Molecular and Clinical Characteristics of Different Toxicity Rates in Anti-CD19 Chimeric Antigen Receptor T Cells: Real-World Experience.

Commercially available anti-CD19 chimeric antigen receptor T cells (CARΤ cells) have offered long-term survival to a constantly expanding patient population. Given that novel toxicities including cytokine release syndrome (CRS) and neurotoxicity (ICANS) have been observed, we aimed to document the safety and toxicity of this treatment in a real-world study. We enrolled 31 adult patients referred to our center for CAR T therapy. Tisagenlecleucel was infused in 12 patients, axicabtagene ciloleucel in 14, and brexucabtagene autoleucel in 5. Cytokine release syndrome was noted in 26 patients while neurotoxicity was observed in 7. Tocilizumab was administered for CRS in 18 patients, along with short-term, low-dose steroid administration in one patient who developed grade III CRS and, subsequently, grade I ICANS. High-dose steroids, along with anakinra and siltuximab, were administered in only two MCL patients. With a median follow-up time of 13.4 months, nine patients were then in CR. The progression-free (PFS) and overall survival (OS) rates were 41.2% and 88.1% at one year, respectively. MCL diagnosis, which coincides with the administration of brexucabtagene autoleucel, was the only factor to be independently associated with poor OS (p < 0.001); meanwhile, increased LDH independently predicted PFS (p = 0.027).In addition, CRP at day 14 was associated with a poor OS (p = 0.001). Therefore, our real-world experience confirmed that commercial CAR T therapy can be administered with minimal toxicity.

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.

Dysfibrinogenemia and multiple sclerosis: spuriously associated or causally linked?

BACKGROUND: The inherited dysfibrinogenemias comprise rare congenital coagulation disorders which are clinically characterized by bleeding diathesis and, in occasional patients, by thrombotic tendency or combined bleeding-thrombotic events. In recent years, accumulating evidence suggested that fibrinogen has a critical role in the pathogenesis of neuroinflammatory disorders, including multiple sclerosis. We describe the presentation and long-term follow-up of a patient with inherited dysfibrinogenemia and concomitant clinical and laboratory evidence of demyelinating disease.   Case description:  A 16-year-old male patient presented in 2003 with bilateral sensory symptomatology preceded by an episode of epistaxis. His past medical history included episodes of spontaneous nosebleeds as well as Duane syndrome and mild atrophy of the right upper limb. Coagulation testing of the patient and his asymptomatic father revealed in both the presence of a clotting defect, consistent with inherited dysfibrinogenemia (named Fibrinogen Thessaloniki). Within seven months, the patient presented with a new episode of motor semiology whereas serial brain magnetic resonance imaging (MRI) scans revealed T2 lesions with bilateral distribution, some of which with gadolinium enhancement. The cerebrospinal fluid examination disclosed the presence of oligoclonal bands in the central nervous system compartment. The patient was started on azathioprine (2.5 mg/kg/24h) which led to clinical and radiological stabilization for nine years. In 2013, the dose of azathioprine was reduced, due to an elevation of his amylase levels, resulting in radiological deterioration with an increased T2 lesion load. The reinstitution of azathioprine at therapeutic doses led to radiological improvement and clinical stability as of today. CONCLUSION: The described case of inherited dysfibrinogenemia and concomitant multiple sclerosis provides speculative evidence for a causal link, rather than a chance association, between these two entities. Further studies are warranted to corroborate this hypothesis in experimental and clinical settings. HIPPOKRATIA 2017, 21(1): 49-51.

Central motor pathways in tropical spastic paraparesis: a combined transcranial magnetic stimulation and diffusion tensor imaging study.

BACKGROUND: Previous transcranial magnetic stimulation (TMS) studies in patients with tropical spastic paraparesis (TSP) have focused on central motor conduction time measurements while other TMS parameters remained unexplored. From a neuroradiological point of view, pyramidal tract involvement with magnetic resonance imaging and diffusion tensor imaging (DTI) has been rarely reported in TSP.  Accordingly, the present study investigated the mean threshold (MT) and silent period (SP) as well as DTI measurements in TSP. CASE DESCRIPTION: A 35-year-old female patient presented with a 15-year history of spastic paraparesis with minimal upper-limb involvement. Serum and cerebrospinal fluid samples were positive for HTLV-I. TMS was performed with a figure-of-eight coil (recording, abductor hallucis and first dorsal interosseous muscles). Thr was measured at 1 % steps. SPs were elicited at 5 % increments from 0 to 100 % maximum stimulus intensity (SI), and data were used to construct a stimulus/response (S/R) curve of SI vs SP. The resulting S/R curves were fitted to a Boltzmann equation and statistically compared to control data. Voxel-based DTI analysis was performed with SPM 99. Corticospinal tractography was based on diffusion tensor data. The TMS examination disclosed that MT was significantly increased (54.5 ± 6.36 % vs 41.08 ± 7.85 % in a group of 82 controls, p=0.019). The patient's SP S/R curve had significantly reduced Max values compared to 13 age-matched controls (160.4 ± 0.91 ms vs 228.36 ± 38.69 ms, p <0.001). Fractional anisotropy was decreased in a cluster of voxels corresponding to the area of the pyramidal tract (0.388 ± 0.015 vs 0.506 ± 0.02 in 20 age-matched controls, p <0.001). CONCLUSION: The described results provide novel neurophysiological and imaging evidence for central motor pathways malfunctioning in TSP. HIPPOKRATIA 2017, 21(4): 191-193.

The Hemiconvulsions-Hemiplegia-Epilepsy (HHE) syndrome: a transcranial magnetic stimulation-EEG study.

BACKGROUND: The Hemiconvulsions-Hemiplegia-Epilepsy (HHE) syndrome is currently regarded as an extremely rare condition. The etiological and pathophysiological mechanisms underlying this medical rarity as well as the optimal therapeutic approaches remain poorly defined and understood. We present the clinical, radiological and electroencephalography (EEG) findings of a patient with the HHE syndrome and describe the response of the continuously present epileptiform abnormalities to transcranial magnetic stimulation (TMS). CASE DESCRIPTION: A 33-year old male patient was referred to our department for investigation and management of intractable epilepsy. His seizures began at the age of three months when, during the course of a common febrile illness, he developed repetitive clonic seizures involving the left upper and lower limbs, followed by permanent left hemiplegia. After extensive investigations, he was diagnosed with "idiopathic" HHE syndrome. Currently, he suffers from left hemiplegia, severe intellectual impairment [Intelligence Quotient (IQ) <30] and asymmetric, bilateral tonic seizures occurring 1-3 times daily despite treatment with valproate, topiramate, lamotrigine, rufinamide, and perampanel. Brain magnetic resonance imaging revealed atrophy of the right hemisphere and serial EEGs disclosed continuous sharp waves, the generators of which were localized by electrical source imaging (ESI) to two distinct sources within the right hemisphere. Repetitive TMS [210 stimuli of 1 Hz at 100 % corticomotor threshold applied with a circular coil over the generators of epileptic discharges (EDs)] resulted in a statistically significant decrease of ED counts compared to sham stimulation and the post-verum TMS period. CONCLUSION: We present the clinical-laboratory profile and the long-term follow up of a patient with the HHE syndrome. Further, we describe the effects of TMS on EDs. The latter observation raises the possibility that TMS-EEG may be used in select cases with intractable epilepsy as a surrogate marker of responsiveness to more invasive modalities (i.e., cortical stimulation). HIPPOKRATIA 2017, 21(2): 101-104.

Transcranial magnetic stimulation (TMS) coupled with electroencephalography (EEG): Biomarker of the future.

INTRODUCTION: In recent years, a number of novel brain-stimulation techniques have been developed (such as TMS-EEG, TMS-fMRI and TMS-NIRS), yet they remain underutilized in the field of epilepsy. Accumulating evidence suggests that transcranial magnetic stimulation (TMS) combined with electroencephalography (TMS-EEG) is a highly relevant technique for exploration of the pathophysiology of human epilepsies as well as a promising biomarker with diagnostic and prognostic potential. RESULTS: In genetic generalized epilepsies, TMS-EEG has provided pathophysiological insight by revealing quasi-stable, covert states of excitability, a subclass of which is associated with the generation of TMS-induced epileptiform discharges (EDs). In focal epilepsy, TMS-induced EDs were successfully employed to identify the epileptogenic zone. In addition, TMS trains applied during focal EDs can terminate them, and appear to restore the effective connectivity of the brain network significantly altered by EDs. This abortive effect of TMS on EDs may possibly serve as a biomarker of response to invasive neuromodulatory techniques. CONCLUSION: TMS-EEG-based stimulation paradigms can provide insight into the mechanisms underlying human epilepsies and, thus, warrant further study as diagnostic and prognostic biomarkers.

The impact of oxaliplatin-based chemotherapy for colorectal cancer on the autonomous nervous system.

BACKGROUND: The oxaliplatin (ΟΧΑ)-based regimens FOLFOX and XELOX can cause peripheral neuropathy. It is unknown if ΟΧΑ, alone or in combination regimens, affects the Autonomous Nervous System (ANS). Accordingly, we evaluated the impact of ΟΧΑ-based chemotherapy on the ANS. METHODS: We enrolled 36 patients with colorectal cancer, treated with adjuvant mFOLFOX6 or XELOX chemotherapy, and 22 healthy volunteers. For the assessment of ANS function, participants completed a questionnaire and underwent neurophysiological examination at three time points (baseline, 3-4 months and 6-8 months after the first chemotherapy cycle). ANS testing included assessment of the adrenergic cardiovascular function (orthostatic hypotension-OH), parasympathetic heart innervation (ratio 30/15) and Sympathetic Skin Response (SSR). RESULTS: The values of the 30/15 ratio were significantly reduced at the two time point assessments compared to baseline (Wilcoxon signed ranks test, both P < 0.001), while patients had more often diastolic OH at the 6-8 month evaluation compared to baseline (P = 0.039). In contrast, SSR was not affected. The incidence of positive responses in the questionnaire assessing the subjective impact of symptoms attributable to ANS dysfunction was higher at the two time points compared to baseline (P = 0.036 and P = 0.020). CONCLUSIONS: Oxaliplatin-based chemotherapy is associated with significant effects on the adrenergic cardiovascular reaction and the parasympathetic heart innervation, whereas SSR remains untouched.

Topiramate promotes neurological recovery in a new model of traumatic brain injury in rats.

The aim of this study is to investigate the neuroprotective effects of the anticonvulsant topiramate in a new model of traumatic brain injury in rats. A new model of traumatic brain injury, based on the weight-drop technique, was developed for the purpose of this study. Seventy-five male Wistar rats weighing 320-470 g were studied. All rats were anesthetized, subsequently submitted to a round craniectomy in the left parietal region and a weight of 50 g was used for the production of a cortical contusion. In study I, 44 rats were randomized in three groups to receive either topiramate 40 mg/kg (n=13), topiramate 60 mg/kg (n=14), or water for injection (n=17) i.p. 30 min after the injury and every 12 h thereafter for 3 days. The rats were tested clinically 24 h, 72 h, 10 days and 20 days after the injury. On day 21 the animals were sacrificed and the brains were removed and prepared for histopathological analysis. In study II, 19 rats were randomized to receive either topiramate 60 mg/kg (n=10) or water for injection (n=9) i.p. 30 min after the injury and every 12 h (four doses in total). 48 h after the injury the animals were sacrificed and the brains were rapidly removed and analyzed for water content with the dry-wet weight technique. The animals that received topiramate performed significantly better in neurological tests compared to the animals that received vehicle ten (P<0.05) and 20 (P<0.001) days after the injury. There was no difference between the high and the low dose of the drug. Topiramate had no effect on the anatomic volume of the lesion. The animals that received topiramate had a tendency to present with less cerebral edema formation, but the difference was not statistically significant (P>0.05). These findings suggest that topiramate promotes neurological recovery in rats after traumatic brain injury without affecting the final size of the traumatic lesion and that it might play a role in the reduction of post-traumatic cerebral edema.

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.

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.

Combination of P300 and CSF ß-amyloid(1-42) assays may provide a potential tool in the early diagnosis of Alzheimer's disease.

BACKGROUND/AIMS: The aim of this study was to investigate the diagnostic role of CSF beta amyloid(1-42) levels and auditory event-related potentials (AERPs) in the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHODS: In fifty three MCI patients a lumbar puncture was performed and beta amyloid(1-42) levels were determined. Twenty patients were re-examined after 11 months. During this period five of them progressed to AD. Neuropsychological and ERP examinations were performed in all patients at both exams. RESULTS: Compared to MCI stable patients, AD-converters showed significantly lower beta-amyloid(1-42) values both for group 1 (Mann Whitney test, Z=-2.952, p=0.003, effect size r=-0.41) and group 2 (Z=-2.458, p=0.011; effect size r=-0.55). On the other hand, the patients of group 1 who converted to AD had prolonged latencies and lower amplitudes of the P300 wave compared to those of the MCI-stable patients, although the differences were not significant. CONCLUSIONS: Compared to the separate use of CSF beta-amyloid(1-42) and AERPs, higher values of sensitivity and specificity were achieved by the combined use of beta-amyloid(1-42) levels and P300 latencies (80% and 98%) or amplitudes (100% and 89%) in the discrimination between AD converters and MCI stable patients. Therefore the combination of an electrophysiological and a biological marker is potentially of high diagnostic value for the early diagnosis of AD converters.

Progression of mild cognitive impairment to Alzheimer's disease: improved diagnostic value of the combined use of N200 latency and beta-amyloid(1-42) levels.

BACKGROUND/AIMS: The aim of this study was to investigate the role of cerebrospinal fluid beta-amyloid(1-42) levels and auditory event-related potentials (AERPs) in the progress of mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHODS: In 53 MCI patients, lumbar puncture was performed and beta-amyloid(1-42) levels were determined. Twenty patients were reexamined after 11 months. During this period, 5 of them progressed to AD. Neuropsychological and ERP analyses were performed on all patients during both baseline and endpoint examinations. RESULTS: Compared to stable MCI patients, those that progressed to AD had significantly lower beta-amyloid(1-42) levels (Mann-Whitney test, Z = -2.952, p = 0.003; effect size r = -0.41) and significantly prolonged N200 latencies (Mann-Whitney test, Z = -3.561, p < 0.001, effect size r = -0.49). From ERP variables, only the N200 latency significantly correlated with beta-amyloid(1-42) levels (baseline examination: r(s) = -0.421, p = 0.002; follow-up examination: r(s) = -0.574, p = 0.008). CONCLUSIONS: The combined use of these two parameters enabled discrimination of stable MCI patients from those who developed AD, with 100% sensitivity and specificity. Therefore, this method could be of high diagnostic value for the early diagnosis of AD.

Prediction of conversion from mild cognitive impairment to Alzheimer's disease by CSF cytochrome c levels and N200 latency.

The aim of the present study was to investigate the role of CSF cytochrome c levels and auditory event-related potentials (AERPs) on the progress of mild cognitive impairment (MCI) to Alzheimer's disease (AD). Fifty one patients diagnosed with MCI and fourteen healthy individuals underwent lumbar puncture at baseline and their CSF cytochrome c levels were determined. A follow-up examination of cytochrome c levels took place in 20 patients after 11 months and in this period five of the patients progressed to AD. ERP examinations were also performed in all patients both at baseline and follow-up. MCI patients had significantly higher cytochrome c levels compared to healthy controls (Mann-Whitney test, Z=-2.110, p=0.018). Compared to MCI patients who remained stable, the AD-converters, had a higher increase over time in cytochrome c levels (Mann-Whitney test, p=0.002; effect size r=0.63) and significantly prolonged N200 latency (Mann-Whitney test, p<0.001; effect size r=0.50). Amongst investigated ERP variables, only N200 amplitude was significantly correlated with CSF cytochrome c levels (rs=0.310, p=0.03). Both parameters were proved capable of discriminating AD converters from those MCI patients who remained stable, with sensitivity and specificity >75%. Our results suggest that conversion from MCI to AD is associated with a marked elevated N200 latency at baseline and a high increase in cytochrome c levels during a relatively short period of time, and that both parameters could be possibly considered as candidate markers for the discrimination between MCI patients who convert to AD and those who remain stable.

Idiopathic scoliosis: a transcranial magnetic stimulation study.

STUDY DESIGN: Various neurophysiological parameters of the motor system were investigated in 43 female patients with Idiopathic Scoliosis (IS) and 31 sex and age matched controls using transcranial magnetic stimulation (TMS). OBJECTIVE: To investigate whether asymmetries in excitatory and inhibitory brain processes, as studied by TMS, are a causative factor in IS. SUMMARY OF BACKGROUND DATA: Previous studies associated IS with pathological asymmetries of the cerebral cortex and the brain stem at the level of the corticospinal tracts. METHODS: Forty-three female patients with right IS and 31 normal female subjects entered the study. Various TMS parameters, including the study of ipsilateral pyramidal tract, were studied. Electrophysiological data were correlated with clinical data, the degrees of the scoliotic curve and the Perdriolle and Nash & Moe indexes. RESULTS: In upper limbs, detailed testing failed to reveal any statistically significant differences between the patient and the control group. In lower limbs, side-to-side differences of central motor conduction time (CMCT) and facilitated cortical-to-muscle latencies were increased in the scoliotic patients (p<0.05). This finding correlated significantly with Nash & Moe and Perdriolle indexes (Spearman's r=0.406 and 0.575, respectively, p<0.05). Following the Bonferroni adjustment, however, differences in CMCT SSDs were not statistically significant (p>0.05). CONCLUSION: The present TMS data do not support the concept of a generalized brain asymmetry in IS. In lower limbs, a trend towards increased asymmetries in side-to-side differences of CMCT and cortical latencies was detected probably representing subclinical involvement of the corticospinal tracts secondary to mechanical compression. Finally, it is concluded that non-decussation of the pyramidal tracts is not involved in the pathogenesis of IS.

Lorazepam-induced effects on silent period and corticomotor excitability.

TMS studies on the CNS effects of benzodiazepines have provided contradictory results. The objective of this study is to describe the effects of lorazepam on silent period (SP) and corticomotor excitability. Twelve healthy male subjects (median age 35 years) were studied at baseline, following i.v. lorazepam administration and after reversal of the benzodiazepine effects with i.v. flumazenil. Lorazepam was given at a low-dose in one subject (0.0225 mg/kg bolus + 2 microg/kg/h infusion) and at a high-dose (0.045 mg/kg bolus + 2.6 microg/kg/h infusion) in the rest. Threshold (Thr) was measured at 1% steps. SPs were investigated with two complementary methods. First, SPs were elicited using a wide range of stimulus intensities (SIs) (from 5 to 100% maximum SI at 5% increments). At each SI, four SPs were obtained and the average value of SP duration was used to construct a stimulus/response (S/R) curve of SI versus SP .The resulting S/R curves were then fitted to a Boltzman function, the best-fit values of which were statistically compared for each experimental condition (i.e., baseline vs. lorazepam vs. flumazenil). Second, a large number of SPs (n=100) was elicited during each of the three experimental conditions using blocks of four stimuli with an intensity alternating between MT and 200% MT. This method was employed so as to reveal the dynamic, time-varying effects of lorazepam and flumazenil on SP duration at two stimulus intensity (SI) levels. MEP recruitment curves were constructed at rest and during activation and fitted to a Boltzman function the best-fit values of which were statistically compared for each experimental condition. Lorazepam at a low dose did not affect Thr, SP, or the active MEP recruitment curves. The high dose also had no effect on Thr and the active MEPs whereas the resting MEP recruitment curves were depressed post-lorazepam at the higher range of stimulus intensities. With regard to SP, the Max value of the S/R curve decreased from 251+/-4.6 ms at baseline to 215.2+/-3.1 ms post-lorazepam (P<0.01). V50 also decreased significantly (from 47.92+/-0.9% to 43.73+/-0.81%, P<0.01) whereas there was no significant change regarding slope and SP Thr. The statistical analysis of the SP S/R curves as well as the study of SPs at two SI levels revealed that lorazepam reduced SP duration when high intensity stimuli were used (>60%). In contrast, at low SIs a small increase in SP duration was noted post-drug. Enhancement of GABAergic inhibition by lorazepam results in a reduction of SP duration when high SIs is used. At the lower range of SIs, a small but statistically significant increase in SP duration is observed. The kinetic behavior of this phenomenon as well as the possible underlying mechanisms are discussed.

Add-on topiramate in the treatment of refractory partial-onset epilepsy: clinical experience of outpatient epilepsy clinics from 11 general hospitals.

An open, prospective, observational study was performed to assess efficacy and adverse-event profile of topiramate as add-on therapy in epilepsy. Outpatient neurology clinics from 11 general hospitals in Greece participated in the study. In total, 211 patients with treatment resistant partial-onset seizures who met the inclusion criteria, were studied. After baseline evaluation, topiramate was given at a target dose of 200mg/day over a 1-month titration period. In the subsequent maintenance period, the topiramate dose could be varied according to the clinical results. Patients were followed for in total 6 months, with monthly visits and regular physical, neurological and laboratory examinations. Seizure frequencies decreased to 35--40% of baseline values following 3 months of treatment and remained relatively constant thereafter. The average monthly seizure frequency over the 6-month study period was 4.61, compared to 9.21 at baseline. The number of responders (patients with at least 50% reduction in seizure frequency) followed a similar pattern, i.e., increase during the first 3 months levelling off at a final 80--85% response rate. Of those completing the study, 30% had been seizure-free for at least 3 months and 12% for 5 months. Topiramate was well tolerated, no deviations in laboratory values were found. Adverse events appeared to occur less frequently, and antiepileptic effects were more pronounced in this prospective open-label study than in earlier reports from randomised controlled trials. The nature of the patient population and the application of individualised dose optimisation are proposed as contributing factors to explain the favourable results of this study.

Changes in blood neurotransmitter and steroid levels during evoked vertigo.

HYPOTHESIS AND BACKGROUND: Experimental evidence suggests that steroids as well as various neurotransmitters are critically involved in the functioning of the vestibular system in health and disease. Yet there are no pertinent human data. We hypothesized that changes in the serum levels of cortisol and plasma levels of excitatory and inhibitory neurotransmitters may occur during evoked vertigo. SUBJECTS AND METHODS: Ten healthy volunteers (median age 37, range 21-57) entered the study. Subjects were investigated at rest and at the time of maximal nystagmic reaction during caloric irrigation. The determination of glutamate, aspartate, and gamma-aminobutyric acid (GABA) was performed by reverse phase high-performance liquid chromatography, whereas cortisol measurements were performed with an immunoenzymatic assay with fluorescence polarization. RESULTS: During evoked vertigo, cortisol levels increased from a baseline value of 11.86 (+/-1.272) microg/dl to 14.375 (+/-2.183) microg/dl (p < 0.01), whereas all neurotransmitter levels decreased significantly. Glutamate levels, for instance, fell from a resting value of 25.99 (+/-6.30) ng/ml to 17.40 (+/-5.50) ng/ml (p < 0.001), and aspartate and GABA decreased as well. CONCLUSION: Evoked vertigo is consistently associated with an increase in steroid serum levels and accompanying decreases in the plasma levels of glutamate, aspartate, and GABA. The possible underlying mechanisms and the functional significance of these findings are discussed.

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.

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.