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

BACKGROUND: Rasmussen'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. METHODS: Patients 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. RESULTS: Four 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-1ß, 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-1ß, which was inhibited by the caspase inhibitor, zVAD-fmk. Major histocompatibility complex (MHC) class II, IL-1ß, 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. CONCLUSION: Inflammasome activation likely contributes to the disease process underlying RE and offers a mechanistic target for future therapeutic interventions.

Depth electrodes in pediatric epilepsy surgery.

BACKGROUND: The surgical removal of the epileptogenic zone in medically intractable seizures depends on accurate localization to minimize the neurological sequelae and prevent future seizures. To date, few studies have demonstrated the use of depth electrodes in a pediatric epilepsy population. Here, we report our study of pediatric epilepsy patients at our epilepsy center who were successfully operated for medically intractable seizures following the use of intracranial depth electrodes. In addition, we detail three individuals with distinct clinical scenarios in which depth electrodes were helpful and describe our technical approach to implantation and surgery. METHODS: We retrospectively reviewed 18 pediatric epilepsy patients requiring depth electrode studies who presented at the University of Alberta Comprehensive Epilepsy Program between 1999 and 2010 with medically intractable epilepsy. Patients underwent cortical resection following depth electrode placement according to the Comprehensive Epilepsy Program surgical protocols after failure of surface electroencephalogram and magnetic resonance imaging to localize ictal onset zone. RESULT: The ictal onset zone was successfully identified in all 18 patients. Treatment of all surgical patients resulted in successful seizure freedom (Engel class I) without neurological complications. CONCLUSION: Intracranial depth electrode use is safe and able to provide sufficient information for the identification of the epileptogenic zone in pediatric epilepsy patients previously not considered for epilepsy 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.

Neuroimaging in pediatric temporal lobe epilepsy: Does neuroimaging accurately predict pathology and surgical outcome?

Temporal lobe epilepsy (TLE) in children is considered different from that in adults. As such, characterizing the structural lesions present in pediatric patients with TLE and their association with long-term seizure control is important. Here, we aimed to assess the concordance between preoperative imaging and postoperative histopathological diagnoses and their associations with seizure outcomes in pediatric patients with TLE undergoing temporal lobe surgery. We retrospectively reviewed the charts of pediatric patients with TLE who underwent surgical treatment between 1988 and 2020 as a part of the Comprehensive Epilepsy Program at the University of Alberta. Demographic, age at seizure onset, age at surgery, preoperative electroencephalography (EEG), long-term video EEG, imaging (magnetic resonance imaging [MRI] and computed tomography), neuropathology, and long-term seizure outcome data were acquired and analyzed. One hundred and seventeen patients underwent surgery for refractory TLE; the preoperative MRI diagnosis was concordant with the histopathological diagnosis in 76 % of cases. Tumors were identified with high accuracy (91 %). Mesial temporal sclerosis (MTS) was strongly associated with an excellent outcome after surgery (94 %). Patients with normal imaging results or non-specific pathologies were more likely to experience poor seizure outcomes after surgery (50 %). The radiological identification of lesions was associated with good long-term seizure outcomes, whereas normal MRI results were associated with significantly poorer long-term seizure outcomes. An accurate preoperative MRI is essential to epilepsy surgery since it impacts all stages of management; these results will thereafter help inform practitioners' efforts to predict seizure outcome.

Selective amygdalohippocampectomy: surgical outcome in children versus adults.

INTRODUCTION: The objective of the study was to review our experience with selective amygdalohippocampectomy (SAH) in children and adults with intractable temporal lobe epilepsy. METHODS: A retrospective case series was used in the setting of a tertiary care hospital which provides epilepsy care to both children and adults. All patients underwent a selective amygdalohippocampectomy procedure and had at least one year of follow-up. Adults and children were divided into two groups and the data was compared between children and adults. RESULTS: Twenty three patients, 9 children and 14 adults were studied. Age of surgery varied from 6 to 58 years. Surgical outcome was variable between the two groups. Amongst the children, three patients (33%) were seizure-free (Engel Class I), two patients (22%) had rare seizures (Engel Class II), one patient (11%) had a worthwhile decrease in seizures (Engel class III) and three patients (32%) had refractory seizures that required re-operation with an anterior temporal lobectomy. This differed from the adults, who all had a good outcome. Ten patients (71%) were seizure-free (Engel Class I) and the remainder (29%) had rare seizures (Engel Class II). CONCLUSION: Selective amygdalohippocampectomy can lead to excellent seizure surgical outcome in adults with refractory temporal lobe epilepsy. However, preliminary results show less favorable results in children. The difference is probably related to the different pathology between the two groups. Anterior temporal lobe resection may prove to be a more successful operation than SAH in children with intractable temporal lobe epilepsy.

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.

Seizure outcome in pediatric medically refractory temporal lobe epilepsy surgery: selective amygdalohippocampectomy versus anterior temporal lobectomy.

OBJECTIVE The aim of this study was to investigate long-term seizure outcome, rate of reoperation, and postoperative neuropsychological performance following selective amygdalohippocampectomy (SelAH) or anterior temporal lobectomy (ATL) in pediatric patients with medically refractory temporal lobe epilepsy (TLE). METHODS The authors performed a retrospective review of cases of medically refractory pediatric TLE treated initially with either SelAH or ATL. Standardized pre- and postoperative evaluation included seizure charting, surface and long-term video-electroencephalography, 1.5-T MRI, and neuropsychological testing. RESULTS A total of 79 patients treated initially with SelAH (n = 18) or ATL (n = 61) were included in this study, with a mean follow-up of 5.3 ± 4 years (range 1-16 years). The patients' average age at initial surgery was 10.6 ± 5 years, with an average surgical delay of 5.7 ± 4 years between seizure onset and surgery. Seizure freedom (Engel I) following the initial operation was significantly more likely following ATL (47/61, 77%) than SelAH (8/18, 44%; p = 0.017, Fisher's exact test). There was no statistically significant difference in the proportion of patients with postoperative neuropsychological deficits following SelAH (8/18, 44%) or ATL (21/61, 34%). However, reoperation was significantly more likely following SelAH (8/18, 44%) than after ATL (7/61, 11%; p = 0.004) and was more likely to result in Engel I outcome for ATL after failed SelAH (7/8, 88%) than for posterior extension after failed ATL (1/7, 14%; p = 0.01). Reoperation was well tolerated without significant neuropsychological deterioration. Ultimately, including 15 reoperations, 58 of 79 (73%) patients were free from disabling seizures at the most recent follow-up. CONCLUSIONS SelAH among pediatric patients with medically refractory unilateral TLE yields significantly worse rates of seizure control compared with ATL. Reoperation is significantly more likely following SelAH, is not associated with incremental neuropsychological deterioration, and frequently results in freedom from disabling seizures. These results are significant in that they argue against using SelAH for pediatric TLE surgery.

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.

Benign epilepsy of childhood with rolandic spikes: typical and atypical variants.

Clinical course and outcome were compared for 126 children with typical and atypical features of benign epilepsy of childhood with rolandic spikes (BECRS). A retrospective case series design was used, in the setting of a tertiary-care pediatric hospital. The subjects were subdivided into two groups, based on clinical presentation. Group A comprised children with typical features of BECRS (n = 66; 52%) and Group B, those with atypical features (n = 60; 48%). Patients' charts were reviewed for demographic data, family history, comorbid conditions, atypical clinical features, anti-epileptic drugs, and outcome data. Comorbid disorders (e.g., attention deficit hyperactivity disorder, behavioral problems) were slightly more frequent in the atypical group. Overall, there was no difference between the time to become seizure free between the groups: by two years, 41 of 66 in Group A (62%) and 44 of 60 in Group B (71%) were controlled on medication and seizure free. Twenty of the 126 children (16%) required trial of a second anti-epileptic drug: 7 in Group A and 13 in Group B. Resolution of the epilepsy occurred in about the same length of time in both groups (but at different ages, consistent with different age of onset). Both groups had similar long-term outcome.

Discontinuation of antiepileptic drugs after pediatric epilepsy surgery.

In children with medically intractable seizures, epilepsy surgery is now a widely accepted option. Successful discontinuation of antiepileptic drugs after epilepsy surgery has been reported in adults, but rarely in children. Surgical outcome and need for antiepileptic drugs after temporal and extratemporal lobe resection were retrospectively reviewed for 80 pediatric patients from the Comprehensive Epilepsy Program at the University of Alberta. For 1 year after surgery, children were maintained on at least one antiepileptic drug. Antiepileptic drug discontinuation was attempted in all patients with a nonepileptic electroencephalogram after 1 year seizure-free. Less than half of the patients (44%) eventually relapsed without antiepileptic drugs. Of the 40 patients in the temporal lobe group, 13 (32%) relapsed without antiepileptic drugs, as did 22 of the 40 extratemporal lobe resection patients (55%). Success rates for antiepileptic drug discontinuation after surgery were higher in the temporal lobe than in the extratemporal lobe group. Long-term antiepileptic drugs are not necessary in all cases, and for many children medication can be withdrawn after epilepsy surgery.

Tuberous sclerosis with open lipped schizencephaly.

Tuberous sclerosis is a multisystem disorder that is transmitted in an autosomal dominant fashion. It affects approximately 1 in 10,000 live births. A growing body of evidence implicates a defect of cell maturation and migration in the pathogenesis of many of the lesions in tuberous sclerosis affecting the central nervous system. There have been numerous case reports of various abnormalities of neuronal migration associated with tuberous sclerosis. To our knowledge, there has only been one case of schizencephaly reported in a patient with tuberous sclerosis. The present report describes a male with tuberous sclerosis and an extensive open lipped schizencephalic cleft affecting his right frontoparietal lobe. This case supports the hypothesis that the cerebral lesions in tuberous sclerosis are secondary to a defect in neuronal maturation and migration.

Clinical significance of photic stimulation during routine EEGs of adult patients.

Intermittent photic stimulation (IPS) is an activating procedure meant to elicit or accentuate epileptiform discharges during an EEG. There is insufficient clinical data to advocate IPS in the routine EEGs of all adult patients. We therefore sought to address the clinical significance of routine IPS in the adult population. We retrospectively reviewed 100 consecutive abnormal EEGs in adult patients (inpatients and outpatients) who had undergone photic stimulation in our laboratory. Nine patients had abnormalities noted during IPS. The abnormalities consisted of sharp waves in four patients and focal slowing in five patients. Only one patient had abnormalities on IPS that provided information additional to that seen on the baseline record.

Corticosteroids for the treatment of Landau-kleffner syndrome and continuous spike-wave discharge during sleep.

Landau-Kleffner syndrome and its variants such as continuous Spike-Wave Discharge during Sleep (CSWS) are progressive epileptic encephalopathies of childhood. The treatment of this unusual group of patients is controversial. We describe our experience in treating patients with Landau-Kleffner syndrome and CSWS with corticosteroids. The patients received Prednisone 1 mg/kg/day for 6 months, 1 year, then yearly. Follow-up was for 1-10 years (mean 4 years). Ten patients, 3 females, 7 males were studied. Age of onset ranged from 2 to 11 years (mean 7.5 years). Eight patients manifested Landau-Kleffner syndrome, and two had CSWS. Most patients had seizures (8/10); however, two patients did not have clinical seizures. MRI was normal in all patients. SPECT scan was abnormal in four patients, normal in three, and not available in three. All but one patient manifested significant improvement in language, cognition, and behaviour, which continued after the corticosteroid trial. Side effects were few (4/10) and transient and consisted of weight gain (2), behavioral change (1), and hypertension (1). Corticosteroids are a safe and effective treatment for patients with Landau-Kleffner syndrome and CSWS. Most patients had improvement in language, cognition, and behaviour after treatment. Side effects are few and reversible, and benefits appear long lasting. Corticosteroids should be considered as a treatment option in children with Landau-Kleffner syndrome and CSWS.

Neuroimaging features of acute disseminated encephalomyelitis in childhood.

Acute and disseminated demyelination of the central nervous system in children may have many causes. This study reports a retrospective cohort of 10 consecutive pediatric cases (5 to 17 years; mean [S.D.] 12.1 [4.3] years) with a presenting diagnosis of acute disseminated encephalomyelitis and the clinical and radiologic follow-up. The evolution of magnetic resonance imaging abnormalities was determined from serial studies in nine patients with a mean (S.D.) follow-up of 334.2 (312.8) days. Resolution of magnetic resonance imaging T(2) prolongation (i.e., demyelination) within 6 months of presentation was associated most commonly with a final clinical diagnosis of acute disseminated encephalomyelitis (including the multiphasic form), but failed to meet statistical significance (Fisher's exact test; P = 0.083). Incomplete resolution of the magnetic resonance imaging signal abnormalities yielded a statistically significant association (Fisher's exact test; P = 0.048) with an abnormal neurologic outcome. In summary, we conclude that early resolution of magnetic resonance imaging signal abnormalities or recurrent demyelination within 6 months of an acute and disseminated demyelinating event suggests the diagnosis of acute disseminated encephalomyelitis in children, although this association failed to meet statistical significance. However, a statistically significant association between complete resolution of magnetic resonance imaging signal abnormalities and a normal neurologic outcome was observed.

Atypical presentations of leigh syndrome: a case series and review.

Patients with Leigh syndrome classically present in early childhood with developmental regression, ataxia, and hypotonia with subsequent respiratory and brainstem dysfunction. However, the clinical presentation can be highly variable. This report presents five cases of Leigh syndrome with atypical presentations. The first patient is a 17-month-old female who presented with progressive limb weakness diagnosed as Guillain-Barre syndrome. Postmortem examination demonstrated Leigh syndrome confined to the spinal cord. The case series then describes two sisters one of whom presented at 11 years of age with central respiratory failure and encephalopathy. Her 15-year-old sister presented with a progressive diplegia. The fourth patient presented with bronchiolitis and apnea at 3 months of age due to bilateral brainstem lesions. Her second cousin presented at 6 months of age with hypotonia, blindness, and tonic seizures. All patients had laboratory and radiologic findings consistent with Leigh syndrome. Evidence of spinal cord involvement was observed on magnetic resonance imaging in four of the five patients. Leigh syndrome can involve any level of the neuroaxis, resulting in a wide variety of presentations. Many atypical variants are observed, of which clinicians should be aware. Evidence of brainstem or spinal cord involvement should also be sought in patients with Leigh syndrome.

Posterior resection for childhood epilepsy.

We reviewed our experience with posterior resection for intractable childhood epilepsy. Fifteen patients, seven males and eight females, were studied. Age of surgery was 18 months to 16 years. Nine patients had a parietal resection and six patients had an occipital resection. Surgical outcome was variable. Nine patients had an excellent outcome (Engel Class I or II), two patients had a poor outcome (Engel Class III), and four patients had a very poor outcome (Engel Class IV). Pathology at surgery included focal cortical dysplasias (4), brain tumors (4), tubers of tuberous sclerosis (2), cerebrovascular accidents (2), porencephalic cysts (1), and normal pathology (2). Complications included visual field loss in the occipital lobe patients (4/6). Posterior resection can be successful for children with intractable epilepsy originating in the parietal and occipital lobes. Invasive monitoring is necessary in some patients to establish the extent of the epileptic zone before surgery. A good surgical outcome is dependent on the presence of a circumscribed lesion on MRI and ability to surgically remove all the pathology. Visual abnormalities are an expected complication of surgery in the occipital lobe, but may improve over time.

Epilepsia partialis continua: acute disseminated encephalomyelitis or Rasmussen's encephalitis?

This report describes a 15-year-old male presenting with headaches and seizures after a viral illness progressing to intractable seizures of the right hand and face. This patient presented with diffuse white matter lesions on magnetic resonance imaging which disappeared with treatment. A relapse 6 months later involving the left temporal and insular regions produced epilepsia partialis continua involving the right face and hand. The relevant literature is reviewed with an emphasis on possible etiologies, including both acute disseminated encephalomyelitis and Rasmussen's encephalitis.

Multifocal myoclonus following group A streptococcal infection.

Movement disorders as postinfectious manifestation of group A streptococcal infections have been reported and are thought to occur on an autoimmune basis. We describe an unusual case of multifocal myoclonus following strep throat infection. Clinical description and chart review were the method used. A 10-year-old boy developed focal myoclonus involving his right arm and shoulder 1 week after streptococcal throat infection treated with penicillin. His magnetic resonance image was normal, and he initially responded to clonazepam but did not sustain a response. The myoclonus spread to involve all limbs and the trunk becoming multifocal over the next few weeks. He did not have choreoathetosis of Syndenham's chorea. He was given one course of intravenous immunoglobulin and became asymptomatic after treatment. He remained symptom free for 8 months following intravenous immunoglobulin treatment. Various symptoms have been reported following group A streptococcal infections in children. These neurobehavioral abnormalities may be mediated through antineuronal antibodies. Our case demonstrates multifocal myoclonus as a poststreptococcal autoimmune phenomenon. To our knowledge, only two other cases of poststreptococcal myoclonus have been reported in the literature. Recognition of this unusual condition as a manifestation of autoimmune poststreptococcal disease in children is essential to avoid overinvestigation and to ensure early treatment.

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 children's 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 micromol/L (therapeutic range 350-800 micromol/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 Angelman's 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.