Dongmei An

Association between carbamazepine-induced cutaneous adverse drug reactions and the HLA-B*1502 allele among patients in central China

The aim of this study was to investigate the association between carbamazepine (CBZ)-induced cutaneous adverse drug reactions (cADRs) and the HLA-B*1502 allele among patients from central China. Eight patients with Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), 28 with mild maculopapular eruptions (MPEs), 50 CBZ-tolerant controls, and 71 healthy volunteers were recruited. HLA genotyping was performed using the polymerase chain reaction sequence-based typing (SBT) method. As a result, the HLA-B*1502 allele was observed at the following rates: (1) 100% (8/8) among those with CBZ-induced SJS/TEN, (2) 10.7% (3/28) among those with CBZ-induced MPEs; (3) 8.0% (4/50) among CBZ-tolerant controls; (4) 8.5% (6/71) among healthy volunteers. The eight patients with SJS/TEN positive for the HLA-B*1502 allele had an odds ratio (OR) of 184 compared with CBZ-tolerant controls. There was no significant difference in frequency between patients with MPEs and CBZ-tolerant controls (P>0.05). Thus, CBZ-induced SJS/TEN, but not MPEs, is strongly associated with HLA-B*1502. Testing for HLA-B*1502 should be recommended for patients from central China prior to initial CBZ treatment.

Altered Functional and Structural Connectivity Networks in Psychogenic Non-Epileptic Seizures

Psychogenic non-epileptic seizures (PNES) are paroxysmal behaviors that resemble epileptic seizures but lack abnormal electrical activity. Recent studies suggest aberrant functional connectivity involving specific brain regions in PNES. Little is known, however, about alterations of topological organization of whole-brain functional and structural connectivity networks in PNES. We constructed functional connectivity networks from resting-state functional MRI signal correlations and structural connectivity networks from diffusion tensor imaging tractography in 17 PNES patients and 20 healthy controls. Graph theoretical analysis was employed to compute network properties. Moreover, we investigated the relationship between functional and structural connectivity networks. We found that PNES patients exhibited altered small-worldness in both functional and structural networks and shifted towards a more regular (lattice-like) organization, which could serve as a potential imaging biomarker for PNES. In addition, many regional characteristics were altered in structural connectivity network, involving attention, sensorimotor, subcortical and default-mode networks. These regions with altered nodal characteristics likely reflect disease-specific pathophysiology in PNES. Importantly, the coupling strength of functional-structural connectivity was decreased and exhibited high sensitivity and specificity to differentiate PNES patients from healthy controls, suggesting that the decoupling strength of functional-structural connectivity might be an important characteristic reflecting the mechanisms of PNES. This is the first study to explore the altered topological organization in PNES combining functional and structural connectivity networks, providing a new way to understand the pathophysiological mechanisms of PNES.

Association study of lamotrigine-induced cutaneous adverse reactions and HLA-B*1502 in a Han Chinese population

Antiepileptic drugs including lamotrigine (LTG) and carbamazepine (CBZ) are among the most common causes of cutaneous adverse reactions (cADRs). Human leukocyte antigen (HLA)-B*1502 has been strongly associated with CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). To investigate this relationship, we performed high-resolution HLA genotyping on LTG-tolerant controls, healthy volunteers, and patients affected by LTG-induced cADRs, ranging from maculopapular exanthema (MPE) to SJS/TEN. Patients with LTG-induced cADRs (n=25, including three with SJS/TEN and 22 with MPE), 21 LTG-tolerant controls, and 71 healthy volunteers were enrolled. The differences in the starting dosage of LTG among the SJS/TEN, MPE, and LTG-tolerant control groups were not statistically significant. HLA-B*1502 frequency was 33.3% (1/3; LTG-induced SJS/TEN group), 9.1% (2/22; LTG-induced MPE group), 4.8% (1/21; LTG-tolerant group), and 8.5% (6/71; healthy volunteers). There was no significant difference in the frequency of subjects with the HLA-B*1502 allele between the SJS/TEN group and LTG-tolerant group (p=0.239, OR=10.0, 95% CI 0.44-228.7), and healthy volunteers (p=0.26, OR=5.42, 95% CI 0.43-68.8), MPE and LTG-tolerant groups (p=1.0, OR=1.08, 95% CI 0.20-5.8), and healthy volunteers (p=1.0, OR=2.0, 95% CI 0.17-23.9). None of the HLA alleles detected were associated with LTG-induced cADRs. In conclusion, HLA-B*1502 and other HLA alleles are not directly associated with LTG-induced MPE. The possibility that HLA-B*1502 is associated with an increased risk of LTG-induced SJS/TEN could not be excluded.

Electroencephalography/functional magnetic resonance imaging responses help predict surgical outcome in focal epilepsy

Simultaneous electroencephalography/functional magnetic resonance imaging (EEG/fMRI) recording can noninvasively map in the whole brain the hemodynamic response following an interictal epileptic discharge. EEG/fMRI is gaining interest as a presurgical evaluation tool. This study aims to determine how hemodynamic responses related to epileptic activity can help predict surgical outcome in patients considered for epilepsy surgery.

Abnormal functional connectivity density in psychogenic non-epileptic seizures

PURPOSE Psychogenic non-epileptic seizures (PNES) are paroxysmal behaviors that resemble epileptic seizures but lack abnormal electrical activity. Some neuroimaging studies have reported that PNES exhibits aberrant functional connectivity in specific brain networks. Thus, advanced neuroimaging technologies may aid clinical diagnosis and treatment of PNES. METHODS We investigated changes in brain functional connectivity in 18 patients with PNES and 20 healthy controls. Functional connectivity density mapping (FCDM), a voxelwise data-driven technique, was employed to compute local and global FCD maps. Then, short-range and long-range FCD values were calculated and group analyses performed between patents with PNES and healthy controls. A correlation analysis with clinical variables was also performed. RESULTS We found that patients with PNES showed abnormal FCD regions mainly in the frontal cortex, sensorimotor cortex, cingulate gyrus, insula and occipital cortex. Seed-voxel correlation analyses also showed disrupted functional connectivity between these regions. In addition, the occipital cortex FCD correlated with duration of disease. CONCLUSION The present results support the hypothesis that patients with PNES are associated with altered attention, sensorimotor and emotion systems. Furthermore, correlations between altered regions in the occipital cortex and duration of disease may reflect an adaptation in these patients for long-term hypervigilance and increased response to external stimuli. This study adds new knowledge to our understanding of the pathophysiological mechanisms underlying PNES.

Pilot association study of oxcarbazepine-induced mild cutaneous adverse reactions with HLA-B*1502 allele in Chinese Han population

BACKGROUND Recent study demonstrated that HLA-B*1502 was a common risk allele in aromatic antiepileptic drugs (AEDs) induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. However, the association of AEDs-induced mild maculopapular eruption (MPE) with HLA-B*1502 remains unclear until recently. In the present study, we conducted a pilot study to detect a possible association of oxcarbazepine (OXC)-induced MPE with HLA-B*1502 allele in Chinese Han population. METHODS We enrolled 90 subjects involving 9 patients with OXC-induced MPE and two groups of controls, 9 OXC-tolerant and 72 normal controls. High-resolution HLA genotyping was performed by specific kit. The results of HLA genotyping are expressed as positive or negative for HLA-B*1502 allele. Differences in genotype frequencies between groups were assessed by the Fishers exact test. RESULTS Four cases were detected as positive for HLA-B*1502 amongst 9 patients. However, only 1 subject was positive amongst 9 tolerant controls, and 6 subjects were positive amongst 72 normal controls. The difference in HLA-B*1502 allele frequencies between the MPE group and normal controls was statistically significant (OR: 8.8; 95% CI: 1.853-41.790; P=0.011). In addition, we also observed an increased frequency of HLA-B*1502 allele in patients (44.44%) compared with tolerant controls (11.11%), although it failed to reach statistical significance (P=0.294). CONCLUSIONS Our findings indicate that HLA-B*1502 allele may contribute to the genetic susceptibility to OXC-induced MPE in Chinese Han population. In order to safer AEDs use, we recommend that HLA-B*1502 allele should be tested for patients with OXC-induced MPE before changing to other AEDs, and AEDs with similar chemical structure should be avoided in individuals who test positive for HLA-B*1502 allele. It should be pointed out that, however, our results may well be just by chance owing to the small sample size and should be further confirmed in future studies.

Resting-state fMRI study of treatment-naïve temporal lobe epilepsy patients with depressive symptoms.

BACKGROUND Patients with temporal lobe epilepsy are at high risk for comorbid depression, and it is hypothesized that these two diseases are share common pathogenic pathways. We aimed to characterize regional brain activation in treatment-naïve temporal lobe epilepsy patients with depressive symptoms and compare the results to epilepsy patients without depressive symptoms and to healthy controls. SUBJECTS AND METHODS We recruited 23 treatment-naïve patients (including anti-epilepsy drugs (AEDs) and antidepressants) and 17 matched healthy controls for this study. The patients were further divided into two groups: patients with depressive symptoms and patients without; the patients then used a self-rating depression scale (SDS) to assess their depression. All participants underwent resting functional magnetic resonance imaging (fMRI) scans using the Trio Tim magnetic resonance (MR) image system (3.0 T). The data were processed and analyzed using REST and SPSS11.5 software. RESULTS The patients with depressive symptoms showed significantly higher activity in the bilateral thalamus, insula and caudate and right anterior cingulate compared with the two other groups (p<0.05, corrected). Brain network connectivity analysis revealed that connectivity decreased in the prefrontal-limbic system and increased within the limbic system and angular gyrus in patients with depressive symptoms (p<0.05, corrected). CONCLUSION The epilepsy patients with depressive symptoms showed regional brain activity alterations and disruption of the mood regulation network at the onset of seizures. The present study offers further insight into the underlying neuropathophysiology of epilepsy with depressive symptoms.

Patient-specific connectivity pattern of epileptic network in frontal lobe epilepsy

There is evidence that focal epilepsy may involve the dysfunction of a brain network in addition to the focal region. To delineate the characteristics of this epileptic network, we collected EEG/fMRI data from 23 patients with frontal lobe epilepsy. For each patient, EEG/fMRI analysis was first performed to determine the BOLD response to epileptic spikes. The maximum activation cluster in the frontal lobe was then chosen as the seed to identify the epileptic network in fMRI data. Functional connectivity analysis seeded at the same region was also performed in 63 healthy control subjects. Nine features were used to evaluate the differences of epileptic network patterns in three connection levels between patients and controls. Compared with control subjects, patients showed overall more functional connections between the epileptogenic region and the rest of the brain and higher laterality. However, the significantly increased connections were located in the neighborhood of the seed, but the connections between the seed and remote regions actually decreased. Comparing fMRI runs with interictal epileptic discharges (IEDs) and without IEDs, the patient-specific connectivity pattern was not changed significantly. These findings regarding patient-specific connectivity patterns of epileptic networks in FLE reflect local high connectivity and connections with distant regions differing from those of healthy controls. Moreover, the difference between the two groups in most features was observed in the strictest of the three connection levels. The abnormally high connectivity might reflect a predominant attribute of the epileptic network, which may facilitate propagation of epileptic activity among regions in the network.

Altered intrinsic functional connectivity of the salience network in childhood absence epilepsy

Intrinsic connectivity analysis provides an original way for evaluating functional impairments in epilepsy. Disturbances in the salience network (SN) have been positing an important interplay in disorders of consciousness and attention. This study aims to assess the intrinsic connectivity of the SN in childhood absence epilepsy (CAE). Resting state fMRI was performed in 21 patients with CAE and 21 healthy controls. The SN was extracted using group independent component analysis with dual-regression. Intrinsic functional integration was evaluated through voxelwise comparisons between patients and controls. Patients showed a decreased functional integration of the SN in the right anterior insula, anterior temporoparietal junction, and bilateral dorsolateral frontal cortex and increased connectivity in the anterior and middle cingulate gyrus and caudate nuclei. A leftward lateralization was observed in the anterior insula and anterior temporoparietal junction in CAE. Moreover, the lateralized index in the anterior insula was significantly correlated with the duration of epilepsy. These results support the disturbance of intrinsic activity in the SN which may be linked to the interruption of salient information processing and associated with the attentional dysfunction in CAE. Our findings demonstrate the potential value of intrinsic activity in the SN for the investigation of attention process and may help to better understand the association between intrinsic activity in the SN and consciousness.

Predictive markers for carbamazepine and lamotrigine-induced maculopapular exanthema in Han Chinese

The aims of this study were to clarify the possible associations of carbamazepine (CBZ)- and lamotrigine (LTG)-induced maculopapular exanthema (MPE) with the human leukocyte antigen (HLA) alleles in Chinese patients. A total of 249 subjects, including 40 patients with CBZ-induced MPE (CBZ-MPE), 43 patients with LTG-induced MPE (LTG-MPE), 52 CBZ-tolerant controls, 42 LTG-tolerant controls and 72 healthy controls, were included in this study. High-resolution HLA genotyping was performed by a specific kit. Differences in the allele frequencies among the groups were assessed. The allele frequencies of HLA-A*0201 and HLA-DRB1*1405 were significantly higher (P=0.033 and P=0.003, respectively), but those of HLA-B*5801 and HLA-DRB1*0301 (P=0.037 and P=0.024, respectively) were lower in the CBZ-MPE patients when compared with the CBZ-tolerant group. We also observed two significantly increased alleles of HLA-A*3001 and HLA-B*1302 (P=0.013 and P=0.013, respectively) and a decreased allele of HLA-A*3303 (P=0.048) in the LTG-MPE patients when compared with those in the LTG-tolerant group. Our results support the hypothesis that these HLA alleles contribute to the genetic susceptibility to CBZ/LTG-MPE and may be valuable as potential biomarkers for CBZ/LTG-MPE in Han Chinese.