Highlights • Numerous studies have shown that repetitive transcranial magnetic stimulation (rTMS) produced significant clinical effects in patients with various neurological and psychiatric ...disorders. • This review presents guidelines on the therapeutic use of rTMS issued by a group of European experts. • Level A or B evidence supports an efficacy of rTMS protocols in depression, pain, motor stroke and schizophrenia.
Abstract A 65-year-old woman presented with three “convulsive” events that were preceded by stabbing pain extending from the left submandible zone to the neck and ipsilateral ear. ...Video-electroencephalography captured a typical attack, where electrocardiography showed bradycardia for 17 seconds and asystole for at least 9 seconds. The patient lost consciousness while her head/gaze turned right. She then manifested tonic extension of her left limbs followed by adduction of her left limb and flexion of her right upper limb. Her gaze deviated upward and her left upper limb manifested swimming-like automatisms. The full episode lasted about 70 seconds, and the EEG showed progressive diffuse high-amplitude slowing. A diagnosis of convulsive syncope resulting from classic glossopharyngeal neuralgia was made. Carbamazepine led to steady remission. Glossopharyngeal neuralgia is a rare condition (incidence of 0.7/100.000/year), whereas the occurrence of syncope is about 20%, and that of convulsive syncope is about 5%.
In 25 normal subjects, we studied the EMG silent period following the magnetic motor evoked potential (MEP) when the target muscle was tonically contracted (post-EMP silent period PMSP). In the first ...dorsal interosseous muscle (FDI), PMSP duration increased in linear proportion to stimulus intensity, but not to the size of the preceding MEP. The PMSP was longer in hand and forearm muscles than in upper arm muscles. In the FDI, PMSP was longer than the peripheral silent period (PSP) even when multiple peripheral stimuli were used to get M responses whose twitch force was equivalent to that of MEPs. Weak magnetic stimuli evoked silent periods preceded by no MEP in several subjects. Spinal alpha-motoneurons (alpha-MNs) were partially inhibited during the first PMSP portion, but later this effect recovered. MEPs due to weak electrical stimuli to motor cortex were only slightly inhibited during the late PMSP. Segmental inhibitory loops evoked by the muscle twitch and inhibitory projections descending to alpha-MNs from the cortex predominantly underlie earlier PMSP portions, but recurrent intracortical inhibition may also contribute. Later portions are predominantly due to other stimulus-related cerebral inhibitory or suppressing phenomena.
To assess the frequency and clinical characteristics of patients with mutations of major amyotrophic lateral sclerosis (ALS) genes in a prospectively ascertained, population-based epidemiologic ...series of cases.
The study population includes all ALS cases diagnosed in Piemonte, Italy, from January 2007 to June 2011. Mutations of SOD1, TARDBP, ANG, FUS, OPTN, and C9ORF72 have been assessed.
Out of the 475 patients included in the study, 51 (10.7%) carried a mutation of an ALS-related gene (C9ORF72, 32; SOD1, 10; TARDBP, 7; FUS, 1; OPTN, 1; ANG, none). A positive family history for ALS or frontotemporal dementia (FTD) was found in 46 (9.7%) patients. Thirty-one (67.4%) of the 46 familial cases and 20 (4.7%) of the 429 sporadic cases had a genetic mutation. According to logistic regression modeling, besides a positive family history for ALS or FTD, the chance to carry a genetic mutation was related to the presence of comorbid FTD (odds ratio 3.5; p = 0.001), and age at onset ≤54 years (odds ratio 1.79; p = 0.012).
We have found that ∼11% of patients with ALS carry a genetic mutation, with C9ORF72 being the commonest genetic alteration. Comorbid FTD or a young age at onset are strong indicators of a possible genetic origin of the disease.
A large meta‐analysis of genome‐wide association studies has recently identified a number of risk loci for migraine without aura (MwoA). In this study, we tested the hypothesis that a genetic risk ...score based on single‐nucleotide polymorphisms (SNPs), previously reported to be associated with MwoA at genome‐wide significance, may influence headache response to triptans in patients with migraine without aura. Genotyping of rs9349379, rs2078371, rs6478241, rs11172113, rs1024905, and rs6724624 was conducted with a real‐time PCR allelic discrimination assay in 172 MwoA patients, of whom 36.6% were inconsistent responders to triptans. Each genetic risk score model was constructed as an unweighted score, calculated by adding the number of risk alleles for MwoA across each SNP at selected loci. The association with headache response to triptans was evaluated by logistic regression analysis adjusted for triptan, and the P values were corrected for the false discovery rate. The genetic risk score including susceptibility risk alleles at TRPM8 rs6724624 and FGF6 rs1024905 was found to be inversely associated with risk of inconsistent response to triptans (OR, 0.62; 95%CI, 0.43‐0.89; false discovery rate q value, 0.045). In addition, adding this genetic risk score to the triptan‐adjusted logistic regression model significantly improved (P = .037) the discrimination accuracy, from 0.57 (95%CI, 0.50‐0.65) to 0.64 (95%CI, 0.57‐0.72). A modest but significant effect on risk of inconsistent response to triptans was identified for a genetic risk score model composed of 2 known risk alleles for MwoA, suggesting its potential utility in predicting headache response to triptan therapy.
Abstract This article is based on a consensus conference, which took place in Certosa di Pontignano, Siena (Italy) on March 7–9, 2008, intended to update the previous safety guidelines for the ...application of transcranial magnetic stimulation (TMS) in research and clinical settings. Over the past decade the scientific and medical community has had the opportunity to evaluate the safety record of research studies and clinical applications of TMS and repetitive TMS (rTMS). In these years the number of applications of conventional TMS has grown impressively, new paradigms of stimulation have been developed (e.g., patterned repetitive TMS) and technical advances have led to new device designs and to the real-time integration of TMS with electroencephalography (EEG), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Thousands of healthy subjects and patients with various neurological and psychiatric diseases have undergone TMS allowing a better assessment of relative risks. The occurrence of seizures (i.e., the most serious TMS-related acute adverse effect) has been extremely rare, with most of the few new cases receiving rTMS exceeding previous guidelines, often in patients under treatment with drugs which potentially lower the seizure threshold. The present updated guidelines review issues of risk and safety of conventional TMS protocols, address the undesired effects and risks of emerging TMS interventions, the applications of TMS in patients with implanted electrodes in the central nervous system, and safety aspects of TMS in neuroimaging environments. We cover recommended limits of stimulation parameters and other important precautions, monitoring of subjects, expertise of the rTMS team, and ethical issues. While all the recommendations here are expert based, they utilize published data to the extent possible.
LncRNA PCR arrays containing 90 common LncRNAs were used to screen lncRNA expression levels in PBMC from a discovery population of patients with MS. Data from discovery and replications cohorts ...showed a generalized dysregulation of lncRNA levels in MS patients compared with controls. MALAT1, MEG9, NRON, ANRIL, TUG1, XIST, SOX2OT, GOMAFU, HULC, BACE-1AS were significantly downregulated in MS patients in comparison with controls. Therefore, we performed a validation analysis in an independent cohort of Belgian origin. In this study, NRON and TUG1 downregulations in MS patients compared with controls were confirmed (p ≤ .05 and p ≤ .0001 respectively), whereas considering the other lncRNAs, the statistical threshold was not reached. LncRNAs profiling could thus represent a new challenge in the research of easy detectable biomarkers of disease susceptibility and progression.
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•Long non coding RNAs (lncRNAs) have recently found to be dysregulated in MS patients.•LncRNA PCR arrays were used to screen lncRNA expression levels in PBMC from MS patients.•Several lncRNAs were significantly downregulated in MS patients.•NRON and TUG1 downregulations were then confirmed in the Belgian population.•LncRNAs profiling could represent a new challenge in the research of easy detectable biomarkers of disease.
We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal ...cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board.
Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials.
No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease.
We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material.
EudraCT:2009-014484-39 .
Genetic variation in the COMT gene is thought to have clinical implications for pain perception and pain treatment. In the present study, we first evaluated the association between COMT rs4680 and ...the analgesic response to intrathecal morphine in patients with chronic low back pain to provide confirmation of previously reported positive findings. Next, we assessed the relationship between rs4680 and headache response to triptans in 2 independent cohorts of migraine patients. In patients with chronic low back pain (n = 74), logistic stepwise regression analysis showed that age (odds ratio OR: .90, 95% confidence interval CI: .85-.96, P = .002) and the presence of the COMT Met allele (vs Val/Val, OR: .21, 95% CI: .04-.98, P = .048) were predictive factors for lower risk of poor analgesic response to intrathecal morphine. Intriguingly, in migraine patients, the COMT rs4680 polymorphism influenced headache response to triptans in the opposite direction. Indeed, in an exploratory cohort of migraine patients without aura (n = 75), homozygous carriers of the COMT 158Met allele were found at increased risk to be poor responders to frovatriptan when compared to homozygous patients for the Val allele (OR: 5.20, 95% CI: 1.25-21.57, P = .023). In the validation cohort of migraine patients treated with triptans other than frovatriptan (n = 123), logistic stepwise regression analysis showed that use of prophylactic medications (OR: .43, 95% CI: .19-.99, P = .048) and COMT Met/Met genotype (vs Val/Val, OR: 4.29, 95% CI: 1.10-16.71, P = .036) were independent risk factors for poor response to triptans.
This study highlights the importance of COMT rs4680 in influencing the clinical response to drugs used for chronic pain, including opioid analgesics and triptans. These findings also underline a complex relationship between COMT genotypes and pain responder status.
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