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1.
Isr Med Assoc J ; 25(9): 617-621, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37698313

ABSTRACT

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.


Subject(s)
Amyotrophic Lateral Sclerosis , Cardiovascular Diseases , Humans , Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/epidemiology , Israel/epidemiology , Morbidity , Antiviral Agents
2.
PLoS One ; 18(9): e0292123, 2023.
Article in English | MEDLINE | ID: mdl-37768998

ABSTRACT

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.


Subject(s)
Amyotrophic Lateral Sclerosis , Muscular Diseases , Neuromuscular Diseases , Polyneuropathies , Humans , Fasciculation/diagnostic imaging , Muscle, Skeletal/diagnostic imaging , Amyotrophic Lateral Sclerosis/diagnostic imaging , Electromyography , Neuromuscular Diseases/diagnostic imaging , Ultrasonography , Polyneuropathies/diagnostic imaging
3.
Can J Neurol Sci ; 50(2): 228-233, 2023 03.
Article in English | MEDLINE | ID: mdl-35190003

ABSTRACT

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.


Subject(s)
Amyotrophic Lateral Sclerosis , Humans , Amyotrophic Lateral Sclerosis/diagnostic imaging , Muscle, Skeletal/diagnostic imaging , Sensitivity and Specificity , Ultrasonography
4.
J Clin Neurophysiol ; 40(6): 529-534, 2023 Sep 01.
Article in English | MEDLINE | ID: mdl-35066529

ABSTRACT

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.


Subject(s)
Amyotrophic Lateral Sclerosis , Humans , Amyotrophic Lateral Sclerosis/diagnostic imaging , Muscle, Skeletal/diagnostic imaging , Sensitivity and Specificity , Diagnosis, Differential , Ultrasonography/methods
5.
Neuromuscul Disord ; 32(6): 451-459, 2022 06.
Article in English | MEDLINE | ID: mdl-35527201

ABSTRACT

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.


Subject(s)
Muscular Atrophy, Spinal , Spinal Muscular Atrophies of Childhood , Adult , Child , Follow-Up Studies , Humans , Middle Aged , Muscular Atrophy, Spinal/drug therapy , Oligonucleotides/adverse effects , Spinal Muscular Atrophies of Childhood/drug therapy , Young Adult
6.
J Neuroimmunol ; 358: 577635, 2021 09 15.
Article in English | MEDLINE | ID: mdl-34217018

ABSTRACT

Background Paraneoplastic motor neuron disease (PMND) is a rare, non-classical form of paraneoplastic neurological syndrome (PNS). Anti-Hu and anti-CV2/CRMP5 PNS are mostly associated with small-cell lung cancer (SCLC) and consist of highly variable clinical syndromes, including sensory neuronopathy, cerebellar ataxia and/or limbic encephalitis. However, substantial motor impairment is uncommon, particularly when no sensory dysfunction co-exists. Case A 72-year-old man with a recent diagnosis of amyotrophic lateral sclerosis (ALS) was referred to our department of neurology for evaluation. The patient sub-acutely developed progressive neurological dysfunction including erectile dysfunction, behavioral changes, limb weakness, dysphagia, anorexia, as well as worsening stridor that necessitated tracheostomy due to bilateral vocal cord paralysis (BVCP). Neurological examination revealed motor weakness of upper and lower motor neuron origin with autonomic and cognitive dysfunction. Cerebrospinal fluid (CSF) analysis demonstrated pleocytosis, elevated protein, presence of oligoclonal bands (OCB), and neuronal antibody testing was positive for anti-Hu and anti-CV2/CRMP5. Based on these findings a diagnosis of a PNS was made. Evaluation for malignancy was negative, and immunosuppressive/immunomodulatory treatment was initiated but had little effect during fifteen months of follow-up. Conclusions Although PMND is very rare, in an atypical presentation, especially with features that are not usually present in ALS such as autonomic dysfunction, sensory disturbance or cognitive decline, this etiology should be in the differential diagnosis.


Subject(s)
Amyotrophic Lateral Sclerosis/cerebrospinal fluid , Amyotrophic Lateral Sclerosis/diagnosis , Diagnostic Errors , Paraneoplastic Syndromes, Nervous System/cerebrospinal fluid , Paraneoplastic Syndromes, Nervous System/diagnosis , Aged , Amyotrophic Lateral Sclerosis/blood , Humans , Male , Paraneoplastic Syndromes, Nervous System/blood
7.
Muscle Nerve ; 63(2): 204-208, 2021 02.
Article in English | MEDLINE | ID: mdl-33216387

ABSTRACT

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.


Subject(s)
Amyotrophic Lateral Sclerosis/diagnostic imaging , Fasciculation/diagnostic imaging , Muscle, Skeletal/diagnostic imaging , Aged , Amyotrophic Lateral Sclerosis/physiopathology , Arm , Disease Progression , Fasciculation/physiopathology , Female , Hand , Humans , Male , Middle Aged , Muscle Strength , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Organ Size , Quadriceps Muscle/diagnostic imaging , Quadriceps Muscle/pathology , Quadriceps Muscle/physiopathology , Severity of Illness Index , Time Factors , Ultrasonography
8.
Clin Neurophysiol ; 131(8): 1721-1725, 2020 08.
Article in English | MEDLINE | ID: mdl-32504931

ABSTRACT

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.


Subject(s)
Amyotrophic Lateral Sclerosis/diagnostic imaging , Hand/diagnostic imaging , Muscle, Skeletal/diagnostic imaging , Muscular Atrophy, Spinal/diagnostic imaging , Ultrasonography , Adult , Aged , Female , Humans , Male , Middle Aged , Prospective Studies , Sensitivity and Specificity
9.
Clin Neurophysiol ; 131(7): 1480-1486, 2020 07.
Article in English | MEDLINE | ID: mdl-32387966

ABSTRACT

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.


Subject(s)
Amyotrophic Lateral Sclerosis/diagnostic imaging , Muscle Contraction , Muscular Atrophy, Spinal/diagnostic imaging , Ultrasonography/methods , Adult , Female , Humans , Male , Middle Aged , Muscle Relaxation , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/physiopathology , Sensitivity and Specificity , Ultrasonography/standards
10.
Article in English | MEDLINE | ID: mdl-32253937

ABSTRACT

Objective: To identify the genetic background of ALS segregating in a large Bedouin family in Israel. Methods: Exome sequencing was carried out on three siblings in a family segregating ALS, two affected and one without neurological symptoms. Filtering for causative variants and for modifiers was carried out. Eight variants were confirmed by Sanger sequencing and genotyped on nine available members of the family (three affected and six unaffected). Results: We report the identification of a novel mutation in TARDBP, p.Ala321Asp, segregating in the family. The patients are affected with early onset (average age 34.5, 21-43 years old) and fast progressive disease. The mutation is in exon 6, in the glycin-rich domain, and is predicted to be deleterious. Additional rare, potentially deleterious variants were observed in the three patients, only one of them, PLEKHG5-Phe538Leu, which is located 4.5 Mb upstream to the TARDBP, was also fully segregating in the family. Conclusion: We identified a novel mutation in TARDBP which segregates with the disease in a large family. Additional rare variants were identified, and the combination of next-generation-sequencing together with linkage analysis was optimal to identify causality and modification, emphasizing the importance of combining the two analyses. Burden of deleterious variants may be associated with early age at onset.


Subject(s)
Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/genetics , Arabs/genetics , DNA-Binding Proteins/genetics , Disease Progression , Mutation/genetics , Adult , Age of Onset , Female , Genetic Variation/genetics , Humans , Male , Middle Aged , Pedigree , Time Factors , Young Adult
11.
Muscle Nerve ; 61(2): 234-238, 2020 02.
Article in English | MEDLINE | ID: mdl-31725905

ABSTRACT

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.


Subject(s)
Fasciculation/diagnostic imaging , Fasciculation/epidemiology , Muscle, Skeletal/diagnostic imaging , Adult , Aged , Aged, 80 and over , Electromyography , Female , Hamstring Muscles/diagnostic imaging , Healthy Volunteers , Humans , Male , Middle Aged , Prevalence , Prospective Studies , Reference Values , Ultrasonography , Young Adult
12.
Muscle Nerve ; 60(6): 687-692, 2019 12.
Article in English | MEDLINE | ID: mdl-31478199

ABSTRACT

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.


Subject(s)
Muscle, Skeletal/diagnostic imaging , Neuromuscular Diseases/diagnostic imaging , Action Potentials/physiology , Adult , Aged , Amyotrophic Lateral Sclerosis/diagnostic imaging , Amyotrophic Lateral Sclerosis/pathology , Amyotrophic Lateral Sclerosis/physiopathology , Electromyography , Female , Humans , Male , Medically Unexplained Symptoms , Middle Aged , Muscle Strength , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Muscular Atrophy, Spinal/diagnostic imaging , Muscular Atrophy, Spinal/pathology , Muscular Atrophy, Spinal/physiopathology , Muscular Diseases/diagnostic imaging , Muscular Diseases/pathology , Muscular Diseases/physiopathology , Neural Conduction/physiology , Neuromuscular Diseases/pathology , Neuromuscular Diseases/physiopathology , Organ Size , Polyneuropathies/diagnostic imaging , Polyneuropathies/pathology , Polyneuropathies/physiopathology , Prospective Studies , Radiculopathy/diagnostic imaging , Radiculopathy/pathology , Radiculopathy/physiopathology , Ultrasonography
13.
J Neurol Sci ; 402: 62-68, 2019 Jul 15.
Article in English | MEDLINE | ID: mdl-31108397

ABSTRACT

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.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Genetic Predisposition to Disease , Homozygote , Mutation , Adult , Age of Onset , Disease Progression , Female , GTP Phosphohydrolases/genetics , Genetic Association Studies , Genotype , Humans , Male , Middle Aged , Mitochondrial Proteins/genetics , Exome Sequencing
14.
Article in English | MEDLINE | ID: mdl-30784320

ABSTRACT

Introduction: Treatment with edaravone has shown efficacy in a subgroup of patients with amyotrophic lateral sclerosis (ALS). However, it has been estimated that <7% of ALS patients fulfill the stringent inclusion criteria of the trial. In the current study, we aimed to explore retrospectively the efficacy of edaravone in unselected ALS patients. Methods: Demographic and clinical data were retrospectively collected for 22 patients who opted for treatment with edaravone and 71 untreated ALS patients attending the ALS clinic at Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, between May 2017 and January 2018. Clinical data were extracted for a baseline visit at treatment onset, and for pre-baseline and post-baseline visits, roughly 6 months apart from the baseline visit. Results: Baseline demographic and clinical characteristics were similar between edaravone treated and untreated patients, except for shorter disease duration in edaravone treated patients. Muscle strength, ALS Functional rating scale (ALSFRS-R), and respiratory function were similar between edaravone treated and untreated patients, including monthly rate of decline before and after baseline visit. Among treated patients, 7 had major respiratory complications occurring between 8 days to 7 months after treatment initiation, during or within hours following infusions. Discussion: Results of our study comparing edaravone treated and untreated patients in a real-life setting showed no differences in the rate of monthly decline of ALSFRS-R, in line with previous reports in ALS patients not treated with edaravone, and a previous clinical trial. Our findings might suggest that edaravone is not effective in unselected ALS patients.


Subject(s)
Amyotrophic Lateral Sclerosis/drug therapy , Edaravone/therapeutic use , Neuroprotective Agents/therapeutic use , Aged , Cohort Studies , Disease Progression , Female , Humans , Male , Middle Aged , Muscle Strength , Product Surveillance, Postmarketing , Respiration Disorders/etiology , Respiration Disorders/physiopathology , Respiratory Function Tests , Retrospective Studies , Socioeconomic Factors , Treatment Outcome
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