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.

Carney complex syndrome manifesting as cardioembolic stroke: a case report and review of the literature.

BACKGROUND: "Carney Complex (CNC) is a familial lentiginosis syndrome, caused by PRKAR1A mutations that lead to cyclic AMP-dependent protein kinase (PKA) signaling pathway abnormalities, predisposing to a variety of skin tumors, myxomas and endocrine tumors. METHODS/RESULTS: We describe a Greek family diagnosed with CNC after recurrent embolic strokes, secondary to left-sided atrial myxomas. There are limited cases in the literature describing this type of presentation for CNC; typically, most cases present with an endocrine syndrome. Our case serves as a reminder of this rare, underdiagnosed syndrome and its wide phenotypic spectrum. It is followed by a review of the current literature on cases with cerebrovascular disease as a manifestation of CNC. CONCLUSION: The co-occurrence of emboligenic cardiac myxomas and skin lesions should be an indication for screening for CNC.

Huntington's disease with comorbid myasthenia gravis: a case report.

BACKGROUND:   In the literature, several reports are describing the coexistence of Huntington's disease (HD) or myasthenia gravis (MG) with other neurodegenerative and autoimmune disorders. Herein, we report a rare case of HD in a 66-year-old male with MG. Description of the case:  The diagnosis of MG was established by acetylcholine receptor antibodies testing and compatible clinical presentation. The diagnosis of HD was based on clinical features, family history, and DNA testing. Several immunologic mechanisms have been proposed regarding the pathogenesis of HD and MG, respectively. Sharing a common autoimmune aspect could be an uncertain but potential association between the two disorders. CONCLUSION:   The probability of HD and MG occurring in the same patient is extremely small. While a number of neurological and autoimmune disorders have been reported with HD and MG, this is the first described coexistence of these two entities. HIPPOKRATIA 2019, 23(1): 28-29.

Non-pharmacological interventions for agitation/aggressive behaviour in patients with dementia: a randomized controlled crossover trial.

Agitation/aggressive behaviour is a common behavioural and psychological symptom in people with dementia (PwD), occurring with a frequency of between 13-50.4% according to recent studies, and the rate increases as the severity of cognitive decline increases. The burden on caregivers is considerable. This trial is a randomized controlled crossover trial conducted in Greece. The following measures were used: the Mini-Mental State Examination, Addenbrooke's Cognitive Examination Revised, Geriatric Depression Scale, Functional Rating Scale for Symptoms in Dementia and Neuropsychiatric Inventory. According to the results the most effective nonpharmacological intervention for reducing agitation/aggressive behaviour in PwD was music therapy, followed by aromatherapy and massage, and finally physical exercise.

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.

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.

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.

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.

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.

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

BACKGROUND: Cognitive 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 METHODS: We 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 Wechsler's 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). RESULTS: We 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. CONCLUSIONS: Our 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.

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.

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.

Sensorineural hearing loss and word deafness caused by a mesencephalic lesion: clinicoelectrophysiologic correlations.

OBJECTIVE: To assess the role of inferior colliculi as a generator of Wave V of brainstem auditory evoked potentials and in modulating the olivocochlear efferent auditory system. STUDY DESIGN: Case review. SETTING: University and tertiary referral centers. PATIENTS: Case report of a patient with word deafness caused by mesencephalic hemorrhage according to audiologic and electrophysiologic findings. RESULTS: The patient is a 48-year-old woman who suffered word deafness caused by hemorrhage localized at the quadrigeminal plate (including the inferior colliculi). At a follow-up visit, her pure-tone audiogram revealed symmetric severe sensorineural hearing loss that had partially resolved, whereas speech audiometry showed persistent word deafness. Acoustic reflexes were elicited, with normal thresholds bilaterally. Transient evoked otoacoustic emissions were recorded from both ears, with normal response and signal-to-noise ratio, but there was a failure for their amplitude to be suppressed with contralateral sound stimulation. Brainstem auditory evoked potentials were of normal amplitude and latencies bilaterally. CONCLUSION: The finding of normal brainstem auditory evoked potentials supports the view that the neural generator of Wave V lies caudally to the inferior colliculi. Moreover, the abnormal suppression of transient evoked otoacoustic emissions indicates that descending collicular input is capable of modulating levels of excitability within the olivary nucleus and the cochlea.

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.