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.

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.

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.

The repeatability of corticomotor threshold measurements.

Threshold (Th) is a neurophysiological parameter frequently used in TMS studies. The present study was designed to investigate the repeatability of the Th measurements by reexamining healthy subjects over various time points. Overall, 82 subjects (median age: 19 years, range: 12-65) entered the study. Following a baseline examination, there were six retest sessions: S0 (n = 8 hemispheres reexamined, mean interval x = 19 min), S1 (n = 34 hemispheres reexamined, mean interval x = 4 days), S2 (n = 32 hemispheres, x = 29 days), S3 (n = 30 hemispheres, x = 106 days), S4 (n = 30 hemispheres, x = 183 days) and S5 (n = 30 hemispheres, x = 1867 days). Stimulation was performed with a figure of eight coil and Th was defined at 1% steps. At baseline, controls had an MT of 41.1 +/- 8. Mean difference of MT from baseline was 0.62 on S0 (95% confidence interval (CI) of the difference: -1.04 to +2.29), 0.13 on S1 (95% CI: -1.2 to +1.5), -0.03 on S2 (95% CI: -1.1 to +1.06), -2.07 on S3 (95% CI: -4.33 to +0.19), 0.15 on S4 (95% CI: -0.98 to +1.28) and 0.87 on S5 (95% CI: -0.49 to +2.23). None of these differences were statistically significant (repeated measures ANOVA, P > 0.05). The upper limit of MT difference that an individual subject might have with a probability of 95% (measurement error) was 8. The repeatability of the method was found to be independent from the age of the subjects, the magnitude of threshold or the test-retest interval. The topography of corticomotor threshold was also investigated. Minimal threshold values were obtained from a restricted area of scalp sites that always included the fixed stimulation point of the current protocol. Therefore, using a fixed stimulation point is an adequate technique for measuring threshold. In conclusion, threshold is a stable parameter on an individual and group basis. These data quantify the repeatability of the method and may prove useful in the interpretation of findings during longitudinal studies.