The clinical practice guideline for the management of amyotrophic lateral sclerosis in Japan-update 2023.

Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.

Far-field potential of the compound muscle action potential as a reliable marker in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Reliable neurophysiological markers in amyotrophic lateral sclerosis (ALS) are of great interest. The compound muscle action potential (CMAP) amplitude has been a conventional marker, although it is greatly influenced by the electrode position. We propose the far-field potential of the CMAP (FFP-CMAP) as a new neurophysiological marker in ALS. METHODS: Patients with ALS and age-matched healthy controls were enrolled. We used a proximal reference (pref) in addition to the conventional distal reference (dref). Routine CMAP was recorded from the belly-dref lead and FFP-CMAP from the dref-pref lead for the ulnar and tibial nerves. Multiple point stimulation motor unit number estimation (MUNE) was also examined in the ulnar nerve. Inter-rater reproducibility was evaluated by two examiners, and some patients were followed up every 3 mo for 1 y. RESULTS: We tested 17 patients with ALS and 10 controls. The amplitudes of routine CMAP and FFP-CMAP in the ulnar and tibial nerves, and hypothenar MUNE value in the ulnar nerve were significantly decreased in ALS compared to controls. Ulnar FFP-CMAP achieved the highest inter-rater intraclass correlation coefficient (ICC) value (0.942) when compared with routine CMAP (0.880) and MUNE (0.839). The tibial FFP-CMAP had a higher ICC value (0.986) than the routine CMAP (0.697). In this way, the FFP-CMAP showed high inter-rater reproducibility because its shape was not much influenced by the electrode position. During 1-y follow-up, decline of CMAP, FFP, and MUNE showed significant correlations with the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R). DISCUSSION: The FFP-CMAP shows promise as a reliable marker for ALS.

[Medical Treatment of Chronic Pain].

Antinociceptive therapy for chronic neuropathic pain is anecdotal in nature based on a physician's preference. However, evidence-based therapy is expected, following the chronic pain guideline established in 2021, supported by 10 pain-associated Japanese medical societies. The guideline strongly recommends the use of Ca2+-channel α2δ ligands (pregabalin, gabapentin, and mirogabalin) and duloxetine for pain relief. International guidelines also recommend administration of tricyclic antidepressants as first-line agents. Recent studies have described three classes of medicines that show comparable antinociceptive effects in painful diabetic neuropathy. Furthermore, a combination of first-line agents can improve efficacy. Antinociceptive medical therapy should be individualized based on the patient's condition and adverse effect profile of each medication.

Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Importance: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. Objective: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design, Setting, and Participants: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo. Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups. Conclusions and Relevance: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period. Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.

Ultrasound assessment of sarcopenia in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the efficacy of ultrasound (US) as a diagnostic tool for sarcopenia in patients with rheumatoid arthritis (RA). METHODS: Female RA patients aged >50 years and matched controls were cross-sectionally assessed. Sarcopenia was diagnosed based on the 2019-updated Asian Working Group for Sarcopenia definition. The cross-sectional area (CSA) and echo intensity (EI) of the biceps brachii, rectus femoris, and EI of the vastus lateralis were examined bilaterally. Correction for subcutaneous fat and calculation of the recorrected EI (rcEI) were performed. We performed logistic regression using both muscle rcEI and CSA with receiver operating curve analysis to evaluate the discriminative performance per muscle group. RESULTS: Seventy-eight consecutive RA patients and 15 age-and sex-matched controls were assessed. Sarcopenia was diagnosed in 34 RA patients (43.6%). The rcEI of examined muscles were significantly higher, whereas CSA were significantly lower in sarcopenic RA patients than in non-sarcopenic patients and matched controls. The combined discriminative performance of rcEI and CSA was superior to those of rcEI or CSA alone. CONCLUSIONS: This study suggests the use of US for the diagnosis of sarcopenia in RA patients. The diagnostic performance increases when both echogenicity and CSA are considered together rather than individually.

LSTM Neural Network for Inferring Conduction Velocity Distribution in Demyelinating Neuropathies.

Waveform analysis of compound muscle action potential (CMAP) is important in the detailed analysis of conduction velocities of each axon as seen in temporal dispersion. This understanding is limited because conduction velocity distribution cannot be easily available from a CMAP waveform. Given the recent advent of artificial intelligence, this study aimed to assess whether conduction velocity (CV) distribution can be inferred from CMAP by the use of deep learning algorithms. Simulated CMAP waveforms were constructed from a single motor unit potential and randomly created CV histograms (n = 12,000). After training the data with various recurrent neural networks (RNNs), CV inference was tested by the network. Among simple RNNs, long short-term memory (LSTM) and gated recurrent unit, the best accuracy and loss profiles, were shown by two-layer bidirectional LSTM, with training and validation accuracies of 0.954 and 0.975, respectively. Training with the use of a recurrent neural network can accurately infer conduction velocity distribution in a wide variety of simulated demyelinating neuropathies. Using deep learning techniques, CV distribution can be assessed in a non-invasive manner.

Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

OBJECTIVE: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). METHODS: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety. RESULTS: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). CONCLUSION: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02573467. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

Diagnostic usefulness of denervation edema in the multifidus muscles using 3-Tesla magnetic resonance imaging in cervical radiculopathy.

BACKGROUND: Diagnosing cervical radiculopathy (CR) can be difficult because of symptomatic overlap with peripheral neuropathies. In this retrospective observational study, we aimed to determine whether short-tau inversion recovery (STIR) magnetic resonance imaging (MRI) sequences are useful for detecting signs of denervation in the multifidus muscles in patients with CR. METHODS: We analyzed the data of 18 patients with CR who developed arm weakness within 1 year. We also included 10 patients with sensorimotor symptoms involving the upper extremities who did not have intervertebral foraminal stenosis on MRI as controls. For each patient with CR, the signal intensity (SI) of the affected multifidus muscles was measured and compared to that on the contralateral side (signal intensity ratio: SIR). RESULTS: Control patients without CR did not exhibit STIR signal abnormalities in the multifidus muscles. Most of the 18 patients with CR were male (83.3%), and the mean age was 59.4 years. Thirteen of 18 CR patients (72.2%) were determined to have STIR signal abnormalities by a radiologist. The mean SIR in the 13 patients with increased SI was significantly higher than that in the five patients without signal abnormalities (1.23 vs 0.97, P = .004), supporting the radiologist's diagnosis. The distribution of signal abnormalities closely followed those identified via clinical and electrophysiological tests, especially severe weakness (P = .044). CONCLUSIONS: Denervation edema of the multifidus muscles can be detected in CR and correlates with clinical/electrophysiological tests and weakness severity, which may aid in CR diagnostics.

Utility of phrenic nerve ultrasound in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the upper and lower motor neurons causing progressive weakness. It eventually involves the diaphragm which leads to respiratory paralysis and subsequently death. Phrenic nerve (PN) conduction studies and diaphragm ultrasound has been studied and correlated with pulmonary function tests in ALS patients. However, PN ultrasonography has not been employed in ALS. This study aims to sonographically evaluate the morphologic appearance of the PN of ALS patients. Thirty-eight ALS patients and 28 normal controls referred to the neurophysiology laboratory of two institutions were retrospectively included in the study. Baseline demographic and clinical variables such as disease duration, ALS Functional Rating Scale-Revised score, and ALS region of onset were collected. Ultrasound was used to evaluate the PN cross-sectional area (CSA) of ALS and control subjects. The mean PN CSA of ALS patients were 1.08 ± 0.39 mm on the right and 1.02 ± 0.34 mm on the left. The PN CSA of ALS patients were significantly decreased compared to controls (p value < 0.00001). The PN CSA of ALS patients was not correlated to any of the demographic and clinical parameters tested. This study demonstrates that ALS patients have a smaller PN size compared to controls using ultrasonography.

Detection of nerve enlargement with ultrasound and correlation with skin biopsy findings in painful sensory neuropathy associated with Sjögren's syndrome.

OBJECTIVES: We evaluated usefulness of peripheral nerve ultrasound (US) in detecting abnormality in painful sensory neuropathy (PSN) associated with primary Sjögren's syndrome (pSS), and associations among various clinical factors, US findings, and intraepidermal nerve fiber density (IENFD). METHODS: We conducted a retrospective, single-center, observational study of patients with pSS-PSN. US image was obtained to measure cross sectional area (CSA) of peripheral nerves and compared with matched pSS control. RESULTS: We included 11 patients with pSS-PSN (10 women; age 70.5 ± 5.66) and 17 pSS controls (15 women; age 62.5 ± 16.7). Sural nerve CSA were significantly increased in pSS-PSN group (3.48 ± 1.0 mm2 vs 2.05 ± 0.65 mm2, p = .001). US of sural nerve showed the area under the ROC curve of 0.872 (95% CI, 0.732 - 1). Sural nerve CSA and IENFD of lower leg showed positive correlation. Compared with pSS-PSN patients with abnormal IENFD, those with normal IENFD showed significantly larger sural nerve CSA, and trends toward less systemic disease activity and small fiber impairment with sparing of large fibers. CONCLUSION: US was useful in discriminating pSS patients with PSN from those without. Additionally, US may disclose distinct subsets of pSS-PSN with different clinical findings and IENFD.

AANEM - IFCN glossary of terms in neuromuscular electrodiagnostic medicine and ultrasound.

Modern neuromuscular electrodiagnosis (EDX) and neuromuscular ultrasound (NMUS) require a universal language for effective communication in clinical practice and research and, in particular, for teaching young colleagues. Therefore, the AANEM and the IFCN have decided to publish a joint glossary as they feel the need for an updated terminology to support educational activities in neuromuscular EDX and NMUS in all parts of the world. In addition NMUS has been rapidly progressing over the last years and is now widely used in the diagnosis of disorders of nerve and muscle in conjunction with EDX. This glossary has been developed by experts in the field of neuromuscular EDX and NMUS on behalf of the AANEM and the IFCN and has been agreed upon by electronic communication between January and November 2019. It is based on the glossaries of the AANEM from 2015 and of the IFCN from 1999. The EDX and NMUS terms and the explanatory illustrations have been updated and supplemented where necessary. The result is a comprehensive glossary of terms covering all fields of neuromuscular EDX and NMUS. It serves as a standard reference for clinical practice, education and research worldwide.

AANEM - IFCN Glossary of Terms in Neuromuscular Electrodiagnostic Medicine and Ultrasound.

Modern neuromuscular electrodiagnosis (EDX) and neuromuscular ultrasound (NMUS) require a universal language for effective communication in clinical practice and research and, in particular, for teaching young colleagues. Therefore, the AANEM and the IFCN have decided to publish a joint glossary as they feel the need for an updated terminology to support educational activities in neuromuscular EDX and NMUS in all parts of the world. In addition NMUS has been rapidly progressing over the last years and is now widely used in the diagnosis of disorders of nerve and muscle in conjunction with EDX. This glossary has been developed by experts in the field of neuromuscular EDX and NMUS on behalf of the AANEM and the IFCN and has been agreed upon by electronic communication between January and November 2019. It is based on the glossaries of the AANEM from 2015 and of the IFCN from 1999. The EDX and NMUS terms and the explanatory illustrations have been updated and supplemented where necessary. The result is a comprehensive glossary of terms covering all fields of neuromuscular EDX and NMUS. It serves as a standard reference for clinical practice, education and research worldwide. HIGHLIGHTS: Optimal terminology in neuromuscular electrodiagnosis and ultrasound has been revisited. A team of international experts have revised and expanded a standardized glossary. This list of terms serves as standard reference for clinical practice, education and research.

IncobotulinumtoxinA for upper- and lower-limb spasticity in Japanese patients.

Introduction: The safety and tolerability of incobotulinumtoxinA 400 U for upper- and lower-limb post-stroke spasticity was assessed in a small cohort of Japanese patients during the open-label lead-in tolerability periods (LITP) of two phase 3 studies (CTI-153029 and CTI-153030; Japan Pharmaceutical Information Centre).Methods: Adult patients received a single incobotulinumtoxinA injection session (total dose of 400 U) in the upper (J-PURE) or lower limb (J-PLUS). Adverse events (AEs) were assessed at 1, 4, 8 and 12 weeks post-injection during the 12 week follow-up.Results: The LITP of J-PURE and J-PLUS included 11 patients each. Mild/moderate AEs were reported by 5/11 (45.5%) and 8/11 (72.7%) patients in J-PURE and J-PLUS, respectively. No serious AEs were reported. Non-serious, transient AEs of special interest reported by two patients in J-PURE comprised muscular weakness and eyelid ptosis. No patient discontinued due to AEs.Conclusion: Preliminary results in this small population suggest that incobotulinumtoxinA 400 U is well tolerated for treating upper- or lower-limb post-stroke spasticity in Japanese patients.

[Late phase II/III study of BYM338 in patients with sporadic inclusion body myositis (RESILIENT): Japanese cohort data].

A global, randomized, double-blind placebo-controlled study was conducted to confirm that BYM338 (bimagrumab), an anti-activin type II receptor antibody, improves motor function in patients with sporadic inclusion body myositis after 52 weeks' treatment consisting of intravenous administration every 4 weeks at doses of 10, 3, and 1 mg/kg. In a Japanese sub-population (20 patients in total, 5 per dose group), no significant differences in the change from baseline of the 6-minute walking distance at Week 52 (primary endpoint) were observed between the placebo group and each BYM338 dose group. Furthermore, the lean body mass as an indicator of skeletal muscle mass increased in all BYM338 groups compared with the placebo group and the effects were dose-dependent. Overall, the Japanese sub-population showed similar trends as observed in the entire population (251 patients in total).

[Development of Diagnostic Criteria].

Among the proposed ALS diagnostic criteria, the revised El Escorial diagnostic criteria was the most frequently utilized in clinical trials and clinical practice. However, its low sensitivity in early stage ALS prompted development of the Awaji electrodiagnostic criteria that incorporated fasciculation potentials and resulted in greater diagnostic sensitivity than the revised El Escorial criteria. Further improvements could include the updated Awaji criteria that is concordant between clinically- and electrodiagnostically-diagnosed cases, as well as the inclusion of ultrasound-detected fasciculations.

Texture analysis of sonographic muscle images can distinguish myopathic conditions.

Given the recent technological advent of muscle ultrasound (US), classification of various myopathic conditions could be possible, especially by mathematical analysis of muscular fine structure called texture analysis. We prospectively enrolled patients with three neuromuscular conditions and their lower leg US images were quantitatively analyzed by texture analysis and machine learning methodology in the following subjects :  Inclusion body myositis (IBM) [N=11] ; myotonic dystrophy type 1 (DM1) [N=19] ; polymyositis/dermatomyositis (PM-DM) [N=21]. Although three-group analysis achieved up to 58.8% accuracy, two-group analysis of IBM plus PM-DM versus DM1 showed 78.4% accuracy. Despite the small number of subjects, texture analysis of muscle US followed by machine learning might be expected to be useful in identifying myopathic conditions. J. Med. Invest. 66 : 237-240, August, 2019.

Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.

Co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis: a clinical-pathological case report.

BACKGROUND: The coexistence of distinct neurodegenerative diseases in single cases has recently attracted greater attention. The phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, the clinicopathological comorbidity of these two diseases has not been demonstrated. CASE PRESENTATION: A 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5 months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP. CONCLUSIONS: Our case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course.