Diagnostic modelling and therapeutic monitoring of immune-mediated necrotizing myopathy: role of electrical myotonia.

Delayed diagnosis of immune-mediated necrotizing myopathy leads to increased morbidity. Patients with the chronic course without 3-hydroxy-3-methylglutaryl-coenzyme-A reductase-IgG or signal recognition particle-IgG are often challenging to diagnose. Immunotherapy response can also be difficult to assess. We created a statistical model to assist immune-mediated necrotizing myopathy diagnosis. Electrical myotonia versus fibrillations were reviewed as biomarkers for immunotherapy treatment response. Identified were 119 immune-mediated necrotizing myopathy cases and 938 other myopathy patients. Inclusion criteria included all having electrophysiological evaluations, muscle biopsies showing inflammatory/necrotizing myopathies, comprehensively recorded neurological examinations, and creatine kinase values. Electrical myotonia was recorded in 56% (67/119) of retrospective and 67% (20/30) of our validation immune-mediated necrotizing myopathy cohorts, and significantly (P < 0.001) favoured immune-mediated necrotizing myopathy over other myopathies: sporadic inclusion body myositis (odds ratio = 4.78); dermatomyositis (odds ratio = 10.61); non-specific inflammatory myopathies (odds ratio = 8.46); limb-girdle muscular dystrophies (odds ratio = 5.34) or mitochondrial myopathies (odds ratio = 14.17). Electrical myotonia occurred in immune-mediated necrotizing myopathy seropositive (3-hydroxy-3-methylglutaryl-coenzyme-A reductase-IgG 70%, 37/53; signal recognition particle-IgG 29%, 5/17) and seronegative (51%, 25/49). Multivariate regression analysis of 20 variables identified 8 (including electrical myotonia) in combination accurately predicted immune-mediated necrotizing myopathy (97.1% area-under-curve). The model was validated in a separate cohort of 30 immune-mediated necrotizing myopathy cases. Delayed diagnosis of cases with electrical myotonia occurred in 24% (16/67, mean 8 months; range 0-194). Half (8/19) had a chronic course and were seronegative, with high model prediction (>86%) at the first visit. Inherited myopathies were commonly first suspected in them. Follow-up evaluation in patients with electrical myotonia on immunotherapy was available in 19 (median 21 months, range 2-124) which reduced from 36% (58/162) of muscles to 7% (8/121; P < 0.001). Reduced myotonia correlated with immunotherapy response in 64% (9/14) as well as with median creatine kinase reduction of 1779 U/l (range 401-9238, P < 0.001). Modelling clinical features with electrical myotonia is especially helpful in immune-mediated necrotizing myopathy diagnostic suspicion among chronic indolent and seronegative cases. Electrical myotonia favours immune-mediated necrotizing myopathy diagnosis and can serve as an adjuvant immunotherapy biomarker.

Two Years of Improved Neurological Function With Nusinersen in a 48-Year-Old Patient With Spinal Muscular Atrophy Type 3.

INTRODUCTION: Nusinersen antisense oligonucleotide infusions have been shown to be effective in the treatment spinal muscular atrophy. The majority of the evidence has been collected in young type 1 and type 2 patients, and evidence of efficacy in adult patients is limited. CASE REPORT: A 48-year-old woman with spinal muscular atrophy type 3 who has received the loading dose and 8 maintenance infusions over an 8-month period. Grip and pinch strength, measured by hand-held dynamometry measured at baseline and in 6 to 12 months interval improved over a 24-month period. She also reported multiple other subjective improvements in function. CONCLUSIONS: This is the first published case of nusinersen in a middle-aged adult with spinal muscular atrophy. Sustained clinically meaningful improvement may be possible with nusinersen initiation in mid adulthood.

A systematic review of Gamma-aminobutyric Acid Receptor Type B autoimmunity.

OBJECTIVE: To review the available research to describe the clinical characteristics and neoplastic associations of patients with gamma-aminobutyric acid receptor type B (GABAB-R) autoantibodies. METHODS: Literature was reviewed on PubMed, Mendeley literature search, and the American Academy of Neurology database for articles published from June 2008 to October of 2018 using a variety of key words. These key words include: "gamma-aminobutyric acid seizures," "gamma-aminobutyric acid limbic encephalitis", "GABA(B) receptor antibodies," "autoimmune encephalitis," "autoimmune epilepsy," "GABA(B) encephalitis, " and "GABA paraneoplastic." With the results, the papers were reviewed in a systematic manner. RESULTS: A total of 10 studies were reviewed. A summary of the demographic, clinical, and serological findings of the cases detailed in the literature are provided. An additional illustrative case is described. In total, 94 patients were reviewed. CONCLUSIONS: GABAB-R autoimmune disease is characterized by refractory seizures or status epilepticus and frequent association with small cell lung cancer. Additionally, a substantial minority of patients have non-inflammatory CSF.

Needle electromyography and histopathologic correlation in myopathies.

INTRODUCTION: Needle electromyography (EMG) findings help confirm myopathy and may indicate specific pathologic changes on muscle biopsy. METHODS: We conducted a retrospective chart review of 218 consecutive patients referred for muscle biopsy. Presence of specific needle EMG findings was correlated with pathologic findings of inflammation, necrosis, splitting, and vacuolar changes. Sensitivity, specificity, and positive and negative predictive values of specific EMG findings for pathologic changes were calculated. RESULTS: Short-duration motor unit potentials (MUP) were sensitive (83%-94%) but not specific (34%-49%) for pathologic changes. Fibrillation potentials were 65%-74% sensitive and 58%-81% specific for inflammation, necrosis, splitting, or vacuolar changes. The absence of fibrillation potentials had high negative predictive value (82%-93%) for inflammation, splitting, or vacuolar changes. DISCUSSION: Fibrillation potentials and short-duration MUPs predict pathologic changes of muscle fiber necrosis, splitting, and/or vacuolar changes (as seen with inflammatory myopathies and muscular dystrophies). Absence of fibrillation potentials suggests other myopathologic changes (e.g., congenital myopathy). Muscle Nerve 59:315-320, 2019.

Needle EMG of Thenar Muscles in Less Severe Carpal Tunnel Syndrome.

INTRODUCTION: The value of needle electromyography (EMG) in thenar muscles in patients with less severe carpal tunnel syndrome is controversial. METHODS: Patients referred for electrodiagnostic testing for carpal tunnel syndrome, in which nerve conduction study demonstrated median sensory nerve conduction study abnormalities and either normal median motor nerve conduction study or only prolonged median motor distal latencies (DLs) (with normal amplitudes) were prospectively studied. Patients with low-median compound muscle action potential amplitudes or any other EMG abnormality were excluded. Needle EMG of a thenar muscle was performed to assess for the presence and grade of fibrillation potentials and motor unit potential abnormalities. The frequency of abnormalities was recorded. Statistical comparison between patients with and without needle EMG abnormalities was performed. RESULTS: One-hundred two patients were included (50 with normal median motor DLs and 52 with abnormal DLs). Minimal or equivocal thenar needle EMG abnormalities were found in 12% of subjects with normal DLs. In patients with abnormal DLs, 32.6% had abnormalities, 15.4% with a mild degree of fibrillation potentials, and 25.0% with mild motor unit potential abnormalities. Patients with abnormal DLs and needle EMG abnormalities had significantly lower compound muscle action potential amplitudes compared to those without needle EMG changes. CONCLUSIONS: Patients with carpal tunnel syndrome with no involvement of the median motor nerve conduction study are unlikely to demonstrate prominent abnormalities on needle EMG of thenar muscles, and needle EMG of the thenar muscles is not necessary. However, in patients with carpal tunnel syndrome in which the median motor DL is prolonged but compound muscle action potential amplitudes are absolutely normal, needle EMG should be considered, as it may provide value in indicating some axonal loss despite a normal median compound muscle action potential amplitude.

Rheumatology and Neurology.

PURPOSE OF REVIEW: This article reviews the various rheumatologic disorders that have neurologic complications and manifestations. RECENT FINDINGS: Recent advances have improved the understanding of the true epidemiology of many rheumatologic diseases and their complications. Many years of observation have clarified findings even in rarer disorders. Classification and diagnostic criteria have been updated and validated. As newer pharmacologic agents have become available, new information regarding efficacy and toxicity has emerged. SUMMARY: Rheumatologic disorders are common, as can be their neurologic complications. In many instances, these complications are treatable, but clinicians' understanding of the underlying disorder, its neurologic risks, and the risk of therapy is required.

Whole exome sequencing of a patient with suspected mitochondrial myopathy reveals novel compound heterozygous variants in RYR1.

BACKGROUND: Pathogenic variants in ryanodine receptor 1 (RYR1, MIM# 180901) are the cause of congenital myopathy with fiber-type disproportion, malignant hyperthermia susceptibility type 1, central core disease of muscle, multiminicore disease and other congenital myopathies. METHODS: We present a patient with global developmental delay, hypotonia, myopathy, joint hypermobility, and multiple other systemic complaints that were noted early in life. Later she was found to have multiple bone deformities involving her spine, with severe scoliosis that was corrected surgically. She was also diagnosed with ophthalmoplegia, chronic hypercapnic respiratory failure, and hypertension. At 22 years of age she presented to the genetics clinic with a diagnosis of mitochondrial myopathy and underwent whole exome sequencing (WES). RESULTS: Whole exome sequencing revealed two novel compound heterozygous variants in RYR1 (c.7060_7062del, p.Val2354del and c.4485_4500del, p.Tyr1495X). CONCLUSION: Review of her clinical, pathologic, and genetic findings pointed to a diagnosis of a congenital myopathy with fiber-type disproportion.

Eosinophilic fasciitis with subjacent myositis.

INTRODUCTION: Eosinophilic fasciitis (EF) is a rare disorder that can present with muscle symptoms that mimic other neuromuscular diseases. METHODS: We report the case of a 43-year-old woman with chronic muscle aches, tightness, and stiffness with hypertrophied, well-defined muscles despite physical inactivity, and thickened skin with reduced elasticity and discoloration. RESULTS: Except for mild peripheral eosinophilia, laboratory studies, including blood count, electrolytes, paraneoplastic panel, muscle enzymes, thyroid function, and serum protein electrophoresis, were normal. Nerve conduction studies and needle electromyography were normal. Magnetic resonance imaging of the thighs demonstrated superficial and deep fascial thickening with T2 hyperintensity and post-gadolinium enhancement. Fascial and muscle biopsy demonstrated an inflammatory exudate in the perimysium and endomysium with fragmented perimysial connective tissue and thickened, inflamed fascia. EF was diagnosed. The patient was treated with methotrexate and prednisone followed by improvement of muscle stiffness and tightness. CONCLUSION: EF should be considered when patients present with muscle pain or enlarged muscles. Muscle Nerve 56: 525-529, 2017.

Early Absent Pupillary Light Reflexes After Cardiac Arrest in Patients Treated with Therapeutic Hypothermia.

Loss of pupillary light reactivity is one recognized indicator of poor prognosis after cardiopulmonary resuscitation (CPR). However, drug overdose, low cardiac output, and/or resuscitation drugs can lead to impaired pupillary light reflex. To investigate pupillary light reflex status before therapeutic hypothermia (TH) in relation to neurological outcome, we retrospectively reviewed the data of a prospectively implemented TH protocol in patients with cardiac arrest (CA) at Mayo Clinic in Jacksonville, Florida (January 2006-January 2012), and Mayo Clinic in Scottsdale, Arizona (August 2010-March 2014). During this period, all CA patients who underwent hypothermia were included. These patients were selected from an institutional database and hypothermia data set. The Cerebral Performance Category (CPC) at time of discharge was our primary outcome measure. A CPC of 1 to 2 was defined as good outcome and a CPC from 3 to 5 was defined as poor outcome. We identified 99 patients who had CA treated with TH. Twenty-nine patients (29%) had pupils that were nonreactive to light on admission examination before TH, eight of whom later had return of pupil reactivity by day 3. Two of these 29 patients (6.9%) had good outcome, compared to 24 of 70 patients (34.3%) with pupils that were reactive to light (p = 0.005). Both of these patients had CA after illicit drug overdose. Early nonreactive pupils occurred in almost a third of patients after CPR and before TH in our patient population. Recovery of pupillary light reactivity is possible, and in a small minority of those cases (particularly when CA is preceded by the use of illicit drugs), a good outcome can be achieved.

Whole Exome Sequencing Leading to the Diagnosis of Dysferlinopathy with a Novel Missense Mutation (c.959G>C).

Dysferlinopathy is an uncommon, progressive muscular dystrophy that has a wide phenotypic variability and primarily supportive management (Nguyen et al., 2007; Narayanaswami et al., 2014). Amyloid myopathy is a distinct, rare disorder that can present similarly to inflammatory myopathies and requires a high clinical suspicion for early intervention to prolong survival. Amyloid myopathy is typically associated with other systemic manifestations of amyloidosis, but rare cases of isolated amyloid myopathy have been described (Mandl et al., 2000; Hull et al., 2001). Positive Congo red stains on tissue biopsy remain the gold standard for diagnosis (Spuler et al., 1998; Karacostas et al., 2005). A high clinical suspicion and meticulous diagnostic workup that includes novel techniques are necessary for identifying these rare disorders. We report a middle-aged man with progressive leg muscle weakness who was initially treated as having amyloid myopathy but was later diagnosed as having dysferlinopathy by Whole Exome Sequencing (WES) analysis. We also report a novel missense mutation (c.959G>C) to help correlate in any patient with presumed dysferlinopathy and to add to the already known genotype of this disorder.

Milestone-compatible neurology resident assessments: A role for observable practice activities.

OBJECTIVE: Beginning in 2014, US neurology residency programs were required to report each trainee's educational progression within 29 neurology Milestone competency domains. Trainee assessment systems will need to be adapted to inform these requirements. The primary aims of this study were to validate neurology resident assessment content using observable practice activities (OPAs) and to develop assessment formats easily translated to the Neurology Milestones. METHODS: A modified Delphi technique was used to establish consensus perceptions of importance of 73 neurology OPAs among neurology educators and trainees at 3 neurology residency programs. A content validity score (CVS) was derived for each neurology OPA, with scores ≥4.0 determined in advance to indicate sufficient content validity. RESULTS: The mean CVS for all OPAs was 4.4 (range 3.5-5.0). Fifty-seven (78%) OPAs had a CVS ≥4.0, leaving 16 (22%) below the pre-established threshold for content validity. Trainees assigned a higher importance to individual OPAs (mean CVS 4.6) compared to faculty (mean 4.4, p = 0.016), but the effect size was small (η(2) = 0.10). There was no demonstrated effect of length of education experience on perceived importance of neurology OPAs (p = 0.23). Two sample resident assessment formats were developed, one using neurology OPAs alone and another using a combination of neurology OPAs and the Neurology Milestones. CONCLUSIONS: This study provides neurology training programs with content validity evidence for items to include in resident assessments, and sample assessment formats that directly translate to the Neurology Milestones. Length of education experience has little effect on perceptions of neurology OPA importance.

Colchicine-induced myoneuropathy mimicking polyradiculoneuropathy.

We report a patient with colchicine-induced myoneuropathy. Myoneuropathy is an under-recognized complication of colchicine. The weakness seen in our patient improved fairly rapidly after discontinuation of colchicine.

Popliteus muscle hemorrhage as a rare cause of a proximal tibial neuropathy.

Proximal tibial neuropathy is an uncommon focal mononeuropathy that is most often caused by trauma, ischemia, or neoplastic infiltration or compression of the tibial nerve. We report a patient who presented with a tibial neuropathy following a leg injury, which initially mimicked a lumbosacral radiculopathy but which was the result of a proximal tibial neuropathy. Electrophysiologic studies confirmed a proximal tibial neuropathy and MRI revealed a popliteus muscle hemorrhage with mass effect on the tibial nerve. Following conservative management the patient had little recovery of function after 15 months.

Improving referring physicians' understanding of electromyography reports when qualifying radiculopathies: a need for standardized terminology.

Electromyographic (EMG) reporting of radiculopathies is not standardized, and the terminology used in reports can be misinterpreted by referring physicians. Physicians who refer patients for EMG studies at the Mayo Clinic were surveyed about their understanding of 6 different EMG interpretations of an S1 radiculopathy. Of 45 responders, the terms "acute, active," "chronic, inactive," and "old" were interpreted consistently by 95%, 98%, and 84% of responders, respectively. Physicians had the most difficulty understanding the meaning of "chronic" in isolation, "chronic, active," or "old with uncompensated denervation." These findings suggest a need to educate referring physicians on the meaning of the terms used in EMG reports and to develop standard guidelines for qualifying radiculopathies. Based on our observations, guidelines for the reporting of radiculopathies have been adopted in the Mayo Clinic Florida EMG laboratory.

Utility of minimum F-wave latencies compared with F-estimates and absolute reference values in S1 radiculopathies: are they still needed?

INTRODUCTION: The utility of F-waves in assessing radiculopathies is debated. The aim of this study is to determine the frequency of abnormal minimum tibial F-wave latencies compared to an F-estimate and an absolute reference value in patients with electromyography (EMG) confirmed S1 radiculopathies. METHODS: A retrospective review of F-waves in patients with an EMG-confirmed isolated S1 radiculopathy was performed. The minimum and mean latencies of 8 tibial F-waves were compared with the calculated F-estimate and to an absolute reference value, and the frequencies of abnormal responses were determined. RESULTS: Of the 50 patients with an S1 radiculopathy, 4% had prolongation of the minimum reproducible F-wave latency, and 8% had prolongation of the mean latency relative to the calculated F-estimate. CONCLUSIONS: The minimum and mean F-wave latencies are infrequently abnormal when compared with an estimated F-wave latency in S1 radiculopathies and are insensitive in the assessment of S1 nerve root injury.

Electrodiagnostic evaluation of ulnar neuropathy and other upper extremity mononeuropathies.

Upper extremity mononeuropathies are some of the common disorders seen in neurophysiology laboratories. Electrophysiologic studies rely on accurate localization based on knowledge of applicable anatomy and features of history and physical examination. Careful electrodiagnostic studies provide an accurate diagnosis, help localize the lesion site, exclude alternate diagnoses, reveal unsuspected diagnoses, determine pathophysiology of lesions, and assess severity, timeframe, and prognosis of lesions. This article discusses the electrodiagnostic approach to ulnar neuropathy, proximal median neuropathy, radial neuropathy, musculocutaneous neuropathy, axillary neuropathy, suprascapular neuropathy, and long thoracic neuropathy. Pertinent aspects of the history and physical examination, nerve conduction studies, and electromyography are presented.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations.

The aim of the study was to determine the prevalence of MNGIE-like phenotype in patients with recessive POLG1 mutations. Mutations in the POLG1 gene, which encodes for the catalytic subunit of the mitochondrial DNA polymerase gamma essential for mitochondrial DNA replication, cause a wide spectrum of mitochondrial disorders. Common phenotypes associated with POLG1 mutations include Alpers syndrome, ataxia-neuropathy syndrome, and progressive external ophthalmoplegia (PEO). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, PEO and/or ptosis, peripheral neuropathy, and leukoencephalopathy. MNGIE is caused by TYMP mutations. Rare cases of MNGIE-like phenotype have been linked to RRM2B mutations. Recently, POLG1 mutations were identified in a family with clinical features of MNGIE but no leukoencephalopathy. The coding regions and exon-intron boundaries of POLG1 were sequence analyzed in patients suspected of POLG1 related disorders. Clinical features of 92 unrelated patients with two pathogenic POLG1 alleles were carefully reviewed. Three patients, accounting for 3.3% of all patients with two pathogenic POLG1 mutations, were found to have clinical features consistent with MNGIE but no leukoencephalopathy. Patient 1 carries p.W748S and p.R953C; patient 2 is homozygous for p.W748S, and patient 3 is homozygous for p.A467T. In addition, patient 2 has a similarly affected sibling with the same POLG1 genotype. POLG1 mutations may cause MNGIE-like syndrome, but the lack of leukoencephalopathy and the normal plasma thymidine favor POLG1 mutations as responsible molecular defect.