The flail-arm syndrome: the influence of phenotypic features.

Objective: The flail-arm syndrome (FAS), one of the Amyotrophic lateral sclerosis (ALS) phenotypes, is characterized by slow progression and predominantly lower motor neuron (LMN) involvement with proximal upper limb (UL) weakness. We aim to characterize the clinical features, progression and survival of FAS associated with distal or proximal onset and presence or absence of upper motor neuron signs (UMN) signs at diagnosis. Methods: Data from 704 ALS patients was analyzed. Of the 190 patients with UL onset; 134 were excluded as not respecting the published criteria for FAS. The included patients were divided into four groups according to distal/proximal onset and presence/absence of UMN signs. Results: 56 FAS patients (8% of the population), median age at onset 59.9 years (Q1/Q3, 50.3-68.1), 75% men, were studied. Distal onset with UMN signs occurred in 37.5%, distal onset without UMN signs in 28.6%, proximal onset with UMN signs in 8.9% and proximal onset without UMN signs in 25%. Age of onset, sex, fasciculations at onset, diagnostic delay, progression rate, time to respiratory involvement and survival were similar among the four groups. Sex ratio was more balanced in patients with UMN signs (p = 0.032) and survival was shorter (69.5 months, 95% CI: 55.4-110.4 vs 152.6 months, 95% CI: 69.0-177.3; p = 0.035). The Cox regression identified rate of progression (p < 0.001) and UMN signs (p = 0.003) as independent predictors of shorter survival. Conclusions: Distal or proximal onset had no influence on clinical characteristics and prognosis but UMN signs at diagnosis are a negative prognostic predictor.

Respiratory onset in amyotrophic lateral sclerosis: clinical features and spreading pattern.

Objective To describe the clinical features and progression of patients with respiratory onset amyotrophic lateral sclerosis (ALS). Methods: We analyzed the clinical features, including respiratory tests, functional score, noninvasive ventilation (NIV) time and survival of ALS patients with respiratory-onset in our database consisting of 1688 patients. In a subset of 625 ALS patients we analyzed the spreading pattern to other bodily regions. Results: We included 1579 patients with ALS. Sixty-three patients (4%) presented respiratory-onset (79.4% men, mean onset-age 67.7 ± 8.9yrs). All had predominant LMN involvement, and significant weight loss (>10%) was identified in 38.9%. The respiratory tests were abnormal in these respiratory-onset patients (p < 0.001). ALSFRS-R respiratory subscore was lower in this population (p < 0.001). NIV was adapted in 84.1%, sooner than in the larger group of ALS patients (p < 0.001), and survival from disease onset was shorter (p < 0.001). Respiratory-onset was a predictor of time to NIV (X2=42.0, p < 0.001) and of survival (X2=7.1, p = 0.008). The spreading pattern was studied in 18 patients with isolated respiratory-onset. The progression interval to the 2nd region was 4.7 ± 5.7mo and to a 3rd region 6.1 ± 8.7mo. Different patterns of spread had no impact on survival. Conclusions: This phenotype is typically seen in emaciated older men with predominant lower motor neuron involvement, and is associated with diaphragm paresis and central respiratory involvement. NIV adaptation is rapid but total survival is shorter than in the other patients. Spreading pattern did not affect time to NIV adaptation or total survival, as NIV support is a modifying treatment in the course of ALS.

Respiratory function tests in amyotrophic lateral sclerosis: The role of maximal voluntary ventilation.

BACKGROUND: Pulmonary function tests are routinely used to measure progression in ALS. This study aimed to assess the change of various respiratory tests, in particular maximal voluntary ventilation (MVV), which evaluates respiratory endurance. METHODS: A group of 51 patients were assessed 3 times (T1, T2, T3, separated by 5.4 months), including slow (SVC) and forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF), maximal inspiratory (MIP) and expiratory (MEP) pressures, MVV, and sniff nasal inspiratory pressure (SNIP). In addition, body mass index (BMI), ALSFRS-R and phrenic nerve responses were obtained 4 times. Patients with dementia and marked bulbar involvement were excluded. RESULTS: Mean ALSFRS-R was high at entry (42.9) and its decline was moderately slow at 0.4/month. FVC and FEV1 declined significantly in the three time frames analysed. MVV reduced significantly only between T1-T3 and SVC between T2-T3, and MIP, MEP, PEF and SNIP did not change significantly. The amplitude and the latency of the motor response of the phrenic nerve changed significantly, and BMI declined significantly in most time periods, and ALSFRS-R changed significantly in the 4 time periods. We found a strong correlation between MVV, and FVC, SVC, FEV1, SNIP, phrenic nerve amplitude/area (p < 0.001), and markedly with PEF (rho = 0.821) and ALSFRS-R (rho = 0.713). CONCLUSIONS: Our study of early affected patients supports the use of a set of volitional and non-volitional respiratory tests to assess disease progression, rather than any single test. We found MVV a potentially useful marker of pulmonary function in ALS.

Assessing inter-rater reproducibility in MScanFit MUNE in a 6-subject, 12-rater "Round Robin" setup.

OBJECTIVE: To assess the inter-rater reliability of MScanFit MUNE using a "Round Robin" research design. METHODS: Twelve raters from different centres examined six healthy study participants over two days. Median, ulnar and common peroneal nerves were stimulated, and compound muscle action potential (CMAP)-scans were recorded from abductor pollicis brevis (APB), abductor digiti minimi (ADM) and anterior tibial (TA) muscles respectively. From this we calculated the Motor Unit Number Estimation (MUNE) and "A50", a motor unit size parameter. As statistical analysis we used the measures Limits of Agreement (LOA) and Coefficient of Variation (COV). Study participants scored their perception of pain from the examinations on a rating scale from 0 (no pain) to 10 (unbearable pain). RESULTS: Before this study, 41.6% of the raters had performed MScanFit less than five times. The mean MUNE-values were: 99.6 (APB), 131.4 (ADM) and 126.2 (TA), with LOA: 19.5 (APB), 29.8 (ADM) and 20.7 (TA), and COV: 13.4 (APB), 6.3 (ADM) and 5.6 (TA). MUNE-values correlated to CMAP max amplitudes (R2-values were: 0.463 (APB) (p<0.001), 0.421 (ADM) (p<0.001) and 0.645 (TA) (p<0.001)). The average perception of pain was 4. DISCUSSION: MScanFit indicates a high level of inter-rater reliability, even with only limited rater experience and is overall reasonably well tolerated by patients. These results may indicate MScanFit as a reliable MUNE method with potential as a biomarker in drug trials.

Electromyographic findings in primary lateral sclerosis during disease progression.

OBJECTIVE: To characterize electromyographic (EMG) findings in patients with primary lateral sclerosis (PLS) during the disease course. METHODS: In PLS patients we scored spontaneous activity and motor unit action potential (MUP) pattern on EMG. We compared patients according to lower (group A) and higher (group B) EMG scores. EMG studies were repeated at intervals longer than 11 months; two or three repeat studies were required for inclusion in the analysis. RESULTS: We studied 22 patients. Fasciculation potentials were found in 13 and fibrillations/positive sharp waves (fibs/sw) in 3 patients. Both were stable over time. Most patients had MUP abnormalities (n = 17), with worsening in the lower limbs in patients with three evaluations (p = 0.010). Compared to group A (n = 12), patients of group B (n = 10) had a significant shorter disease duration (median 10.9 vs 15.2 years, p < 0.001), lower functional score at both first (39 vs 45, p = 0.034) and last (29 vs 38, p = 0.003) evaluations, and had a faster functional decline (0.19 vs 0.08, p = 0.004). CONCLUSIONS: Most PLS patients showed minor and stable EMG abnormalities, without progression to ALS. Patients with more EMG abnormalities have a faster progression. SIGNIFICANCE: EMG abnormalities in most PLS patients are minor and stable.

Neurological complications of cardiomyopathies.

There is a multifaceted relationship between the cardiomyopathies and a wide spectrum of neurological disorders. Severe acute neurological events, such as a status epilepticus and aneurysmal subarachnoid hemorrhage, may result in an acute cardiomyopathy the likes of Takotsubo cardiomyopathy. Conversely, the cardiomyopathies may result in a wide array of neurological disorders. Diagnosis of a cardiomyopathy may have already been established at the time of the index neurological event, or the neurological event may have prompted subsequent cardiac investigations, which ultimately lead to the diagnosis of a cardiomyopathy. The cardiomyopathies belong to one of the many phenotypes of complex genetic diseases or syndromes, which may also involve the central or peripheral nervous systems. A number of exogenous agents or risk factors such as diphtheria, alcohol, and several viruses may result in secondary cardiomyopathies accompanied by several neurological manifestations. A variety of neuromuscular disorders, such as myotonic dystrophy or amyloidosis, may demonstrate cardiac involvement during their clinical course. Furthermore, a number of genetic cardiomyopathies phenotypically incorporate during their clinical evolution, a gamut of neurological manifestations, usually neuromuscular in nature. Likewise, neurological complications may be the result of diagnostic procedures or medications for the cardiomyopathies and vice versa. Neurological manifestations of the cardiomyopathies are broad and include, among others, transient ischemic attacks, ischemic strokes, intracranial hemorrhages, syncope, muscle weakness and atrophy, myotonia, cramps, ataxia, seizures, intellectual developmental disorder, cognitive impairment, dementia, oculomotor palsies, deafness, retinal involvement, and headaches.

Very late-onset amyotrophic lateral sclerosis in a Portuguese cohort.

OBJECTIVE: Although amyotrophic lateral sclerosis (ALS) incidence has been stable among Western countries, population-ageing effect will probably increase the proportion of very-old ALS patients. We aim to study this population. METHODS: A retrospective study was performed, including 1083 ALS patients followed longitudinally in our ALS unit from January 1995 to December 2017. The patients were divided in two groups, according to age at disease onset (

The generator site in acquired autoimmune neuromyotonia.

OBJECTIVE: To investigate the origin of ectopic activity in neuromyotonia (NMT). METHODS: We studied two patients. In addition to routine studies, we tested synchronicity of spontaneous discharges in different motor units in simultaneous recordings made with two needle electrodes in the first dorsal interosseus muscle. Time-locked fasciculations in these double recordings would represent abnormal ectopic activity initiated in a nerve trunk with ephaptic stimulation of a nearby axon. In patient 1, this research protocol was applied once, 15years after regular intravenous immunoglobulin (IvIg) treatment. Patient 2 was investigated before and 1year after IvIg. RESULTS: Both patients improved after IVIg, mirrored by a striking decrease in the amount of spontaneous activity on electromyography. Moreover, our technique did not detect synchronous spontaneous activity (time-locked fasciculations) on the second assessment, although this was predominant before treatment in patient 2. CONCLUSIONS: In NMT, abnormal discharges originate both in distal axonal branches and in more proximal segments. It appears that IvIg is more effective in blocking antibody activity in proximal axonal segments, perhaps related to factors such as blood-nerve barrier, temperature or differing ion channel distributions. SIGNIFICANCE: Treatment effects can shed light on the origin of abnormal activity in NMT.