Mapping Lesion-Related Epilepsy to a Human Brain Network.

Importance: It remains unclear why lesions in some locations cause epilepsy while others do not. Identifying the brain regions or networks associated with epilepsy by mapping these lesions could inform prognosis and guide interventions. Objective: To assess whether lesion locations associated with epilepsy map to specific brain regions and networks. Design, Setting, and Participants: This case-control study used lesion location and lesion network mapping to identify the brain regions and networks associated with epilepsy in a discovery data set of patients with poststroke epilepsy and control patients with stroke. Patients with stroke lesions and epilepsy (n = 76) or no epilepsy (n = 625) were included. Generalizability to other lesion types was assessed using 4 independent cohorts as validation data sets. The total numbers of patients across all datasets (both discovery and validation datasets) were 347 with epilepsy and 1126 without. Therapeutic relevance was assessed using deep brain stimulation sites that improve seizure control. Data were analyzed from September 2018 through December 2022. All shared patient data were analyzed and included; no patients were excluded. Main Outcomes and Measures: Epilepsy or no epilepsy. Results: Lesion locations from 76 patients with poststroke epilepsy (39 [51%] male; mean [SD] age, 61.0 [14.6] years; mean [SD] follow-up, 6.7 [2.0] years) and 625 control patients with stroke (366 [59%] male; mean [SD] age, 62.0 [14.1] years; follow-up range, 3-12 months) were included in the discovery data set. Lesions associated with epilepsy occurred in multiple heterogenous locations spanning different lobes and vascular territories. However, these same lesion locations were part of a specific brain network defined by functional connectivity to the basal ganglia and cerebellum. Findings were validated in 4 independent cohorts including 772 patients with brain lesions (271 [35%] with epilepsy; 515 [67%] male; median [IQR] age, 60 [50-70] years; follow-up range, 3-35 years). Lesion connectivity to this brain network was associated with increased risk of epilepsy after stroke (odds ratio [OR], 2.82; 95% CI, 2.02-4.10; P < .001) and across different lesion types (OR, 2.85; 95% CI, 2.23-3.69; P < .001). Deep brain stimulation site connectivity to this same network was associated with improved seizure control (r, 0.63; P < .001) in 30 patients with drug-resistant epilepsy (21 [70%] male; median [IQR] age, 39 [32-46] years; median [IQR] follow-up, 24 [16-30] months). Conclusions and Relevance: The findings in this study indicate that lesion-related epilepsy mapped to a human brain network, which could help identify patients at risk of epilepsy after a brain lesion and guide brain stimulation therapies.

Brain lesion locations associated with secondary seizure generalization in tumors and strokes.

Structural brain lesions are the most common cause of adult-onset epilepsy. The lesion location may contribute to the risk for epileptogenesis, but whether specific lesion locations are associated with a risk for secondary seizure generalization from focal to bilateral tonic-clonic seizures, is unknown. We identified patients with a diagnosis of adult-onset epilepsy caused by an ischemic stroke or a tumor diagnosed at the Turku University Hospital in 2004-2017. Lesion locations were segmented on patient-specific MR imaging and transformed to a common brain atlas (MNI space). Both region-of-interest analyses (intersection with the cortex, hemisphere, and lobes) and voxel-wise analyses were conducted to identify the lesion locations associated with focal to bilateral tonic-clonic compared to focal seizures. We included 170 patients with lesion-induced epilepsy (94 tumors, 76 strokes). Lesions predominantly localized in the cerebral cortex (OR 2.50, 95% C.I. 1.21-5.15, p = .01) and right hemisphere (OR 2.22, 95% C.I. 1.17-4.20, p = .01) were independently associated with focal to bilateral tonic-clonic seizures. At the lobar-level, focal to bilateral tonic-clonic seizures were associated with lesions in the right frontal cortex (OR 4.41, 95% C.I. 1.44-13.5, p = .009). No single voxels were significantly associated with seizure type. These effects were independent of lesion etiology. Our results demonstrate that lesion location is associated with the risk for secondary generalization of epileptic seizures. These findings may contribute to identifying patients at risk for focal to bilateral tonic-clonic seizures.

Successful suppression of musical hallucinations with low-frequency rTMS of the left temporo-parietal junction: A case report.

BACKGROUND: Inhibitory low frequency repetitive transcranial magnetic stimulation (rTMS) of the temporo-parietal area has been applied to treat both auditory verbal hallucinations as well as tinnitus. OBJECTIVE: We hypothesized that 1 Hz rTMS to the left temporoparietal junction (TPJ) may be beneficial in alleviating musical hallucinations (MH), another condition with auditory experiences in the absence of an external source. METHODS: Here we describe a patient with almost insufferable life-long MH with comorbid depression, who received inhibitory rTMS to the left TPJ as well as the right dorsolateral prefrontal cortex (DLPFC). RESULTS: The intrusiveness and frequency of her MH as well as her depressive symptoms alleviated quickly and substantially, and once-a-week maintenance therapy with rTMS seemed to preserve this amelioration. Future studies will hopefully reveal whether this is a viable treatment approach for other patients suffering from MH with or without comorbid depression.

Non-invasive therapeutic brain stimulation for treatment of resistant focal epilepsy in a teenager.

AIMS: A 13-year-old boy with symptomatic focal epilepsy due to a right parietal dysembryoplastic neuroepithelial tumor (DNET) presented pre- and post-operatively fluctuating tinnitus and sensory symptoms which became persistent after incomplete tumor resection. He received low-frequency rTMS treatment and cathodal tDCS treatment. METHODS: Case report with clinical details and pictures from rTMS and tDCS stimulation targets. RESULTS: The patient became symptom free with an initial low-frequency rTMS treatment series targeted to the EEG-verified epileptic zone followed by maintenance therapy at the same region with cathodal tDCS at home. CONCLUSIONS: Both rTMS and tDCS could be more often used in adolescents when drug treatment and surgery do not cease focal epilepsy, here with fluctuating tinnitus.

Systemic analysis of gene expression profiles identifies ErbB3 as a potential drug target in pediatric alveolar rhabdomyosarcoma.

Pediatric sarcomas, including rhabdomyosarcomas, Ewing's sarcoma, and osteosarcoma, are aggressive tumors with poor survival rates. To overcome problems associated with nonselectivity of the current therapeutic approaches, targeted therapeutics have been developed. Currently, an increasing number of such drugs are used for treating malignancies of adult patients but little is known about their effects in pediatric patients. We analyzed expression of 24 clinically approved target genes in a wide variety of pediatric normal and malignant tissues using a novel high-throughput systems biology approach. Analysis of the Genesapiens database of human transcriptomes demonstrated statistically significant up-regulation of VEGFC and EPHA2 in Ewing's sarcoma, and ERBB3 in alveolar rhabdomyosarcomas. In silico data for ERBB3 was validated by demonstrating ErbB3 protein expression in pediatric rhabdomyosarcoma in vitro and in vivo. ERBB3 overexpression promoted whereas ERBB3-targeted siRNA suppressed rhabdomyosarcoma cell gowth, indicating a functional role for ErbB3 signaling in rhabdomyosarcoma. These data suggest that drugs targeting ErbB3, EphA2 or VEGF-C could be further tested as therapeutic targets for pediatric sarcomas.

EGFR targeting drugs in the treatment of head and neck squamous cell carcinoma.

IMPORTANCE OF THE FIELD: Head and neck cancer is the sixth most common cancer worldwide. Despite intense efforts to improve different treatment modalities, mortality rates in advanced cases remain high. AREAS COVERED IN THE REVIEW: EGFR targeting mAb cetuximab (Erbitux) has been approved for the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) in combination with radiotherapy and for recurrent or metastatic HNSCC. Here, we review recent scientific advances, as well as future research goals regarding EGFR inhibitors in the treatment of HNSCC. Information was compiled by searching the PubMed, Web of Knowledge and American Society of Clinical Oncology databases for articles published before October 2009. The search terms included 'head and neck cancer', 'EGFR', 'cetuximab', 'panitumumab', 'zalutumumab', 'nimotuzumab', 'erlotinib', 'gefitinib' and 'lapatinib'. The National Institutes of Health registry of clinical trials ( www.clinicaltrials.gov ) was used to search for clinical trials in HNSCC. WHAT THE READER WILL GAIN: The background scientific rationale, clinical efficacy and development of EGFR inhibitors in HNSCC are discussed. TAKE HOME MESSAGE: Cetuximab significantly improves survival of patients with locally advanced or metastatic HNSCC. Treatment strategies combining EGFR inhibitors with multimodality approaches may eventually increase cure rate in HNSCC.