Mamede de Carvalho

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS)

A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.

Electrodiagnostic criteria for diagnosis of ALS

A consensus meeting was held to determine the best use and interpretation of electrophysiological data in the diagnosis of ALS. The utility of needle EMG and nerve conduction studies was affirmed. It is recommended that electrophysiological evidence for chronic neurogenic change should be taken as equivalent to clinical information in the recognition of involvement of individual muscles in a limb. In addition, in the context of a suspected clinical diagnosis of ALS, fasciculation potentials should be taken as equivalent to fibrillation potentials and positive sharp waves in recognising denervation. The importance of searching for instability in fasciculation potentials and in motor unit potentials in ALS is stressed. These changes in the interpretation of electrophysiological data render obsolete the category Probable Laboratory-Supported ALS in the modified El Escorial diagnostic criteria for ALS. Methods for detection of upper motor neuron abnormality appear sensitive but require further study, particularly regarding their value when clinical signs of upper motor neuron lesion are uncertain.

EFNS guidelines on the clinical management of Amyotrophic Lateral Sclerosis (MALS) - revised report of an EFNS task force

Background:  The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak.

Controversies and priorities in amyotrophic lateral sclerosis.

Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.

Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

Respiratory assistance with a non-invasive ventilator (Bipap) in MND/ALS patients: survival rates in a controlled trial.

Noninvasive ventilatory assistance, in ALS patients, with the bilevel intermittent positive air pressure (Bipap) was studied, in a prospective and controlled trial, by the authors. Twenty ALS bulbar patients, fulfilling El Escorial criteria for probable or definite disease, were selected. For the follow-up all patients were submitted to evaluation with the Norris scale, modified Barthel score and an analog scale of life satisfaction, every 3 months. All patients were also submitted to respiratory functional testing (RFT). Ten of these patients were treated with palliative management (group I), the remaining ten patients received Bipap support (group II). Clinical evolution curves and clinical parameters were not statistically different in both groups, except for the percentage of actual predicted value of vital capacity (p < 0.03), showing a more advanced disease in group II patients. Analog scale of life satisfaction showed improvement in the group II, even after the beginning of respiratory insufficiency, though without significance probably due to the small sample size (p < 0.1). Since 6 patients in group II are still alive survival rates were compared with log rank test considering cumulative survivals with Kaplan-Meier estimates. Total survival and survival from diurnal abnormalities in gas exchange (survival 1) were significantly longer for group II (p < 0.006 and p < 0.0004, respectively). In spite of the small number of patients, preliminary results strongly support the importance of BIPAP in ALS patients, though further studies must go on in order to optimize the best time for introducing Bipap.

Awaji diagnostic algorithm increases sensitivity of El Escorial criteria for ALS diagnosis

We have tested the sensitivity of a recently published approach to combining clinical and EMG data in the ‘research diagnosis’ of ALS, in 55 consecutive patients clinically diagnosed with ALS. The application of this ‘Awaji algorithm’ to the revised El Escorial diagnostic criteria for diagnosis of ALS achieved a diagnostic sensitivity of 95% for definite ALS compared with 18% using the clinical El Escorial criteria and 53% when the EMG criteria as defined in the El Escorial criteria, were applied to the same dataset. This increased sensitivity was particularly relevant for bulbar onset patients (sensitivity improved from 38% to 87%) and for patients with El Escorial clinically possible ALS (from 50% to 86%). We suggest that, in future, investigators and triallists should use the Awaji algorithm superimposed onto the El Escorial criteria, in selecting patients for research studies.

Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease primarily affecting motor neurons. We recently identified intermediate-length polyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in North American ALS patients. To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patients and 679 matched healthy controls. We observed a significant association between polyQ expansions and ALS (>30 Qs; P= 6.2 × 10(-3)). Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with increased risk for ALS also in the European cohort. The specific polyQ length cutoff, however, appears to vary between different populations, with longer repeat lengths showing a clear association. Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease.

Fasciculation potentials: A study of amyotrophic lateral sclerosis and other neurogenic disorders

We studied fasciculation potentials in amyotrophic lateral sclerosis (ALS), and in other neurogenic disorders, in strength and single‐fiber electromyography‐matched muscles. Benign fasciculations were studied in 3 normal subjects. Fasciculations were more stable and easier to recruit voluntarily in the early phase of ALS; later, fasciculations were more unstable, more complex, and less likely to be voluntarily recruited. Stable fasciculations, representing part of large, reinnervated motor units, and probably arising from distal axonal sprouts, usually had a higher firing rate than more complex and unstable fasciculations. In weak muscles in ALS, fasciculations were generally more unstable than in other neurogenic disorders. In normal‐strength muscles fasciculations are less complex in ALS than in other disorders. Benign fasciculations have a high firing rate and normal morphologic parameters. In ALS fasciculations arise proximally early in the disease and distally in the later stages. Fasciculation may be important in excitotoxic cell death in ALS.

Nocturnal pulse oximetry: a new approach to establish the appropriate time for non‐invasive ventilation in ALS patients

Previous studies have supported non‐invasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS), indicating that it prolongs survival. However, criteria for the use of NIV are yet to be defined. The aim of the present study was to evaluate the potential use of nocturnal pulse oximetry (NPO) as a tool for determining the most appropriate time at which to initiate NIV in ALS patients. We conducted a prospective, comparative, historical‐controlled clinical study of 64 consecutive ALS patients. Group 1 (historical control group) comprised 44 patients, 14 women and 30 men, with a mean age of 60+/−13 years, in whom we used NIV after detecting early signs of diurnal respiratory insufficiency (RI). Group 2 had 20 ALS patients, 8 women and 12 men, with a mean age of 56+/−11 years, for whom we started NIV after detecting more than 15 periods of nocturnal desaturation/hour by NPO. All patients were periodically evaluated with Norris spinal and bulbar scores, respiratory function tests (RFT) and NPO at three month intervals for one year. They were subsequently followed until death or loss of autonomy from the ventilator. We compared survival time or time to loss of autonomy from the ventilator between both groups. Survival was longer in Group 2 (p<0.002). We concluded that NPO is a valuable screening test to establish the need for NIV. Our results also suggest that the early diagnosis of RI and the early use of NIV increase patient compliance with NIV.