Mamede de Carvalho

The sternocleidomastoid muscle (SCM) is an accessory inspiratory muscle, but it is not investigated systematically in patients with amyotrophic lateral sclerosis (ALS). We aimed to study the involvement of the SCM and to evaluate the role of the diaphragm and SCM on respiratory tests performed in ALS patients. We studied 45 patients (mean age +/- SD: 60.6 +/- 13 years). In all patients we evaluated: neck flexion strength; forced vital capacity (FVC); maximal inspiratory pressure (PImax); sniff nasal inspiratory pressure (SNIP); ALS functional scale (ALS-FRS-R); SCM and diaphragm compound muscle action potential (CMAP) amplitudes (SCM Ampl and Diaphr Ampl) and latencies (SCM Lat and Diaphr Lat). In ALS patients, SCM Lat is increased and SCM Ampl is smaller in patients with neck weakness. The subgroup of patients with neck weakness had more abnormal respiratory function tests and lower clinical scores. There is a significant correlation between SCM Amp and Diaphr Ampl, FVC, PImax, and SNIP. Hence, there is a parallel loss of motor units in the SCM and diaphragm. On multiple regression analysis both PImax and SNIP are dependent on SCM Ampl and Diaphr Ampl, but FVC is not. PImax and SNIP determination mostly depend on SCM and diaphragm function, but the FVC is also dependent on expiratory muscle function. We conclude that neck weakness is a clinical sign that indicates a poor prognosis, and the SCM CMAP can contribute to respiratory function evaluation in ALS patients.

Craniovertebral dislocation is uncommon, but its diagnosis is important taking into account the potential severity of the neurologic complications. A number of causes are known; the most common are Down syndrome, rheumatoid arthritis, Paget's disease, other metabolic bone diseases, and craniocervical trauma. Down's syndrome is a relatively common clinical condition but craniovertebral subluxation is only observed in a small percentage of patients. About half of all cervical spine injuries affect the atlanto-occipital region and C2 vertebra. In rheumatoid arthritis, craniocervical dislocation occurs in up to 40% of patients with severe disease. In Paget's disease, involvement of the craniovertebral region occurs in about 30% of all cases. The clinical neurologic syndrome is characterized by local pain, features of upper spinal cord and medullary compression, positive Lhermitte phenomenon, syncope associated with neck flexion, vertebral artery obstruction or dissection leading to stroke, and asymmetrical lower cranial nerve palsies. Neuroimaging is essential to confirm the clinical diagnosis and to categorize severity. The treatment of this disorder is usually surgical, but traction and external immobilization is relevant in some cases. Specific conditions may require additional treatments such as radiotherapy, antibiotics, or chemotherapy.

We aim to describe the clinical and neurophysiological characteristics of a group of patients with a clinical diagnosis of deep palmar branch lesion of the ulnar nerve. We report the clinical and neurophysiological outcome. Eleven patients (six males, mean age: 52 years) were included prospectively. Neurophysiological studies were performed in all patients at diagnosis and longitudinally in five. Occupational trauma was the cause of the nerve lesion in seven patients, neuritis was diagnosed in one and an idiopathic lesion was the final diagnosis in two. In 10 patients, conservative management with interruption of repetitive trauma led to a progressive full recovery. Hand weakness was progressive in one patient who underwent surgical intervention with a diagnosis of ganglion compression, whose removal caused gradual improvement. Neurophysiological studies confirmed severe deep branch lesion, but in four a mild proximal lesion of the ulnar nerve at the wrist was identified. Follow-up neurophysiological studies confirmed the rapid resolution of the lesion. Conservative management should be the first option in patients with deep palmar branch lesion of the ulnar nerve, in particular in patients with a work-related lesion. Electromyography has a central role in diagnosis.

Phrenic nerve motor amplitude (Diaphr Ampl) is predictive of hypoventilation in amyotrophic lateral sclerosis (ALS). We aimed to evaluate its change over disease course and to correlate it to other measurements. Forty-nine unselected patients (35 men, 13 bulbar-onset, 56.5+/-8.9 years) with definitive or probable ALS were included. They were evaluated at entry (time 0) and 4-6 months (5.2+/-1.0) later (time 1) with: functional ALS rating scale (ALS-FRS) and respiratory subscore (ALS-FRSr); forced vital capacity (FVC); maximal inspiratory pressure (MIP); mean O(2) saturation overnight (SpO(2)mean); sniff maximal inspiratory pressure (SNIP); Diaphr Ampl and mean amplitude of the ulnar nerve response (ADM Ampl). ALS-FRS, ALS-FRSr, Diaphr Ampl, FVC, SNIP, ADM Ampl (p<0.01) and SpO(2)mean (p<0.05) declined significantly. MIP did not change significantly (p=0.203). Coefficient of variation was similar for FVC, Diaphr Ampl, ADM Ampl and ALS-FRS but higher for SNIP. The percentage of change for Diaphr Ampl was significantly correlated to FVC and SNIP, but not to ADM Ampl or ALS-FRS. Diaphr Ampl decreased significantly in a short period of time and its change is correlated to other respiratory tests. This test can be useful in patients with marked facial weakness or uncooperative. Diaphr Ampl is useful to monitor respiratory function in ALS patients and can be applied in clinical trials.

Our objective is to describe the results of a phase II/III, 12-months, double-blinded, single-centre, randomized, parallel (1:1), clinical trial performed to evaluate the efficacy and safety of memantine in ALS. Patients with probable or definite ALS of less than 36 months disease duration and progression over a one-month lead-in period were randomly assigned to placebo or memantine at 20 mg/day. The primary endpoint was 12-months ALSFRS decline. Forced vital capacity, manual muscle testing, visual analogue scale, quality of life, motor unit number estimation and neurophysiological index were the secondary endpoints. The number of patients included was based on the assumption of a 50% change in the ALSFRS decline. Safety and adverse events were evaluated. Sixty-three patients were included in the trial. Memantine did not show more adverse events or laboratory changes than placebo. Primary and secondary outcomes were not different between groups by intention-to-treat and per-protocol analysis. The most sensitive measurements were neurophysiological, which declined linearly over time. In conclusion, the results of this study show that memantine is well tolerated and safe in ALS patients. We did not observe any evidence of efficacy for memantine but we cannot exclude a positive outcome on survival.

Paraspinal EMG needle examination is commonly performed in amyotrophic lateral sclerosis (ALS) for diagnosis. Because lower motor neurons for axial muscles and diaphragm are located medially in the anterior horn, we tested if involvement of axial muscles is associated with diaphragm weakness in ALS. Forty-four ALS patients were included with ALSFRS greater than 20/40. We used needle EMG to search for signs of denervation in biceps, tibialis anterior, C6 and T5 paraspinal muscles, and intercostal and diaphragm muscles. We also evaluated phrenic nerve motor responses and forced vital capacity (FVC). We tested specificity, sensitivity, and discriminative strength (ROC analysis). Fibs-sw in C6 and T5 paraspinal muscles, as well as fibs-sw in diaphragm and intercostal muscles showed high specificity and positive predictive value for FVC<80%. Discriminative strength was good for all the above tests, as well as for phrenic nerve amplitude and ALSFRS regarding FVC<80%. Axial muscles denervation is related to diaphragm denervation and therefore to poor respiratory function in ALS. We suggest that medially located lower motor neurons are affected concurrently in ALS.

Our objective was to analyse how patients with amyotrophic lateral sclerosis (ALS) are examined neurophysiologically at different European centres in order to identify possible areas with variation or disagreement in the neurophysiological examination of ALS. Ninety-three prospectively collected examinations from six out of seven neurophysiologists in the European ESTEEM project were analysed. All examinations were peer reviewed with an electromyographic consensus diagnosis of motor neuron disease and the diagnosis of ALS confirmed by clinical follow-up. The examinations were analysed for differences among the physicians in EMG techniques and number and distribution of examined and abnormal muscles and nerve segments. Considerable variation was found among the physicians regarding the average numbers of performed and abnormal EMG and nerve conduction studies per patient, the EMG techniques used, and the topographical distribution of the examined muscles. The existence of two different examination approaches, one with quantitative EMG analyses and relatively few muscles studied, and one with more muscles studied using qualitative methods was clearly confirmed in the present study. The large variation among the physicians indicates that different criteria were used, or that criteria were used inconsistently.

Different forms of motor neuron disease occurring in association with HIV infection have been described. We present two patients with pseudobulbar syndrome and HIV infection, with no clinical or electromyographic signs of lower motor neuron loss. In patient 1, on follow-up, focal seizures led to additional investigations that identified unsuspected HIV infection and progressive multifocal leucoencephalopathy (PML). In patient 2, all investigations excluded an active HIV infection or central nervous system involvement, and the disease progression made primary lateral sclerosis (PLS) with pseudobulbar onset the most likely diagnosis. ALS-like syndrome can occur in association with HIV infection; however, the causal relationship remains uncertain. Patient 1 shows that PML is a possible cause for pseudobulbar syndrome, and our second patient demonstrates that ALS may also occur by chance in patients with HIV infection.

Injuries of the nerves of the thorax are a known complication of thoracic surgery. Diagnosis is not always straightforward, often requiring a multidisciplinary approach and a combination of several investigation techniques. Electrodiagnostic studies are most accurate in terms of confirming the diagnosis, although regarding the thoracic nerves, they are challenging. They are also helpful in determining prognosis, which is variable, with respect to the mechanism of injury. Clinical outcome depends not only on recovery of the nerve function, but also on the extent of the lesion (unilateral vs. bilateral), comorbidities, and compensatory activity of other muscles. Thus, conservative therapy is applied in most instances, while surgical treatment is reserved for cases of severely disabling nerve injuries. In this chapter, we review the following nerves: phrenic, long thoracic, recurrent laryngeal, thoracodorsal, vagus, intercostals, and sympathetic trunk. Anatomy and function, clinical syndromes, etiology, diagnosis, prognosis, and management of nerve injuries are discussed.

A 56-year-old woman was admitted to the intensive care unit due to severe global respiratory failure. Over the 5 days before admission, she progressively developed dyspnea, exercise intolerance, and orthopnea. She had no pain, cough, or fever. She had been diagnosed as having myasthenia gravis (MG) 12 years earlier. At that time, she had fluctuating dysphagia, dysphonia, ptosis, and diplopia that improved on pyridostigmine. Abnormal repetitive nerve stimulation and serum acetylcholine receptor antibodies supported the clinical diagnosis. No thymoma was found, and thymectomy was not performed. She was asymptomatic for the last 10 years on pyridostigmine (120 mg/day). On admission, we observed orthopnea as well paradoxical respiration in the supine position, associated with arterial desaturation. The patient had no ptosis, diplopia, neck or facial paresis, dysphagia, or dysphonia. Routine blood investigation was normal, including thyroid function, C-reactive protein, and serologic tests for Borrelia, herpes virus, and human immunodeficiency virus. A chest radiograph demonstrated bilateral hemidiaphragm elevation but no other abnormality. Neurophysiological investigation showed normal repetitive nerve stimulation (RNS) of abductor pollicis brevis, trapezius, anconeus, and nasalis, and routine diaphragm compound muscle action potentials (DCMAPs) were absent bilaterally.1 Needle electromyography (EMG) of the diaphragm showed fibrillation potentials and positive sharp waves on both sides. EMG of the right hemidiaphragm revealed no motor unit potentials (MUPs), but 2 remaining MUPs were observed on the left. Bilateral EMG of sternocleidomastoid, genioglossus, and intercostal muscles was normal. Cervical and thoracic computerized tomography scans and magnetic resonance imaging of the cervical spine and brachial plexus, bilaterally, were normal. Cerebrospinal fluid examination was normal. Treatment with intravenous immunoglobulin (IVIg; 400 mg/kg/day for 5 days) was not effective, and noninvasive ventilation (NIV) was applied for respiratory support 24 hours/day. She improved slowly over the next 4 months. After this period she was independent of NIV during the day, but she needed respiratory support overnight. A comparative neurophysiological investigation disclosed a delayed small DCMAP on both sides (amplitude: right, 0.05 mV; left, 0.09 mV; latency: right, 9.2 ms; left, 11.4 ms; Fig. 1). EMG showed a few reinnervated MUPs in the diaphragm (Fig. 1). RNS of proximal muscles remained normal. RNS of the phrenic nerve was not performed, as its small amplitude precluded a reliable result. The patient developed subacute respiratory failure with orthopnea and paradoxical respiration on observation. Neurophysiological investigation disclosed severe bilateral phrenic nerve lesions. Maher et al. reported 4 patients with MG and severe bulbar and respiratory muscle weakness in whom small DCMAPs were recorded.4 Their patients improved on medical treatment. However, our patient did not present with bulbar weakness, did not respond to IVIg, and had a slow and incomplete recovery. Thus, we believe this case illustrates a very rare association of two autoimmune disorders—myasthenia gravis and phrenic neuritis. Bilateral phrenic neuropathy associated with arm weakness and neck or shoulder pain is well characterized, and it is usually included in the spectrum of immune brachial plexus neuropathy.2 However, our patient presented with no pain or signs of upper limb neuropathy. Respiratory failure associated with painless bilateral isolated phrenic neuropathy has been reported infrequently.3,5 This condition can be difficult to diagnose as a distinct entity.3,5 Based on this case, we propose that phrenic nerve conduction studies be performed in MG patients who have rapidly progressive respiratory impairment that cannot be explained by the neuromuscular transmission defect.

Phrenic nerve motor amplitude (Diaphr Ampl) is predictive of hypoventilation in amyotrophic lateral sclerosis (ALS). We aimed to evaluate its change over disease course and to correlate it to other measurements. Forty-nine unselected patients (35 men, 13 bulbar-onset, 56.5+/-8.9 years) with definitive or probable ALS were included. They were evaluated at entry (time 0) and 4-6 months (5.2+/-1.0) later (time 1) with: functional ALS rating scale (ALS-FRS) and respiratory subscore (ALS-FRSr); forced vital capacity (FVC); maximal inspiratory pressure (MIP); mean O(2) saturation overnight (SpO(2)mean); sniff maximal inspiratory pressure (SNIP); Diaphr Ampl and mean amplitude of the ulnar nerve response (ADM Ampl). ALS-FRS, ALS-FRSr, Diaphr Ampl, FVC, SNIP, ADM Ampl (p<0.01) and SpO(2)mean (p<0.05) declined significantly. MIP did not change significantly (p=0.203). Coefficient of variation was similar for FVC, Diaphr Ampl, ADM Ampl and ALS-FRS but higher for SNIP. The percentage of ...

Ptosis is not a feature observed in amyotrophic lateral sclerosis (ALS). We describe two old women with bulbar-onset ALS and rapid progression, in whom ptosis and diplopia were noted. They did not improve on pyridostigmine or steroids. Antibodies against acetylcholine receptor were negative, thymoma was excluded, but neurophysiological showed marked neuromuscular transmission failure in orbicularis oculi. We discuss the association between ALS and ocular myasthenia gravis in these cases.

To evaluate sensory nerve conduction studies in ALS in a prospective multicentre study involving 7 neurophysiologists from 6 European countries. Bilateral sural potentials were obtained in 35 ALS patients and 35 age-matched controls according to a standardised examination protocol using antidromic surface technique. The recordings from the right sural nerve of the controls were used for reference values. A reduction from the mean of controls greater than 2 SDs was considered abnormal. Reduced sensory nerve action potential (SNAP) amplitude or reduced conduction velocity (CV), or both, was found in 6 ALS patients (17%). Decrease in CV was the most frequent finding, and was observed in 8 nerves from 5 patients. Reduced SNAP amplitude was found in 2 nerves from 2 patients. All changes were minor ranging from -2.1 to -3.2 SDs. This is the first standardised multicentre study on sensory potentials in ALS. It confirms that although normal sensory findings should be expected in the majority of ALS patients, minor abnormalities are not uncommon. Mild sensory abnormalities do not necessarily exclude a diagnosis of ALS.

We report the clinical and electrophysiological features of three members of a large Portuguese family with HSAN 1 and the C133Y missense mutation. The affected members showed typical clinical features. Electrophysiological findings were consistent with a distal axonal ...

Transcranial magnetic stimulation (TMS) mapping was performed regularly on 11 patients with amyotrophic lateral sclerosis (ALS). Map area decreased by 25% (P = 0.03) and normalized volume decreased by 47% (P = 0.01) in those patients who were mapped four times over a period of 11.6 months. The center of gravity (CoG) position moved randomly along the interaural line by distances larger than could be explained by experimental error (P = 0.002). Central conduction time, threshold, and motor evoked potential:compound muscle action potential (MEP:CMAP) amplitude ratio did not change significantly with time (P > 0.05). There were significant linear correlations between strength and CMAP amplitude and between map area and volume. No correlation was found between strength or CMAP amplitude and area or volume. The changes in map parameters were attributed primarily to loss of cortical cells. These results indicate that map parameters may be more sensitive to cortical neuronal loss than other TMS parameters.

The authors have shown in a recent paper that survival with amyotrophic lateral sclerosis (ALS) can be increased by the use of non-invasive methods of assisted ventilation (Bipap ® ). However, the progression of muscle weakness was not affected and the quality of life ...

In this review we evaluate clinical neurophysiological methods, originally described for use in diagnosis that can be applied to measurement of change during the progress of amyotrophic lateral sclerosis (ALS). Such measurements are potentially important in clinical trials, and also in clinical practice. We have assessed methods for lower and upper motor neuron function, including conventional EMG, nerve conduction and F-wave studies, the derived Neurophysiological Index, motor unit counting methods (MUNE), and transcranial magnetic motor cortex stimulation. We have also addressed the validity of measurements of electromechanical coupling. Methods for measuring muscle strength are beyond the scope of this review. We conclude that MUNE, M-wave amplitude and the Neurophysiological Index are sufficiently reliable, sensitive, and relevant to the clinical problem of ALS, to be used in clinical trials in the disease. Transcranial magnetic stimulation is of limited value, but a combination of the measurements made as part of this technique may also be useful. We conclude that clinical neurophysiological techniques should now be used in measuring change in clinical trials in ALS.

Mutation frequency of the 2 main amyotrophic lateral sclerosis (ALS)-related genes, C9orf72 and SOD1, varies considerably across the world. We analyzed those genes in a large population of Portuguese ALS patients (n = 371) and recorded demographic and clinical features. Familial ALS (FALS) was disclosed in 11.6% of patients. Mutations in either SOD1 or C9orf72 were found in 9.2% of patients and accounted for 40% of FALS and 5.2% of sporadic ALS. SOD1 mutations were rare (0.83%), but a novel and probably disease-causing mutation was identified: p.Ala152Pro (c.457G>C). The C9orf72 hexanucleotide repeat expansion was the commonest abnormality, accounting for 4.6% of sporadic ALS and 37.5% of FALS; in these patients, Frontotemporal Dementia was prevalent. This first report on the frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese ALS patients reiterate that the genetic architecture of ALS varies among different geographic regions. The mutations inci...

Myasthenia gravis (MG) is an autoimmune disease associated with antibodies against the nicotinic muscle acetylcholine receptor (AChR) at the neuromuscular junction. Dysautonomia has been previously described in MG. Electrochemical skin conductance (ESC), assessed by Sudoscan, is a non-invasive method that allows evaluation of sudomotor function. Since sweat glands are innervated by sudomotor, postganglionic, cholinergic sympathetic C-fibers, we hypothesized that ESC could be a reliable method for assessing autonomic dysfunction in MG. ESC measurements were prospectively assessed in patients with generalized MG and in healthy controls. Patients with diabetes mellitus, anticholinergic medication or electrophysiological findings of peripheral neuropathy were excluded. Data regarding demographic and disease features were collected. Presence of autonomic symptoms in patients with MG was assessed by Compass-31. For statistical analysis we performed student t-test and Chi test for comparison between both groups. We included 24 patients (mean age of 46.4±10.6, 75% women, mean disease duration 12.5 years, 62.5% positive for AChR antibodies) and 37 controls. We found no difference in either foot (P=0.13) or hand (P=0.83) ESC measurements between patients and controls, even after correcting for age. We could not prove the presence of autonomic sympathetic dysfunction in our cohort of MG patients when assessed by Sudoscan. In addition, Compass-31 was not a useful questionnaire in this clinical context.

To assess the natural history and treatment effect on survival among patients with transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) stage 1 Val30Met. Multi-institutional, hospital-based study of patients with TTR-FAP Val30Met prospectively followed up until December 2016, grouped into untreated (n = 1,771), liver transplant (LTx)-treated (n = 957), or tafamidis-treated (n = 432) cohorts. Standardized mortality ratios, Kaplan-Meier, and Cox methods were used to estimate excess mortality, survival, and adjusted hazard ratios (HRs) for all-cause mortality. Disease-modifying treatments decreased TTR-FAP excess mortality from 10 to 4 (standardized mortality ratio 3.92, 95% confidence interval [CI] 2.64-5.59). Median overall survival of untreated and LTx-treated cohorts was 11.61 (95% CI 11.14-11.87) and 24.73 years (95% CI 22.90-27.09), respectively, and was not reached in the tafamidis-treated cohort (maximum follow-up, 10 years). Both disease-modifying treatments impr...

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. 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 (</≥80 years). Demographic, clinical, and survival data were compared between groups. Fifty out of 1083 (4.62%) patients were aged 80 or over. Mean onset age in this group was 82.9 ± 2.59 years and 28 (56%) were men. Contrasting with the younger group, bulbar-onset was remarkably the most common presentation form (54%, p < 0.001), but with no gender preference (p = 0.52) and so was significantly shorter disease duration before first visit (13.41 ± 9.42 versus 18.84 ± 21.66 months, p = 0.001). Survival after disease onset (31.87 ± 25.45 versus 45.61 ± ...

To identify common practices of noninvasive ventilation (NIV) use among ALS specialists and how they follow respiratory status in their patients. A 25-item questionnaire on NIV indications/initiation was sent via SurveyMonkey® to ALS specialists identified through membership in NEALS (114 sites in the US) and ENCALS (39 sites in Europe). Descriptive statistics and Cochran-Mantel-Haenszel test for general association were performed. In their initial evaluation, US and European specialists (n = 186) use upright forced vital capacity (FVC) most (92.8% vs 91.1%; p = 0.752). Upright FVC results are most important for US respondents when deciding to prescribe NIV; European respondents consider symptoms of orthopnea and/or dyspnea as most important. European respondents use overnight pulse oximetry (69.8% vs 7.9%; p < 0.001) and arterial blood gas analyses (62.8% vs 3.2%; p < 0.001) more than US respondents. Insurance regulations/national health care coverage impact NIV initiation mo...

Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) is a rare, hereditary, progressive and neurodegenerative disease. We aimed to study -TTR-FAP epidemiology in Portugal. National, observational, prospective and retrospective, case identification of adults with TTR-FAP. Countrywide patient multiple identification sources included reference centers registries and centralized medical electronic prescription database. Crude rates were reported per 100,000 adult inhabitants. Over 2010-2016 period, mean incidence rates was 0.87/100,000 (95% CI 0.68-1.10) corresponding to 71 new patients yearly, that has decreased 31% in the last 7 years. The proportion of late-onset cases (age ≥50 years) among incident cases was 28.7%. Estimated crude 2016 prevalence was 22.93/100,000 adult inhabitants (95% CI 21.90-23.99) corresponding to 1,865 TTR-FAP individuals in Portugal (45.8% male; mean age: 52.3 ± 15.4 years). In 2016, the Portuguese region with the highest TTR-FAP prevalence show...

The efficacy of cardiopulmonary exercise testing (CPET) to determining exercise intensity has not been established in Amyotrophic Lateral Sclerosis (ALS). We studied this intervention. We included 48 ALS patients randomized in 2 groups: G1 ( = 24), exercise intensity leveled by CPET; G2 ( = 24), standard care limited by fatigue, during 6 months. ALS functional scale (ALSFRS-R) and forced vital capacity (FVC) were performed every 3 months; CPET was done at admission (1) and 6 months later (2). We registered oxygen uptake, carbon dioxide output, and ventilation at anaerobic threshold and at peak effort. Primary outcome was functional change. We used parametric statistics for comparisons and multiple regression analyses to identify independent predictors of functional decline. At 1 both groups were identical, except for higher FVC in G1 ( = 0.02). At 2, ALSFRS-R was higher ( = 0.035) in G1. Gas exchange variables at 2 did not change in G1 but had significant differences in G2 ( < 0....

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that causes skeletal muscle weakness, including muscles involved with respiration. Death often results from respiratory failure within 3-5 years. Monitoring respiratory status is therefore critical to ALS management, as respiratory/pulmonary function tests (PFTs) are used to make decisions including when to initiate noninvasive ventilation. Understanding the different respiratory and PFTs as they relate to disease progression and survival may help determine which tests are most suitable. This review describes the tests used to assess respiratory muscle and pulmonary function in patients with ALS and the correlations between different respiratory measures and clinical outcomes measures. The most commonly used measurement, forced vital capacity (VC), has been shown to correlate with clinical milestones including survival, but also requires good motor coordination and facial strength to form a tight seal around ...

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS. We obtained data for patients from 14 specialised ALS centres (each one designated as a cohort) in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK. All patients were diagnosed in the centres after excluding other diagnoses and classified according to revised El Escorial criteria. We assessed 16 patient characteristics as potential predictors of a composite survival outcome (time between onset of symptoms and non-invasive ventilation for more than 23 h per day, tracheostomy...

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis o...

This paper aims to analyze the contribution of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in the detection of microstructural abnormalities in amyotrophic lateral sclerosis (ALS) and to evaluate the degree of agreement between structural and functional changes through concomitant diffusion tensor imaging (DTI), transcranial magnetic stimulation (TMS), and clinical assessment. Fourteen patients with ALS and 11 healthy, age- and gender-matched controls were included. All participants underwent magnetic resonance imaging including DTI. TMS was additionally performed in ALS patients. Differences in the distribution of DTI-derived measures were assessed using tract-based spatial statistical (TBSS) and volume of interest (VOI) analyses. Correlations between clinical, imaging, and neurophysiological findings were also assessed through TBSS. ALS patients showed a significant increase in AD and MD involving the corticospinal tract (CST) and the pre-frontal whi...

Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 × 10-3), both located in a hot-spot in the C-te...

A hexanucleotide repeat expansion in the C9orf72 gene is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. It has been described before four patients with multiple sclerosis (MS) and C9orf72-ALS. However, C9orf72 positivity is not associated with increased risk of MS. Inflammatory pathways related to NF-κB have been linked to ALS and MS, and appear to be important in C9orf72-ALS patients. A 42-year-old woman presented with progressive bulbar symptoms for 9 months. Neurological examination disclosed spastic dysarthria, atrophic tongue with fasciculations, brisk jaw and limb tendon reflexes, and bilateral Hoffman sign. Electrophysiological assessment confirmed ALS. Brain MRI revealed multiple and bilateral juxtacortical and periventricular inflammatory changes, some with gadolinium-enhancement, configuring a probable MS-like pattern. CSF evaluation was unremarkable, with no oligoclonal bands. Visual and somatosensory evoked potentials were normal. Follow-up brain MRI 6 months later showed two new lesions in two relatively characteristic locations of MS, with no gadolinium-enhancement. Genetic screening revealed a C9orf72 expansion. As patient had no clinical manifestation of MS, a diagnosis of radiologically isolated syndrome was considered. We speculate that these demyelinating lesions might facilitate expressivity of C9orf72 expansion, through NF-κB activation. This plausible association may lead to the identification of a therapeutic target in this subgroup of C9orf72-ALS patients.

Riluzole is the only drug approved for the treatment of patients with Amyotrophic Lateral Sclerosis (ALS). It is well tolerated, being the most frequent adverse effects asthenia, nausea and reversible increase of liver enzymes levels. Severe adverse effects are extremely rare. We report for the first time, two patients with sporadic limb-onset ALS who developed recurrent acute pancreatitis (AP), with portal vein thrombosis as complication, during treatment with riluzole. We suggest that AP should be considered asa probable rare and severe side effect of treatment with riluzole in patients with ALS. We believe that in patients who develop AP during treatment with riluzole, its withdrawn may prevent recurrent AP and should be discussed with patients.

Slow (SVC) and forced (FVC) vital capacities are the most used pulmonary function tests in amyotrophic lateral sclerosis (ALS). It is unknown if they equally predict survival in ALS. The aim of the present study was to compare both measures in predicting survival in this disease. Consecutive definite/probable ALS patients (2000-2014) in whom respiratory tests were performed at baseline and four months later were included. All patients were evaluated with the revised ALS functional rating scale (ALSFRS-R), respiratory (RofALSFRS-R), bulbar (ALSFRSb), upper and lower limb subscores, SVC, FVC, maximal inspiratory (MIP) and expiratory (MEP) pressures. King's functional staging system was applied retrospectively. Survival analysis was carried out by univariate Kaplan-Meier log-rank test. Multivariate Cox proportional hazards model determined significant independent variables. We included 469 patients (270 males; mean onset age 61.0 ± 11.5 years; mean disease duration from first sympt...

To define an applicable dataset for ALS patient registries we weighted specific clinical items as scored by worldwide ALS experts. Sixty participants were invited based on relevant clinical work, publications and personal acquaintance. They rated 160 clinical items consensually agreed by the members of our project, incorporating specialists from five European Centres. Scoring scheme was defined as: 1 - essential; 2 - important; 3 - not very important. A mixed effect model was applied to rank items and to find possible correlations with geographical region (Europe vs. outside Europe). We received 40 responses, 20 from Europe and 20 from outside; 42/160 data were scored as essential by >50% of the respondents, including: date of birth, gender, date of disease onset, date of diagnosis, ethnicity, region of onset, predominant upper neuron (UMN) or lower motor neuron (LMN) impairment, proximal versus distal weakness, respiratory symptoms, dysarthria, weight loss, signs of LMN/UMN invo...