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Neuropathology of epilepsy Objectives 4976 Describe pathologically several types of congenital malformations and acquired lesions of the cerebral cortex that may predispose to epilepsy. Epilepsy: definition An episodic disorder of the nervous system arising from the excessively synchronous and sustained discharge of a group of nerve cells. Hughlings Jackson ( 1873) Epilepsy: definition • Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological and social consequences of this condition. • An epileptic seizure is a transient occurrence of signs and/or symptoms caused by the abnormal excessive or synchronous neuronal activity in the brain. Wang YY et al. Brain Pathology 20:1-16, 2010 Epidemiology of Epilepsy • Worldwide • Rate of between 20 and 70 per 100,000 • Incidence frequently evaluated with presumed diagnosis • Highest in first year of life • Commonest causes: head injury, birth trauma, infections and cerebro-vascular diseases Epidemiology (2) • 65% with a major handicapping medical condition • Mental retardation, seen in up to 28% of patients, more likely in early onset cases and with generalized seizures • Neurologic deficits seen usually in focal epilepsy Epilepsy: semiology • Petit mal: absence attacks • Grand mal: tonic-clonic seizures • Generalized: absence, tonic, clonic, tonicoclonic, myoclonic and atonic • Focal or partial: simple partial, complex partial or partial evolving to generalized seizures Classifications • Etiology • Semiology • Morphology Morphological classification Developmental (inherited) lesions Acquired lesions _______________________ Epilepsy can be focal or generalized Neuropathology of the brain with epilepsy: two questions • Can the cause of the epilepsy be identified? • Are there any secondary lesions caused by the epilepsy? Epilepsy: three major categories of problems found at examination • 1) Malformations of cortical development and epilepsy • 2) Acquired lesions and epilepsy ( 1 and 2 are in line with the morphological classification mentioned before) • 3) Effect of epileptic seizures on the brain Malformations of cortical development • Role of neuro-imaging • Role of genetic studies in our understanding of the etiology of these lesions • Range is enormous, many presenting early in life with: - developmental delay - encephalopathy - congenital motor problems - associated malformative/developmental lesions Morphological classification of cortical dysplasia • • • • • Lissencephaly (agyria/pachygyria) Polymicrogyria Heterotopia ( laminar or nodular) Single heterotopic white matter neurons Focal cortical dysplasia (Other rare forms) Key pathogenesis of cortical dysplasia • Abnormality of neuronal migration: endresult of an abnormal cortical “programming” • Selective migrational arrest either within the cortex or between the mantle zone and the cortex Focal cortical dysplasia • Most malformation of cortical development in surgical epilepsy series • Type 1: Abnormal cyto-architecture without ballooned cells or dysmorphic neurons • Type 2: Abnormal neurons or ballooned cells; better results with surgery Case history • 21 month-old boy with a seizure disorder • He had a medically uncontrollable partial epilepsy with secondary generalized • Neuro-imaging showed a focus of increased cortical thickness and blurring of the grey-white junction in the right temporo-parietal area • Scalp EEGs over this area showed continuous spiking Focal cortical dysplasia: etiology • Sporadic • Arrested neuronal migration and differentiation • Abnormality of progenitor cell proliferation and programmed loss of neurons during development Tuberous sclerosis complex • Most severe expression of focal dysplasia type 2 with the presence of dysmorphic neurons and ballooned cells • Hemi-megalencephaly Case History • 4 year-old boy with mental retardation and seizure. Investigation lead to a diagnosis of tuberous sclerosis • Neuro-imaging showed a few cortical/subcortical lesions, frequently with calcifications and subependymal nodules, equally frequently calcified • Decision was made to remove a larger lesion felt to be responsible for the uncontrollable epilepsy Mild malformation of cortical development • Subtle cortical abnormalities • Neuro-imaging generally negative Generalized malformation of cortical development • Lissencephaly (agyria-pachygyria) • Polymicrogyria • Heterotopia, laminar or nodular Acquired epilepsies • • • • • • • • Tumours Trauma Vascular: cerebral palsy, ischemia,stroke Infections Fever, dehydration Vascular malformations Rasmussen’s encephalitis Neurodegeneration, including Alzheimer’s disease Tumors and epilepsy • Frequent cause, around 35% • Slow growing lesions are more likely to be associated with seizures: 70.9% of oligodendrogliomas, 58.5% of astrocytomas, 36.9% of meningiomas and 28.9% of glioblastomas • Frequently the first and only sign Effects of seizures on the brain • Evidence that prolonged seizures and status epilepticus can result in neuronal loss is firmly established • Effect of recurrent short self terminating seizures is less clear. Experimentally, demonstration of increased apoptosis in hippocampi; in human, serial MRI demonstrate evidence of hippocampal atrophy in some patients • Childhood epilepsy carries significant risks for a variety of cognitive and behavioral problems Status epilepticus • Seizure activity, continuous or intermittent but without intervening recovery, lasting a prolonged period: – 60 min. for adults – 30 min. for children If generalized, this is a medical emergency Status epilepticus • More severe damage • If prolonged with significant abnormalities of cardio-respiratory function: - infarcts - death Pathology of seizure-related lesions • Neuronal cell death: apoptosis or acute damage (necrosis), leading to neuronal loss • Key structures are essentially the same as the ones involved in ischemia and early infarcts Hippocampal sclerosis (mesial temporal sclerosis) • Atrophy of the hippocampus • Strong association with drug resistant mesial temporal lobe epilepsy • Surgical indication in carefully selected patients • Considered to be acquired but unknown etiology (link to effect of seizures on neurons) SUDEP • Sudden unexpected death in epilepsy • Occurs in up to 10% of patients • Major causes of death in patients between 20 and 40 years • ? Cardiac arrhythmia or respiratory failure • Pulmonary edema at autopsy, likely of neurogenic origin