifying therapy should be assessed more frequently. Conclusions: The implementation of the consensus-derived OM toolkit will improve monitoring and assessment of adult SMA patients, and enrich the quality of real-world evidence. Regular updates to the toolkit must be considered as new evidence becomes available.

Myasthenia gravis is a treatable autoimmune disease caused by autoantibodies directed against membrane proteins at the neuromuscular junction. While acetylcholine receptor antibodies are most common, a minority of patients have antibodies directed against muscle-specific kinase (MuSK-antibody). Differentiating features often include subacute onset and rapid progression of bulbar, respiratory and neck extensor muscles, with sparing of distal appendicular muscles, most commonly in middle-aged females. Here we present an atypical presentation of MuSK-antibody myasthenic syndrome in a young male consisting of a gradual-onset, insidiously-progressive, non-fatigable and non-fluctuating ocular, bulbar and oesophageal weakness, with a normal frontalis single fibre EMG. This case clinically resembled a mitochondrial myopathy (Mitochondrial Neurogastrointestinal Encephalopathy-MNGIE) with a poor prognosis. Because of the atypical presentation, MuSK antibodies were identified very late in the disease course, at which point the patient responded very well to immunotherapy. We report an unusual presentation of an uncommon but treatable condition, illustrating significant phenotypic heterogeneity possible in MuSK-antibody myasthenic syndrome.

Oculopharyngeal muscular dystrophy (OPMD) is a genetic muscle disease causing ptosis, severe swallowing difficulties and progressive limb weakness, although atypical presentations may be difficult to diagnose. Sensitive biomarkers of disease progression in OPMD are needed to enable more effective clinical trials. This study was designed to test the feasibility of using MRI to aid OPMD diagnosis and monitor OPMD progression. Twenty-five subjects with Dixon whole-body muscle MRI were enrolled: 10 patients with genetically confirmed OPMD, 10 patients with non-OPMD muscular dystrophies, and 5 controls. Using the MRI Dixon technique, muscle fat replacement was evaluated in the tongue, serratus anterior, lumbar paraspinal, adductor magnus, and soleus muscles using quantitative and semi-quantitative rating methods. Changes were compared with muscle strength testing, dysphagia severity, use of gait aids, and presence of dysarthria. Quantitative MRI scores of muscle fat replacement in the tongue could differentiate OPMD from other muscular dystrophies and from controls. Moreover, fat fraction in the tongue correlated with clinical severity of dysphagia. This study provides preliminary support for the use of Dixon-based quantitative MRI images as outcome measures for monitoring disease progression in clinical trials and provides rationale for future prospective studies aimed at methodological refinement and covariate identification.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) refractory to conventional therapy can lead to marked disability and represents a therapeutic challenge. Objective: To report five cases of treatment-refractory disabling CIDP treated with autologous hematopoietic stem cell transplantation (AHSCT). Methods: This was a retrospective cohort study from a tertiary care referral center for both neuromuscular disease and AHSCT. Patients with CIDP treated with AHSCT between 2008 and 2020 were included. All patients had major persistent and disabling neuropathic deficits despite combinations of intensive immunosuppressive therapy. The primary outcome measures were: Medical Research Council sum score, Overall Neuropathy Limitations Scale and requirement for ongoing CIDP immunotherapy after transplantation. We also analyzed safety outcomes by documenting all severe AHSCT-related complications. Results: Five patients with refractory CIDP underwent AHSCT. Three were classified as manifesting a typical syndrome, two were classified as the multifocal Lewis Sumner variant. The mean age at time of CIDP diagnosis was 33.4 years (range 24–46 years), with a median delay of 46 months (range 21–135 months) between diagnosis and AHSCT. The median follow-up period was 41 months. All five patients were able to wean off CIDP-related immunotherapy. Marked improvements in Medical Research Council scale and overall Neuropathy Limitations Scale were noted in 4/5 patients. One patient with longstanding neurogenic atrophy showed no improvement in disability scales. There were no treatment-related deaths or critical illnesses. Conclusions: AHSCT can achieve marked sustained clinical improvement of refractory CIDP and may allow for weaning off long-term complex immunotherapies.

Background and ObjectivesCoenzyme Q10(CoQ10) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ10), the second-to-last step in the CoQ10biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant ofCOQ7with abnormal CoQ10biosynthesis.MethodsAffected family members underwent clinical assessments that included nerve conduction testing, histologic analysis, and MRI. Pathogenicity of theCOQ7variant was assessed in cultured fibroblasts and skeletal muscle using a combination of immunoblots, respirometry, and quinone analysis.ResultsThree affected siblings, ranging from 12 to 24 years of age, presented with a severe length-dependent motor neuropathy with marked symmetric distal weakness and atrophy with normal sensation. Muscle biopsy of the quadriceps revealed chronic denervation pattern. An MRI examination identified moderate to severe fat infiltration in distal muscles. Exome sequencing demonstrated the homozygousCOQ7c.1A > G p.? variant that is expected to bypass the first 38 amino acid residues at the n-terminus, initiating instead with methionine at position 39. This is predicted to cause the loss of the cleavable mitochondrial targeting sequence and 2 additional amino acids, thereby preventing the incorporation and subsequent folding of COQ7 into the inner mitochondrial membrane. Pathogenicity of theCOQ7variant was demonstrated by diminished COQ7 and CoQ10levels in muscle and fibroblast samples of affected siblings but not in the father, unaffected sibling, or unrelated controls. In addition, fibroblasts from affected siblings had substantial accumulation of DMQ10, and maximal mitochondrial respiration was impaired in both fibroblasts and muscle.DiscussionThis report describes a new neurologic phenotype ofCOQ7-related primary CoQ10deficiency. Novel aspects of the phenotype presented by this family include pure distal motor neuropathy involvement, as well as the lack of upper motor neuron features, cognitive delay, or sensory involvement in comparison with cases ofCOQ7-related CoQ10deficiency previously reported in the literature.

Background:Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population.Methods:The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials.Results:The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner.Conclusion:Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.

Advances in DNA sequencing technologies have resulted in a near doubling, in under 10 years, of the number of causal genes identified for inherited neuromuscular disorders. However, around half of patients, whether children or adults, do not receive a molecular diagnosis after initial diagnostic workup. Massively parallel technologies targeting RNA, proteins, and metabolites are being increasingly used to diagnose these unsolved cases. The use of these technologies to delineate pathways, biomarkers, and therapeutic targets has led to new approaches entering the drug development pipeline. However, these technologies might give rise to misleading conclusions if used in isolation, and traditional techniques including comprehensive neurological evaluation, histopathology, and biochemistry continue to have a crucial role in diagnostics. For optimal diagnosis, prognosis, and precision medicine, no single ruling technology exists. Instead, an interdisciplinary approach combining novel and traditional neurological techniques with computer-aided analysis and international data sharing is needed to advance the diagnosis and treatment of neuromuscular disorders.

Background:The antiquated standard reference range of 0.15–0.45 g/L for cerebrospinal fluid total protein (CSF-TP) is well entrenched in medical literature and laboratory operating procedures across the world.Methods:We conducted a web-based survey with a response rate of 34.9% through the listserv of the Canadian Neurological Sciences Federation. Additional laboratory reference data were collated by telephone interview of hospital laboratory technologists across Canada.Results:A total of 142 site responses were obtained: 64.1% from academic/tertiary hospitals and 35.9% from community hospitals. A strong majority (80.4%) of both types of institutions reported using a CSF-TP upper reference limit of 0.45 g/L or less. As a rule, no age adjustments were implemented in CSF-TP-level interpretation.Conclusions:Recent well-powered laboratory reference studies have documented CSF-TP upper reference limits that are above 0.6 g/L starting at age 50, with incremental limits partitioned by subsequent decades of age. The conventional 0.45 g/L limit could lead to false positive results. Our survey suggests there is a need to consider a wide adoption of data-driven, rather than historical, reference values.

To examine the impact of a targeted exome approach for the molecular diagnosis of patients nationwide with a wide range of ataxia-related phenotypes. One hundred and seventy patients with ataxia of unknown etiology referred from clinics throughout the United States and Canada were studied using a targeted exome approach. Patients ranged in age from 2 to 88 years. Analysis was focused on 441 curated genes associated with ataxia and ataxia-like conditions. Pathogenic and suspected diagnostic variants were identified in 88 of the 170 patients, providing a positive molecular diagnostic rate of 52%. Forty-six different genes were implicated, with the six most commonly mutated genes being SPG7, SYNE1, ADCK3, CACNA1A, ATP1A3, and SPTBN2, which accounted for >40% of the positive cases. In many cases a diagnosis was provided for conditions that were not suspected and resulted in the broadening of the clinical spectrum of several conditions. Exome sequencing with targeted analysis provides a high-yield approach for the genetic diagnosis of ataxia-related conditions. This is the largest targeted exome study performed to date in patients with ataxia and ataxia-like conditions and represents patients with a wide range of ataxia phenotypes typically encountered in neurology and genetics clinics.

We report the recruitment activities and outcomes of a multi-disease neuromuscular patient registry in Canada. The Canadian Neuromuscular Disease Registry (CNDR) registers individuals across Canada with a confirmed diagnosis of a neuromuscular disease. Diagnosis and contact information are collected across all diseases and detailed prospective data is collected for 5 specific diseases: Amyotrophic Lateral Sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Myotonic Dystrophy (DM), Limb Girdle Muscular Dystrophy (LGMD), and Spinal Muscular Atrophy (SMA). Since 2010, the CNDR has registered 4306 patients (1154 pediatric and 3148 adult) with 91 different neuromuscular diagnoses and has facilitated 125 projects (73 academic, 3 not-for-profit, 3 government, and 46 commercial) using registry data. In conclusion, the CNDR is an effective and productive pan-neuromuscular registry that has successfully facilitated a substantial number of studies over the past 10 years.

Introduction A distal-predominant demyelinating symmetric pattern is most frequent in patients with neuropathy associated with anti-myelin-associated glycoprotein (MAG) antibodies. The literature however lacks longitudinal data to describe whether this is consistent over time. Methods From the Ottawa Neuromuscular Center database, we identified 23 patients with both IgM gammopathy and anti-MAG antibodies. For median, ulnar and fibular motor conduction studies, we analyzed distal latency and amplitude, negative peak duration, terminal latency index and conduction velocity. For median, ulnar, sural and superficial fibular sensory conduction studies we analyzed distal latency and amplitude. Results were compared for the earliest and the latest data sets. Results The mean time interval between the two assessment points was 6.5 years. Median and ulnar motor nerve conduction studies did not show a significant change for any of the parameters tested. There was disproportionate prolongation of median distal motor latency and reduction in terminal latency index, compared to the ulnar nerve. Deep fibular motor conduction studies showed a marked reduction in amplitudes over time. Sensory potentials were recordable in the upper limb in less than 50% at the first study and less than 25% on the most recent study. There was an even larger attrition of recordable sural and superficial fibular sensory potentials. Discussion Our results highlight the stability of median and ulnar motor conduction study results over a mean observation period of 6.5 years. In contrast, lower limb motor and all sensory potentials show a marked trend towards becoming unrecordable.

Monomelic pure motor amyotrophy may seem to be an ominous syndrome as it leads to consideration of motor neuron disease. We present a series of 3 very similar cases where unilateral pure distal lower motor neuron paresis and atrophy was limited to the C8-T1 myotomes, without long-tract signs. Electrodiagnostic studies were in keeping with a restricted anterior horn cell disorder. Neuroimaging showed very focal spinal cord compression at the C6-7 level. Two patients underwent surgical decompression. All 3 patients were improved or stable at follow-up. Distal spondylotic amyotrophy is characterized by equal involvement of thenar and hypothenar muscles, in contrast to amyotrophic lateral sclerosis or Hirayama disease. We discuss the striking 2-level discrepancy between imaging and clinical localization. Proposed explanations are arterial or venous compromise caudal to the site of compression. Anatomical variation such as a prefixed brachial plexus is unlikely. A similar imaging/clinical discrepancy has been documented in Hirayama disease and spondylotic myelopathy.

Background: Neurolymphomatosis is a process of neoplastic endoneurial invasion, most strongly associated with non-Hodgkin’s lymphoma. It must be distinguished from paraneoplastic, metabolic, nutritional and treatment-related causes of neuropathy that are common in this patient population. Methods: This brief case series illustrates the protean manifestations of neurolymphomatosis of the brachial plexus, ranging from focal distal mononeuropathy to multifocal brachial plexopathy, either as the index manifestation of lymphoma or as a complication of relapsing disease. Results: Prominent asymmetry, pain and nodular involvement on neuroimaging may help distinguish neurolymphomatosis from paraneoplastic immune demyelinating radiculoneuropathy. MR neurography criteria for the diagnosis of neurolymphomatosis include hyperintensity on T2 and STIR sequences, focal and diffuse nerve enlargement with fascicular disorganization and gadolinium enhancement. No specific anatomical distribution within the brachial plexus has, however, been found to be characteristic. Fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging is the imaging modality with the highest sensitivity for detection of nodal or extranodal spread in lymphoma. Conclusions: Brachial plexus neuropathy in neurolymphomatosis is highly protean in its distribution, semiology and relation to lymphoma staging. Dedicated MRI and PET-CT imaging are leading diagnostic modalities.

Muscle magnetic resonance imaging (MRI) and ultrasound (US) are emerging tools to assist in the diagnosis of children with genetic muscle disease. Increasing number of studies demonstrate that these imaging techniques can identify selective patterns of muscle atrophy, fatty degeneration, and muscle edema that help to distinguish between different early-onset genetic myopathies and muscular dystrophies. Recognizing patterns of pathology by muscle imaging can help to guide genetic testing and avoid the more invasive procedure of a muscle biopsy. Conversely, since massive parallel sequencing is now more commonly used as the initial step in diagnostic testing, imaging techniques can help to confirm or exclude if a variant of uncertain significance is indeed disease causing and compatible with a pattern of pathology as detected by muscle imaging. Whereas for diagnostic purposes and pattern recognition, muscle pathology does not need to be quantified, measuring disease progression is increasingly supported by quantitative muscle imaging, which is critical given the recent increment in rare disease therapeutic trials. Here, we discuss the value of muscle imaging techniques in pediatric muscle disease and summarize data identifying specific patterns of involvement in muscle MRI and US in some of the more common genetic myopathies and muscular dystrophies.

At least 15% of the disease-causing mutations affect mRNA splicing. Many splicing mutations are missed in a clinical setting due to limitations of in silico prediction algorithms or their location in noncoding regions. Whole-transcriptome sequencing is a promising new tool to identify these mutations; however, it will be a challenge to obtain disease-relevant tissue for RNA. Here, we describe an individual with a sporadic atypical spinal muscular atrophy, in whom clinical DNA sequencing reported one pathogenic ASAH1 mutation (c.458A>G;p.Tyr153Cys). Transcriptome sequencing on patient leukocytes identified a highly significant and atypical ASAH1 isoform not explained by c.458A>G(p C;p.Lys168Asn) and provided a molecular diagnosis of autosomal-recessive spinal muscular atrophy with progressive myoclonic epilepsy. Our findings demonstrate the utility of RNA sequencing from blood to identify splice-impacting disease mutations for nonhematological conditions, providing a diagnosis for these otherwise unsolved patients.

Perineural invasion is a targeted cellular proliferation guided by neurotrophins, rather than a simple diffusion of tumor in a path of least resistance. Invasion of cranial nerves by squamous cell carcinoma can represent an important diagnostic dilemma. It commonly presents as a distinct clinical neurological syndrome of combined isolated trigeminal and facial neuropathies. The focal cancer source may have been overlooked or remain occult. This case series illustrates diverse clinical presentations and neuroimaging challenges in four patients with squamous cell carcinoma of the cranial nerves. Anatomical pathways linking the trigeminal and facial nerves are reviewed, with emphasis on the auriculotemporal and pterygopalatine nerves. A successful neuroimaging strategy requires a targeted multimodality analysis of specific anatomical loci at the base of the skull. Attention must be directed to subtle radiological findings, such as obliteration of fat planes and linear enhancement along nerve branches, rather than bulky tumor tissue or bony invasion. Despite advances in microsurgical dissection and targeted radiotherapy, recovery of established neuropathic deficits is not expected. The prognosis remains poor in cases of advanced disease, emphasizing the importance early diagnosis by clinical acumen and focused neuroimaging.

Objective Autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) is an emerging syndrome caused by mutations in the C-terminus end of the TS domain of the DNMT1 gene. ADCA-DN is also associated with sensorimotor polyneuropathy, extrapyramidal, and dysautonomic signs, as well as dementia. Little has been reported about the progressive cognitive impairment associated with ADCA-DN. Our objective is to provide a detailed characterization of the cognitive profile of ADCA-DN. Method Three members of a kindred with ADCA-DN underwent comprehensive neuropsychological testing and neuroimaging. Results At baseline, 2 individuals demonstrated cognitive profiles with executive difficulties in some areas consistent with frontal-system dysfunction behaviorally and on standardized testing. The third individual was further in the disease course and exhibited more globally impaired cognition consistent with a diagnosis of dementia. Conclusions This family demonstrated progressive neurodegeneration beginning with isolated areas of executive dysfunction and leading to globally impaired cognition and dementia. Cognitive decline occurred in parallel with neurological deterioration. The cognitive profile is similar to case reports of other individuals with an allelic neurological phenotype, Hereditary Sensory Autonomic Neuropathy 1E, also caused by DNMT1 mutations. (PsycINFO Database Record

Muscular dystrophies (MD) represent a heterogeneous group of rare genetic diseases that often lead to significant weakness due to progressive muscle degeneration. In many forms of MD, cardiac manifestations including heart failure, atrial and ventricular arrhythmias and conduction abnormalities can occur and may be a predominant feature of the disease. Cardiac magnetic resonance (CMR) can assess cardiac anatomy, global and regional ventricular function, volumes and mass as well as presence of myocardial inflammation, infiltration or fibrosis. The role for cardiac MRI has been well-established in a wide range of muscular dystrophies related cardiomyopathies. CMR is a more sensitive technique than echocardiography for early diagnosis of cardiac involvement. It has also great potential to improve the prediction of long-term outcome, particularly the development of heart failure and arrhythmic events; however it still has to be validated by longitudinal studies including large populations. This review will outline the utility of CMR in patients with muscular dystrophies for assessment of myocardial involvement, risk stratification, and in guiding therapeutic management.

Background Neurolymphomatosis (NL) is a direct process of invasion of peripheral nerves by lymphoma. It occurs in roughly 5% of patients with lymphoma and represents a particularly difficult diagnostic dilemma when it is the presenting focal manifestation of occult lymphoma. Case presentation We present 3 examples of invasion of the lumbosacral plexus and its branches. These cases demonstrate a protean clinical picture with regards to the time relationship to the clinical course of lymphoma and the neuroanatomical extent of lumbosacral plexus invasion. We demonstrate the complementary role of different imaging modalities. A review of the literature summarizes 23 reports where lumbosacral plexus invasion was the index manifestation, at the time of first diagnosis or recurrence of lymphoma. This series confirms the strong preponderance of B-cell type (92%). There is a marked predilection for involvement of the sciatic nerve (74%), either focally or in a longitudinally extensive fashion, from the ischium to the popliteal fossa. There can also be restricted and discrete involvement of tibial and fibular branches. In recent years, ultrasound and CT have been given a more limited role, as screening tools or as a guide for biopsy. MRI neurography and PET-CT have become leading diagnostic modalities for diagnosis, staging and assessment of treatment response. Conclusion The diagnosis of NL may be challenging, and it was once only reached at autopsy. Improved diagnostic imaging of focal or even asymptomatic disease offers new hope for earlier diagnosis and successful targeted therapy.

Objective:\ud Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra-neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease.\ud \ud Methods:\ud We analyzed clinical data collected from a large cohort of pediatric SMA type I-III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA.\ud \ud Results:\ud We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/- mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non-alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation.\ud \ud Interpretation:\ud This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.

Background Disuse atrophy from immobilization is the result of decreased neural activity and muscle unloading. Methods We studied the impact of disuse on hand intrinsic compound muscle action potentials (CMAPs) in a cohort of 39 patients with unilateral 6-week immobilization of the hand in a cast, after distal radius fracture. We excluded patients with nerve injury. We compared side-to-side CMAP characteristics at the time of cast removal and at a subsequent follow-up visit, after a mean interval of 7.8 weeks. Results Statistically significant reductions in CMAP amplitude were noted for the abductor pollicis brevis (29.2%), abductor digiti minimi (19.0%), and first dorsal interosseus (24.9%). There was partial repair of the relative CMAP reduction at the follow-up visit (20.1%, 10.7%, and 8.7%, respectively). There was no significant change in CMAP duration. Conclusions These results provide a framework for quantifying the degree of hand intrinsic CMAP amplitude reduction attributed to disuse.

The discriminative value of CSF total protein (CSF-TP) in subtypes of Guillain–Barre syndrome has not been well documented in North-American patients. We reviewed 173 cases from a single institution, comprising the following clinical categories of neuropathy: 134 Sensorimotor (SM) GBS, 13 Motor (M) GBS, 8 Localized (L) GBS, and 18 Miller Fisher syndrome (MFS). We grouped the electrophysiological interpretation in primarily demyelinating, primarily axonal and normal / equivocal categories. Mean CSF-TP were substantially higher for SM and L-GBS, as well as cases classified as Acute-onset chronic inflammatory demyelinating polyneuropathy. They were lower for M-GBS and L-GBS. The most statistically significant correlation was found for elevated CSF-TP in GBS cases showing an electrophysiologic pattern classified as demyelinating (1.56 g/L) compared with axonal (0.68 g/L) or normal/ equivocal patterns (0.65 g/L). There was a correlation between CSF-TP and time interval between symptom onset and lumbar puncture. There was a weak correlation between CSF-TP and maximal overall-clinical severity grade, which was likely mostly determined by the electorphysiological pattern. Though CSF-TP is a sensitive test for GBS in the second week after onset, it may not be a reliable predictor of clinical severity. There is a robust association of CSF-TP elevation and a demyelinative electrophysiologic pattern and a suggestion that lower mean CSF-TP values can be expected in GBS-spectrum disorders thought to represent nodo-paranodopathies.

Objective Recessive null variants of the slow skeletal muscle troponin T1 (TNNT1) gene are a rare cause of nemaline myopathy that is fatal in infancy due to respiratory insufficiency. Muscle biopsy shows rods and fiber type disproportion. We report on 4 French Canadians with a novel form of recessive congenital TNNT1 core-rod myopathy. Methods Patients underwent full clinical characterization, lower limb magnetic resonance imaging (MRI), muscle biopsy, and genetic testing. A zebrafish loss-of-function model using morpholinos was created to assess the pathogenicity of the identified variant. Wild-type or mutated human TNNT1 mRNAs were coinjected with morpholinos to assess their abilities to rescue the morphant phenotype. Results Three adults and 1 child shared a novel missense homozygous variant in the TNNT1 gene (NM_003283.6: c.287T > C; p.Leu96Pro). They developed from childhood very slowly progressive limb-girdle weakness with rigid spine and disabling contractures. They suffered from restrictive lung disease requiring noninvasive mechanical ventilation in 3 patients, as well as recurrent episodes of rhabdomyolysis triggered by infections, which were relieved by dantrolene in 1 patient. Older patients remained ambulatory into their 60s. MRI of the leg muscles showed fibrofatty infiltration predominating in the posterior thigh and the deep posterior leg compartments. Muscle biopsies showed multiminicores and lobulated fibers, rods in half the patients, and no fiber type disproportion. Wild-type TNNT1 mRNA rescued the zebrafish morphants, but mutant transcripts failed to do so. Interpretation This study expands the phenotypic spectrum of TNNT1 myopathy and provides functional evidence for the pathogenicity of the newly identified missense mutation. ANN NEUROL 2020;87:568-583.

This article reports data pertaining to a worldwide web-based survey referenced in the publication “Adult CSF Total Protein: Higher upper reference limits should be considered worldwide ” (P.R. Bourque, et al., 2019). This survey was distributed to corresponding authors of the journal Neurology and the Journal of neurological sciences for the period of Jan–Dec 2017. The response rate was 36.9%. Additional results were collated through networking and national associations. There were 473 unique responses from clinical hospital laboratories in 69 countries: North America 178, South America 26, Europe 139, Africa 20, Asia 102 and Oceania 8. The upper reference limit for cerebrospinal fluid total protein ranged from 0.2 g/L to 0.8 g/L. 86.8% of the survey responses were 0.45 g/L or less. Data is presented separately for tertiary/academic and non-university/community centers.

Introduction The clinical characteristics of unilateral hypoglossal neuropathy have not been systematically analyzed. Methods We documented subjective abnormalities of speech and swallowing, and photographed 9 specific tongue movements and positions. Objective deficits were scored independently by 2 examiners. Results Eight patients were analyzed. Some degree of dysarthria and dysphagia was noticed by 7 and 8 patients, respectively, mostly resolving within a few months. In all subjects, there was contralateral deviation of the tongue at rest and ipsilateral deviation upon forward protrusion. Furthermore, 7 of 8 patients had deficits in using the tongue to indent the ipsilateral cheek and cover the upper lip. Conclusions Unilateral hypoglossal nerve palsy produces mostly subtle and transient patient symptoms, even when complete. Beyond the classic sign of ipsilateral deviation on protrusion, reliable signs are contralateral deviation at rest, paresis of ipsilateral movement inside the mouth, and paresis of elevation of the tongue tip. Muscle Nerve 54: 1055–1058, 2016

Neuromuscular diseases (NMDs) represent a broad group of more than 150 genetic and acquired disorders [1], many of which are debilitating, progressive and cause premature death. Almost one million people in North America are believed to be affected by these disorders [2], which additionally have great socio-economic impact. For many NMDs, no cure or effective treatment exist. Indeed, the causative genetic mutations, and how they contribute to the disease state, or the autoimmune mechanisms underlying many of these disorders remains elusive. In addition, both the clinical and basic NMD research community still requires a more detailed understanding of the biological and biochemical workings of “normal” neuromuscular function. Collectively, we still have much to learn.

Objective. The ability to correctly identify chronic demyelinating neuropathy can have important therapeutic and prognostic significance. The stimulus intensity value required to obtain a supramaximal compound muscle action potential amplitude is a commonly acquired data point that has not been formally assessed as a diagnostic tool in routine nerve conduction studies to identify chronic neuropathies. We postulated that this value was significantly elevated in chronic demyelinating neuropathy. Methods. We retrospectively reviewed electrophysiology laboratory records to compare the stimulus intensity values recorded during median and ulnar motor nerve conduction studies. The groups studied included normal controls (n=42) and the following diagnostic categories: chronic inflammatory demyelinating neuropathy (CIDP) (n=20), acquired inflammatory demyelinating neuropathy (AIDP) (n=13), Charcot Marie Tooth (CMT) type 1 or 4C (n=15), carpal tunnel syndrome (CTS) (n=11), and amyotrophic lateral sclerosis (ALS) (n=18). Results. Supramaximal intensities were significantly higher in patients with CMT (median nerve: 43.4 mA) and CIDP (median nerve: 38.9 mA), whereas values similar to normal controls (median nerve: 25.3 mA) were obtained in ALS, CTS, and AIDP. Conclusions. Supramaximal stimulus intensity may be used as an additional criterion to identify the pathophysiology of neuropathy. We postulate that endoneurial hypertrophic changes may increase electrical impedance and thus the threshold of excitation at nodes of Ranvier.