D. Barry Sinclair

Pediatric Temporal Lobectomy for Epilepsy

Background: Temporal lobectomy in adults is an accepted form of treatment for patients with intractable complex partial seizures. There have been few long-term studies of children undergoing temporal lobectomy for epilepsy. Methods: We reviewed the pediatric cases of temporal lobectomy for intractable epilepsy performed by the Comprehensive Epilepsy Program at the University of Alberta Hospitals between 1988 and 2000. All patients had preoperative and postoperative clinical evaluations, seizure charts, drug levels, EEG, CT/MRI, long-term video EEG monitoring and neuropsychological testing. The patients were reassessed at 6 weeks, 6 months and 1 year postoperatively, then yearly. The duration of follow up was 1–10 years (mean 5 years). Results: Forty-two patients were studied (25 males and 17 females). Age at surgery ranged from 18 months to 16 years. The interictal EEG was abnormal in 38 of the 42 patients. Twenty-two patients had focal epileptic discharge and 1 had generalized epileptic discharge. Focal slowing was seen in 9 patients and diffuse slowing in 5 patients. CT scan was abnormal in 17 of 39 patients and normal in 22 of 39. MRI was abnormal in 34 of 42 patients and normal in 8 of 42. Pathology included brain tumors in 14 patients, mesial temporal sclerosis in 8, focal cortical dysplasia in 4, tuberous sclerosis in 4, dual pathology in 4, porencephalic cyst in 1 and normal pathology or gliosis in 6. Thirty-three of 42 patients (78%) were seizure-free following surgery and an additional 5 (12%) had a decrease in seizure frequency. Three patients had complications, but there were no deaths. Conclusion: Temporal lobectomy is a safe and effective treatment for children with intractable complex partial seizures. Seventy-eight percent of patients are seizure-free following the surgery and there are few complications. MRI is superior to CT scan for detection of temporal lobe pathology yet failed to detect abnormalities in some patients. The most common pathologies found were brain tumors, mesial temporal sclerosis and developmental lesions. In addition to seizure control, many patients experienced improvement in cognitive and psychosocial function following surgery.

Dopamine modulates synaptic plasticity in dendrites of rat and human dentate granule cells

The mechanisms underlying memory formation in the hippocampal network remain a major unanswered aspect of neuroscience. Although high-frequency activity appears essential for plasticity, salience for memory formation is also provided by activity in ventral tegmental area (VTA) dopamine projections. Here, we report that activation of dopamine D1 receptors in dentate granule cells (DGCs) can preferentially increase dendritic excitability to both high-frequency afferent activity and high-frequency trains of backpropagating action potentials. Using whole-cell patch clamp recordings, calcium imaging, and neuropeptide Y to inhibit postsynaptic calcium influx, we found that activation of dendritic voltage-dependent calcium channels (VDCCs) is essential for dopamine-induced long-term potentiation (LTP), both in rat and human dentate gyrus (DG). Moreover, we demonstrate previously unreported spike-timing–dependent plasticity in the human hippocampus. These results suggest that when dopamine is released in the dentate gyrus with concurrent high-frequency activity there is an increased probability that synapses will be strengthened and reward-associated spatial memories will be formed.

Prednisone therapy in pediatric epilepsy

Steroids are often an effective treatment for the Wests syndrome. There have been few reports of steroid use in children with epilepsy outside the first year of life. I report my experience with prednisone for the treatment of older children with intractable epilepsy. Twenty-eight children (17 boys, 11 girls) aged 18 months to 10 years with intractable epilepsy were studied. Prednisone 1 mg/kg/day for 12 weeks (6 weeks daily and 6 weeks alternate therapy) was prescribed in addition to their regular antiepileptic medications. The parents kept seizure diaries, and the patients were regularly assessed for seizure frequency and side effects. The follow-up period was for 1 to 5 years. Thirteen patients (46%) became seizure free on prednisone and another 18 (40%) had a significant decrease in seizure frequency. Five patients (19%) had no change in seizure frequency. The best outcomes were seen in the absence group in which six out of seven patients became seizure free and in the Lennox-Gastaut syndrome group in which seven out of 10 became seizure free. Side effects were uncommon and included weight gain in five patients and aggression in four patients. Prednisone therapy is a safe and effective adjunctive treatment for epilepsy. It should be considered as an alternative treatment for older children with intractable generalized epilepsy who have failed conventional antiepileptic therapy.

Pediatric epilepsy surgery at the University of Alberta: 1988-2000

Epilepsy surgery is considered a treatment option for patients with intractable seizures. Relatively few studies of efficacy, safety, and long-term outcome are available for the pediatric age group. This study describes a 12-year experience with pediatric epilepsy surgery at the University of Alberta. Records of pediatric epilepsy surgery patients admitted to the Comprehensive Epilepsy Program at the University of Alberta between 1988 and 2000 were reviewed. All patients received preoperative and postoperative clinical evaluation, seizure charts, testing of drug levels, electroencephalogram, computed tomography/magnetic resonance imaging, neuropsychologic testing, and long-term video electroencephalogram monitoring. The patients were reassessed after surgery at 6 weeks, 6 months, and 1 year and then yearly. The duration of follow-up was 1 year to 12 years. Forty-two patients underwent temporal lobectomies; 35, extratemporal resection. The age at surgery ranged from 6 months to 16 years. Thirty-two (76%) of temporal lobe patients became seizure-free (Engel Class I) vs 24 (68%) for the extratemporal group (Engel Class I). One patient (2%) in the temporal group had an Engel Class II outcome and one patient (3%) in the extratemporal group had the same Engel Class II outcome. Three patients (4%) manifested postoperative complications, and there were no deaths. Patients reported improvement in cognitive abilities, behavior, and quality of life after the surgery. Epilepsy surgery in children is effective and safe. Many children are seizure-free after the operation and remain so, although the results of temporal lobectomy are better than for extratemporal resections. There are few complications, and children often have an improved quality of life.

Epilepsy surgery in the first 3 years of life: A Canadian survey

Objective:  To determine the clinical characteristics, surgical challenges, and outcome in children younger than 3 years of age undergoing epilepsy surgery in Canada.

Valproic acid-induced pancreatitis in childhood epilepsy: case series and review.

In the past 6 years, 11 children on valproic acid have developed pancreatitis in our childrens hospital. Valproic acid has been used as one of the primary anticonvulsants for generalized seizures in children for the past 25 years. A literature review reveals mostly singular reports of pancreatitis over the past decade. The charts of the 11 patients with valproic acid—induced pancreatitis were reviewed. Dosage, valproic acid serum levels, duration of therapy, and concomitant medications were examined. Families were contacted by telephone to determine the formulation (brand name vs generic) of valproic acid at the time of diagnosis. Six girls and five boys were studied. The ages ranged from 4 to 16 years. Eight of 11 children presented with an acute abdomen. Unexpectedly, three children presented with a flulike illness. Serum lipase values ranged from 341 to 5576 U/L (normal range < 190 U/L). The dose of valproic acid ranged from 20 to 50 mg/kg. Serum levels ranged from 334 to 884 μmol/L (therapeutic range 350—800 μmol/L). Six of the patients were on monotherapy. Seven children were on brand-name drugs. Four of the children had an abnormal neurologic syndromic diagnosis (West syndrome, Rett syndrome, Lowe syndrome, and Angelmans syndrome). Six of the children had a history of drug allergies with a skin rash. Valproic acid was reintroduced in one child and resulted in a second episode of pancreatitis. Resolution of symptoms usually took several weeks following discontinuation of the drug. No association was found with valproic acid dosage, type of preparation, serum levels, duration of therapy, or presence of concomitant medications. Pancreatitis is a severe adverse effect of valproic acid use in children. Dose, duration of treatment, serum valproic acid levels, generic preparation, and the presence of concomitant antiepileptic drugs do not appear to be risk factors. Children with known drug sensitivity might be at risk. Lipase levels at the time of an acute abdomen or a flulike illness in epileptic children taking valproic acid can reveal early stages of pancreatitis and are recommended. (J Child Neurol 2004;19:498—502).

Inflammasome induction in Rasmussen's encephalitis: cortical and associated white matter pathogenesis.

BackgroundRasmussen’s encephalitis (RE) is an inflammatory encephalopathy of unknown cause defined by seizures with progressive neurological disabilities. Herein, the pathogenesis of RE was investigated focusing on inflammasome activation in the brain.MethodsPatients with RE at the University of Alberta, Edmonton, AB, Canada, were identified and analyzed by neuroimaging, neuropsychological, molecular, and pathological tools. Primary human microglia, astrocytes, and neurons were examined using RT-PCR, enzyme-linked immunosorbent assay (ELISA), and western blotting.ResultsFour patients with RE were identified at the University of Alberta. Magnetic resonance imaging (MRI) disclosed increased signal intensities in cerebral white matter adjacent to cortical lesions of RE patients, accompanied by a decline in neurocognitive processing speed (P <0.05). CD3ϵ, HLA-DRA, and TNFα together with several inflammasome-associated genes (IL-1β, IL-18, NLRP1, NLRP3, and CASP1) showed increased transcript levels in RE brains compared to non-RE controls (n = 6; P <0.05). Cultured human microglia displayed expression of inflammasome-associated genes and responded to inflammasome activators by releasing IL-1β, which was inhibited by the caspase inhibitor, zVAD-fmk. Major histocompatibility complex (MHC) class II, IL-1β, caspase-1, and alanine/serine/cysteine (ASC) immunoreactivity were increased in RE brain tissues, especially in white matter myeloid cells, in conjunction with mononuclear cell infiltration and gliosis. Neuroinflammation in RE brains was present in both white matter and adjacent cortex with associated induction of inflammasome components, which was correlated with neuroimaging and neuropsychological deficits.ConclusionInflammasome activation likely contributes to the disease process underlying RE and offers a mechanistic target for future therapeutic interventions.

Bilateral cerebrovascular accidents in incontinentia pigmenti

Incontinentia Pigmenti is an X-linked dominant neurocutaneous disorder with central nervous system manifestations in 30% of cases, including seizures and mental retardation. Ischemic or hemorrhagic cerebrovascular accidents have been reported rarely in incontinentia pigmenti. Chart review and literature search was performed following identification of the index case. We describe a patient with incontinentia pigmenti who developed bilateral cerebrovascular accidents in the neonatal period, with resultant severe neurologic sequelae. This is the second reported case of bilateral cerebrovascular accidents in a patient with incontinentia pigmenti. This finding may be secondary to cerebrovascular anomalies, similar to those observed in the retina. Recognition of cerebrovascular accidents as a complication of incontinentia pigmenti will hopefully lead to earlier recognition and treatment.

Absence Epilepsy in Childhood: Electroencephalography (EEG) Does Not Predict Outcome

Absence epilepsy is a form of generalized epilepsy commonly seen in children. The clinician is often presented with a patient whose electroencephalogram does not fit the typical absence pattern. The purpose of this study is to more closely examine both typical and atypical absence variants and their outcome. A retrospective chart review was performed on children diagnosed with absence epilepsy over the past 5 years at the University of Alberta. A total of 119 patients were reviewed. Patients were classified with typical or atypical absence seizures following International League Against Epilepsy criteria and electroencephalography (EEG) characteristics. Clinical seizure characteristics, magnetic resonance imaging (MRI), initial response to treatment, and outcome were examined. Seizure characteristics were similar in both the typical and atypical absence groups. Aura, complex automatisms, changes in tone, and incontinence were seen in both groups, although status epilepticus was found only in the atypical group. Associated comorbid conditions such as attention-deficit hyperactivity disorder (ADHD), learning disorders, and enuresis were found equally in both groups. Developmental delay was found more often in the atypical group. Of the typical group, 83% responded to an initial antiepileptic drug (either valproic acid or ethosuximide), whereas only 51% of the atypical group came under control. Remission at 2 years however, was similar between groups, with 76% of the typical group and 71% of the atypical group completely seizure free. Absence seizures in childhood, both typical and atypical, share similar clinical and electroencephalographic features and appear to be part of a continuum. Associated comorbid features such as ADHD, learning disorders, and developmental delay are also seen in both groups. The outcome for both types is excellent, although the atypical variants may be initially more difficult to control.

Psychosis With Frontal Lobe Epilepsy Responds to Carbamazepine

Frontal lobe epilepsy is an unusual form of complex partial seizures associated with behavioral changes including fear, agitation, kicking, and screaming. The seizures are often missed or mistaken for psychiatric problems or sleep disorders. We report 2 unusual patients presenting with psychosis who were found to have frequent frontal lobe seizures. Treatment of the seizures with carbamazepine resulted in complete resolution of their psychiatric symptoms. The relationship between frontal lobe seizures and psychosis is explored.