PracticeUpdate

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15 TH INTERNATIONAL CONGRESS ON NEUROMUSCULAR DISEASES 6–10 JULY 2018 • VIENNA, AUSTRIA

THE BEST OF ICNMD 2018 Next-Generation Sequencing Leads to Diagnosis in About Half of Cases of Suspected Neuromuscular Disease • Ultrasonography Valuable in Confirmation of Carpal Tunnel Syndrome • Some Neuromuscular Diseases Linked to Malignant Hyperthermia or Similar Reactions • Thymectomy Continues to be Successful for Myasthenia Gravis

The production and distribution of this publication is sponsored by Sanofi Genzyme.

DYSPHAGIA 1

MUSCLE PAIN 1

PROXIMAL MUSCLE WEAKNESS 1

RESPIRATORY INSUFFICIENCY 1

EXERCISE INTOLERANCE 3

FATIGUE 3

GAIT ABNORMALITIES 1

UNKNOWN CAUSE OF HYPERCKEMIA 2

FREQUENT FALLS 1

IT’S NOT IN YOUR PATIENT’S HEAD

SLEEP APNOEA 3

IT’S IN THEIR MUSCLES

If your patients have discussed experiencing any of these symptoms or test results with you, it’s time to consider Late-Onset Pompe Disease (LOPD). Pompe Disease affects approximately 1 in every 40,000 people, and is a progressive disease that gets worse over time. 1,4 Like many conditions, Pompe Disease can be managed and treated if it is diagnosed early. Test your patients for Late-Onset Pompe Disease using the Dried Blood Spot (DBS) Testing Kit, fully funded by Sanofi Genzyme.

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For more information on Pompe Disease, please visit: https://sanofigenzymeonline.com.au/pompe-disease References: 1. Kishnani PS, et al. Gen Med 2006; 8: 267–88. 2. Lukacs Z, et al. Neurology 2016; 87: 295–8. 3. Chan J, et al. Mol Genet Metab 2017; 120:163–72. 4. American Association of Neuromuscular & Electrodiagnostic Medicine. Muscle Nerve 2009; 40: 149–60. sanofi-aventis Australia pty ltd trading as Sanofi Genzyme ABN 31 008 558 807.Talavera Corporate Centre,Building D, 12–24 Talavera Road,Macquarie Park,NSW 2113.GZANZ.MYOZ.16.08.0142a.Date of Preparation March 2018.AM7338.

PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise. Editor-in-Chief Mark Hallett MD Associate Editors Argye Hillis MD MA, Avindra Nath MD Advisory Board Marinos Dalakas MD, Nina Schor MD PhD Patrick Wen MD Editorial Contributors Shila Azodi MD , Mona Bahouth MD Omar Khan MD Codrin Lungu MD Elisabeth Marsh MD Sarah Matteson Kranick MD

PracticeUpdate ® is a registered trademark of Elsevier Inc. 2018 Elsevier Inc. All rights reserved. ABOUT

For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’s mission is to help medical professionals navigate the vast array of available literature and focus on the most critical information for their patients and practice. PracticeUpdate Conference Series is a collection of key research from leading international conferences, reviewed by the PracticeUpdate editorial and advisory board, made available in print format. These news highlights and more are also available online at PracticeUpdate.com PracticeUpdate and the PracticeUpdate Conference Series are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER The PracticeUpdate Conference Series provides highlights of key international conferences for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the informationcontained in thispublication, includinganyclaimsrelated to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. The production and distribution of this publication is sponsored by Sanofi Genzyme. It contains content published in accordance with the editorial policies of Elsevier’s PracticeUpdate.com. Content was produced by Elsevier with no involvement by Sanofi Genzyme. All content printed in this publication can be found on PracticeUpdate.com SALES Fleur Gill fleur.gill@elsevier.com Matthew Buttsworth m.buttsworth@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Production of this issue was executed by: Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja ISSN 2208-150X (Print) • ISSN 2208-1518 (Online)

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Contents

ICNMD 2018 • 6–10 July 2018 • Vienna, Austria BY THE PRACTICEUPDATE EDITORIAL TEAM

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2 Next-Generation Sequencing Leads to Diagnosis in About Half of Cases of Suspected Neuromuscular Disease 3 Nerve Ultrasound Improves Diagnosis of Neuromuscular Disorders 4 Low Dystrophin Protein Levels Linked to Attenuation of Duchenne Muscular Dystrophy Progression 5 IV Immune Globulin Improves Disability in Chronic Inflammatory Demyelinating Polyneuropathy 6 Ultrasonography Valuable in Confirmation of Carpal Tunnel Syndrome 6 Immune Globulins Continue to Be the Most Effective Treatment for Multifocal Motor Neuropathy 8 Family With Myotonic Dystrophy 1 Shown to Carry Interruptions Exhibiting Milder, Atypical Phenotype 9 Some Neuromuscular Diseases Linked to Malignant Hyperthermia or Similar Reactions 10 DNA Methylation, LXR/RXR Activation, and Multiple Immune Signaling Pathways Likely Play a Role in Diabetic Polyneuropathy

11 Palliative Care Can Be Integrated Into Management of Patients With ALS 12 Inherited Transthyretin-Mediated Amyloidosis: Though Diagnosis and Monitoring Are a Challenge, Treatment is Being Revolutionized 13 Late-Onset Pompe Disease Linked to Polyneuropathy 14 Significant Progress Has Been Made in Immune-Mediated Neuropathies 16 Thymectomy Continues to Be Successful for Myasthenia Gravis 16 Protein Biomarkers of Dysferlinopathy Identified 18 Next-Generation Sequencing Can Be Helpful in Diagnosing and Characterizing Limb Girdle Muscular Dystrophy 20 Transcranial Magnetic Stimulation Can Help Diagnose and Prognose Children With Sequelae of Acute Transverse Myelitis

ELSEVIER AUSTRALIA ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 Printed in Australia. EMCS081802

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Next-Generation Sequencing Leads to Diagnosis in About Half of Cases of Suspected Neuromuscular Disease Next-generation sequencing improves the diagnosis of neuromuscular disease substantially

T he cases of approximately half of individuals with suspected neuromuscular disease are solved using next-generation sequencing, according to a retrospective study presented at ICNMD 2018. Daniel Natera de Benito, MD, of the Hospital Sant Joan de Déu in Barcelona, Spain, and colleagues described results obtained in an extensive study of 151 genetically undiagnosed individuals who presented clinical signs of muscular dystrophies, congenital myopathies, or other neuromuscular conditions. Dr. Natera de Benito told Elsevier’s PracticeUpdate , “We wanted to measure the real usefulness of these new tools in our patients, and studies analyzing the diagnostic yield of next-generation sequencing in patients with neuromuscular disease are relatively scarce.” They reported a huge improvement observed after the application of next-generation sequencing into the field of neuromuscular disease management. Participants who met clinical criteria of a neuro- muscular disease and whose condition had been studied using different strategies of next-gen- eration sequencing were collected. The 151 participants had been evaluated using three dif- ferent methodologies, due to the rapid evolution of next-generation sequencing. The first group of participants (n=58) was studied using a custom panel. The investigators sequenced 4813 genes in the second group (n=40).

Dr. Natera de Benito’s team analyzed the entire exome of the third group (n=53). After sequencing and bioinformatics analysis, they studied only 169 genes associated with neuromuscular disorders to check for candidate mutations. In cases and progenitors, Sanger sequencing was performed in cases of strong candidates. Participants were classified according to clinical phenotype as affected by congenital myopathy (52%), muscular dystrophies (29%), congenital myasthenic syndromes (6%), neuropathies (5%), and other clinical conditions (8%). These other clin- ical conditions included, among others, metabolic myopathy and hereditary spastic paraplegia. Most participants displayed sporadic disease. The majority of samples collected had been previously tested without success, according to the observed phenotype. A total of 80 cases (53%) were diagnosed with known disease-associated variants or with variants of a likely pathogenicity, or variants predicted to affect function in genes corresponding to clinical suspicions. The genetic cause of disease was elucidated in 24 of 40 samples (60%) according to the clinical exome, in 30 of 58 samples (51%) by the custom panel, and in 26 of 53 samples (49%) by selected whole exome sequencing. Dr. Natera de Benito explained that inherited neu- romuscular disorders are chronic genetic diseases

Dr. Daniel Natera de Benito

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Nerve Ultrasound Improves Diagnosis of Neuromuscular Disorders Nerve ultrasoundmay help improve detection of treatment- responsive chronic neuropathies T he detection of treatment-responsive chronic neuropathies may benefit from the use of nerve ultrasound, reported a retrospective study presented at ICNMD 2018.

H. StephanGoedee, MD, of theUniversityMedical CentreUtrecht, The Netherlands, and colleagues evaluated nerve ultrasound for the identification of treatment-responsive chronic neuropa- thies without nerve conduction abnormalities. Overall, 240 incident individuals with a clinical phenotype compatible with chronic inflammatory demyelinating pol- yneuropathy, Lewis Sumner syndrome, or multifocal motor neuropathy were analyzed. Work-up consisted of routine ancillary investigations rec- ommended in diagnostic consensus guidelines and a

Dr. H. Stephan Goedee

standardized sonographic protocol assessing arm nerves and brachial plexus. All individuals without demyelinating features according to nerve conduction study, but with sonographic abnormalities fitting inflammatory neuropathy, underwent stand- ard treatment with IV immune globulin. The treatment effect was evaluated using routine clinical examination and hand grip or myometry. " Our results showed that nerve ultrasound is a reliable diagnostic tool with important added value in identifying patients with treatable neuropathies. Nerve ultrasound confers advantages over MRI in terms of flexible field of view and objective cut-off values for abnormalities. " A total of 17 (7%) individuals were found to harbor a clinical phenotype compatible with chronic inflammatory demyelinating polyneuropathy (n=10), Lewis Sumner syndrome (n=1), or multifocal motor neuropathy (n=6). Three individuals were positive for anti-GM1 autoantibodies. They were also positive for sonographic nerve enlargement of the proximal median nerve segments and/or cervical (nerve) roots. However, they tested negative on nerve conduction studies (n=2 axonal loss only, n=15 normal). In contrast, MRI of the brachial plexus was normal in 8 out of 17 individuals (47%). The protein content of cerebrospinal fluid was normal in 6 out of 17 individuals (35%). All 17 individuals exhibited objective improvement with IV immune globulin treatment. Dr. Goedee explained that diagnostic consensus criteria for inflammatory neuropa- thies rely primarily on results of nerve conduction studies that indicate multifocal demyelination. However, nerve conduction studies can be inconclusive or even normal in individuals with neuropathies that respond to immune-modulating treatment. Dr. Goedee told Elsevier’s PracticeUpdate , “Our results showed that nerve ultrasound is a reliable diagnostic tool with important added value in identifying patients with treatable neuropathies. Nerve ultrasound confers advantages over MRI in terms of flexible field of view and objective cut-off values for abnormalities. “Future revisions of diagnostic consensus criteria,” he added, “should include nerve ultrasound and MRI more prominently.” www.practiceupdate.com/c/70505

that pose a significant burden on individ- ual sufferers and health care systems. Genetic heterogeneity and the use of a conventional gene-by-gene approach have resulted in little knowledge about molecular etiologies in a significant pro- portion of these individuals. Relatively recently, massive parallel sequencing using next-generation sequencing has emerged as a successful approach to interrogate multiple genes simultaneously. It has proven efficient and cost-effective for accelerating diagnosis. Dr. Natera de Benito concluded that in recent years, next-generation sequencing has transformed the study of neuromus- cular disorders completely. His team’s experience indicates that the cases of approximately half of individuals with suspected neuromuscular disease are solved using next-generation sequencing. Despite this transformation, molecular causes remain unknown in 47% of indi- viduals. Some unsolved cases may, in fact, be attributable to the kind of next-gen- eration sequencing strategy applied, to previously undescribed causative genes, or to unknown genetic variations causative genes, or to unknown genetic variations. www.practiceupdate.com/c/70505

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Low Dystrophin Protein Levels Linked to Attenuation of Duchenne Muscular Dystrophy Progression

The findingmay halt clinical evaluations of therapies designed to restore normal dystrophin levels in patients with DMD S pontaneous exon skipping and production of low dystrophin levels may impact the clinical course of

over 2 years than those with mutations amenable to exon 53 or 51 skipping. A separate study showed that individu- als with mutations amenable to exon 44 skipping exhibited higher baseline results in the 6-minute walk test and had more modest declines at 12 months than those with mutations amenable to skipping exons 45 or 53 (difference not significant). Evidence suggests that individuals with DMD and deletions of exons 3 to 7 also experience a milder phenotype and express low levels of dystrophin. A recent case study described an indi- vidual aged 10 years with a nonsense mutation in exon 42 and a mild phenotype presumed as the result of spontaneous exon 42 skipping and subsequent dys- trophin production. Dr. Charleston concluded that these find- ings demonstrate that spontaneous exon skipping and production of low dystrophin levels may impact the clinical course of DMD. Insights are offered in this study regard- ing the interpretation of results of clinical trials evaluating therapeutic interventions designed to restore dystrophin in individ- uals with DMD. www.practiceupdate.com/c/70788

Dr. Charleston and colleagues explored potential associations between low dys- trophin levels in individuals with DMD and the attenuation of disease progression. They conducted a literature search to identify recent, relevant evaluations of the natural occurrence of exon skipping and clinical disease progression in individuals with DMD. A body of evidence indicated that individ- uals with DMD with mutations amenable to exon 44 skipping, experience a milder disease course than other DMD sub- groups. In one natural history study, individuals with mutations amenable to exon 44 skipping, experienced a slower rate of disease progression, with loss of ambulation 2 years later than those with other mutations. However, traces of dystrophin were detected in only three out of six individu- als by immunohistochemistry, and in zero out of four individuals by Western blot analysis using clinical diagnostic methods. Notably, in a sub-analysis of individuals treated with corticosteroids, those with mutations amenable to exon 44 skipping did not achieve a median age of loss of ambulation during follow-up. Those with mutations amenable to exon 51 skipping were a median of 13.0 years of age at loss of ambulation. In a separate analysis of individuals with DMD treated with corticosteroids, median age at loss of ambulation was 15.2 years in those amenable to exon 44 skipping and 10.5 years in those amenable to exon 51 skipping. Spontaneous low-level exon 44 skipping in these individuals is thought to facilitate restoration of the mRNA reading frame. Such restoration facilitates dystrophin expression and/or the presence of dys- trophin-positive muscle fibers. An analysis utilizing the NorthStar Ambulatory Assessment demonstrated that individuals with mutations amenable to exon 44 skipping declined more slowly

Duchenne muscular dystrophy (DMD) and the progression of this disease may be attenuated, suggests a systematic literature review reported at ICNMD 2018. J.S. Charleston,MD, of SareptaTherapeutics, Inc, Cambridge, Massachusetts, explained that DMD is a degenerative, fatal, X-linked recessive disorder that affects one in 3500 to 5000 male newborns worldwide. DMD gene mutations cause the absence of dystrophin in muscle fibers. The absence of dystrophin leads to progressive loss of muscle function. Dystrophin is a protein located between each muscle fiber’s plasma membrane (sarcolemma) and the outermost layer of myofilaments in themuscle fiber (myofiber). It is a cohesiveprotein, linkingactin filaments to another support protein that resides on the inside surface of each muscle’s sarco- lemma. In turn, this support protein on the inside surface of the sarcolemma links to two other consecutive proteins for a total of three linking proteins. The final linking pro- tein is attached to the fibrous endomysium of the entire muscle fiber. Dystrophin supports muscle fiber strength. The absence of dystrophin reduces muscle stiffness, increases sarcolemmal deform- ability, and compromises the mechanical stability of costameres and their connec- tions to nearby myofibrils. Biomechanical properties of the sarcolemma and its links through costameres to the con- tractile apparatus have been measured. Dystrophin helps prevent muscle fiber injury. Movement of thin filaments (actin) creates a pulling force on the extracellular connective tissue that eventually becomes the tendon of the muscle. The precise amount of dystrophin associ- ated with clinically meaningful benefit in DMD is unclear, though numerous findings indicate that small amounts of dystrophin, associated with natural mechanisms such as spontaneous exon skipping, may lead to slower disease progression.

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IV ImmuneGlobulin Improves Disability inChronic InflammatoryDemyelinating Polyneuropathy Disability improvement was seen after 10-13 weeks of treatment IV immune globulin has been shown to improve

reactions were reported in 105 individuals (44.7%), a rate of 0.144 adverse drug reactions per infusion. Dr. Merkies concluded that pooled PRIMA and PATH data showed improvement in disability with IV immune globulin in this large cohort of individuals with chronic inflammatory demyelinating polyneuropathy. Improvement was seen at up to 10 to 13 weeks, which suggested that some individuals may need multiple immune globulin doses. Re-stabilization treatment after IV immune globulin withdrawal In PATH, IV immune globulin was withdrawn before ran- domization. Individuals who did not deterioratewithin 12 weeks of withdrawal, discontinued the study because immune globulin dependency was not confirmed. On deterioration (increase in adjusted INCAT score), individuals underwent IV immune globulin re-stabili- zation. The induction dose was 2 g/kg. Maintenance doses were 1 g/kg every 3 weeks for up to 10 to 13 weeks. Of 245 individuals in whom IV immune globulin was withdrawn, 28 (11.4%) did not deteriorate within 12 weeks. Another 10 individuals withdrew for other reasons, leaving 207 in the re-stabilization phase. Of these, 91% improved in at least one efficacy measure (one point improvement in adjusted INCAT score, four points in Rasch-built overall disability score, 8 kPa in mean grip strength, or three points in Medical Research Council score) by 10 to 13 weeks. Adjusted INCAT score improved in 72.9%, with approx- imately 21% of individuals improving beyond baseline status. Improvements were seen in all secondary scores. Post-study follow-up of participants who did not improve revealed that most had improved. Dr. Merkies explained that in individuals with chronic inflammatory demyelinating polyneuropathy, it is rec- ommended that the dose or frequency of IV immune globulin administration be reduced periodically to assess the need for ongoing therapy. Little is known about the effectiveness of IV immune globulin re-sta- bilization in individuals who worsen after withdrawal of IV immune globulin. Dr. Merkies concluded that withdrawal of IV immune globulin was effective in detecting individuals who did not require IV immune globulin therapy. For individu- als dependent on IV immune globulin, re-stabilization with IV immune globulin was effective in reversing observed deteriorations within 12 weeks. www.practiceupdate.com/c/70784

disability in chronic inflammatory demyelinating polyneuropathy, and its withdrawal has been shown to detect individuals who do not need it. These outcomes from the prospective, open- label, single-arm PRivigen Impact on Mobility and Autonomy (PRIMA) and randomized, double-blind Polyneuropathy And Treatment with Hizentra (PATH) studies were reported at ICNMD 2018. Efficacy and safety Ingemar S.J. Merkies, MD, of the Maastricht University Medical Center in The Netherlands, and colleagues assessed the efficacy and safety of IV immune globulin in individuals with chronic inflammatory demyelinating polyneuropathy in the PRIMA and PATH studies. In PRIMA, 28 individuals with chronic inflammatory demyelinating polyneuropathy received induction IV immune globulin (2 g/kg of body weight) and main- tenance therapy (1 g/kg every 3 weeks for 21 weeks). This regimen was also used in 207 individuals who were pre-treated with IV immune globulin during the 10 to 13-week PATH re-stabilization period, before randomization to subcutaneous immune globulin versus placebo. Both studies investigated response (defined as a one- point decrease or greater in adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] score), changes in mean grip strength, and Medical Research Council score, as well as safety. Separate and pooled results were analyzed from both studies.

INCAT response rate at last observation was 76.9% (95% CI 49.7–91.8) in IV immune globu- lin – pre-treated participants in PRIMA (60.7% in all participants in PRIMA) and 72.9% (95% CI 66.5–78.5) in individuals rand- omized to PATH. In the pooled cohort (n=235), the INCAT response rate was 71.1% (95% CI 65.0–76.5). Most responders improved by week 4. Additional responses occurred up to week 13. No clear differences in charac- teristics were noticed between early (responding before week 7) and late responders. In the pooled cohort, 271 adverse drug

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Ultrasonography Valuable in Confirmation of Carpal Tunnel Syndrome

U ltrasonography has been found to be valuable for confirming carpal tunnel syndrome, suggest outcomes from two prospective studies reported at ICNMD 2018. Atchayaram Nalini, MD, of the National InstituteofMentalHealthandNeurosciences in Bengaluru, India, explained that carpal tunnel syndrome is the most common entrapment neuropathy (prevalence 3.8%). Ultrasonographic measurements are suffi- ciently accurate in the diagnosis of carpal tunnel syndrome, allow differential diagno- sis, and support the surgeon. Dr. Nalini and colleagues compared the sensitivity of electrodiagnosis and high resolution nerve ultrasound in carpal tunnel syndrome. “Some patients fear electrical stimulation and may be good candidates for exam- ination using ultrasonography,” Dr. Nalini told Elsevier’s PracticeUpdate . Ultrasonography was performed using the Philips Epiq 7G, linear 5 to 18Hz globulin use and treatment outcomes were assessed. The point prevalence of multifocal motor neuropathy in Austria was found to be 0.65 out of 100,000. The male-to-female ratio was 2.2:1, and median age of symp- tom onset was 45 years. Mean diagnostic delay was 5.4 ± 8.33 years. Mean diagnostic delay was 17 years when symptoms began between 1982 and 1986, and 0.9 years when symptom onset was between 2012 and 2017. Multifocal motor neuropathy typically began in the upper extremity (77.2%) and in distal muscles (87.7%). Conduction block was found in 95% of individuals, most fre- quently in the ulnar and median nerves. Forty-three percent showed immune globulin M antibodies against GM1.

Ultrasonography is an effective, sensitive, and less expensive alternative toMRI to confirmcarpal tunnel syndrome

transducer. Median nerve cross-sectional area was recorded transversely at level of pisiform and scaphoid bones parallel to each other (carpal tunnel inlet). Distal-to- proximal ratio was calculated 4 cm from the distal crease in the forearm. Nerve conductions were performed as per standard procedure. Magnetic resonance neurography axial and sagittal images employed a tempo- romandibular surface coil, fat saturation, and flow suppression. A total of 30 participants were studied. Female to male ratio was 4:1. Mean age

Dr. Atchayaram Nalini

Immune Globulins Continue to Be theMost Effective Treatment for Multifocal Motor Neuropathy Most patients still deteriorate over the long term

I mmune globulins continue to be effective, but most patients still deteriorate over the long term. Eva-Maria Oberreiter, MD, of the Medical University of Innsbruck, Austria, and col- leagues surveyed Austrian individuals with multifocal motor neuropathy to review epi- demiological and clinical features and their response to treatment. They also compared results with those of published studies. Austrian neurologists were contacted through the Austrian Neurological Society and asked to provide anonymized data on individuals with multifocal motor neurop- athy in their care. A total of 57 individuals reported were diagnosed between 1993 and 2017. Clinical, electrophysiological, and lab- oratory data, as well as IV immune

Overall, 51 of 57 individuals were treated with IV immune globulin at median inter- vals of 4 weeks at a mean dosage of 1.55 g/kg of body weight. High muscle strength was a favorable prognostic fac- tor. Elevated serum immune globulin M anti-GM1 antibody titer, muscle atrophy, and long intervals of treatment were neg- ative prognostic factors. Duration of treatment correlated with outcome: the longer the treatment, the worse the outcome. IV immune globulin improved muscle strength but frequently lost effectiveness after >7 years. Dr. Oberreiter explained that multifocal motor neuropathy is a rare immune-me- diated neuropathy that leads to slowly progressive, asymmetric muscle weak- nesses. Electrophysiological motor

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case of multifocal motor neuropathy that highlighted the complementary role of ultrasonography. A 40-year-old man presented with a 2-year history of progressive left-sided weakness without sensory symptoms. A nerve conduction study revealed partial conduction block in two nerves. Anti-GM1 antibody was negative and other labora- tory studies, unremarkable. Ultrasonography showed focal nerve enlargement of the right median nerve at the forearm and left ulnar nerve at the elbow. His weakness improved com- pletely after intravenous immune globulin. Ultrasonography revealed focal enlarge- ment of the median and ulnar nerves. Cross-sectional areas of the right and left median nerves at the wrist were normal, as were those of the left median nerve at the forearm, the right and left median nerves at the upper arm, and the right ulnar nerve at the elbow. However, cross-sectional areas of the right median nerve at the forearm and In sex-matched controls (37 cases; 75 hands, n=39 female, n=6 male), mean distal cross-sectional area was 0.79 ± 0.13 cm 2 (0.59 to 0.11 cm 2 ) and 0.77 ± 0.1 cm 2 (0.53 to 0.1 cm 2 ) in the right and left median nerves, respectively. Mean cross-sectional area of participants was significantly higher than in controls. Nerve conduction studies in 27 participants revealed absent evoked motor response in four individuals (n=3 right, n=1 left). In 24 cases, mean distal motor latency and com- pound muscle action potential of the right median nerve was 5.8 ± 1.4 (4.2 to 11.4) s and 8.65 ± 3.0 (3.3 to 10.3) mV, respectively. On the left (26 cases), it was 5.5 ± 1.8 (3.3 to 10.3) s and 8.3 ± 3.7 (0.6 to 15.8) mV, respectively. Median nerve sensory nerve action potentials were absent in 16 participants (n=10 bilateral, n=4 right, n=2 left). Mean sensory latencies were 4.5 ± 2.4 (2.5 to 12) s and 3.4 ± 0.7 (2 to 4) s in the right (n=13) and left (n=14) sides, respectively. Corresponding mean sensory amplitudes were: ƒ ƒ Right 7.2 ± 5.3 (1.5 to 23) mV ƒ ƒ Left: 9.9 ± 5.9 (2.3 to 22.1) mV Conduction velocities were: ƒ ƒ Right 35.6 ± 11 (11.7 to 58) m/s ƒ ƒ Left 43.7 ± 13 (22.2 to 68.6) m/s

the left ulnar nerve were increased at 15.2 mm 2 and 11.1 mm 2 , respectively. Cross-sectional area of the right and left median nerves at the upper arm was normal. Cross-sectional area of the right and left ulnar nerves at the wrist was normal. Cross-sectional area of the right ulnar nerve at the elbow was normal (3.5 mm 2 ), but of the left ulnar nerve, increased at 11.1 mm 2 . Dr. Im Suk explained that multifocal motor neuropathy is treatable, and its differen- tiation from lower motor neuron disease is crucial. Evidence of conduction block or positive immune globulin M anti-GM1 is considered an important diagnostic marker. Some individuals with atypical multifocal motor neuropathy, however, exhibit no detectable conduction block nor anti-GM1 antibodies. Dr. Im Suk concluded that ultrasonography can be valuable in supporting the diagno- sis of multifocal motor neuropathy. www.practiceupdate.com/c/70783 MRI in 19 individuals showed mean distal cross-sectional area of the right median nerve of 1.55 ± 0.49 (range 1 to 2.7) cm 2 and left median nerve, 1.57 ± 0.4 (range 1 to 2.7) cm 2 . Dr. Nalini noted, “Ultrasound of the nerves is an emerging, painless, easily accessi- ble, affordable, and sensitive modality to study peripheral as well as proximal nerves to understand their involvement in carpal tunnel syndrome. Particularly in this disorder, if we need objective follow-up assessment of any specific therapy, ultra- sonography may be used repeatedly. These features of ultrasonography and its great utility in entrapment neuropathies prompted us to take up this study, also to obtain data in normal controls for com- parison and correlation. We plan to utilize ultrasonography to assess all our cases of carpal tunnel syndrome.” Dr. Nalini emphasized the importance of ultrasonography as a sensitive, cheaper, and effective alternate to MRI to confirm carpal tunnel syndrome. Cross-sectional area of the proximal median nerve may be used to predict severity of carpal tunnel syndrome. Moreover, mean and inlet cross-sectional area may be valid and easy-to-acquire parameters for routine clinical use in con- firming carpal tunnel syndrome. www.practiceupdate.com/c/70789

conduction block is the hallmark of the disorder. With early diagnosis and treatment with intravenous immune globulins, multifocal motor neuropathy is treatable, at least during the first years of disease. The rarity of multifocal motor neuropathy has limited the number of studies of clin- ical features and response to long-term treatment. Dr. Oberreiter concluded that the preva- lence of multifocal motor neuropathy in Austria is similar to the few reports from other countries. The present results cor- roborate previous results in terms of clinical, electrophysiological, and laboratory fea- tures of multifocal motor neuropathy. Intravenous immune globulins continue to be the most effective treatment for mul- tifocal motor neuropathy. In most cases, however, deterioration occurs over the long term. Jung Im Suk, MD, of the Catholic University of Daegu, School of Medicine in Daegu, South Korea, and colleagues described a All participants voiced sensory complaints. A total of nine patients (30%) also suffered from motor deficits. Sensitivity of Tinel sign/Phalen’s maneuver was 40% and 63.3%, respectively. Using ultrasonogra- phy, cross-sectional area at the pisiform bone level was >0.1 cm 2 . at presentation was 41.6 ± 10.5 (27 to 61) years. Clinically, 28 (93.3%) suffered from bilateral carpal tunnel syndrome (n=4 symmetrical, n=24 asymmetrical) and 2 exhibited unilateral involvement. The duration of illness varied from 2 months to 8 years.

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Family With Myotonic Dystrophy 1 Shown to Carry Interruptions Exhibiting Milder, Atypical Phenotype MD1 interruptions may carry potential consequences for diseasemanagement A family with myotonic dystrophy 1 has been shown to carry interruptions showing a milder and atypical phenotype, according to a case report presented at ICNMD 2018. disease paternally. Participant 4 (P4) was the son of participant 3 and mother and son exhibited the same interruption pattern. The remaining sisters harbored a different interruption pattern. The male interrupted participant (P4, age 37 years) was com- pletely asymptomatic on clinical examination, despite the 108 CTG progenitor allele.

Emma A. Koehorst, MSc, of the Institute for Health Science Research Germans Trias i Pujol Research Center in Badalona, Spain, and colleagues described a family with myotonic dystrophy 1 that was shown to carry interruptions showing a milder and atypical phenotype.

The three sisters exhibited most typical features of myotonic dystrophy 1, but without predominant distal weakness. The most remarkable observation was that the three sisters’ symptoms began at a later age (>50 years). This classified them as suffering from late-onset myotonic dystrophy 1. Their symptoms largely resembled a classic/adult phenotype. Ms. Koehorst explained that in recent years, individuals with myotonic dystrophy 1 who carry variant repeat patterns in CTG expansion have been described. Phenotypical consequences of interrupted CTG expansion remain highly controversial. Variant repeat patterns have been associated with a com- plex co-segregated neurological phenotype, including an intermediate Charcot-Marie-Tooth neuropathy, deafness, and encephalopathy. A milder phenotype with later age of onset, absence of muscle atrophy, CNS involvement, or an atypical phenotypewith symptoms resemblingmyotonic dystrophy 2 has also been found. The number of described individualswithmyotonic dystrophy 1 who exhibit these interruptions is low (estimated prevalence 3% to 5%). Ms. Koehorst concluded that the presence of four interrupted cases was reported in a cohort of 50 individuals with myotonic dystrophy 1. Prevalence was 3.4 % in these families with myotonic dystrophy 1. The cohort exhibited inheritability of the interruption pattern, an exact replica in terms of maternal transmission. “We found classic symptoms in our interrupted patients,” Ms. Koehorst asserted, “including cardiac involvement and myoto- nia. Age of onset, however, was surprisingly late (>50 years of age), uncommon with these presenting symptoms. In addition, the male interrupted patient is still asymptomatic, despite his age of 37 years. Furthermore, our interrupted patients show a shift in muscle involvement to a more proximal rather than distal weakness, mostly observed in uninterrupted patients with myotonic dystrophy 1.” She continued, “The prevalence of 2.7% of interrupted cases in our cohort is similar to the previously observed prevalence of 3% to 5%. Our dataset is small, however, and we will continue to collect data and introduce new patients into our cohort to further analyze the effect these interruptions exert and their potential consequences for disease management.” The results contribute to observations of a milder and/or atypical clinical phenotype of variant repeat carrying in patients with myotonic dystrophy 1. Age of onset is later than expected and weakness is predominantly proximal. The latter resembles the phenotype of myotonic dystrophy 2. www.practiceupdate.com/c/70785

Ms. Emma A. Koehorst Ms. Koehorst explained to Elsevier’s PracticeUpdate , “Myotonic dystrophy 1 is a muscle dystrophy characterized by wide phenotypic variability. Myotonic dystrophy 1 can be explained only partly by underlying RNA toxicity, meaning that other disease modifiers influence the clinical phenotype.” She continued, “Until recently, it was thought that CTG expansion was an uninterrupted sequence. However, variant repeat expan- sions have been found such as CTC, CCG, CGG, and CAG. The effect that these interruptions exert on the clinical phenotype is controversial and data are scarce due to low prevalence of the interruptions. Speculations range from a milder phenotype to a complex co-segregated neurological phenotype. This con- troversy and lack of data led us to undertake this case study.” Ms. Koehorst and colleagues analyzed a cohort of 50 individuals with myotonic dystrophy 1 to find new individuals carrying inter- ruptions and to determine their clinical phenotypes. Blood DNA was obtained from participants and triplet-primed polymerase chain reaction at the 5’ and 3’ sites was performed. Acil digestion and sequencing was used to determine the pres- ence of these interruptions and type of interruption present (CCG, CTC, or GGC). Of the 50 individuals with myotonic dystrophy 1, four were found to harbor CCG interruptions in the 3’ end of CTG expansion. These individuals were found to belong to the same family, in which participants 1, 2, and 3 were sisters who inherited the including cardiac involvement and myotonia. Age of onset, however, was surprisingly late (>50 years of age), uncommon with these presenting symptoms. " " We found classic symptoms in our interrupted patients,

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SomeNeuromuscular Diseases Linked toMalignant Hyperthermia or Similar Reactions Neurologists may need to take or advise perioperative precautions in patients with diverse muscular diseases C ertain muscular disorders may be linked with malignant hyperthermia or malignant hyperthermia-like reac- tions, concluded a systematic literature review presented at ICNMD 2018. Muscular dystrophies such as Duchenne and Becker muscular dystrophies can also be associated with a malignant hyperther- mia-like reaction to succinylcholine. hyperthermia. Such case reports can cause neurologists to feel uncertain, and can lead to excessive presumption of individuals as being susceptible to malignant hyperthermia, or even worse, missed diagnosis.

Dr. Claeys explained that malignant hyperthermia is a life-threatening hypermetabolic reaction that attacks susceptible individuals. It is caused by excessive calcium release from the sar- coplasmic reticulum in skeletal muscles in response to primarily volatile halogenated anesthetics and the depolarizing muscle relaxant succinylcholine. Mutations in the gene encoding the ryanodine receptor 1 (RYR1) are the most frequently identified underlying genetic defects. Mutations in other genes have also been described, such as CACNA1S, STAC3, SCN4A, and CACNL2A. In susceptible individuals, medications induce the release of stored calcium ions within muscle cells. The resulting increase in calcium concentrations within the cells causes the muscle fibers to contract. This generates excessive heat and results in metabolic acidosis. Although, various laboratory investiga- tions may prove confirmatory, diagnosis is primarily based on symptoms. These include a raised creatine kinase level, elevated potassium, increased phosphate (leading to decreased calcium) and – if determined – raised myoglobin resulting from damage to muscle cells. Severe rhabdomyolysis may lead to acute kidney failure, so kidney function is measured frequently. Individuals may also develop premature ventricular contractions due to increased levels of potassium released from the muscles during the episode. Typical signs of malignant hyperthermia are due to a hypercatabolic state, which presents as a very high temperature, increased heart rate, and abnormally rapid breathing, increased carbon dioxide production, increased oxygen consump- tion, mixed acidosis, rigid muscles, and rhabdomyolysis. These signs can develop at any time during the administration of the anesthetic agents. Over the years, case reports have linked an increasing number of muscular phe- notypes with a susceptibility to malignant

Bram De Wel, MD, and Kristl G. Claeys, MD, PhD, of University Hospitals Leuven in Belgium, explored muscular disorders that may be linked with malignant hyper- thermia or malignant hyperthermia-like reactions and to suggest an appropriate approach to interpret accompanying risks. They searched studies published from the 1960s to 2018 and included case reports, reviews, and retrospective cohort studies. In 1012 papers, participants with myopa- thies caused by mutations in the gene encoding the ryanodine receptor 1 (RYR1) were assumed to be susceptible to malig- nant hyperthermia, unless an in vitro contracture test proved otherwise. This is a good, pragmatic assumption, though only approximately 30% of these partici- pants are estimated to be susceptible to malignant hyperthermia. The spectrum of myopathies and clinical syndromes linked to malignant hyper- thermia through RYR1 mutations now includes, among others, central core disease, multi-minicore myopathy, con- genital myopathy with cores and rods, King-Denborough syndrome, centronu- clear myopathy, and nemaline myopathy. In addition, idiopathic hyperCKemia and exertional rhabdomyolysis are also part of the spectrum of RYR1 disease. Mutations in CACNA1S mainly cause periodic paral- ysis. STAC3 mutations are a known cause of Native American myopathy. Finally, muscle diseases long presumed to be linked to increased risk of malignant hyperthermia, such as myotonic dystro- phy type 1, are now known to carry equal risk of developing malignant hyperther- mia in response to volatile anesthetics as the general population. However, succinylcholine should still be avoided in these individuals because unpredictable muscle contractures can occur after administration. An exagger- ated hyperkalemic response, such as a malignant hyperthermia-like reaction, can occur.

Malignant hyperthermia-like reactions in response to succinylcholine, and possi- bly volatile anesthetics, have also been reported and are associated with severe hyperkalemia and rhabdomyolysis. The cause of these malignant hyperther- mia-like reactions is thought to differ from that of true malignant hyperthermia. Dr. Claeys concluded that certain neuro- muscular diseases have been associated with perioperativemalignant hyperthermia or malignant hyperthermia-like reactions. Neurologists may need to take or advise perioperative precautions in individuals

with diverse muscular diseases. www.practiceupdate.com/c/70787

© ICNMD 2018

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DNA Methylation, LXR/RXR Activation, and Multiple Immune Signaling Pathways Likely Play a Role in Diabetic Polyneuropathy These pathways may provide newmechanism-based therapeutic targets

D NA methylation, LXR/RXR activa- tion, and multiple immune signaling pathways have been found to play a possible role in diabetic polyneuropathy. These outcomes from a DNA methylation study and a transcriptional signature study were reported at ICNMD 2018. Eva L. Feldman, MD, PhD, of the University of Michigan in Ann Arbor, Michigan, assessed the DNA methylation profiles of 12 individuals with diabetic peripheral neuropathy. Examination of sural nerve biopsies from these individuals revealed that six of them exhibited significant nerve regeneration, whereas other six displayed significant nerve degeneration over a period of 52 weeks. These samples underwent reduced representation bisulfite sequencing for analysis of DNA methylation between individuals who exhibited sural nerve regeneration and those who exhibited degeneration. A total of 3460 differentially methylated correlations between differentially meth- ylated 5'-C-phosphate-G-3's and 246 differentially methylated regions were revealed between the two cohorts. Analyses of genes associated with the differentially methylated 5'-C-phosphate- G-3's identified pathways highly enriched in neuron development and differentia- tion, as well as pathways associated with cancer. Dr. Feldman explained that, DNA methyl- ation is an important epigenetic regulator in both health and disease. However, no investigations of possible alterations in DNA methylation in the peripheral nerves DNA methylation helps regulate diabetic peripheral neuropathy

These sub-networks were further merged into a single network of 688 genes. Functional analyses of the identified shared networks between murine and human datasets revealed that genes involved in LXR/RXR activation and adipo- genesis were highly affected by diabetes and conserved across both species. Centrality analysis detected the most highly connected genes that may play important roles in this cross-species shared network of diabetic peripheral neuropathy, including PIK3CA, MAPK8, CD44, MAPK1, CREB1, LEP, CCL2, JUN, ESR1, FOS, CD36, IL1B, HGF, and PLAT. These genes indicate enrichment of different pathways. The most significant pathways include glucocorticoid receptor signaling, multiple cytokine pathways, and chemokine signaling. Dr. Feldman explained that diabetic peripheral neuropathy is among the most common complications of diabetes. Despite extensive research, underlying mechanisms leading to diabetic periph- eral neuropathy are not fully understood. Multiple murine models and human sam- ples have been examined, but a unified systematic approach is yet to compare observed changes between groups. Such comparison may help to identify a pos- sible conserved mechanism of diabetic peripheral neuropathy. Dr. Feldman concluded that the systems biology approach identified highly con- served pathways across human and murine models. These pathways include LXR/RXR activation and multiple immune signaling pathways, and likely play a role in the pathogenesis of diabetic periph- eral neuropathy providing possible new mechanism-based targets of therapy. www.practiceupdate.com/c/70786

of individuals with diabetic neuropathy have been performed. Dr. Feldman concluded that DNA methyl- ation plays an important role in regulating nervous system development and cellular proliferation in the progression or regres- sion of diabetic peripheral neuropathy. Additionally, these novel results provide insights into possible epigenetic regula- tion of diabetic peripheral neuropathy and offer useful information for future research in the disorder. Transcriptional signature provides possible new therapeutic targets Dr. Feldman also identified transcriptional pathways related to diabetic peripheral neuropathy that were conserved across human and various murine models of dia- betes using a systems biology approach. She collected eight microarray datasets of peripheral nerve samples from murine models of type 1 (streptozotocin-treated) and type 2 (db/db [diabetic] and ob/ ob [obese]) diabetes at different ages and from humans with non-progressive and progressive diabetic peripheral neuropathy. Dr. Feldman identified differentially expressed genes between control and diabetic samples in murine models. Non- progressive and progressive human samples using a unified analysis pipeline. She constructed a transcriptional network for each differentially expressed gene set based on literature-derived gene-gene interaction information. Dr. Feldman identified shared sub-networks between human and murine networks using a net- work-comparison program. Overall, seven pairwise human-ver- sus-murine comparisons resulted in sub-networks including 46 to 396 genes.

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Palliative Care Can Be Integrated Into Management of Patients With ALS Close collaboration and communication are essential among teams caring for patientswithALS F or the first time, palliative care has been integrated into a Moscow service for individuals with amyotrophic lateral

decisions about life-sustaining interven- tions. These discussions were particularly important when individuals and families lacked information and symptoms were not controlled adequately nor were unwanted hospitalizations and prolonged ventilator support prevented. Such inter- ventions may affect quality of life. Moreover, according to Russian law, interventions such as ventilation cannot be withdrawn. Among the most prevalent end-of-life symptoms is dyspnea, and 40% of individuals in this cohort suffer from persistent dyspnea (median Borg score 5 out of 10). Dyspnea is also a main reason underlying admission to intensive care, a topic needing discussion as it relates to life-sustaining interventions. Dr. Brylev’s team was the first in Russia to use morphine for dyspnea in individuals with ALS. Their experience showed that morphine can be used safely. There is no evidence of an increase in pCO2 in arterial blood. Morphine can be used effectively as well as safely. In fact, 50% of individuals evaluated their response as good, 40% as partial, and only 10% as ineffective. Dr. Brylev concluded that neurologists and palliative care specialists continue to work together closely, with the aim of integrating palliative care principles into the standard of care for individuals with ALS. Numerous challenges remain.

David J. Oliver, BSc, MBBS, of the University of Kent, Canterbury, UK, determined the optimal timing to begin palliative care in individuals with ALS. He reviewed the literature as well as his clinical experience. Though palliation is often associated with care at the end of life, its role is much greater. For an individual with progressive neuromuscular disease such as ALS, it may be argued that care should be palli- ative from diagnosis. For example, the manner in which the diagnosis is communicated to the individ- ual and family can exert a significant effect on later stages of care. An individual who believes that death may involve choking or breathlessness may continue to fear these symptoms despite explanation that these risks are minimal. All professionals involved in the care of individuals with neuromuscular disease need to provide palliative care inasmuch as they look to maximize quality of life of individual and family. Care is usually by a multidisciplinary team, and may improve not only quality, but also length of life. Dr. Oliver concluded that close collab- oration and communication is essential among all teams involved in the care of individuals with ALS. www.practiceupdate.com/c/70782

sclerosis (ALS). The process of integration was described in a cohort of 672 partici- pants at ICNMD 2018. Lev Brylev, MD, of the Buyanov City Hospital in Moscow, Russian Federation, explained that the first specialized multidisciplinary out-patient center for individuals with ALS in Moscow opened in 2012 and is now a part of the European Network to Cure ALS network. The Moscow ALS Center at St. Alexey Hospital follows about 200 families with ALS every year and is funded by the “Live Now” Foundation (www.ALSFund.ru). Before 2012, individuals with ALS had no access to palliative care because hos- pices would not accept them and national legislation on the provision of palliative care to individuals without cancer was not passed until 2011. No specialized education in palliative care for neurological individuals was available in Russia, so foreign experts were invited to teach Dr. Brylev’s team. A palliative care physician who had studied palliative care abroad was invited to multidisciplinary discussions. Multidisciplinary out-patient consultations began and the palliative care approach, with its emphasis on individual auton- omy, dignity, and quality of life changed Dr. Brylev’s practice completely. Analyzing data from 672 participants, the investigators found that median disease duration was 1188 (range 791 to 1787) days, time from first symptom to diagnosis, 365 (range 191 to 587) days, and from diagno- sis to referral to the team, 320 (range 132 to 630) days. On admission to the service, individ- uals had been suffering from ALS for approximately 2 years. Their median vital capacity was 51% (range 38% to 80%). It was apparent that they had not talked about advance planning. Only 30% had ever discussed their prognosis and death with their family or physician. The training enhanced the communication skills of Dr. Brylev’s team. They learned to talk with individuals about prognosis and

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