Towards a practical use of text mining approaches in electrodiagnostic data

Objective:To determine if inflammation in proximity of the motor unit may contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS). Methods: We identified all patients diagnosed in Sweden with concurrent ALS and multiple sclerosis (MS), myasthenia gravis (MG), inflammatory polyneuropathies (IP), or dermatopolymyositis (DMPM) during 1991–2014 according to the Swedish Patient Register (N = 263). We validated medical records for 92% of these patients (18 records were not retrieved and three did not contain enough information) and compared patients with a confirmed overlap (N = 28) with an independent sample of patients with solely ALS (N = 271). Results: Ninety-one patients were deemed as not having ALS (34.6%). Among the remaining 151 with validated ALS, 12 had also a confirmed MS diagnosis, nine a confirmed MG diagnosis, four a confirmed IP diagnosis, and three a confirmed DMPM diagnosis. Seventeen of the patients were women and 11 were men. Seventy-nine percent of the patients with a confirmed overlap had MS, MG, IP, or DMPM diagnosed prior to ALS. Compared to patients with only ALS, the concurrent patients were significantly older at symptoms onset, had higher prevalence of bulbar onset, but used Riluzole and noninvasive ventilation less frequently. Conclusions: We found that a high concurrence of ALS and MS/MG/IP/DMPM diagnoses is largely due to diagnostic uncertainty. A minority of patients had a true concurrence, where MS, MG, IP, and DMPM preceded the ALS diagnosis, which might be due to chance alone. Four patients were diagnosed with MG shortly after onset of ALS, suggesting that neurodegeneration might trigger autoimmunity.

Unusual association of amyotrophic lateral sclerosis and myasthenia gravis: A dysregulation of the adaptive immune system?

The article provides a brief overview of current knowledge about the key mechanisms of pathogenesis, clinical manifestations, and approaches to the treatment of two neuromuscular pathologies: myasthenia gravis and amyotrophic lateral sclerosis. Myasthenia gravis is a chronic autoimmune disease in which the structures of the neuromuscular junction are affected. The clinical picture has a wide heterogeneity, a variety of its phenotypic variants, and symptoms range from local to generalized forms. However, the key is pathological muscle weakness and fatigue. Amyotrophic lateral sclerosis is a neurodegenerative, steadily progressive disease characterized by the death of motor motor neurons in the brain and spinal cord. This pathology is manifested by the development of muscle weakness, atrophy, severe bulbar disorders with increasing respiratory and nutritional insufficiency. The clinical case of a 60‑year-old patient with myasthenia gravis, which transformed into amyotrophic lateral sclerosis, is presented. The diagnosis is confirmed by the presence of diagnostic criteria corresponding to myasthenia gravis at the onset of the disease, their subsequent regression upon the appearance of the first symptoms of amyotrophic lateral sclerosis. Subsequently, the patient experienced a steady progression of symptoms with an increase in bulbar disorders to anarthria, severe dysphagia while taking anticholinesterase drugs and glucocorticosteroids, which required the installation of a gastrostomy. The article also provides a literature review of the frequency of occurrence, the period of development of the transformation of one disease into another both in Russia and in foreign countries. The modern understanding of the pathogenesis of this phenomenon is considered, which is associated with common immunological mechanisms and changes in the structures of the neuromuscular junction.

Camptocormia is a marked anterior curvature of the thoracolumbar spine that may be caused by parkinsonism, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG) and muscle disease. The interest of a systematic muscle biopsy has not been evaluated until now. In our study, the aim was to prospectively evaluate the proportion of patients with isolated camptocormia without ALS, MG and parkinsonism who have an underlying myopathy. Twenty consecutive patients (75% female, mean age 70 years) with isolated camptocormia were enrolled in a single centre in this 5-year prospective study. ALS, MG and parkinsonism had been excluded in all cases. A left deltoid muscle biopsy was performed in all patients and processed with standard techniques for histology and immunohistochemistry. Additional biochemical and genetic studies were performed when pathological analysis was consistent with myopathy. A myopathy was identified in seven patients (35%). Three patients presented with mitochondrial myopathy, including two patients harbouring a heterozygous POLG gene pathogenic variant and one patient with a heterozygous RRM2B gene pathogenic variant. Two patients presented with an inflammatory myopathy, including one with anti-PM/Scl antibodies. One patient presented with facioscapulohumeral muscular dystrophy and one patient with an MYH7 gene-related myofibrillar myopathy. No obvious myopathy was found in the 13 remaining cases. In this prospective study, an underlying myopathy was found in 35% of patients with isolated camptocormia. These results suggest that a muscle biopsy should be systematically performed in patients with isolated camptocormia when ALS, MG and parkinsonism have been excluded.

The speed of completion of the decremental responses on repetitive nerve stimulation

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition producing symptoms of varying severity depending on the extent and progression of the disease pathology most importantly respiratory insufficiency and pulmonary complications. Myasthenia gravis (MG) on the other hand is an autoimmune condition due to the pathology involving failure of neuromuscular transmission causing muscle weakness exacerbated by activity and involvement of the respiratory muscles leading to respiratory failure. Overlap syndrome is a condition wherein both motor neuron disease (MND) and MG are present in the same patient. The safety of using muscle-relaxing agents in patients with MG undergoing major surgical procedures has so far been assessed as insufficient. There have been many concerns regarding anesthetic management in relation to complications with respiratory function in patients with ALS, with regional anesthesia being considered slightly safer. An 81-year-old female presented with a closed injury to her left hip, and she was diagnosed to have a left neck of femur fracture. She was also a known case of bulbar MND with an overlap syndrome of MG. She was hypertensive and controlled with regular medication. She was planned for a left hip bipolar arthroplasty. Anesthetic requirements and management of these patients require a high degree of expertise and anesthesia in patients undergoing surgery is prone to more complications and mortality. In addition, as the patient had an overlap of both MG and MND, more meticulous assessment and management strategies were necessary. The importance and purpose of this study are to highlight a case of overlap syndrome of MND and MG patients who sustained a left neck femur fracture and underwent bipolar arthroplasty highlighting the anesthetic considerations in the patient for the procedure. We concluded that the choice of mode of anesthesia needs to be individualized based on each patient's requirements after careful analysis of the risk-benefit ratio of general versus regional. Regional anesthesia was successfully administered for this patient.

The presence of anti-acetylcholine receptor antibody should alert clinicians not just to the possibility of myasthenia gravis but to other motor neurone diseases. Spinal muscular atrophy (SMA) is a form of neurodegenerative disorder affecting the anterior horn neuron of the spinal cord due to an abnormality such as in a telomeric survival motor neuron gene (SMN) [6]. We present here a case of SMA type 1 with an increase in the level of anti-acetylcholine receptor antibody (A-AchR-Ab) which is a specific marker for myasthenia gravis (MG) [5]. The patient was born following a normal pregnancy and delivery. His parents were non-consanguineous and the family history was negative. Impairment of his ability of rolling and head control was evident at around 6 months of age and he could not sit unsupported. On examination at 1 year of age, he had marked muscular atrophy in his upper and lower extremities. He could not keep the position of his arms and legs against gravity. His myotactic reflexes of the triceps, biceps and brachioradialis muscles, knees and ankles were absent. Sensation, cognate and speech abilities were normal. Laboratory findings including the serum creatine kinase level (68 IU/l) were within the appropriate reference ranges. Brain and spinal MRI did not show any abnormality. The muscle conductivity velocities of his legs were within normal limits. An increase in the serum A-AchR-Ab level was observed (binding radioimmunoassay using bungarotoxin: 1st 1.0 nmol/l, 2nd 1.0 nmol/l, 3rd 0.9 nmol/l, and 4th 1.22 nmol/l; normal <0.2 nmol/l). Antinuclear antibody and anti-striated muscle antibody were negative. Clinical investigations could not reveal any positive findings related to MG including thymoma or a decremental response in stimulated EMG. Our patient did not receive snake venom or immunoglobulin therapy before examination. He was diagnosed as having SMA type 1 based on clinical criteria [6]. The presence of a homozygous genetic deletion in exons 7 and 8 of the SMN gene and the absence of a deletion in the NAIP gene were confirmed by PCR analysis [6]. A muscle biopsy has not yet been performed. A-AchR-Ab is a highly specific marker for MG with a diagnostic value, but an increase in the A-AchR-Ab level has been reported in patients with motor neuron diseases such as amyotrophic lateral sclerosis (ALS) (Table 1) [1, 2, 3, 4]. In the 19 reported cases, there was only one patient who had MG simultaneously with motor neuron disease. In the other patients, ten had experienced snake venom injection before analysis and they had relatively high A-AchR-Ab titres. The increase in the A-AchR-Ab level after a neurotoxin therapy is assumed to be a reaction against snake venom. Although some of the other patients had thyroid abnormalities with immunological disorders [2], our patient did not have any evidence of MG, thyroid abnormality, or other immunological disorders. The genetic cause of SMA is distinct from that of ALS or other motor neuron diseases, but histological changes such as neuromuscular junction degeneration are similar [6]. The presence of A-AchR-Ab in motor neuron diseases might be an auto-immune reaction against a degenerative acetylcholine receptor at the neuromuscular junction [3]. Clinicians should be aware of the possibilities of the presence of A-AchR-Ab in motor neuron diseases for precise diagnosis or for appropriate therapeutic approaches [6]. Eur J Pediatr (2002) 161: 293–294 DOI 10.1007/s00431-002-0937-5

Objective: To assess the added prognostic value of the aggregated clinical and electrodiagnostic data, which define a given diagnostic category according to the Awaji or revised El Escorial criteria at time of diagnosis in patients with amyotrophic lateral sclerosis (ALS). Methods: Clinical signs and electrodiagnostic test results were collected at time of diagnosis in 396 patients with ALS between January 2009 and January 2016. Significant predictors of prognosis were identified using a univariate model, and later combined in a multivariate Cox regression model. Results: Known factors associated with reduced survival included older age at onset, shorter diagnostic delay, higher ALSFRS-R slope and presence of C9orf72 mutation (all p < 0.05). Diagnostic category according to Awaji (p < 0.0001) or to revised El Escorial (p = 0.0177) criteria, definite ALS according to Awaji (p < 0.0001) or to revised El Escorial (p = 0.0343) and number of regions with LMN involvement (p < 0.0001) were all associated with shorter survival. Discussion: Clinical and electrodiagnostic data at time of diagnosis provide additional prognostic information compared to other known prognostic factors. Diagnostic category according to Awaji and the extensiveness of LMN involvement contain the most additional value.

A 1.5-year-old female entire French bulldog was referred for neurological evaluation, further diagnostic tests, and treatment 24 h after a road traffic accident. Initial emergency treatment, diagnostic tests, and stabilization had been performed by the referring veterinarian. Neurological examination revealed severe spastic non-ambulatory tetraparesis and was consistent with a C1-5 myelopathy. A magnetic resonance imaging (MRI) study revealed an irregular to elongated ovoid intramedullary lesion centered over the body of C2. The lesion showed marked signal heterogeneity with a central T2W and T2* hyperintense region, surrounded by a hypointense rim on both sequences. The lesion appeared heterogeneously T1W hypointense. The lesion was asymmetric (right-sided), affecting both white and gray matter. The C2-3 intervertebral disk appeared moderately degenerate with a Pfirrmann grade of 3. No evidence of vertebral fracture or luxation was found on radiographs or MRI of the vertebral column. Additional soft tissue abnormalities in the area of the right brachial plexus were suggestive of brachial plexus and muscle injury. A diagnosis of traumatic hemorrhagic myelopathy at the level of C2 and concurrent brachial plexus injury was formed. Conservative treatment was elected and consisted of physiotherapy, bladder care with an indwelling urinary catheter, repeated IV methadone based on pain scoring (0.2 mg/kg), oral meloxicam 0.1 mg/kg q24h, and oral gabapentin 10 mg/kg q8h. The dog was discharged after 4 days, with an indwelling urinary catheter and oral medication as described. The catheter was replaced two times by the referring veterinarian and finally removed after 10 days. Thereafter, voluntary urination was seen. During the 2 months after the road traffic accident, slow recovery of motor function was seen. The right thoracic limb recovery progressed more slowly than the left limb, also showing some lower motor neuron signs during follow-up. This was judged to be consistent with a right-sided brachial plexus injury. The dog was reported ambulatory with mild residual ataxia and residual monoparesis of the right thoracic limb at the last follow-up 3 months post-injury. This case report highlights the MRI-based diagnosis of traumatic hemorrhagic myelopathy in a dog. A fair short-term outcome was achieved with conservative treatment in this case.

Objective: To identify differences in demographics, disease characteristics, treatments, and co-morbidities between patients with “amyotrophic lateral sclerosis (ALS) reversals” and those with typically progressive ALS. Methods: Cases of possible ALS reversals were found in prior publications, in the Duke ALS clinic, through self-referral or referral from other Neurologists, and on the internet. Of 89 possible reversals identified, 36 cases were included because chart or literature review confirmed their diagnosis and a robust, sustained improvement in at least one objective measure. Controls were participants in the Pooled Resource Open-Access ALS Clinical Trials database and the National ALS Registry. Cases and controls were compared using descriptive statistics. Results: ALS reversals were more likely to be male, have limb onset disease, and initially progress faster. The prevalences of myasthenia gravis (MG) and purely lower motor neuron disease in cases were higher than estimates of these prevalences in the general population. The odds of taking curcumin, luteolin, cannabidiol, azathioprine, copper, glutathione, vitamin D, and fish oil were greater for cases than controls. Conclusions: When compared to patients with typically progressive ALS, patients with reversals differed in their demographics, disease characteristics, and treatments. While some of these patients may have had a rare antibody-mediated ALS mimicker, such as atypical myasthenia gravis, details of their exams, EMGs and family histories argue that this was unlikely. Instead, our data suggest that ALS reversals warrant evaluation for mechanisms of disease resistance and that treatments associated with multiple ALS reversals deserve further study.

BackgroundRare diseases present a substantial patient burden, but the impact on non-professional caregivers is poorly understood. We explored the health-related quality of life (HRQoL) and productivity burden on caregivers of adults with rare diseases.MethodsWe analysed physician- and caregiver-reported real-world data from France, Germany, Italy, Spain, the United Kingdom, and the United States of America collected July 2017–March 2021 via Adelphi Disease Specific Programmes™ in amyotrophic lateral sclerosis (ALS), eosinophilic esophagitis (EoE), graft versus host disease (GvHD), Huntington’s disease (HD), myasthenia gravis (MG), and progressive supranuclear palsy (PSP). Non-professional caregivers completed the EQ-5D-5L and Work Productivity and Activity Impairment questionnaire. Multivariate regression analysis modelled the relationship of care recipient/caregiver characteristics with caregiver HRQoL and productivity.ResultsData were provided by 365 caregivers; 114, 89, 75, 32, 29 and 26 in GvHD, PSP, ALS, MG, EoE and HD, respectively. Care recipients’ mean (standard deviation [SD]) age was 58.7 (15.6) years, 59% were male and 23% had both professional and non-professional caregivers. Patients’ mean (SD) EuroQol visual analogue scale (EQ VAS) score was 50.9 (23.3) and mean EQ-5D utility was 0.460 (0.350). Caregivers’ mean age was 55.8 (13.8) years, 66% were female. Caregivers’ EQ-5D-5L indicated their greatest problems in anxiety/depression. Overall, 45% of caregivers were employed, mostly part-time. In the past 7 days, mean (SD) caregiver absenteeism was 5.2% (13.1%), presenteeism was 28.0% (23.7%), and activity impairment was 43.1% (27.2%). Regressions identified multiple significant associations with caregivers’ HRQoL and productivity. Caregivers’ HRQoL (EQ-5D utility and EQ VAS) was associated with care recipients’ EQ-5D utility and caregivers’ age. Outcomes relating to caregivers’ employment and productivity (hours spent caring, employment status, hours in employment, hours of employment missed, absenteeism, presenteeism, work impairment and activity impairment) were most frequently associated with care recipients’ EQ-5D utility, caregivers’ age and sex, caregiver living with the care recipient, the presence of a professional caregiver, and the care recipient having HD.ConclusionsThe substantial burden of providing non-professional caregiving to adults with rare diseases is associated with multiple factors. Interventions improving care recipient HRQoL could enhance caregiver HRQoL and productivity.

Chapter 16 - Motor unit and peripheral nervous system disorders

Introduction: Even though neuromuscular diseases are not the first association in the elderly, the results of previous epidemiological studies record an increase in the incidence of acquired immune-mediated neuropathies, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), inflammatory myopathies (IM) and inclusion body myositis (IBM). Bearing that in mind, this study aims to review neuromuscular diseases in people over 65 years of age. Discussion: In the population of elderly people, there is a significant increase in the incidence of ALS, with the peak of the disease between the ages of 70 and 80. Myasthenia gravis (MG) represents a heterogeneous group of diseases whose common features is weakness and excessive fatigue of skeletal muscles during prolonged or repeated activity. It is known to have two peaks. The first peak is recorded between the ages of 20 and 29, with more frequent disease in women, while the second peak is registered between the ages of 60 and 69 with a more frequent occurrence of the disease in men. Regarding acquired polyneuropathies CIDP and dysimmune polyneuropathies show a significant incidence in the geriatric population. Inflammatory myopathies such as polymyositis and dermatomyositis are of particular importance because they most often occur in patients over 65 years of age. Conclusion: Although neuromuscular diseases are not the first association when considering the differential diagnosis of neurological diseases in elderly patients, it can still be said that this group of diseases is often present in the geriatric population. The importance of early recognition of neuromuscular diseases in elderly patients is great, bearing in mind that most of them are curable neurological diseases. Timely diagnosis and early initiation of adequate treatment is a prerequisite for a favorable course and outcome of the disease in these patients.

Defects in neuromuscular transmission suggestive of myasthenia gravis have been found in association with a wide variety of disorders, including hyperthyroidism, 1-8 myopathies, 9-10 lupus erythematosis, 11-12 malignancy, 13-15 and polymyositis. 16 A similar relationship has been reported in various neuropathies, viz., poliomyelitis, 17-19 syringomyelia, 1,20 amyotrophic lateral sclerosis, 2,16,18,21 and a variety of other conditions affecting the anterior horn cells 22 ; however, in none of these cases did myasthenia gravis appear as the primary disease. This report is a study of a patient with apparent myasthenia gravis who developed striking resistance to conventional therapy, who ultimately proved to respond in part to repeated courses of rest therapy with curare, and who late in her illness showed unexpected evidence of motor neuron disease. Report of Case During November, 1955, it was noted that the patient, a previously healthy 12-year-old girl, was unable to smile, and that the corners of

Objective: To provide a detailed and differentiated description of the path to receiving the correct amyotrophic lateral sclerosis (ALS) diagnosis, including delay times, referrals, alternate diagnoses, and clinical progression. Methods: Medical records until the date of ALS diagnosis were reviewed and linked to the Swedish Motor Neuron Disease Quality Registry. Results: The study included 353 Stockholm ALS patients diagnosed in 2016–2021. Patients were divided into four groups: 117 (33.1%) with lower extremity (LE), 85 (24.1%) with upper extremity (UE), 136 (38.5%) with bulbar, and 15 (4.2%) with respiratory onset. The time from onset to diagnosis was 16.0 (9.4–27.5) months in LE, 12.9 (8.8–17.8) months in UE, 11.7 (7.4–16.0) months in bulbar, and 8.3 (4.7–15.6) months in respiratory onset. Patients with UE or LE onset were often referred to orthopedics or a spinal/hand surgery clinic (29.3% for LE and 41.8% for UE), while bulbar patients were more frequently referred to ENT (66.3%). For those with LE or UE onset, the most common alternate diagnosis was spinal/foraminal stenosis whereas myasthenia gravis and stroke were more common for bulbar onset patients. For the respiratory group, cardiopulmonary diagnoses predominated. The proportion of all patients in King’s stage 3 or 4 increased from 11.3% to 46.1% from the initial health care visit to diagnosis. Conclusions: There was great variation in the path to ALS diagnosis according to the onset clinical phenotype. In all groups, the diagnostic delay and clinical progression was substantial. We identified subgroups where the delay was the longest and might be reduced.