Jibril Osman Farah

Bilateral deep brain stimulation for cervical dystonia: long-term outcome in a series of 10 patients.

BACKGROUND:Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) was shown to be effective in cervical dystonia refractory to medical treatment in several small short-term and 1 long-term follow-up series. Optimal stimulation parameters and their repercussions on the cost/benefit ratio still need to be established. OBJECTIVE:To report our long-term outcome with bilateral GPi deep brain stimulation in cervical dystonia. METHODS:The Toronto Western Spasmodic Torticollis Rating Scale was evaluated in 10 consecutive patients preoperatively and at last follow-up. The relationship of improvement in postural severity and pain was analyzed and stimulation parameters noted and compared with those in a similar series in the literature. RESULTS:The mean (standard deviation) follow-up was 37.6 (16.9) months. Improvement in the total Toronto Western Spasmodic Torticollis Rating Scale score as evaluated at latest follow-up was 68.1% (95% confidence interval: 51.5-84.6). In 4 patients, there was dissociation between posture severity and pain improvement. Prevalently bipolar stimulation settings and high pulse widths and amplitudes led to excellent results at the expense of battery life. CONCLUSION:Improvement in all 3 subscale scores of the Toronto Western Spasmodic Torticollis Rating Scale with bilateral GPi deep brain stimulation seems to be the rule. Refinement of stimulation parameters might have a significant impact on the cost/benefit ratio of the treatment. The dissociation of improvement in posture severity and pain provides tangible evidence of the complex nature of cervical dystonia and offers interesting insight into the complex functional organization of the GPi.

Subdural empyema secondary to sinus infection in children

ObjectiveTo evaluate the impact, on morbidity and mortality, of aggressive surgical management of subdural empyema of sinus origin in children.MethodThe authors conducted a retrospective review of 20 children admitted between 2000–2007 to Alder Hay Children Hospital and The Walton centre for Neurology and Neurosurgery for subdural empyema secondary to sinus infection. Clinical presentation, duration of symptoms, radiological investigations, surgical treatment and post-operative outcome were evaluated.ResultsOutcome was favourable in 19 cases. In four cases, there were re-accumulation requiring surgical evacuation, four patients experienced post-operative seizures but were seizure-free at follow-up. There was only one mortality in the series.ConclusionSubdural empyema secondary to sinus infection, although uncommon, it could be associated with a relative high morbidity and mortality rate. Early aggressive surgical and medical management with drainage of intracranial or sinus collections and antibiotics therapy lead to a low mortality or morbidity rate and good clinical outcome.

Early adjuvant radiotherapy in the treatment of atypical meningioma

Atypical meningiomas have a greater propensity to recur than benign meningiomas and the benefits of early adjuvant radiotherapy are unclear. Existing studies report conflicting results. This retrospective cohort study evaluated the role of early adjuvant radiotherapy following surgical resection of atypical meningioma. A triple center case-note review of adults with newly-diagnosed atypical meningiomas between 2001 and 2010 was performed. Pathology diagnosis was made according to the World Health Organization classification in use at the time of surgery. Patients with multiple meningiomas, neurofibromatosis type 2 and radiation-induced meningiomas were excluded. Extent of resection was defined as gross total resection (GTR; Simpson Grade I-III) or subtotal resection (STR; Simpson Grade IV-V). Survival analysis was performed using the Kaplan-Meier method. One hundred thirty-three patients were identified with a median age of 62years (range 22-86years) and median follow-up of 57.4months (range 0.1-152.2months). Tumors were mostly located in the convexity (50.4%) or falcine/parasagittal regions (27.1%). GTR (achieved in 85%) was associated with longer progression free survival (PFS) (5year PFS 81.2% versus 40.08%, log-rank=11.117, p=0.001) but not overall survival (OS) (5year OS 76.6% versus 39.7%, log-rank=3.652, p=0.056). Following GTR, early adjuvant radiotherapy was administered to 28.3% of patients and did not influence OS (5year OS 77.0% versus 75.7%, log-rank=0.075, p=0.784) or PFS (5year PFS 82.0% versus 79.3%, log-rank=0.059, p=0.808). Although extent of resection emerged as an important prognostic variable, early adjuvant radiotherapy did not influence outcome following GTR of atypical meningiomas. Prospective randomized controlled trials are planned.

Identifying the Biological Pathways Underlying Human Focal Epilepsy: From Complexity to Coherence to Centrality

Numerous diverse biological pathways are dysregulated in the epileptic focus. Which of these pathways are most critical in producing the biological abnormalities that lead to epilepsy? Answering this question is key to identifying the primary causes of epilepsy and for discovering new therapeutic strategies with greater efficacy than currently available antiepileptics (AEDs). We have performed the largest genome-wide transcriptomic analysis to date comparing epileptic with normal human hippocampi. We have identified 118 differentially expressed and, for the first time, differentially connected pathways in the epileptic focus. Using network mapping techniques, we have shown that these dysregulated pathways, though seemingly disparate, form a coherent interconnected central network. Using closeness centrality analysis, we have identified that the most influential hub pathways in this network are signalling through G protein-coupled receptors, in particular opioid receptors, and their downstream effectors PKA/CREB and DAG/IP3. Next, we have objectively demonstrated that genetic association of gene sets in independent genome-wide association studies (GWASs) can be used to identify causally relevant gene sets: we show that proven causal epilepsy genes, which cause familial Mendelian epilepsy syndromes, are associated in published sporadic epilepsy GWAS results. Using the same technique, we have shown that central pathways identified (opioid receptor and PKA/CREB and DAG/IP3 signalling pathways) are genetically associated with focal epilepsy and, hence, likely causal. Published functional studies in animal models provide evidence of a role for these pathways in epilepsy. Our work shows that these pathways play a central role in human focal epilepsy and that they are important currently unexploited antiepileptic drug targets.

Genetic regulation of gene expression in the epileptic human hippocampus

&NA; Epilepsy is a serious and common neurological disorder. Expression quantitative loci (eQTL) analysis is a vital aid for the identification and interpretation of disease‐risk loci. Many eQTLs operate in a tissue‐ and condition‐specific manner. We have performed the first genome‐wide cis‐eQTL analysis of human hippocampal tissue to include not only normal (n = 22) but also epileptic (n = 22) samples. We demonstrate that disease‐associated variants from an epilepsy GWAS meta‐analysis and a febrile seizures (FS) GWAS are significantly more enriched with epilepsy‐eQTLs than with normal hippocampal eQTLs from two larger independent published studies. In contrast, GWAS meta‐analyses of two other brain diseases associated with hippocampal pathology (Alzheimers disease and schizophrenia) are more enriched with normal hippocampal eQTLs than with epilepsy‐eQTLs. These observations suggest that an eQTL analysis that includes disease‐affected brain tissue is advantageous for detecting additional risk SNPs for the afflicting and closely related disorders, but not for distinct diseases affecting the same brain regions. We also show that epilepsy eQTLs are enriched within epilepsy‐causing genes: an epilepsy cis‐gene is significantly more likely to be a causal gene for a Mendelian epilepsy syndrome than to be a causal gene for another Mendelian disorder. Epilepsy cis‐genes, compared to normal hippocampal cis‐genes, are more enriched within epilepsy‐causing genes. Hence, we utilize the epilepsy eQTL data for the functional interpretation of epilepsy disease‐risk variants and, thereby, highlight novel potential causal genes for sporadic epilepsy. In conclusion, an epilepsy‐eQTL analysis is superior to normal hippocampal tissue eQTL analyses for identifying the variants and genes underlying epilepsy.

Serial imaging and management of ganglioglioma with unusual presentation and meningeal spread

Dear Editor, We report the case of a 28-year-old female with migrainous headaches and refractory epilepsy from a ganglioglioma with leptomeningeal extension treated with serial imaging, stepwise medical management, and surgical resection. Gangliogliomas are rare intra-axial tumors (around 1% of cranial CNS neoplasms) of mixed neuronal and glial origin that most commonly occur in the temporal lobes and present with refractory epilepsy predominantly in children and young adults [3, 7]. She described 20 months of a constant left fronto-temporal headache with daily throbbing exacerbations, aggravated by movement, sound, and light. She had no neurological deficits and an ECOG (Eastern Cooperative Oncology Group) score of 1. Her past medical history included depression. Her family history included brain tumors, depression, breast and cervical cancer, but no epilepsy. She developed intermittent diplopia without any obvious ocular cause, 6 weeks of weight loss, and reduced appetite. Moderate pleocytosis on CSF analysis suggested chronic inflammation. MR imaging showed left hippocampal head expansion with T2 hyperintensity and T1 hypointensity. The left postero-lateral midbrain, superior left cerebellar hemisphere cortex and the vermis with its adjacent white matter on the right showed T2 hyperintensity. Contrast demonstrated a homogenously enhancing ovoid lesion arising from the left hippocampal head, extending into the left lateral ventricle temporal horn. Florid thick dural and leptomeningeal enhancement along the left cerebellar convexity, right side of the vermis, left temporal lobe convexity, postero-lateral midbrain, and anterior pons (with enhancement along the left trigeminal nerve) was present. Certain areas suggested intraaxial extension. Enhancing nodules were identified at the right lateral ventricle anterior pole and along the right side of the anterior falx. Figure 1 shows representative images. Her gallium scan was normal. Biopsy in December 2009 was compatible with a low-grade glioma, and possibly a ganglioglioma. Her MRI in July 2010 was unchanged. Biopsy of the meningeal enhancement to exclude a second pathology was considered too hazardous given her symptoms. Despite reporting worsening memory in March 2011, neuropsychological assessment found her cognitive functioning to be average or better in all domains tested, but identified signs of severe anxiety and moderate depression. Nearly 2 years post presentation, partial and generalized tonic clonic seizures developed. Lamotrigine was commenced in May 2012, increasing to 50 mg BD. After MR imaging demonstrated lesion growth, it was excised in October 2012. The histology showed a biphasic tumor composed of ganglioid cells demonstrating a large amphophilic cytoplasm containing vesicular nuclei with prominent nucleoli and * Andrew Dapaah andrewdapaah@silver-rain.com

Upper cervical spinal cord stimulation as an alternative treatment in trigeminal neuropathy

OBJECTIVE To describe the indications and outcomes of upper cervical cord stimulation in trigeminal neuropathy. METHODS A consecutive single-center series of patients was retrospectively reviewed. It included 12 patients with trigeminal neuropathy treated with upper cervical spinal cord stimulation. Clinical features, complications, and outcomes were reviewed. RESULTS All patients had a successful trial before the definitive implantation of a spinal cord stimulator at the level of the craniocervical junction. The mean follow-up period was 4.4 years (range, 0.3-21.1 years). The average coverage in the pain zone was 72% and the median baseline, trial, and postoperative numeric rating scale (NRS) was 7, 3, and 3, respectively. When compared with the baseline, the mean reduction achieved in the postoperative average numeric rating scale was 4 points, accounting for a 57.1% pain reduction. The long-term failure rate was 25%. CONCLUSIONS Despite there being enough evidence to consider upper cervical spinal cord stimulation as an effective treatment for patients with neuropathic trigeminal pain, a randomized controlled trial is needed to fully assess its indications and outcomes and compare it with other therapeutic approaches.

The long-term outcomes of epilepsy surgery

Objective Despite modern anti-epileptic drug treatment, approximately 30% of epilepsies remain medically refractory and for these patients, epilepsy surgery may be a treatment option. There have been numerous studies demonstrating good outcome of epilepsy surgery in the short to median term however, there are a limited number of studies looking at the long-term outcomes. The aim of this study was to ascertain the long-term outcome of resective epilepsy surgery in a large neurosurgery hospital in the U.K. Methods This a retrospective analysis of prospectively collected data. We used the 2001 International League Against Epilepsy (ILAE) classification system to classify seizure freedom and Kaplan-Meier survival analysis to estimate the probability of seizure freedom. Results We included 284 patients who underwent epilepsy surgery (178 anterior temporal lobe resections, 37 selective amygdalohippocampectomies, 33 temporal lesionectomies, 36 extratemporal lesionectomies), and had a prospective median follow-up of 5 years (range 1–27). Kaplan-Meier estimates showed that 47% (95% CI 40–58) remained seizure free (apart from simple partial seizures) at 5 years and 38% (95% CI 31–45) at 10 years after surgery. 74% (95% CI 69–80) had a greater than 50% seizure reduction at 5 years and 70% (95% CI 64–77) at 10 years. Patients who had an amygdalohippocampectomy were more likely to have seizure recurrence than patients who had an anterior temporal lobe resection (p = 0.006) and temporal lesionectomy (p = 0.029). There was no significant difference between extra temporal and temporal lesionectomies. Hippocampal sclerosis was associated with a good outcome but declined in relative frequency over the years. Conclusion The vast majority of patients who were not seizure free experienced at least a substantial and long-lasting reduction in seizure frequency. A positive long-term outcome after epilepsy surgery is possible for many patients and especially those with hippocampal sclerosis or those who had anterior temporal lobe resections.

PO074 The devastating thalamic stroke tremor: does dbs help?

Latero-posterior thalamic strokes are reported to result in delayed onset action tremor, dystonia, pseudoathetosis, chorea and myoclonus. This complex disorder is usually associated with proprioceptive sensory loss and limb ataxia. The tremor has a large amplitude postural component whichworsens on targeted movements; this with the associated sensory loss renders it incapacitating. Thalamic VIM ablation has been reported to improve this tremor. However, deep brain stimulation (DBS) has not. We report 3 cases with post-thalamic stroke tremor, 2 of which have been successfully treated with thalamic DBS; the third is being considered. The first was a 41 year old female who presented with a left sided tremor resulting from a right thalamic stroke after a vertebral artery dissection. The second was a 69 year old male with a right sided tremor resulting from an ischaemic stroke of the left thalamus and the third had bilateral arm tremor resulting from bilateral latero posterior thalamic strokes following a syringomyelia decompression surgery. The tremor in all was of the cerebellar type with joint position sense loss up to the wrist; pseudoathetosis and dystonic posturing. Thalamic DBS ameliorated the large amplitude component of the tremor improving arm function.

An integrative in silico system for predicting dysregulated genes in the human epileptic focus: Application to SLC transporters.

Many different gene families are currently being investigated for their potential role in epilepsy and in the response to antiepileptic drugs. A common research challenge is identifying the members of a gene family that are most significantly dysregulated within the human epileptic focus, before taking them forward for resource‐intensive functional studies. Published data about transcriptomic changes within the human epileptic focus remains incomplete. A need exists for an accurate in silico system for the prediction of dysregulated genes within the epileptic focus. We present such a bioinformatic system. We demonstrate the validity of our approach by applying it to the solute carrier (SLC) gene family. There are >400 known SLCs. SLCs have never been systematically studied in epilepsy.