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.

Infliximab induced chronic inflammatory demyelinating polyneuropathy: a case report.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated disease of the peripheral nervous system characterized by motor weakness, sensory symptoms, areflexia, and specific electrophysiological findings. Rarely, Anti-Tumor Necrosis Factor-alpha (anti-TNFa) agents, which are used as a treatment for immune-mediated diseases, can cause neurological adverse effects on the central nervous system, as well as peripheral nervous system demyelination. CASE REPORT: We describe the case of a 63-year-old woman with ankylosing spondylitis who developed chronic inflammatory demyelinating polyneuropathy after infliximab initiation. Considering the absence of other trigger agents from her medical history and the symptom onset, we assume that the development of CIDP is secondary to the anti-TNFa treatment. CONCLUSION: Although demyelinating neurological complications of anti-TNF are rare, pharmacovigilance is required. HIPPOKRATIA 2019, 23(4): 179-180.

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.

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.

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.