Dimitrios Kazis

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.

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

Novel mutation of the PRNP gene of a clinical CJD case

BackgroundTransmissible spongiform encephalopathies (TSEs), a group of neurodegenerative diseases, are thought to be caused by an abnormal isoform of a naturally occurring protein known as cellular prion protein, PrPC. The abnormal form of prion protein, PrPSc accumulates in the brain of affected individuals. Both isoforms are encoded by the same prion protein gene (PRNP), and the structural changes occur post-translationally. Certain mutations in the PRNP gene result in genetic TSEs or increased susceptibility to TSEs.Case presentationA 70 year old woman was admitted to the hospital with severe confusion and inability to walk. Relatives recognized memory loss, gait and behavioral disturbances over a six month period prior to hospitalization. Neurological examination revealed Creutzfeldt-Jakob disease (CJD) related symptoms such as incontinence, Babinski sign and myoclonus. EEG showed periodic sharp waves typical of sporadic CJD and cerebrospinal fluid analysis (CSF) was positive for the presence of the 14-3-3-protein. As the disease progressed the patient developed akinetic mutism and died in the tenth month after onset of the disease symptoms. Unfortunately, no autopsy material was available. PRNP sequencing showed the occurrence of a point mutation on one allele at codon 193, which is altered from ACC, coding for a threonine, to ATC, encoding an isoleucine (T193I).ConclusionHere we report a novel mutation of the PRNP gene found in an elderly female patient resulting in heterozygosity for isoleucine and threonine at codon 193, in which normally homozygosity for threonine is expected (T193). The patient presented typical clinical symptoms of CJD. EEG findings and the presence of the 14-3-3 protein in the CSF, contributed to CJD diagnosis, allowing the classification of this case as a probable CJD according to the World Health Organization (WHO) accepted criteria.

The role of SOAT-1 polymorphisms in cognitive decline and delirium after bypass heart surgery

AbstractBackgroundCognitive decline (CD) and delirium (PD) are commonly observed complications after bypass heart surgery. In this study we aimed to investigate whether certain genetic factors (alleles of the SOAT-1 gene) play a role in their appearance.Patients and methodsWe examined 137 patients receiving coronary bypass surgery with a neuropsychiatric test battery consisting of the Mini Mental State Examination (MMSE), the Brief Psychiatric Rating Scale (BPRS), the Wechslers Memory Scale-Revised (WMS-R) on admission and one month after surgery, and the Delirium Rating Scale postoperatively, when indicated, and genotyped them in relation to the SOAT–1 genotypes (AA positive group with augmented protection of the nerve cells against stress and the AA negative group – AC and CC subgroups – with diminished protection against stress).ResultsWe noted a significant decline in test results postoperatively and a high frequency of delirium (29.92% of the patients). None of these complications could be associated to the SOAT-1 genotypes.ConclusionsOur study confirmed the expected cognitive decline and highly frequent delirium after bypass heart surgery and excluded the possible role of SOAT-1 genotype polymorphisms in their genesis.

Frequency distribution of dextromethorphan O-demethylation in a Greek population

OBJECTIVE To determine the CYP2D6 phenotype in a Greek population by using dextromethorphan (DM) as a probe drug. METHODS DM (30 mg) was given orally to 102 unrelated Greek subjects and 8-hour urine samples were collected. Concentrations of DM and its metabolite dextrorphan (DX) were determined using a validated HPLC assay. Metabolic molar ratio (MR) of DM to free DX in log form was used as an in vivo index of metabolic status. RESULTS The frequency distribution histogram of MR was bimodal. An antimode of 0.25 for the mean log MR was determined using probit analysis. Seven of 102 subjects (6.9%) were poor metabolizers (PMs). CONCLUSION The PM frequency of CYP2D6 in Greek subjects was similar to other Caucasian populations.

An open-label, add-on study of pregabalin in patients with partial seizures: A multicenter trial in Greece

INTRODUCTION Pregabalin efficacy and safety as an adjunctive treatment for partial seizures was evaluated using an open-label, flexible-dose. STUDY DESIGN In 98 adults with refractory partial epilepsy taking 1-3 anti-epileptic drugs with ≥2 seizures during an 8-week baseline period. METHODS Pregabalin was increased to ≤600 mg/day during a 9-week dose optimization period with dosage maintained for 12 additional weeks. Primary endpoint was the percentage change in partial seizure frequency between the 8-week baseline and 12-week observation period. RESULTS Pregabalin treatment was associated with a significant reduction in partial seizure frequency: median percent change in partial seizure frequency from baseline to 12 weeks was -33% and -22% in patients with a baseline seizure frequency of ≤3 and >3 per 28 days, respectively. The 50% and 75% responder rates were 41.94% (95% CI: 31.91-51.96) and 30.11% (95% CI: 20.78-39.43), respectively. Nineteen percent of subjects were seizure-free throughout the last 12 weeks. Pregabalin administration resulted in a significant reduction in anxiety (mean reduction in Hospital Anxiety and Depression Scale scores of 1.68 units, 95% CI: -2.60 to -0.76). Most patients were much improved or very much improved on Patient Global Impression of Change (53.8%) and Clinical Global Impression of Change (53.8%). The most frequently self-reported adverse events (AEs) were mild or moderate somnolence (20.4%) and dizziness (5.1%) with a low AE discontinuation rate (5.1%). CONCLUSIONS The efficacy and side-effect profile of pregabalin were similar to previous pregabalin double-blind, controlled studies. Additionally, pregabalin, as an add-on treatment for partial epilepsy, exhibits significant anti-anxiety properties.

Miller-Fisher Syndrome: Are Anti-GAD Antibodies Implicated in Its Pathophysiology?

Miller-Fisher syndrome (MFS) is considered as a variant of the Guillain-Barre syndrome (GBS) and its characteristic clinical features are ophthalmoplegia, ataxia, and areflexia. Typically, it is associated with anti-GQ1b antibodies; however, a significant percentage (>10%) of these patients are seronegative. Here, we report a 67-year-old female patient who presented with the typical clinical features of MFS. Workup revealed antibodies against glutamic acid decarboxylase (GAD) in relatively high titers while GQ1b antibodies were negative. Neurological improvement was observed after intravenous gamma globulin and follow-up examinations showed a continuous clinical amelioration with simultaneous decline of anti-GAD levels which finally returned to normal values. This case indicates that anti-GAD antibodies may be associated with a broader clinical spectrum and future studies in GQ1b-seronegative patients could determine ultimately their clinical and pathogenetic significance in this syndrome.

Diagnostic challenge of non-specific visual symptoms: consideration of Heidenhain variant of Creutzfeldt-Jakob disease

Sporadic Creutzfeldt-Jakob disease (sCJD) belongs to the human transmissible spongiform encephalopathies or prion diseases that are caused by the propagation of the abnormally conformed infectious protein named prion (PrPSc). Typically sCJD manifests as rapidly progressive dementia and myoclonus, often associated with ataxia, pyramidal and extrapyramidal signs. Visual symptoms are described in about 10 per cent to 15 per cent of the patients at disease onset and in about 50 per cent during the course of the disease. However, there are some rare cases in which the disease is presented with isolated visual disturbances and without cognitive decline, which can persist for weeks or even months. This subclass of the disease is known as ‘Heidenhain’ variant. Here, we report a case of Heidenhain variant of sCJD (HvCJD) underlining the importance of clinical suspicion of this variant for patients presenting with persistent isolated visual symptoms. CASE REPORT

Investigation of the motor system in two siblings with Canavan’s disease: a combined transcranial magnetic stimulation (TMS) – diffusion tensor imaging (DTI) study

Canavan’s disease (CD) is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to spongiform degeneration of the white matter and severe impairment of psychomotor development. We present the cases of two non-Jewish sisters with CD that have a milder and protracted clinical course compared to typical CD. MRI imaging revealed bilateral high-signal-intensity areas in the thalami and the internal capsule and MR spectroscopy showed typical findings for CD (a marked increase in N-acetylaspartate (NAA) levels). FA values of the right and left corticospinal tracts at the level of the posterior limb of the internal capsule, and the centrum semiovale were found to be significantly reduced compared to healthy controls. From a neurophysiological point of view, the peripheral motor system was normal. In contrast, cortical stimulation at maximal intensity failed to elicit facilitated or resting MEPs and silent periods (SPs) in upper and lower limbs, providing evidence for significant upper motor pathway dysfunction.

P11-14 Transcranial magnetic stimulation terminates epileptiform discharges in patients with partial epilepsy: a combined EEG-TMS study

Chronic stroke patients with moderate-to-severe hemiparesis often suffer from motor deficits associated with flexor hypertonia, as well as motor weakness in their paretic upper-limbs. The enhancement of the extensor function, to counteract the flexor hypertonia, might be useful for those patients. However, the beneficial effects of training in chronic-phase patients are relatively limited. Additional extensor training of the affected hand did not change the clinical outcome (Trombly, 1986). As presented before, we found that combining extensor training with repetitive transcranial magnetic stimulation (rTMS; EEx-TMS) could facilitate use-dependent plasticity (UDP) both in stroke and healthy people, and can achieve functional recovery that cannot be attained by either intervention alone in stroke patients. In previous reports, therapeutic TMS protocols for stroke patients could induce long-lasting effects by repeating the stimulation for 1 month (Khedr et al., 2005; Fregni et al., 2006). Therefore, we examined whether 12 times (once a day, on two days a week for 6 week) of repeating the EEx-TMS session (EEx: voluntary upper-limb extensors contraction of wrist and fingers in paretic side supported by neuromuscular stimulation, TMS: 5 Hz high frequency stimulation) could induce the long-term effects, resulting in sustained functional improvements of paretic upper limbs in nine chronic stroke patients. As a result, we found that repeating the EEx-TMS sessions over 6 weeks (12 times in total) could produce sustained improvements of function (active range of movement of hands, grip power and pinch force) and hypertonia of the paretic upper limb for >2 weeks in chronic stroke patients. The 12 times repeating of the EEx-TMS session could induce the long-term effects, resulting in sustained functional improvements of paretic upper limbs in chronic stroke patients. This method could be a powerful rehabilitative approach for hemiparetic stroke patients.