Combined tendon reflex and motor evoked potential recordings in amyotrophic lateral sclerosis.

OBJECTIVE: This retrospective (case-control) collaborative study evaluates tendon reflex recordings combined with transcranial magnetic stimulation motor evoked potentials recordings (T-MEPs) at lower limbs in amyotrophic lateral sclerosis (ALS). METHODS: T-MEPs were recorded in 97 ALS patients distinguished according to their patellar reflex briskness. Patients' electrophysiological data were compared with values measured in 60 control patients matched for age and height. Correlations studies between parameters or with some patients' clinical characteristics were also performed. RESULTS: The central motor conduction time yields the highest sensitivity (82%) and specificity (93%), allowing twice more upper motor neuron (UMN) dysfunction detection than clinical examination, and being more altered in late stages of the disease. The T response to MEP response amplitude ratio (T/MEP ar) is nearly as sensitive to detect ALS and better identifies abnormal hyperreflexia. It is not correlated with evolutive stage, contrarily to conduction time-related parameters. In addition, T-MEPs detect asymmetries escaping clinical examination. CONCLUSIONS: The corticospinal conduction to lower limbs is slowed in ALS. The T/MEP ar helps deciding when patellar reflexes are abnormal in a given patient suspected of ALS. SIGNIFICANCE: The T-MEP technique provide powerful electrophysiological biomarkers of UMN involvement in ALS. This simple and painless procedure introduces the clinically useful concept of electrophysiological hyperreflexia and might be expanded to future exploration of proximal upper limbs and bulbar territories.

Early advance care planning in amyotrophic lateral sclerosis patients: results of a systematic intervention by a palliative care team in a multidisciplinary management programme - a 4-year cohort study.

INTRODUCTION: Although recommended, the implementation of early advance care planning is suboptimal in amyotrophic lateral sclerosis (ALS) patients. Barriers to advance care planning include healthcare professionals’ and patients’ reluctance, and uncertainty about the right time to initiate a discussion. AIM OF THE STUDY: To determine how often advance care planning was initiated, and the content of the discussion in a first routine palliative care consultation integrated within a multidisciplinary management programme. METHODS: Between June 2012 and September 2016, a prospective cohort study was conducted in Geneva University Hospitals. Sixty-eight patients were seen every 3 months for a 1-day clinical evaluation in a day care centre. RESULTS: The patients’ mean ± standard deviation age was 68.6 ± 11.9 years, 50% were women. Four patients were excluded because of dementia. Advance care planning was initiated with 49 (77%) patients in the first palliative care consultation. Interventions most often addressed were cardiopulmonary resuscitation (49%), intubation and tracheostomy (47%) and palliative sedation (36.7%). Assisted suicide was discussed with 16 patients (36.6%). Functional disability was the only factor associated with initiation of advance care planning. Nearly half of the patients wrote advance directives (45%) or designated a healthcare surrogate (41%). Bulbar onset, functional disability and noninvasive ventilation were not associated with the completion of advance directives. CONCLUSION: Early initiation of advance care planning is feasible in most ALS patients during a routine consultation, and relevant treatment issues can be discussed. All ALS patients should be offered the opportunity to write advance directives as completion was not associated with disease severity. .

Sporadic late onset nemaline myopathy with monoclonal gammopathy of undetermined significance: two cases with long term stability.

Monoclonal gammopathy of undetermined significance (MGUS) associated to sporadic late onset nemaline myopathy (SLONM) is a rare and severely disabling condition of quickly progressive limb girdle acquired myopathy. It is believed by some authors to be due to myotoxicity of light chain deposits. Two female patients were diagnosed with MGUS associated SLONM. In the first case, diagnosis was delayed by 6 years thus giving time for a severe generalized myopathy and cardiomyopathy to develop. A single anti-myeloma chemotherapy with lenalidomide markedly improved and stabilized the patient's condition despite respiratory and cardiac insufficiency. In our second patient the condition was identified one year after onset of the first symptom and markedly improved after autologous bone marrow transplantation and lenalidomide. Clinicians should be aware of monoclonal gammopathy associated sporadic late onset nemaline myopathy as this acquired muscle disorder, although extremely rare, may be reversed by adequate management.

Impaired conduction of Ia sensory fibers in multifocal motor neuropathy: An electrophysiological demonstration.

OBJECTIVES: To report the clinical and electrophysiological findings in two patients with multifocal motor neuropathy (MMN) and bilateral absent patellar and Achilles tendon reflexes despite normal strength of quadriceps and calf muscles. METHODS: The medical history and clinical evaluation were completed by electrophysiological tests: sensory and motor nerve conduction studies, needle electromyography, motor-evoked potentials (MEPs) after transcranial magnetic stimulation, patellar T (tendon) responses, quadriceps and soleus H (Hoffman) reflex recordings. RESULTS: In the two patients, history, clinical evaluation, nerve conduction studies, favorable response to intravenous immunoglobulins, and positive anti-GM1 antibodies fulfilled the diagnosis of MMN. The lower limbs were asymptomatic, except for a unilateral weakness of foot dorsiflexion. The patellar and Achilles tendon reflexes disappeared during the course of the disease. The sensory nerve conduction studies were normal or minimally modified, M-wave and MEP/M amplitude ratio to the quadriceps were normal, patellar T (tendon) responses were virtually absent, and H-reflex to the quadriceps and soleus muscles were absent. CONCLUSIONS: These observations, which show the interruption of the reflex afferent pathway, raise the question of Ia afferent involvement in the lower limbs of these two patients with MMN. Further investigations should determine the frequency and significance of these findings in this disorder.

Multidisciplinary care in amyotrophic lateral sclerosis: a 4-year longitudinal observational study.

Over a four-year period, ALS patients complied with the modalities of the multidisciplinary management follow-up without any drop-outs. The multidisciplinary management structure also contributes to increasing the experience and knowledge of the clinicians involved in managing patients suffering from this rare disease.

Assessing Inspiratory Muscle Strength for Early Detection of Respiratory Failure in Motor Neuron Disease: Should We Use MIP, SNIP, or Both?

BACKGROUND: Motor neuron disease (MND) invariably impacts on inspiratory muscle strength leading to respiratory failure. Regular assessment of sniff nasal inspiratory pressure (SNIP) and/or maximal mouth inspiratory pressure (MIP) contributes to early detection of a requirement for ventilatory support. OBJECTIVES: The aim of this study was to compare the feasibility, agreement, and performance of both tests in MND. METHODS: Patients with MND followed by a multidisciplinary consultation were prospectively included. Pulmonary follow-up included forced expiratory volumes, vital capacity (VC) seated and supine, MIP, SNIP, pulse oximetry, and daytime arterial blood gases. RESULTS: A total of 61 patients were included. SNIP and MIP could not be performed in 14 (21%) subjects; 74% of the subjects showed a decrease in MIP or SNIP at inclusion versus 31% for VC. Correlation between MIP and SNIP (Pearson's rho: 0.68, p < 0.001) was moderate, with a non-significant bias in favor of SNIP (3.6 cm H2O) and wide limits of agreement (-34 to 41 cm H2O). Results were similar in "bulbar" versus "non-bulbar" patients. At different proposed cut-off values for identifying patients at risk of respiratory failure, the agreement between MIP and SNIP (64-79%) and kappa values (0.29-0.53) was moderate. CONCLUSIONS: MIP and SNIP were equally feasible. There was no significant bias in favor of either test, but a considerable disparity in results between tests, suggesting that use of both tests is warranted to screen for early detection of patients at risk of respiratory failure and avoid over diagnoses. SNIP, MIP, and VC all follow a relatively linear downhill course with a steeper slope for "bulbar" versus "non-bulbar" patients.

Does executive functioning contribute to locomotion in amyotrophic lateral sclerosis patients?

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is associated with co-existing motor and cognitive impairment in almost half of the patients; however, the relationship between cognitive and motor functioning has rarely been studied in ALS. We hypothesized that impaired executive functioning would be linked to poor mobility in ALS patients. METHODS: A total of 49 non-demented ambulant ALS patients (mean age: 68.4 ± 12.6 years; 53% female), were evaluated in the Centre for ALS and Related Disorders of Geneva University Hospitals. We assessed executive function and locomotion using bedside tests: the Frontal Assessment Battery (FAB), the Timed Up and Go (TUG) and its imagined version (iTUG). RESULTS: The mean (SD) FAB was 16.4 (1.9), mean TUG was 15.7 (13.9) s, and the mean iTUG was 8.9 (7.6) s. No correlation was found between the FAB, TUG, and iTUG. There was also no correlation between the total FAB score and its 6 subtests with global disability assessed by the ALSFRS-R score. CONCLUSIONS: No correlation between executive function and locomotion was found in a group of non-demented ambulant ALS patients, as measured by screening tools of cognitive function. This absence of correlation suggests that locomotion is mainly affected by other factors than cognition, such as muscle strength or pyramidal symptoms.

Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features.

OBJECTIVE: To assess the clinicopathological and therapeutic features of patients with low (≥1000 to <10 000 Bühlmann Titre Units) (BTU), medium (10 000-70 000) or high (≥70 000) anti-myelin-associated glycoprotein (anti-MAG) antibody titres. METHODS: We retrospectively and prospectively analysed standardised report forms and medical records of 202 patients from 14 neuromuscular centres. RESULTS: Mean age at onset and mean time between symptom onset to last follow-up were respectively 62.6 years (25-91.4) and 8.4 years (0.3-33.3). Anti-MAG antibody titres at diagnosis were low, medium or high in 11%, 51% and 38% of patients. Patients presented with monoclonal gammopathy of undetermined significance in 68% of cases. About 17% of patients presented with 'atypical' clinical phenotype independently of anti-MAG titres, including acute or chronic sensorimotor polyradiculoneuropathies (12.4%), and asymmetric or multifocal neuropathy (3%). At the most severe disease stage, 22.4% of patients were significantly disabled. Seventy-eight per cent of patients received immunotherapies. Transient clinical worsening was observed in 12% of patients treated with rituximab (11/92). Stabilisation after rituximab treatment during the 7-12-month follow-up period was observed in 29% of patients. Clinical response to rituximab during the 6-month and/or 7-12-month follow-up period was observed in 31.5% of patients and correlated with anti-MAG titre ≥10 000 BTU. CONCLUSION: Our study highlights the extended clinical spectrum of patients with anti-MAG neuropathy, which appears unrelated to antibody titre. Besides, it may also suggest beneficial use of rituximab in the early phase of anti-MAG neuropathy.

Gait Performance and Use of Mental Imagery as a Measure of Disease Progression in Amyotrophic Lateral Sclerosis.

OBJECTIVE: Gait and balance are key determinants of disease status in amyotrophic lateral sclerosis (ALS). This study aims at testing the relationship between the imagery of gait and disability in patients with ALS. METHODS: Twenty-five consecutive patients (63.8 ± 2.4 years; 52% female) performed the timed up and go (TUG) test and a validated imagined version of the TUG between March 2011 and May 2012. The revised ALS functional rating score (ALSFRS-R) was assessed simultaneously. RESULTS: The mean duration of TUG (16.7 ± 2.2 s) was significantly longer than imagined TUG (iTUG; 10.5 ± 1.4 s, p < 0.001). The TUG (R2 = 0.40, p = 0.001) and the iTUG (R2 = 0.30, p = 0.007) were significantly associated with results of the ALSFRS-R score (37.0 ± 7.3) as well as with muscle strength in arms (TUG R2 = 0.42, p < 0.001, iTUG R2 = 0.38, p = 0.001) and legs (TUG R2 = 0.47, p < 0.001, iTUG R2 = 0.46, p < 0.001). TUG and iTUG increased with age (TUG R2 = 0.18, p = 0.04, iTUG R2 = 0.12, p = 0.05). CONCLUSION: ALS patients performed the imagined gait faster than the real gait. Both TUG and iTUG correlated with disability measured by the ALSFRS-R score and by muscle strength. These inexpensive and easy clinical tests represent promising tools in clinical practice to study gait in ALS.

Long-term efficacy of rituximab in IgM anti-myelin-associated glycoprotein neuropathy: RIMAG follow-up study.

The Rituximab vs. Placebo in Polyneuropathy Associated With Anti-MAG IgM Monoclonal Gammopathy (RIMAG) study showed no improvement using the inflammatory neuropathy cause and treatment sensory score (ISS) as primary outcome in patients with IgM anti-myelin-associated glycoprotein neuropathy (IgM anti-MAG neuropathy) treated with rituximab, when compared with placebo. However, some secondary outcomes seemed to improve in the per protocol analysis. Patients from one participating center in the RIMAG study underwent a new evaluation after a median follow-up of 6 (interquartile range (IQR) 4.9; 6.5) years, using the same outcome measures used in the original study. Data were recorded in seven rituximab patients (group 1) and in eight placebo patients (group 2). In group 2, six of eight patients received immunotherapy during follow-up, while only two of seven did in group 1. No significant change was observed in either the ISS or the secondary outcomes in both groups, with the exception of worsening in the 10-m walk time in group 2 (p = 0.016). The RIMAG follow-up study failed to find any significant change in most outcome measures in patients from the RIMAG study, some of them having received new immunotherapies. This study stresses the lack of useful clinical scales sensitive enough to capture small, even meaningful, improvement in IgM anti-MAG neuropathy.

The pathogenesis of multifocal motor neuropathy and an update on current management options.

Multifocal motor neuropathy (MMN) is a rare and disabling disease. Several experimental studies and clinical data are strongly suggestive of an immune-mediated pathogenesis, although underlying mechanisms in MMN seem to be very specific, mainly because of the presence of IgM anti-GM1 serum antibodies and the dramatic response to intravenous immunoglobulins (IVIg). The origin of antiganglioside antibodies and the way in which they act at the molecular level remain unclear. Several studies have demonstrated the key role of complement activation in the underlying mechanisms of MMN, as well as in animal models of acute motor axonal neuropathy (AMAN). Deposition of the membrane attack complex may disrupt the architecture of the nodes of Ranvier and paranodal areas, causing local disruption of nodal sodium-channel clusters. In patients with MMN, muscle weakness is the consequence of conduction blocks (CB), which leads to secondary axonal degeneration, consequently the aim of the treatment is to reverse CB at early stages of the disease. High-dose immunoglobulin is to date the only therapy which has proven efficacy in MMN patients in providing transient improvement of muscle strength, but long-term follow-up studies show a progressive motor decline. Therefore, other therapies are needed to improve the conduction nerve properties in long-term design. The reduction of complement activation and more generally the gain in paranodal stabilization could be directions for future therapeutic strategies.

Is tracheostomy still an option in amyotrophic lateral sclerosis? Reflections of a multidisciplinary work group.

QUESTION UNDER STUDY: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a poor prognosis. Survival and quality of life of ALS patients have improved through the implementation of multidisciplinary approaches, the use of percutaneous gastrostomy and of noninvasive (NIV) or invasive ventilation. The question of whether or not to propose invasive ventilation (by tracheostomy: TPPV) to ALS patients remains a matter of debate. METHODS: The study reviews the medical literature, the practice in three Swiss and two large French ALS expert centres and reports the results of a workgroup on invasive ventilation in ALS. RESULTS: Improved management of secretions and use of different interfaces allows NIV to be used 24-hours-a-day for prolonged periods, thus avoiding TPPV in many cases. TPPV is frequently initiated in emergency situations with lack of prior informed consent. TPPV appears associated with a lesser quality of life and a higher risk of institutionalisation than NIV. The high burden placed on caregivers who manage ALS patients is a major problem with a clear impact on their quality of life. CONCLUSIONS: Current practice in Switzerland and France tends to discourage the use of TPPV in ALS. Fear of a "locked-in syndrome", the high burden placed on caregivers, and unmasking cognitive disorders occurring in the evolution of ALS are some of the caveats when considering TPPV. Most decisions about TPPV are taken in emergency situations in the absence of advance directives. One exception is that of young motivated patients with predominantly bulbar disease who "fail" NIV.