Vasilios K. Kimiskidis

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.

Silent period to transcranial magnetic stimulation: construction and properties of stimulus-response curves in healthy volunteers

Silent period (SP) is widely used in transcranial magnetic stimulation studies. Methodologically, SP is usually elicited at stimulus intensities corresponding to a certain percentage of corticomotor threshold. Because this approach might lead to factitious SP changes, the present study was designed to develop, in a stepwise manner, a method for investigating SP independently of corticomotor threshold. First, stimulus–response (S–R) curves of SP against stimulus intensity (SI) were constructed and quantitatively described in healthy volunteers. Second, various methodological issues such as the optimum model for describing the relationship between SP duration and SI and the importance of the type of stimulating coil were addressed. Finally, the proposed method and a commonly used method (eliciting SPs at 130% MT SI) were directly compared for a group of epileptic patients for whom administration of oxcarbazepine resulted in significant corticomotor threshold elevation. Twenty-one subjects (eleven females, median age, 38 years) were studied. SPs were obtained with a figure-of-eight coil using a standardized procedure (recording, FDI). Pilot experiments indicated that at least four trials were required, at each intensity level, to estimate the mean SP duration within 10% of the true mean. Therefore, SPs were determined from the average of four trials with 5% increments from 5 to 100% maximum SI. In a second set of experiments, SPs were obtained for fifteen subjects using a circular coil. In a third set of experiments, eight epileptic patients were studied before and after administration of oxcarbazepine (mean dose 1553 mg, range 900–1800 mg). The S–R curves were fitted to a Boltzman function and to first-order to fourth-order polynomial and sigmoid functions. The Boltzman function described the data accurately (R2=0.947–0.990). In addition, direct comparison of the six models with an F-test proved the superiority of the first. The best-fit parameters of the reference curve, i.e. the maximum and minimum values, the slope, and V50 (the SI at which SP duration is halfway between Min and Max) were 230.8±3.31 ms (x±SEM), −11.51±3.31 ms, 11.56±0.65%, and 49.82±0.65%, respectively. When the curves obtained with the circular coil were compared with those obtained with the figure-of-eight coil, there were differences between V50 (51.69±0.72 vs 47.95±0.82, P<0.001) and SP threshold (31.15 vs 24.77, P<0.01) whereas the other best-fit values did not differ significantly. Oxcarbazepine increased corticomotor threshold from 45.3±5.8% at baseline to 59.4±10.4% (P<0.001). According to the commonly used method, the drug significantly prolonged SP (from 117.6±42.4 ms to 143.5±46.5 ms, P<0.001) and, consequently, enhanced brain inhibition. In contrast, study of the SP curves led to the conclusion that oxcarbazepine does not affect the Max value and slope but significantly increases V50 and SP threshold (from 54.5±4.9% to 59.9±7.2% and from 29.1±6.4% to 34.6±6.8%, respectively, P<0.01). These findings imply that oxcarbazepine does not enhance brain inhibitory mechanisms. Thus, in situations characterized by significant changes in corticomotor threshold the proposed method provides results clearly different from a commonly used approach. It is concluded that S–R curves obtained with a figure-of-eight coil in 5% increments and fitted to a Boltzman function provide an accurate, comprehensive, and clinically applicable method for exploring SP.

Depression and anxiety in epilepsy: the association with demographic and seizure-related variables

BackgroundDepression and anxiety are common psychiatric symptoms in patients with epilepsy, exerting a profound negative effect on health-related quality of life. Several issues, however, pertaining to their association with psychosocial, seizure-related and medication factors, remain controversial. Accordingly, the present study was designed to investigate the association of interictal mood disorders with various demographic and seizure-related variables in patients with newly-diagnosed and chronic epilepsy.MethodsWe investigated 201 patients with epilepsy (51.2% males, mean age 33.2 ± 10.0 years, range 16–60) with a mean disease duration of 13.9 ± 9.5 years. Depression and anxiety were assessed in the interictal state with the Beck Depression Inventory, 21-item version (BDI-21) and the state and trait subscales of the State-Trait Anxiety Inventory (STAI-S and STAI-T), respectively. The association of mood disorders with various variables was investigated with simple and multiple linear regression analyses.ResultsHigh seizure frequency and symptomatic focal epilepsy (SFE) were independent determinants of depression, together accounting for 12.4% of the variation of the BDI-21. The STAI-S index was significantly associated with the type of epilepsy syndrome (SFE). Finally, high seizure frequency, SFE and female gender were independent determinants of trait anxiety accounting for 14.7% of the variation of the STAI-T.ConclusionOur results confirm the prevailing view that depression and anxiety are common psychological disorders in epileptics. It is additionally concluded that female gender, high seizure frequency and a symptomatic epilepsy syndrome are independent risk factors for the development of anxiety and/or depression.

Long-term results of stem cell transplantation for MS A single-center experience

Objective: To report long-term results of a phase I/II study conducted in a single center in order to investigate the effect of hemopoietic stem cell transplantation (HSCT) in the treatment of multiple sclerosis (MS). Methods: Clinical and MRI outcomes of 35 patients with aggressive MS treated with HSCT are reported after a median follow-up period of 11 (range 2–15) years. Results: Disease progression-free survival (PFS) at 15 years is 44% for patients with active CNS disease and 10% for those without (p = 0.01); median time to progression was 11 (95% confidence interval 0–22) and 2 (0–6) years. Improvements by 0.5–5.5 (median 1) Expanded Disability Status Scale (EDSS) points were observed in 16 cases lasting for a median of 2 years. In 9 of these patients, EDSS scores did not progress above baseline scores. Two patients died, at 2 months and 2.5 years, from transplant-related complications. Gadolinium-enhancing lesions were significantly reduced after mobilization but were maximally and persistently diminished post-HSCT. Conclusion: HSCT is not a therapy for the general population of patients with MS but should be reserved for aggressive cases, still in the inflammatory phase of the disease, and for the malignant form, in which it can be life-saving. HSCT has an impressive and sustained effect in suppressing disease activity on MRI. Classification of evidence: This study provides Class IV evidence that HSCT results in PFS rates of 25%. PFS rate was significantly better in patients with active MRI lesions; HSCT also resulted in a significant reduction in the number and volume of gadolinium-enhancing lesions on MRI.

Transcranial magnetic stimulation (TMS) modulates epileptiform discharges in patients with frontal lobe epilepsy: a preliminary EEG-TMS study.

BACKGROUND TMS is being increasingly used as a noninvasive brain stimulation technique for the therapeutic management of partial epilepsies. However, the acute effects of TMS on epileptiform discharges (EDs, i.e. interictal epileptiform activity and subclinical electrographic seizure patterns) remain unexplored. OBJECTIVE To investigate whether TMS can modulate EDs in partial epilepsy. METHODS In Experiment Set 1, the safety of the TMS protocol was investigated in 10 well-controlled by anti-epileptic drugs (AEDs) epileptic patients. In Experiment Set 2, the effects of TMS on EDs were studied in three subjects with intractable frontal lobe epilepsies, characterized by particularly frequent EDs. TMS was applied over the electrographic focus with a circular and a figure of eight coil while recording EEG with a 60-channel TMS-compatible EEG system. The effectiveness of TMS in aborting EDs was investigated using survival analysis and brain connectivity analysis. RESULTS The TMS protocol was well-tolerated. TMS was an effective method to abort EDs even when adjusting for its latency with respect to ED onset (CMH test, p < 0.0001). While the effective brain connectivity around the epileptic focus increased significantly during EDs (p < 0.01), with TMS administration the increase was not statistically significant. CONCLUSION TMS can modulate EDs in patients with epileptogenic foci in the cortical convexity and is associated with reversal of ED-induced changes in brain connectivity.

Cognitive event-related potentials: Longitudinal changes in mild cognitive impairment

OBJECTIVE To measure changes over time in the latency and amplitude of the major waves of auditory event-related potentials (AERP) and their correlation with the memory status of patients with mild cognitive impairment (MCI). METHODS AERPs were recorded in 22 MCI patients (mean±SD age=67.4±7.8, median (interquartile range-IQR) MMSE score=28 (27-29) in three consecutive exams and in 30 age-matched controls at baseline. During this time period, 3 patients converted to Alzheimer disease (AD). Latencies and amplitudes of N200, P300 and Slow Wave and the N200-P300 peak-to-peak amplitudes and latencies were determined, and correlation coefficients (CC) between them and MMSE scores were calculated. RESULTS A significant increase in the P300 latency and a decrease in the N200 amplitude were observed between the exams. Only N200 latency correlated with baseline MMSE scores, whereas P300 and Slow Wave latencies correlated with age. CONCLUSIONS N200 amplitude is more sensitive in identifying differences over time at the early stages of the disease, whereas P300 latency at later stages. SIGNIFICANCE A new N2-P3 inter-peak index that incorporates changes in N200 and P300 latencies and amplitudes into a single parameter is introduced in order to adequately describe the gradual progress of MCI and its transition to AD.

Transcranial Magnetic Stimulation for Drug-Resistant Epilepsies: Rationale and Clinical Experience

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique which, over the last 25 years, has greatly expanded from a simple method for stimulating the motor cortex to an invaluable tool with multiple research, diagnostic and even therapeutic applications. In this review, we discuss the use of repetitive TMS as a means of suppressing cortical hyperexcitability in drug-resistant epilepsies. The theoretical background and the experimental evidence in favor of this novel therapeutic approach are presented, and a number of open-label and controlled studies in patients with various forms of focal epilepsy are reviewed. It is concluded that, although the therapeutic effects of repetitive TMS in epilepsy appear rather limited, further clinical testing of this rapidly evolving technology is warranted.

Autologous stem-cell transplantation in malignant multiple sclerosis: a case with a favorable long-term outcome.

Malignant multiple sclerosis (MS) is a rare but clinically important subtype of MS characterized by the rapid development of significant disability in the early stages of the disease process. These patients are refractory to conventional immunomodulatory agents and the mainstay of their treatment is plasmapheresis or immunosuppression with mitoxantrone, cyclophosphamide, cladribine or, lately, bone marrow transplantation. We report on the case of a 17-year old patient with malignant MS who was treated with high-dose chemotherapy plus anti-thymocyte globulin followed by autologous stem cell transplantation. This intervention resulted in an impressive and long-lasting clinical and radiological response. It is concluded that intensive immunosuppression followed by autologous stem cell transplantation is a viable therapeutic option in patients with malignant MS unresponsive to conventional forms of treatment. Multiple Sclerosis 2008; 17 : 278—283. http://msj.sagepub.com

Transcranial magnetic stimulation for the diagnosis and treatment of epilepsy.

PURPOSE OF REVIEW The aim is to critically review recent advances emerging from the application of transcranial magnetic stimulation (TMS) as a research and clinical tool in the field of epilepsy. RECENT FINDINGS A number of TMS-electromyography (EMG) and TMS-electroencephalography (EEG) studies have identified distinct changes of cortical excitability associated with specific epilepsy syndromes and in asymptomatic siblings of patients with epilepsy. Pharmaco-TMS studies have shed additional light on the effects of traditional and recently introduced antiepileptic drugs on excitatory and inhibitory brain microcircuits as well as cortical plasticity mechanisms. In addition, stronger evidence has emerged that TMS may serve as a biomarker with prognostic (i.e. predicting response to pharmacologic or surgical interventions) and diagnostic potential (for instance aiding in the noninvasive localization of the epileptogenic zone). Finally, the role of repetitive TMS in the therapeutic management of drug-resistant epilepsies and refractory status epilepticus has been further defined and is expected to become more prominent by the optimization of the stimulation parameters. SUMMARY TMS has provided important insight into the pathophysiological substrate of human epilepsies and emerges as a valuable tool with diagnostic, prognostic and therapeutic potential. The recent advent of TMS-EEG can be reasonably expected to contribute further significant advances to the field of epilepsy.

Increased plasma homocysteine levels in patients with multiple sclerosis and depression

BackgroundThe aim of the study was to assess the plasma levels of homocysteine in patients with multiple sclerosis (MS) and to investigate whether an association with depression exists.MethodsPlasma homocysteine (Hcy), vitamin B12 and plasma folate were measured in 65 moderately disabled patients with relapsing/remitting MS (RR-MS) and 60 healthy controls. All subjects were assessed with the Beck Depression Inventory (BDI).ResultsHcy levels were significantly increased in MS patients compared to controls (13.5 ± 4.7 μmol/l vs 8.5 ± 3.1, p < 0.001). A significant correlation was found between Hcy levels and BDI scores (Pearson r = 0.3025, p < 0.05). Plasma Hcy was not related to Extended Disability Status Scale (EDSS) score, age, disease duration or vitamin B12 and folate.ConclusionModerately disabled MS patients with elevated Hcy levels are particularly prone to develop depressive symptomatology. Further study is warranted in order to elucidate the prognostic and therapeutic implications of this novel finding.