Quantitative sonographic assessment of muscle thickness and fasciculations distribution is a sensitive tool for neuromuscular disorders.

INTRODUCTION: Loss of muscle thickness can be demonstrated in a wide spectrum of neuromuscular disorders, while fasciculations are more frequent in amyotrophic lateral sclerosis (ALS). In the current study, we aimed to determine the sensitivity and specificity of quantitative sonographic assessment of muscle thickness and the presence of fasciculations for diagnosing various neuromuscular disorders. METHODS: The thickness and the presence of fasciculations in eight muscles were determined by sonography in patients with myopathy (22), polyneuropathy (36), ALS (91), and spinal muscular atrophy (SMA) (31) and compared to normative values determined in 65 heathy control subjects. RESULTS: Reduced muscle thickness in at least one relaxed muscle showed 92-100% sensitivity for diagnosing a neuromuscular disease, with a specificity of 85% for differentiating patients from heathy controls (AUC = 0.90). Subtracting distal from proximal muscle thickness may differentiate between myopathy and polyneuropathy. Fasciculations in ≥1 proximal muscle showed good diagnostic accuracy (AUC = 0.87) for diagnosing ALS. DISCUSSION: Sonographic assessment of muscle thickness is a sensitive tool for diagnosing a wide spectrum of neuromuscular diseases, and may facilitate diagnosis even in patients with normal strength on neurological examination, while the presence of fasciculations in proximal muscles may facilitate ALS diagnosis.

Myasthenia gravis patients exhibiting an eyelid myotonia-like phenomenon.

We report here a retrospective case series of 3 MG patients suffering from difficulty opening eyes that appeared together with a diagnosis of MG. All are male patients with late-onset MG who are seropositive for anti-acetylcholine receptor antibodies. The phenomenon was characterized by difficulty opening the eyes after forced closure or reflex eye closure, improving with the ice pack test and with repeated forced eye closure but worsening with pyridostigmine treatment. We provide a detailed clinical, serological, imaging and electrophysiological examination of these patients. Electromyography evaluation did not show spontaneous muscle activity or myotonia at rest in the orbital part of the orbicularis oculi muscle. However, there was sustained muscle activity lasting several seconds in the pre-tarsal and pre-septal parts of this muscle. Videos of those reported symptoms were produced and provided. We discuss the possible neurological pathophysiology of this disorder and suggest to name this rare ocular disorder "myotonia-like disorder of the pre-tarsal and pre-septal parts of the orbicularis oculi". This study expands our knowledge of this rare clinical feature of MG and highlights the need for increased awareness of it and further investigation of this ocular manifestation.

Pre-morbid Laboratory Tests, Diseases, and Medications in Amyotrophic Lateral Sclerosis in Israel.

BACKGROUND: There is an unmet need for real-world data regarding laboratory results, co-morbidities, and medication use prior to the first symptoms of amyotrophic lateral sclerosis (ALS). Researchers must identify specific subpopulations at risk for developing ALS and understand pathogenic mechanisms preceding the clinical presentation of ALS as well as possible subclinical disease manifestations. OBJECTIVES: To valuate the role of laboratory results, co-morbidities, and medication use prior to the first symptoms of patients with ALS in Israel so that specific subpopulations at risk for developing ALS can be identified and for possible subclinical disease manifestations. To understand pathogenic mechanisms preceding the clinical presentation of ALS. METHODS: At the ALS clinic at Tel Aviv Sourasky Medical Center, 259 ALS patients insured by Maccabi Healthcare Services and seen between January 1998 and December 2017 were included. Comparisons of demographics, co-morbidities, medications taken, history of trauma, and laboratory tests prior to disease onset were performed between patients and 1295 matched controls. RESULTS: Prior to disease presentation, ALS patients had a higher frequency of hypertension and cardiovascular disease; presented more frequently with trauma and viral infections; more frequently used analgesics, non-steroidal anti-inflammatory drugs, narcotics, antibiotics, and antiviral medications; and had higher creatine kinase levels. CONCLUSIONS: ALS patients showed higher frequency of cardiovascular disease prior to diagnosis, as well as higher frequency of trauma, infections, and pain medication usage.

Systematic Comparison of Muscle Ultrasound Thickness in Polyneuropathies and Other Neuromuscular Diseases.

BACKGROUND: We have aimed to assess whether muscle thickness ultrasound (US) shows differences between patients with chronic inflammatory demyelinating polyneuropathy (CIDP), chronic axonal polyneuropathy (CAP), and other neuromuscular (NM) diseases compared to controls and to each other. METHODS: We performed a cross-sectional study from September 2021 to June 2022. All subjects underwent quantitative sonographic evaluation of muscle thickness in eight relaxed muscles and four contracted muscles. Differences were assessed using multivariable linear regression, correcting for age and body mass index (BMI). RESULTS: The study cohort consisted of 65 healthy controls, and 95 patients: 31 with CIDP, 34 with CAP, and 30 with other NM diseases. Both relaxed and contracted muscle thickness in all patient groups were lower than in the healthy controls, after controlling for age and body mass index (BMI). Regression confirmed that the differences persisted between patient groups and healthy controls. Differences between patient groups were not apparent. CONCLUSION: The current study shows that muscle ultrasound thickness is not specific in NM disorders, but shows a global reduction in thickness compared with healthy controls after corrections for age and BMI.

The Sensitivity and Specificity of Split-Hand Index Using Muscle Sonography.

BACKGROUND: The split-hand index (SHI) (first dorsal interosseous (FDI) × abductor pollicis brevis (APB)/abductor digiti minimi muscle (ADM)) has been suggested as a useful measure for amyotrophic lateral sclerosis (ALS) diagnosis, using electrophysiological and sonographic indices. In the present study, we aimed to explore the specificity of SHI derived by muscle ultrasound (MUS) for the diagnosis of ALS and spinal muscular atrophy (SMA). METHODS: Healthy controls (n = 65) were prospectively recruited at the Prosserman Family Neuromuscular clinic at Toronto General Hospital, from October to December 2018. In addition, 181 patients with ALS (n = 91), SMA (n = 33), polyneuropathy (n = 35), and myopathy (n = 22) were prospectively recruited at the neuromuscular clinic at Tel Aviv Sourasky Medical Center, from December 2018 to December 2020. All subjects underwent quantitative sonographic evaluation of muscle thickness, including the right APB, FDI, and ADM muscles. Area under curve (AUC), sensitivity, and specificity were determined for differentiating between groups. RESULTS: Although SHI showed good to excellent accuracy for differentiating each patient subgroup from controls (AUC 0.83-0.92), poorer diagnostic accuracy was shown for differentiating between different patient subgroups (AUC 0.54-0.74). CONCLUSIONS: Sonographic SHI is useful for differentiating patients from healthy controls, but might be not specific for motor neuron disease.

The Sensitivity of Quantitative Sonographic Assessment of Muscle Thickness for Amyotrophic Lateral Sclerosis Diagnosis.

PURPOSE: In the current proof-of-concept study, we aimed to examine the sensitivities and specificities of previously reported normal values for muscle ultrasound thickness in amyotrophic lateral sclerosis. METHODS: Muscle ultrasound was performed in 65 healthy control subjects and 91 amyotrophic lateral sclerosis patients using a standardized assessment of eight relaxed muscles and four contracted muscles. Normal values for muscle thickness were determined as values above the 5th percentile stratified by age and gender using the weighted average method. Sensitivity for amyotrophic lateral sclerosis diagnosis was determined for muscles with and without the addition of muscle contraction. RESULTS: Amyotrophic lateral sclerosis patients showed reduced muscle sum thickness both in relaxed and in contracted states compared with control subjects. Muscle ultrasound of muscles with and without contraction showed excellent diagnostic accuracy for differentiating amyotrophic lateral sclerosis patients from control subjects (area under curve = 0.96, sensitivity: 93%-95%, specificity: 84-87). Muscle ultrasound sensitivity was lower within 6 months of symptom onset (83%) compared with longer disease duration (>92%). CONCLUSIONS: Quantitative sonographic assessment of muscle thickness can be complementary in the diagnosis of amyotrophic lateral sclerosis with excellent accuracy for differentiating patients from healthy subjects, and might be useful in other neuromuscular disorders, although additional studies are required.

Longer-term follow-up of nusinersen efficacy and safety in adult patients with spinal muscular atrophy types 2 and 3.

The effectiveness of nusinersen treatment in patients with spinal muscular atrophy (SMA) was established in clinical trials only for pediatric patients. Few cohort studies confirmed its benefit in adults up to 22 months of treatment. We report a longer-term observation of nusinersen treatment effects and safety in a large cohort of adult patients. Patients with SMA type 2 and 3 treated with nusinersen at Tel-Aviv Medical Center between March 2018 and September 2020 were prospectively recruited. Neurological impairment, motor, respiratory function, and side effects were recorded. We compared baseline measurements with those after 6, 14, and 26 months of treatment and calculated the annual rates of change. Overall, 37 patients were treated (21-64 years old). 16 completed 26 months, and 8 completed 30 months of treatment. The median score on the Medical Research Council strength scale increased from baseline to visits at 6 and 14 months (p ≤ 0.03), but not afterwards, with a median increase of 1.85 points per year. Revised Hammersmith Scale median score increased only from baseline to 6 months (p = 0.02), with a calculated annual rate of change of 0 points. No significant change was noticed in the respiratory function. The only side effect was post lumbar puncture headache. In conclusion, our study further supports the efficacy and safety of nusinersen treatment in adult patients with SMA2 and SMA3, with modest improvement in muscle strength, and stabilization of motor function over a relatively long period of observation.

Electrodiagnostic Assessment of Neuromuscular Junction Disorders.

Please verify edits, "These techniques", or specify. This article reviews advanced electrodiagnostic techniques used to assess for neuromuscular junction disorders, including repetitive nerve stimulation, conventional or concentric-needle single-fiber electromyography (SFEMG), and stimulated SFEMG. These techniques have high sensitivity but limited specificity. Novel methods currently under investigation are discussed, including vestibular ocular myogenic potential and oculography analysis.

The complex association between pain and neuropathy.

BACKGROUND: Several studies of patients with polyneuropathy failed to show differences between patients with and without pain. In the current study, we aimed to explore the association between neuropathic symptoms, mainly pain, and polyneuropathy characteristics. METHODS: A prospective cross-sectional study recruiting 151 patients with non-diabetic polyneuropathy was performed between November 2016 and May 2017. A total of 38 patients with chronic inflammatory demyelinating neuropathy were excluded. Patients underwent clinical, electrophysiological and functional assessments of their polyneuropathy. Polyneuropathy characteristics were compared depending on the presence and severity of neuropathic symptoms. RESULTS: The presence and the severity of weakness were associated with a more severe neuropathy as measured by clinical, electrophysiological and functional assessments, while the presence of pain was associated with higher sural amplitudes, and the severity of pain showed a curvilinear association with neuropathy severity. CONCLUSIONS: Our study shows a novel finding of a curvilinear association between pain and polyneuropathy severity.

Fasciculation frequency at the biceps brachii and brachialis muscles is associated with amyotrophic lateral sclerosis disease burden and activity.

INTRODUCTION: Fasciculations are most commonly seen in the biceps brachii muscle in amyotrophic lateral sclerosis (ALS). In this study we have explored the association between fasciculation frequency in a single location-biceps brachii and brachialis muscles (BB), and disease burden and activity. METHODS: Sonographic muscle studies were performed in 90 ALS patients, 47 of whom were seen in subsequent follow-up. The association between fasciculations frequency at the BB and ALS Functional Rating Scale-Revised (ALSFRS-R) and manual muscle testing (MMT) scores was determined. RESULTS: High fasciculation frequency at the BB, where detection rate was the highest, was associated with shorter disease duration, greater muscle thickness, higher MMT scores, and faster rate of decline in ALSFRS-R initially, and MMT subsequently. DISCUSSION: High fasciculation frequency at the BB as determined by sonography, is associated with less impairment at time of examination, and a more active disease with a more rapid progression.

Prospective study of stress, depression and personality in myasthenia gravis relapses.

BACKGROUND: Psychopathology and personality traits may influence the course of autoimmune disorders. With this prospective longitudinal cohort study, we aimed to assess personality, stress and depression in myasthenia patients who relapse and those who remain stable or improve (non-relapsers). METHOD: We collected data from 155 consecutive adult patients with confirmed MG attending the Neuromuscular Clinic, Toronto General Hospital, between March 2017 and July 2018, for this study. Patients were assessed at baseline and 6 months, or at the time of MG relapse. At both visits, the patients were assessed clinically and were asked to complete self-administered questionnaires for disease severity, chronic stress and depression. Personality type was assessed at baseline only. Relapsing patients were defined as those patients with MGII score increasing by more than 5.5 points from visit 1 to visit 2. RESULTS: Relapsers had higher baseline scores for depression (p = 0.01) and the change in disease severity correlated with the change in depression score (r = 0.2534, p = 0.0015, 95% CI: 0.098 0.3961). Higher levels of stress at baseline and neuroticism predicted higher relapse rates (p = 0.01 and p < .0001, respectively). In the linear regression model, with change of the MGII score as the dependent variable, change in depression scores (p = 0.0004) and age (p = 0.03) predicted change in disease severity. CONCLUSIONS: Since emotional factors and personality type may influence MG, attention to these factors might improve care in MG patients.

Split-hand phenomenon in motor neuron diseases: Sonographic assesment of muscle thickness.

OBJECTIVE: To explore the diagnostic accuracy of the split-hand index (SHI) for amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) using sonographic assessment of muscle thickness. METHODS: We performed a prospective sonographic assessment of hand muscle thickness in 59 controls, 87 patients with ALS, and 33 patients with SMA. We determined the diagnostic accuracy of SHI for differentiating patients with ALS and SMA from controls. RESULTS: Patients with ALS and SMA had significantly lower muscle thickness and SHI values compared with controls. SHI showed excellent diagnostic accuracy for differentiating ALS from controls, and good diagnostic accuracy for differentiating SMA from controls. CONCLUSIONS: SHI determined by sonographic measurement of hand muscle thickness seems to be a promising tool for the diagnosis of ALS and may be added easily when performing neuromuscular ultrasound. SIGNIFICANCE: SHI determined by sonographic measurement of hand muscle thickness can differentiate between healthy subjects and patients with ALS and SMA.

Superiority of sonographic evaluation of contracted versus relaxed muscle thickness in motor neuron diseases.

OBJECTIVE: To compare the correlations of relaxed and contracted limb muscle thickness with clinical scales in patients with amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). METHODS: Patients with ALS and SMA were prospectively recruited from December 2018 to November 2019. All patients underwent clinical assessment and sonographic muscle thickness measurement of eight relaxed muscles (biceps brachii, abductor pollicis brevis (APB), first dorsal interosseous, abductor digiti minimi, quadriceps, tibialis anterior, extensor digitorum brevis, and abductor hallucis brevis), and four contracted muscles (biceps brachii, APB, quadriceps, and tibialis anterior). RESULTS: 91 patients with ALS and 31 patients with SMA were recruited. Contracted muscle thickness compared to relaxed muscle showed higher reliability and similar or better correlations with muscle strength and clinical scales, especially in ALS patients with hyperreflexia. Strong to very strong correlations with clinical scales were observed with multivariate analysis of relaxed and contracted muscle thickness (0.64-0.87). CONCLUSIONS: Sonographic evaluation of contracted muscle thickness is an objective measure that correlates with disease burden. It is feasible, quick, valid and reliable, and may be superior to evaluation of relaxed muscles. SIGNIFICANCE: Sonographic evaluation of contracted muscle thickness is superior to evaluation of relaxed muscles.

The utility of a single simple question in the evaluation of patients with nondiabetic polyneuropathy.

INTRODUCTION: A single and simple question, namely "What percentage of normal (PoNL) do you feel regarding your disease?" is feasible and valid in myasthenia gravis. In this study, we aimed to determine the validity of this question in patients with nondiabetic polyneuropathy. METHODS: Clinical, electrophysiological, and functional and disability assessments were performed in 151 patients with nondiabetic polyneuropathy. One hundred forty patient answers were recorded for the PoNL question, and these were included in the current study. RESULTS: The PoNL correlated moderately with functional and disability scales. DISCUSSION: "What PoNL do you feel?" is a simple, quick, and valid question, which correlates moderately with functional and disability scales in nondiabetic polyneuropathy, and it may be incorporated in polyneuropathy assessment.

Quantitative sonographic evaluation of muscle thickness and fasciculation prevalence in healthy subjects.

BACKGROUND: In the current study, we aimed to determine normative values for muscle thickness and fasciculation prevalence in healthy subjects. METHODS: We performed a prospective study from October to December 2018 in 65 healthy subjects. All subjects underwent quantitative sonographic evaluation of muscle thickness and fasciculation prevalence in the following 8 muscles: Biceps brachii, abductor pollicis brevis, first dorsal interosseous, abductor digiti minimi, quadriceps, tibialis anterior, extensor digitorum brevis, and abductor hallucis brevis. RESULTS: Subject ages ranged from 21 to 82 years, with 63% women. Normative values for muscle thickness were determined using the fifth percentile. Multivariate regression analysis showed that sex, age, body mass index, and hand dominance affected muscle thickness. Fasciculations were observed frequently only in distal muscles. CONCLUSIONS: Normal values for muscle thickness were determined, and may enhance neuromuscular ultrasound sensitivity and serve as a basis for future studies. Larger series are needed to confirm these values.

Muscle thickness measured by ultrasound is reduced in neuromuscular disorders and correlates with clinical and electrophysiological findings.

INTRODUCTION: Nerve imaging has a limited role in axonal and muscle fiber loss. In this study, we sought to explore the utility of standardized muscle ultrasound (US) assessment in these clinical scenarios. METHODS: We performed a prospective study from March to August 2018 of patients attending the neuromuscular clinic. All patients underwent clinical evaluation and standardized muscle thickness measurement by US in seven muscles. RESULTS: The study cohort consisted of 114 participants, including patients with polyneuropathy, motor neuron disease, and myopathy. The smallest distal muscle thickness was found in patients with polyneuropathy, while the smallest proximal muscle thickness was found in patients with myopathy. Muscle thickness was strongly correlated with muscle strength (r 2 = 0.62), electrophysiological findings (r 2 : 0.44-0.55), and disability score (r 2 = 0.53). DISCUSSION: Standardized muscle thickness measured by US shows diagnostic usefulness in a spectrum of neuromuscular disorders and correlates with clinical and electrophysiological findings.

European Federation of Neurological Societies cutoff values significantly reduce creatine kinase sensitivity for diagnosing neuromuscular disorders.

INTRODUCTION: Elevated creatine kinase (CK) level was redefined by the European Federation of Neurological Societies)EFNS(as 1.5 times the upper limit of normal. In the current study we sought to determine the sensitivity and specificity of CK testing for the diagnosis of neuromuscular disorders. METHODS: Demographics and CK levels were retrospectively extracted from an electronic database for 234 patients with neuromuscular disorders. Sensitivity, specificity, and likelihood ratios and the area under curve were determined for each diagnosis and different cutoff CK values. RESULTS: Using the EFNS cutoff values significantly reduced CK test sensitivity. Creatine kinase values >1000 IU/L showed a high likelihood (11.04) for myopathies and a low likelihood for polyneuropathies (0). DISCUSSION: European Federation of Neurological Societies cutoff values significantly reduce CK sensitivity for diagnosing neuromuscular disorders. While low CK values cannot exclude a neuromuscular disease, values >1000 IU/L are associated with a high likelihood of myopathy.

Evidence of small-fiber neuropathy in neurofibromatosis type 1.

INTRODUCTION: Large-fiber neuropathy is rare in neurofibromatosis type 1, but small-fiber neuropathy has not been studied. METHODS: Patients with neurofibromatosis type 1 underwent nerve conduction studies for large-fiber assessment. Small-fiber tests included quantitative thermal thresholds, laser Doppler flare imaging, intraepidermal nerve fiber density, and corneal nerve fiber length. RESULTS: Of the 52 patients enrolled, 31 (60%) were female and the mean age was 33.0 ± 12.3 years. Four (8%) patients had abnormal nerve conduction studies. Small-fiber tests were frequently abnormal: thermal thresholds in 7 (13%); laser Doppler flare imaging in 10 (19%); intraepidermal nerve fiber density in 11 (22%); and corneal nerve fiber length in 27 (52%). The mean corneal nerve fiber length was below normative level (10.1 ± 2.7 mm/mm3 ). DISCUSSION: Small-fiber neuropathy may be common in neurofibromatosis type 1, and should be investigated in symptomatic patients.

Baseline Decrement in Patients with Mild Myasthenia Gravis Predicts Immunomodulation Treatment.

To explore whether higher degrees of electrophysiological abnormalities are associated with a more frequent exposure to a more aggressive treatment regimen, we performed a retrospective chart review of patients attending the neuromuscular clinic from June 2012 to December 2015 and included 87 patients. We compared treatment regimens during the follow-up period between patients with high and low jitter and decrement. Myasthenia gravis patients with high jitter or decrement at baseline were more frequently treated with intravenous immunoglobulins (IVIG) and/or plasma exchange (PLEX) during the follow-up period. In patients with mild disease, IVIG or PLEX treatment was associated with high decrement.

La diminution initiale du potentiel moteur de patients atteints de myasthénie grave peut permettre de prédire le type d'immuno-modulation thérapeutique prodiguée. Afin d'explorer dans quelle mesure des niveaux plus élevés d'anomalies électro-physiologiques peuvent être associés à une exposition davantage fréquente à des régimes de traitement plus vigoureux, nous avons effectué un examen rétrospectif des dossiers de patients, 87 au total, s'étant présentés à une clinique neuromusculaire de juin 2012 à décembre 2015. Nous avons alors comparé les régimes de traitement des patients montrant de basses mesures de gigue (jitter) et une faible diminution d'amplitude du potentiel d'action au cours de leur période de suivi avec les régimes de traitement d'autres patients pour qui ces mesures étaient élevées. Les patients atteints de myasthénie grave (MG) dont les mesures de gigue et la diminution d'amplitude du potentiel d'action étaient initialement élevées ont été plus fréquemment traités, lors d'un suivi, avec des immunoglobulines intraveineuses et/ou des échanges plasmatiques. Chez les patients atteints de la forme bénigne de cette maladie, ces deux traitements ont été associés à une diminution d'amplitude du potentiel d'action plus élevée.

Rare homozygosity in amyotrophic lateral sclerosis suggests the contribution of recessive variants to disease genetics.

OBJECTIVE: to determine the occurrence of homozygous rare, in-silico damaging variants in a genetically relatively homogenous group of amyotrophic lateral sclerosis (ALS) patients. METHODS: Whole-exome-sequencing of 43 ALS patients of North-Africa Jewish origin was performed. Data were filtered to identify very rare homozygous recessive in-silico damaging variants, in genes annotated to ALS-associated cellular pathways. RESULTS: We identified a rare missense homozygous variant, p.Arg663Cys in MFN2, predicted to be damaging, in a patient with an early age at disease onset (36 years) and fast progression. An additional ALS patient carried the mutation and together established its association to ALS (p = .01). Additional homozygous variants were identified, including the risk allele p.Arg261His in NEK1, as well as variants in genes known to be associated with other neurodegenerative diseases, such as HTT (Huntington's disease), ATM (Ataxia-Telangiectasia), and ZFYVE26 (SPG15), and variants in genes previously reported as upregulated (LZTS3) or downregulated (ARMC4, CFAP54, and MTHFSD) in ALS patients. Altogether, 13 patients (30%) carried at least one homozygous rare in-silico damaging variant, of them 10 carried either another rare homozygous variant and/or a variant in a known ALS gene, which is categorized as pathogenic, likely-pathogenic or variant of uncertain significance. CONCLUSIONS: Our results suggest the contribution of recessive alleles to ALS and the possibility of burden of mutations, emphasizing the complexity of ALS genetics.