1
LITHUANIAN UNIVERSITY OF HEALTH SCIENCES
FACULTY OF MEDICINE
DEPARTMENT OF NEUROLOGY
STRUCTURAL EPILEPSIES IN CHILDHOOD: ETIOLOGY,
CLINICAL AND RADIOLOGICAL SYMPTOMS.
LITERATURE REVIEW.
Author: Roderick Raguel John Stephen Singarayar
Supervisor:
Prof. dr. Milda Endzinienė
2 TABLE OF CONTENT SUMMARY …..…...3 ACKNOWLEDGEMENTS …...4 CONFLICT OF INTEREST …...4 ABBREVIATION …...5 TERMS …...7 INTRODUCTION …...10
AIMS AND OBJECTIVES …...12
METHODS …...13
LITERATURE REVIEW …... 14-38 CONCLUSION …...39 REFERENCES …...40-43
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SUMMARY
Author name: Roderick Raguel John Stephen Singarayar
Research title: Structural epilepsies in childhood: etiology, clinical and radiological symptoms.
Research aim: The aim of this research is to provide an up-to-date comprehensive literature review and systematic review on etiology, clinical manifestations, and radiological symptoms of structural epilepsies in childhood.
Objectives: To systematically review the literature on the etiology, pathophysiology, clinical manifestations and radiological findings of structural epilepsies in childhood.
Methodology: A comprehensive literature search was performed to detect articles regarding structural epilepsies in childhood, the etiology, clinical manifestations and radiological findings. The search was conducted on the databases Pubmed/NCBI, Sciencedirect and BMJ journal using the search terms ‘structural epilepsies in childhood’, ‘malformations of cortical development’, ‘infection and epilepsy’, ‘auto-immune epilepsy’, ‘tumor related epilepsy’, ‘post traumatic epilepsy’, ‘post stroke epilepsy’, ‘neurocutaneous disorders’. There were no quality assessments concerning the included studies.A total of 55 references were used in this review, in which 40 are review articles and 15 are clinical studies.
Conclusions:
1. Genetically determined structural epilepsies represent a big group in childhood population and may prompt a multidisciplinary approach and specific treatment options. In epilepsies related to tumours, mesial temporal sclerosis or cortical malformations, surgical interventions should be considered.
2. Acquired acute structural brain damage is a risk factor for epilepsy. The identification of risk factors after traumatic brain injury, stroke or infection may lead to adequate prevention options regarding epilepsy. Infectious causes of epilepsy are the most preventable. Awareness of the causes and their geographical distribution, proper sanitation and immunization may help in prevention on these infections.
3. Clinical features of structural epilepsies depend on the site of lesion and the extent of brain damage and may include additional symptoms of different severity, mostly developmental, cognitive and behavioural disorders.
4. Radiological findings may be specific and are very important in the diagnosis of structural epilepsies as they may help to identify specific radiological markers which may be crucial for management decisions.
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ACKNOWLEDGMENT
The author wants to express his gratitude towards the supervisor of the work, Prof. dr. Milda Endzinienė, for the opportunity to learn about this interesting topic.
CONFLICT OF INTEREST
There was not any conflict of interest.ETHICS COMMITTEE CLEARANCE
It was not required.5
ABBREVIATION
AE- Autoimmune encephalitis
AIS- Arterial ischemic stroke
BBB- Blood brain barrier
CNS- Central nervous system
CJD- Creutzfeldt-Jakob disease
CMV- Cytomegalovirus
CT – Computed tomography
CM- Cerebral malaria
DNET- Dysembryoplastic neuroepithelial tumor EPSS- Early post stroke seizures
EEG- electroencephalogram
EIEE – early infantile epileptic encephalopathy
FCD- Focal cortical dysplasia
GABA- gamma-aminobutyric acid
HHV- Human herpes virus
HIV- Human immunodeficiency virus
HS- Hippocampal sclerosis
ISS- infantile spasm
IS- Ischemic stroke
LGS- Lennox- Gastaut syndrome
LPSS- Late post stroke seizures
LEAT- Long term epilepsy associated tumors
6 MT-MRI - Magnetization transfer (MT) in a magnetic resonance imaging (MRI)
MRI – Magnetic resonance imaging
NF1- Neurofibromatosis type 1
NCC- Neurocysticercosis
PTS – Post traumatic seizures
PTE- Post traumatic epilepsy
SWS- Sturge Weber Syndrome
TSC- Tuberous sclerosis complex
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TERMS
Angiomatosis - a condition characterized by the formation of multiple angiomas. Angiomyolipomas (AMLs) - most common benign renal tumours. Renal AMLs are typically composed of smooth muscle, blood vessels, and adipose tissue.
ARX mutations- ARX is a crucial gene for the development of interneurons in the fetal brain, and a polyalanine expansion mutation of ARX (300382.0002) causes mental retardation and seizures, including those of West syndrome, in males.
Bilateral perisylvian polymicrogyria (BPP) - a rare neurological disorder that affects the cerebral cortex (the outer surface of the brain). BPP is a subtype of a broader condition known as polymicrogyria. The cerebral cortex of the brain normally consists of several deep folds and grooves.
Chorioretinitis - inflammation of the choroid (thin pigmented vascular coat of the eye) and retina of the eye.
Cerebral palsy - a group of permanent movement disorders that appear in early childhood.
Cobblestone lissencephaly - a rare central nervous system malformation which includes a group of diseases that are characterized by a bumpy (or pebbled) appearance of the cerebral cortex.
Congenital muscular dystrophies – a group of genetic conditions that cause muscle
weakness and wasting (atrophy).
Early Infantile Epileptic Encephalopathy (EIEE) -a neurological disorder characterized by seizures. The disorder affects newborns, usually within the first three months of life (most often within the first 10 days) in the form of epileptic seizures.
Extra pyramidal signs - symptoms include dystonia (continuous spasms and muscle contractions), akathisia (motor restlessness), parkinsonism (characteristic symptoms such as rigidity), bradykinesia (slowness of movement), tremor, and tardive dyskinesia (irregular, jerky movements).
Electrographic seizures- seizures that are evident on EEG monitoring. They are common in critically ill children and neonates with acute encephalopathy.
8 Focal cortical dysplasia - heterogeneous group of cortical lesions, described as malformation of cortical development, cortical dysplasia, cortical dysgenesis or neuronal migration disorder.
Focal lesions - circumscribed areas of injury to brain tissue following brain injury. Focal seizures - seizures which affect initially only one hemisphere of the brain. A focal seizure is generated in and affects just one part of the brain – a whole hemisphere or part of a lobe.
Fukuyama congenital muscular dystrophy - an inherited condition that predominantly
affects the muscles, brain, and eyes. very early in life.
Hydrocephalus - a condition in which fluid accumulates in the brain, typically in young children, enlarging the head and sometimes causing brain damage.
Hemimegalencephaly - a rare neurological condition in which one-half of the brain, or one side of the brain, is abnormally larger than the other.
Infantile spasms - a rare seizure disorder that occurs in young children, usually under one year of age.
Lennox-Gastaut syndrome - a severe condition characterized by recurrent seizures (epilepsy) that begin early in life. The most common seizure type is tonic seizures, which cause the muscles to stiffen (contract) uncontrollably, accompanied by atypical absences and atonic seizures.
Lissencephaly - a set of rare brain disorders where the whole or parts of the surface of the brain appear smooth.
Lymphocytic pleocytosis - is an abnormal increase in the amount of lymphocytes in the cerebrospinal fluid (CSF).
Miller–Dieker lissencephaly syndrome (MDLS) - micro deletion syndrome characterized by congenital malformations.
Megalencephaly - brain volume which exceeds the mean by more than twice the standard deviation.
Microcephaly - abnormal smallness of the head, a congenital condition associated with incomplete brain development.
9 Multifocal seizures - seizures that start from several different areas of the brain. Muscle eye brain disease - less severe within the same spectrum as WWS, with subtle eye abnormalities, less significant neurological deficit and a milder muscular dystrophy is muscle–eye–brain disease.
Polymicrogyria- condition characterized by abnormal development of the brain before birth. The surface of the brain normally has many ridges or folds, called gyri. In people with polymicrogyria, the brain develops too many folds, and the folds are unusually small.
Periventricular heterotopia - a condition in which nerve cells (neurons) do not migrate properly during the early development of the fetal brain, from about the 6th week to the 24th week of pregnancy. Heterotopia means "out of place." In periventricular heterotopia, some neurons fail to migrate to their proper position and form clumps around the ventricles.
Posterior reversible encephalopathy syndrome (PRES) - a syndrome characterized by headache, confusion, seizures and visual loss.
Paraneoplastic syndromes - rare disorders that are triggered by an altered immune system response to a neoplasm.
Rhabdomyomas- a benign tumor of striated muscle.
Schizencephaly - a developmental disorder of the brain characterized by abnormal slits, or clefts, in the cerebral hemispheres.
Secondarily generalized seizures -partial seizures evolving into generalized seizures, most often with tonic-clonic convulsions.
Subcortical band heterotopia (SBH) - a related disorder in which there are bilateral bands of gray matter interposed in the white matter between the cortex and the lateral ventricles.
Tubulinopathies - wide and overlapping range of brain malformations caused by mutation of one of seven genes encoding different isotypes of tubulin.
Visuo-spatial ability - capacity to understand, reason and remember the spatial relations among objects or space.
Walker–Warburg syndrome (WWS) - also known under HARD+/−E eponym (hydrocephalus, agyria, retinal dysplasia, encephalocele) is characterized by major neurological deficit, visual and muscular impairment and a rapid fatal outcome.
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INTRODUCTION
Seizures in children are among the most common neurological disorders with a prevalence of 0.5-1% in the general population. The incidence of epilepsy in children ranges between 41-187/100,000 [1].
A transient alteration of consciousness with a specific behavioral and motor activity due to excessive electrical discharges from a group of cerebral neurons is defined as seizure. Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and it requires the occurrence of at least one epileptic seizure [1]. A specific seizure type(s) including the age of onset, electroencephalographic (EEG) findings, genetics/natural history, and responsiveness to particular drugs reveals an epilepsy syndrome [2].
An episode of seizure is due to abnormal firing of neurons, when there is an imbalance between the excitation (E) and inhibition (I) in one or more areas of the brain. An E/I imbalance can be caused by molecular, cellular or structural pathology [3].
Practically, epilepsy is defined as having two unprovoked seizures > 24 hours apart. The International League Against Epilepsy (ILAE) has accepted some recommendations of a task force altering the definition for circumstances that do not meet the two unprovoked seizures criteria [4].
The task force proposed that epilepsy can be considered to be a disease of the brain defined by any of the following conditions:
(1) At least two unprovoked (or reflex) seizures occurring >24 h apart;
(2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years;
(3) diagnosis of an epilepsy syndrome [4].
Epilepsy classification is a main tool in evaluating an individual presenting with seizures, and its classification has evolved since its inception [2]. The seizure type, epilepsy type, epilepsy syndrome and the etiology has been included in the new classification of epilepsy [2]. The new classification emphasizes to consider etiology at every step of diagnosis, as it often carries significant treatment implication [2]. Etiology of epilepsy are divided into six
11 groups, which includes structural, genetic, infectious, metabolic and immune, as well as an unknown group [2].
Structural etiology refers to abnormalities that are visible on structural neuroimaging. The electroclinical assessment together with imaging findings should lead to a reasonable interference that the imaging abnormality is the likely cause for the seizures. Epilepsy caused by structural abnormalities are more common and it may be acquired such as brain tumors, brain trauma, vascular accidents, cerebral infections or genetic such as many malformations of cortical development [2].
The underlying basis for structural abnormalities may be acquired, genetic or both. For example, polymicrogyria may be secondary to mutations in GPR56 genes, or can also be acquired due to intrauterine cytomegalovirus infection [2]. Structural lesions can also be of genetic cause such as tuberous sclerosis and many other malformations of cortical development [2].
Structural epilepsy may show variable distribution by etiology and clinical symptoms in different age groups. As epilepsy often manifests in childhood, it is important to be aware of structural pathologies that are most common in children.
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AIM AND OBJECTIVES OF THE THESIS
The aim of this systematic review is the assessment of the latest evidence investigating structural epilepsy in children by identifying, appraising and synthesizing all latest available data found on PubMed, sciencedirect, British medical journals & further databases regarding our topic in question.
Objectives:
1. To report the etiology of structural epilepsies children.
2. To report the clinical symptoms of structural epilepsies in children.
3. To report the radiological symptoms of structural epilepsies in children.
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METHODS
Methodology
A comprehensive literature search was performed to detect articles regarding structural epilepsies in childhood, the etiology, clinical manifestations and radiological findings. The search was conducted on the databases Pubmed/NCBI, Sciencedirect and BMJ journal using the search terms, ‘structural epilepsies in childhood’, ‘malformations of cortical development’, ‘infection and epilepsy’, ‘auto-immune epilepsy’, ‘tumor related epilepsy’, ‘post traumatic epilepsy’, ‘post stroke epilepsy’, ‘neurocutaneous disorders’.
The comprehensive search was restricted to English language articles, published from 2000 to 2019 with no geographical restrictions. The search continued until January 2019 and the collected articles were continuously revaluated for their relevance regarding the aim and objective of this paper. For any articles that were deemed eligible the full text was obtained and examined to see if they were relevant or not. Other articles were chosen from the reference lists of the articles already chosen. There were no quality assessments concerning the included studies. A total of 55 references were used in this review, in which 40 are review articles and 15 are clinical studies.
Selection Criteria
Publications older than 10 years were not considered during the primary online search. However, the secondary search brought forth 5 studies published previous to 2009, which were used in the literature review.
In all cases, articles not specific to epilepsies in childhood, published prior to 2000, and articles in which the data were not classified properly were excluded.
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LITERATURE REVIEW
1. Malformations of cortical development
1.1 General Description
Malformations of cortical development represent an important cause of epilepsy and developmental delay. MCD includes a group of disorders of varying genetic etiologies and clinical manifestations [5]. MCD is estimated in up to 40% of children with refractory epilepsy [6]. The different types of MCD are associated with more than 100 genes [7].
1.2 Etiology/Pathopysiology
The pathogenesis of these malformations of cortical development are multifactorial, depending on the type of genetic mutation, environmental influences, its timing and severity [6]. The exact mechanism underlying the genesis of epilepsy in MCD is not well known. Some studies have shown a role for gamma-aminobutyric acid (GABA) or glutamate dysfunction in some malformations. Malformations of cortical development leads to preservation and malpositioning of substantial number of subplate and radial glial like cells. Depolarizing actions similar to immature developing networks are caused due to the dysmatured neuronal networks and GABA synaptic activity. There is spontaneous depolarization and bursting observed in cytomegalic interneurons. The other factors and mechanisms involved in the epileptogenic circuitry may differ according to the underlying genetic or structural abnormalities in MCD [7].
MCD is classified based on the developmental steps as malformations of cell proliferations, neuronal migration and cortical organization [8]. Malformations due to abnormal glial and neuronal proliferation constitutes group I. Group II includes those malformations due to abnormal neuronal migration and Group III constitutes the malformations due to abnormal migrational and postmigrational development, as the process of cortical organization begins before the termination of neuronal migration [8].
Guerrini and Dobyns, suggested a classification of MCD based on pathway disruption and imaging phenotype [8].
15 Table 1. Guerrini and Dobyns’s classification of malformations of cortical development
1.3 Clinical Manifestations
Based on the clinical presentation and severity, MCD can be loosely divided into two large overlapping groups: early diffuse MCD with poor neurological and developmental outcomes and late-onset MCD with variable outcomes due to patchy brain involvement [8].
Severe disabilities
Early feeding problems, seizures, poor developmental and neurological outcomes are common in early diffuse MCD. Other children with MCD, might be recognized due to the abnormally small or large head size, hydrocephalus and other congenital abnormalities [8].
Children presenting with these clinical manifestations have severe congenital microcephaly, lissencephaly, dysplastic megalencephaly (including hemimegalencephaly), cobblestone malformation, polymicrogyria-like malformations, or classic polymicrogyria. Language deficits, disturbed social interactions, visual and hearing loss, abnormalities in mood, attention, sleep, and dysregulation of autonomic (especially gastrointestinal) system are common in severely disabled children. There is an increased risk for reduced life span and severe neurological outcomes [8].
Less severe disabilities
Children or adolescents with FCD are often brought to medical attention after the onset of focal epilepsy. Mild to moderate learning disability, attention deficit and epilepsy of variable severity are present in less severely affected individuals. Malformations such as periventricular nodular or subcortical heterotropia, mild forms of subcortical band heterotropia or polymicrogyria may cause less severe disabilities [8].
Table 2. Presenting signs and predictors for prognosis in malformations of cortical development
Group Malformation type
Group I Megalencephaly and focal cortical dysplasia (FCD) Group II Tubulinopathies (TUB) and lissencephalies
Group III Polymicrogyria (PMG) syndromes Group IV Heterotropia syndromes
16 Neurologic
symptoms
Most severe Intermediate Least severe Head size (OFC) Microcephaly (<−3
SD)
Megalencephaly (>+3)
Normal head size
Tone Spasticity Hypotonia Normal tone
Seizure onset Early (0–3 months) Infancy (3–12 months)
Later (after 1 year)
Seizure type EIEE-ISS-LGS-myoclonic
Nonspecific generalized
Focal, other types
MCD distribution Diffuse Frontal-perisylvian Posterior or other MCD symmetry Bilateral symmetric Bilateral asymmetric Unilateral
Abbreviations: EIEE, early infantile epileptic encephalopathy; ISS, infantile spasms; LGS, Lennox-Gastaut syndrome; MCD, malformations of cortical development; OFC, occipito-frontal circumference; SD, standard deviations.
Adapted from Guerrini R, Dobyns WB. Malformations of cortical development: clinical features and genetic causes. Lancet Neurol. 2014;13(7):710–726. doi:10.1016/S1474-4422(14)70040-7
Table 3. Malformations of cortical development with associated genes and clinical features [6]
Cortical malformation
Genetic cause Clinical features
Microcephaly ASPM Mental retardation, not generally associated with epilepsy, autosomal recessive
inheritance Microcephalin
CDK5RAP2 CENPJ
Hemimegalencephaly Unknown Mental retardation, early onset seizures (frequently intractable epilepsy), +/- neurocutaneous syndrome
Focal cortical dysplasia
Unknown Most common, focal and generalized Seizures
Periventricular heterotopia
FLNA Normal intelligence, adolescent onset seizures, X-linked disorder with male lethality
ARFGEF2 Mental retardation, microcephaly, autosomal recessive inheritance, rare Subcortical band
heterotopia
DCX Subcortical band heterotopia in females, mental retardation, epilepsy, X-linked disorder
Lissencephaly LIS1 Miller-Dieker syndrome (characteristic facial features), autosomal dominant inheritance
17 TUBA1A Lissencephaly, clinical features similar
those caused by LIS1 and DCX, de novo mutations
ARX Associated with ambiguous genitalia, hypothalamic dysfunction, neonatal epilepsy, X-linked disorder
RELN Associated with cerebellar hypoplasia, epilepsy, autosomal recessive inheritance Cobblestone
lissencephaly
Fukutin Fukuyama congenital muscular dystrophy
POMGnT1 Muscle-eye-brain disease
POMT1 Walker-Warburg Syndrome
Polymicrogyria GPR56 Bilateral frontoparietal polymicrogyria, Epilepsy
Schizencephaly EMX2 Type 2 (open cleft)
Adapted from Pang T, Atefy R, Sheen V. Malformations of cortical development. Neurologist. 2008;14(3):181–191. doi:10.1097/NRL.0b013e31816606b9
1.4 Radiological Findings
1.4.1. Group 1
Megalencephaly
MRI: Dysplastic megalencephaly is characterized by severe cortical changes with either a part or all of the hemisphere enlarged without any consistent preference for which part of the brain is enlarged. Poor differentiation between grey and white matter, variable hypointense and hyperintense T2 weighted abnormalities in white matter in the central and subcortical regions, asymmetrical enlargement of the lateral ventricle and the dysplastic side is usually larger [8].Perisylvian polymicrogyria is typically seen in megalencephaly [8].
Enlarged gyri with either smooth or irregular cortical surface and the subcortical intensity is increased in patients with focal cortical dysplasia. In cases of FCD type 2b transmantle dysplasia is present [8].
1.4.2. Group 2
18 MRI: The malformation ranges from extreme lissencephaly to less severe lissencephaly. Extreme lissencephaly is seen with completely absent gyri, severe cerebellar hypoplasia and total agenesis of the corpus callosum. Moderate to severe cerebellar hypoplasia is seen in less severe lissencephaly. Classic lissencephaly is presented by atypical polymicrogyria like cortical malformation with cerebellar hypoplasia. The malformation has a thick cortex, variable appearance of the cortical surface and smooth or pebbled boundary between cortical and white matter, sparse or absent intracortical microsulci and a paucity of deep gyral
infolding [8].
Lissencephaly and subcortical band heterotopia
MRI: Agyria (absent gyri) and pachygyria (abnormally wide gyri) are seen in all cases of lissencephaly. Subcortical band heterotropia represents an atypical manifestation of
lissencephaly in which the brain surface appears normal, except for shallow sulci. There is a smooth band of misplaced neurons beneath the cortex. Thick bands(5-10mm) are seen
beneath the deepest sulci in the subcortical white matter, and thin bands can follow the cortex into the gyrus [8].
The severity ranges from grade 1 to grade 6.
Table 4. The severity of lissencephaly and subcortical band heterotopia
Grade Severity
1 Complete agyria
2 Nearly complete agyria 3 Mixed agyria-pachygyria 4 Pachygyria only
5 Mixed pachygyria-subcortical band heterotropia 6 Subcortical band heterotropia only
To recognize different genetic forms, the anterior and posterior gradient, sex
distribution and associated malformations are essential. ARX mutations in boys is suggestive in cases of severe lissencephaly with agenesis of the corpus callosum. Completely smooth brain surface with no gradient is seen severe mutations [8].
1.4.3. Group 3
19 MRI: High field strength MRI can be used to differentiate the classic forms of polymicrogyria and various other forms from cortical malformations. The actual morphological extent of the malformation can be visualized by ultra-high field MRI (7T). The cortex may not appear thickened because of the immature state of myelination in children with polymicrogyria. T2 signal within the cortex is usually normal. Diffusely abnormal signal in white matter suggests in utero infection (cytomegalovirus),peroxismal disorders or severe rare polymicrogyria or polymicrogyria like syndromes. Patients with cobblestone malformations have abnormal white matter signals in infancy [8]
In schizencephaly, the cleft lined by the grey matter has an appearance of polymicrogyria with an irregular surface, mildly thick cortex, deeply infolding cleft and slightly differentiating between grey and white matter. Usually, it is bilateral and often asymmetrical. Milder clefts or polymicrogyria wihout cleft should be looked for in the contralateral hemisphere [8].
Bilateral perisylvian polymicrogyria is the most common pattern, and it can bilateral symmetrical, bilateral asymmetrical or unilateral. Polymicrogyria may be seen in overlying periventricular nodular heterotopia [8].
1.4.4. Group 4
Heterotropia syndromes
MRI: Bilateral contiguous periventricular nodular heterotropia is common in patients with X-linked form. It is characterized by sparring of the temporal horns and mild hypoplasia of the cerebellar vermis with megacisterna magna. Autosomal recessive is rare, presented with severe congenital microcephaly and thin cortex with abnormal gyri. Periventricular nodular heterotropia is confined to the trigons, temporal and occipital horns in posterior predominant syndromes. In some cases, it can be associated with overlying polymicrogyria, hydrocephalus or cerebellar and hippocampal hypoplasia [8].
2. Neurocutaneous Disorders
2.1. General Description
Neurocutaneous disorders are heterogenous group of disorders affecting the skin, brain and other organs. Tuberous sclerosis complex (TSC), neurofibromatosis type I (NF1),
20 and Sturge–Weber syndrome (SWS) are common neurocutaneous disorders [9]. Genetic mutations in the cell growth pathways leads to developmental dysfunction of skin, brain and other organs [9].
2.2. Etiology/pathophysiology
Tuberous sclerosis complex (TSC) is a multiorgan system disorder caused by mutation in TSC1or TSC2, which are tumor suppressor genes that controls the activity of mechanistic target of rapamycin (mTOR) signaling pathway. Overactivaton of the mTOR pathway stimulates the mRNA translation and causes excessive protein synthesis and cell growth leading to tumors in several organs and the features of TSC. Seizure generation and epileptogenesis in TSC are complex and multifactorial related to the dysfunction of the mTOR signaling pathway (abnormal cellular excitation) and the neuropathological substrates (hyperexcitability circuits) [9].
Neurofibromatosis type 1 (NF1), is an autosomal dominant neurocutaneous disorder and de novo mutations are seen in half of the cases. The numerous focal lesions, tumors and malformations of cortical development might lead to seizures in NF1 [9].
Sturge Weber Syndrome (SWS) is a developmental disorder caused by somatic mutations in a nucleotide transition in GNAQ, a gene that is typical for blood vessel development [9,10,11]. The mechanism of epileptogenesis in SWS is unclear, but abnormal blood vessel development is a major factor. The clinical features of SWS are associated with the venous stasis and congestion which leads to decreased regional perfusion and causes hypoxic brain injury with neuronal loss and gliosis. Cortical malformations with inherent circuit dysfunction might contribute to epileptogenesis and seizures originate adjacent to the leptomeningeal angioma in the cortex [9].
2.3. Clinical Manifestations
2.3.1. Tuberous Sclerosis Complex
Hypopigmented macules (ash leaf spots) and facial angiomatoses are the typical skin manifestations. Cardiac rhabdomyomas and renal angiomyolipomas are common in TSC patients. In 90% of TSC patients seizures are present and appear within first year of life in about 63%. Focal, multifocal, infantile spasm or combination or other seizure types are seen.
21 Infantile spasm, a subtype of epileptic spasms occurs in the first year of life and is very common [9].
Hamartomas (tubers), subependymal giant cell astrocytomas (SEGAs), radially oriented heterotropias are the three major neuropathological findings that characterize TSC. Hamartomas (tubers), a mixture of abnormal cells, including dysplastic, immature, cytomegalic neurons and glia lacking a normal pattern are extremely epileptogenic. Subependymal nodules (SEN’s), which are abnormal neuronal and glial tissue arise in the periventricular regions and can transform into subependymal giant cell astrocytomas (SEGAs). SEGA’s located near the foramen or Monro, causes blockage of cerebrospinal fluid at the site and leads to hydrocephalus. Within the white matter are radially oriented heterotropias, consistent with disordered neuronal migration might lead to epileptogenesis as well as behavioural problems [9].
2.3.2. Neurofibromatosis Type 1
Disease manifestations are diverse related to the variable penetrance of mutation. Typical manifestations include Café-au-lait macules (Develop in first 2 years of life) or hyperpigmented skin markings, axillary freckling, disease specific Lisch nodules (hematomas of the iris), optic pathway gliomas and neurocognitive deficits [9].
Sleep disorders and anxiety are very common. Mild or moderate cognitive deficits and learning problems may be present and it affects the academic performance and quality of life. Visual spatial and visual motor abilities, executive function, verbal and nonverbal language abilities, fine and motor coordination, and attention are affected. Skeletal (long bone dysplasia, scoliosis) and vascular (blood vessel stenosis, especially the renal artery; aneurysms; hypertension) systems are also involved [9].
The incidence of epilepsy is 6-10% and seizures are focal onset and generalize secondarily. Seizures in NF1 have good prognosis with one or more conventional anti-seizure drugs [9].
2.3.3. Sturge–Weber Syndrome
The main clinical features of SWS are facial angiomas (port-wine birthmarks), ocular angiomas causing glaucoma and malformations of leptomeningeal blood vessels. Recurrent stroke and stroke like episodes often lead to hemiparesis, cognitive deterioration, visual field
22 defects and developmental delays involving language and behavior. Early handedness or a gaze preference may be noticeable in children. Specific learning disabilities, attention deficit disorder, hormone deficiencies (growth hormone, thyroid hormone) can manifest later in life [9].
Epilepsy in SWS is characterized by frequent cluster of seizures and episodes of status epileptics. Seizures are most common in the first year of life, and generally by 2 years of age, about 10% can begin later in childhood, adolescence, or adulthood. Focal seizures with or without impaired consciousness are often seen and generalized seizures can also occur [9]. Focal cortical dysplasia or polymicrogyria and infantile spasms that respond to hormone therapy are present in some cases. There is progressive cerebral atrophy, calcifications and clinical deficits in infants and young children [9].
2.4. Radiological Findings
2.4.1. Tuberous Sclerosis Complex
MRI: Cortical tubers typically appear as well circumscribed areas of low signal intensity on T1 weighted and high signal intensity on T2 weighted sequences. Subependymal nodules show intermediate signal intensity on T1- weighted images and isointense to hyperintense signals on T2- weighted images [12].
SEGAs are hypo- to isointense compared with cortex on T1-weighted images and heterogeneously iso- to hyperintense on T2-weighted images. Superficial white matter abnormalities are seen as hyperintense areas on T2 weighted images and hypointense areas on T1 weighted images. Radial migration lines are thin, straight, or curvilinear bands of hyperintensity in T2 weighted images and show iso- to hypo intensity on T1-weighted sequences. Cyst-like WM lesions are small well-demarcated lesions with intensity similar to that of cerebrospinal fluid. They are seen in deep WM, typically near the lateral ventricles [12].
2.4.2. Neurofibromatosis Type 1
MRI: Gliomas and central nervous system lesions are common in NF1. T2 hyperintesities on MRI scan show the presence of ‘unidentified bright objects’(UBO’s) which are vacuolar changes in myelin sheath with dysplastic glial proliferation. UBO’s are a frequent finding and often seen in the cerebellum, basal ganglia, subcortical white matter and thalamus [9].
23
2.4.3. Sturge–Weber Syndrome
MRI: A newborn with port wine stain in the V1 distribution (forehead to one side and/or upper eyelid) should be suspected for brain involvement. The risk of brain involvement increases with the size, extent and bilaterality of the birthmark [13].
T1 and T2 weighted MRI with gadolinium contrast and post contrast FLAIR is the ideal standard to detect brain involvement [11].Occipital and posterior parietal or temporal lobes are the most common locations involved [10]. Transient hyperperfusion with accelerated myelin maturation, leptomeningeal enhancement and decreased diffusion if there is associated acute ischemic event are seen in the early phase. Later, increased T2 signal in the region of gliosis with decreased pial enhancement and cortical atrophy is seen. [10]. T2* or SWI shows gyriform calcifications that appear as areas of signal loss along the gyri in a serpemtine pattern. Brain involvement is less likely in patients with normal brain MRI at one year of age with cutaneous and ocular manifestations [10].
3.Infection and Epilepsy
3.1. General Description
Infections are one of the most common causative factors of acquired epilepsy and the most preventable cause as well. Infections may cause seizures at any age, ranging from toxoplasma in the newborn, human herpesvirus (HHV)-6 in early childhood to Creutzfeldt-Jakob disease (CJD) in the elderly [14]. The most common central nervous system (CNS) infectious disorders causing epilepsy include, viral encephalitis, parasitic infections and bacterial meningitis [15].
3.2. Etiology/pathpysiology
The neurotropic infectious agents that target the CNS may induce brain alterations which may include immune/inflammatory - mediated responses intrinsic to the infected brain tissue. Immune responses to the systemic infections (Non CNS), proinflammatory cytokine induced alterations in BBB integrity and subsequent neuronal hyperexcitability may lead to the seizures [14].
The mechanism of epilepsy after CNS infections depends on the pathogen, degree of cortical involvement, the host inflammatory response and the delay in treatment [15].
24 Seizures and epilepsy are also caused due to the primary infection of HHV-6 or reactivation of latent virus [16]. In case of herpes simplex virus, structural damage such a cortical necrosis is present, infarction in meningitis, gliosis around calcified neurocysticercosis
(NCC), hypoxic ischemic injury in malaria may all lead to the epileptogenic foci [14]. Neuronal hyperexcitability may also be due to hyperthermia associated with herpes simplex virus [14]. The most common parasitic infections associated with seizures and epilepsy are cerebral malaria and neurocysticercosis [15].
Anerobic bacteria such as Bacteroides, Fusobaterium, Prevotella and Actinomyces sp and aerobic bacteria particularly Haemophilus species are causative organisms for cerebral abscess. Cerebral abscess in general are associated with predisposing factors like sinusitis, otitis media, dental abscess or congenital heart disease [14].
TORCH infections classically comprise toxoplasmosis, Treponema pallidum , rubella, cytomegalovirus (CMV), herpes simplex virus (HSV), hepatitis viruses, human immunodeficiency virus (HIV), and other infections, such as varicella and parvovirus B19 [17].Transmission of the pathogens may occur prenatally, perinatally, and postnatally, through transplacental passage of organisms, from contact with blood and vaginal secretions, or from exposure to breast milk for CMV, HIV, and HSV [17].
Congenital cytomegalovirus (CMV) infection is the most common intrauterine infection [18]. Transplacental transmission of Toxoplasma gondii after maternal primary infection during pregnancy leads to congenital toxoplasma infection [19]. The epileptogenic mechanisms of toxoplasmosis are multifactorial. T.gondii cysts in the brain mature slowly and ruptures inducing localized inflammation, and later forms microglial scars, which is one of the main causes of epilepsy. The incidence and severity of seizures depend on the location and the number of cysts [19].
Table 5. The infectious agents depending on the geographical location [20]
Infection Geographical distribution Comment
Malaria Sub‐Saharan Africa, South
East Asia, Latin America
Plasmodium falciparum dominant in Africa, Plasmodium vivax outside Africa
25 Neurocysticercosis Latin America, India, China,
South East Asia, some parts of Africa
Extraparenchymal forms much more common in Latin America than in India/Asia Japanese encephalitis India, China, Japan, South
East Asia, eastern
Mediterranean region, Papua New Guinea, Australia
Virus continually spreading across geographical regions
Human immunodeficiency virus (HIV)
Sub‐Saharan Africa, Central Asia, Latin America, Eastern Europe
Variations within countries also
Tuberculosis India, China, South East Asia, sub‐Saharan Africa, Latin America
Coinfection with HIV increasing
Adapted from SINGHI, P. (2011), Infectious causes of seizures and epilepsy in the developing world. Developmental Medicine & Child Neurology, 53: 600-609. doi:10.1111/j.1469-8749.2011.03928.x
3.3. Clinical Manifestations
3.3.1. Viral Encephalitis
The involvement of the highly epileptogenic frontal and mesial temporal lobe in herpes simplex encephalitis (HSE) causes the high frequency of seizures. Due to the widespread injury, epilepsy secondary to encephalitis is often multifocal and generalized [21].
3.3.1.1 HSV encephalitis
Seizures are present in more than 50 % of individuals with HSV type 1 encephalitis. The involvement of the mesial temporal lobe including the hippocampus leads to the increased frequency of seizures. Children are often presented with generalized convulsions, absence of periodic lateralized epileptiform discharges and atypical features. Older children and adults experience behavioural disturbances. About 42-60% of individuals experience late unprovoked seizures and epilepsy, and are often intractable [20].
3.3.1.2. Japanese encephalitis
In Japanese encephalitis, acute symptomatic seizures are present in about 85% of children and in 10 % of adults. Seizures are present in 50% to 80% of cases, and are often more frequent in children than in adults. The most common presentation is generalized seizures or
26 focal seizures with secondary generalization, single or multiple. Seizures are often present in cases with low Glasgow coma scale, cortical or thalamic lesions on neuroimaging, and raised intracranial pressure. In Japanese encephalitis, late onset epilepsy is rare and about one third of children have extrapyramidal signs [20].
3.3.2. Malaria
P. falciparum malaria is associated with most of the neurological complications including cerebral malaria. Plasmodium vivax causes seizures in children and is frequent in Asia [20].Seizures are most often during the acute stage in both cerebral malaria as well as uncomplicated malaria. Focal seizures with or without secondary generalization are most common, but may be generalized or even subtle or purely electrographic seizures. One third of children are presented with status epilepticus in addition with increased intracranial pressure and brain swelling on neuroimaging. Sequestration of the parasitized red blood cells in cerebral microvasculature is an important indication in pediatric cerebral malaria [20]. Repeated seizures, hypoglycemia, deep coma, shock, severe metabolic acidosis, slow and symmetric background on EEG are signs of poor prognosis. Post malaria epilepsy is seen in about 10% of affected individuals [20].
3.3.3. Intracranial abscess
Acute symptomatic seizures are the presenting symptom of abscess. Drug resistant, focal epilepsy is seen in cases of temporal abscess [14]. Localized arteritis and encephalitis may result due to abscess, which triggers inflammatory process in the surrounding area and the development of acute seizures. Late seizures are due to the localized damage caused by the abscess and from surgical drainage leads to gliosis [14].
3.3.4. TORCH infections
Table 6. Clinical findings associated with selected TORCH infections [22]
Hepato spleno megal y Cardiac lesions
Skin lesions Hydroc
ephalus Microce phaly Intracranial Calcifications Ocular Disease Hearin g Deficits Toxoplas mosis + (−) Petechiae/purpura , maculopapular rash ++ + Diffuse intracranial calcifications Chorioretinitis (−)
27
CMV + + Petechiae/purpura (−) ++ Periventricular
calcifications
Chorioretinitis ++
Adapted from Remington J, Klein J, Wilson C, et al, editors. Infectious diseases of the fetus and newborn infant. 7th edition. Philadelphia: Elsevier Saunders, 2011
3.3.4.1. Toxoplasmosis
Chorioretinitis, hydrocephalus and intracranial infections are the classic diagnostic triad of symptoms in T.gondii infection [17].
The most prevalent manifestations include anemia, seizures, jaundice, splenomegaly, hepatomegaly and thrombocytopenia. Severe manifestation is an indication of infection at an early gestation. Most infections with T.gondii are asymptomatic at birth. Newborns without any symptoms or mild symptoms are still at increased risk for the development of late manifestations, such as chorioretinitis, motor and cerebellar dysfunction, microcephaly, seizures, intellectual disability (mental retardation), sensorineural hearing loss [17].
3.3.4.2. Congenital cytomegalovirus infection
Most affected infants are asymptomatic at birth and about 10-15 % are symptomatic and show signs of congenital infection at birth [18].
Most common manifestations are smallness for gestational age, petechiae (purpura) or thrombocytopenia, hepatomegaly, splenomegaly, jaundice at birth, chorioretinitis, hearing impairment, microcephaly, unexplained neurologic abnormality and intracranial calcifications. Neurodevelopmental sequelae such as sensorineural hearing loss, mental retardation, visual defects, seizures and cerebral palsy are seen in 90% of symptomatic patients and about 10-15% of asymptomatic patients [18].
3.4. Radiological Findings
3.4.1. Post encephalitic epilepsy
MRI findings shows local or diffuse atrophy and signal changes in addition to mesial temporal lobe involvement in patients with post encephalitic epilepsy [20,21]. Temporal and extratemporal abnormalities were seen in about 51% of post encephalitic patients in the
28 Montreal series. Pronounced regional temporal atrophy and widespread T2 signal changes are seen in perisylvian and periinsular regions [21].
CT findings reveal bilateral hypodense lesions in thalamus, basal ganglia, midbrain, pons and medulla in majority of patients with Japanese encephalitis [23].
Hyperintense signals, bilaterally in thalamus, midbrain and cerebral hemispheres are seen in MRI, and helps in differentiation from other viral encephalitis. In HSV encephalitis there is predominant involvement of fronto-temporal regions [23].
3.4.2. Cerebral Malaria
MRI: Brain swelling is a typical feature in cerebral malaria and the increase in brain volume is graded from 1-8 [25].
White matter increased T2 signals with primarily periventricular/peritrigoneal and primarily subcortical can be seen, the latter being more common [25]. Increased T2 signal and cortical swelling with generally diffuse and posterior predominant pattern is seen. Posterior reversible encephalopathy syndrome (PRES) is frequent in acute stages of CM [25]. Normal physiological intravascular and circumventricular organ enhancement is seen in gadolinium enhancement [25].
SWI findings: The ferromagnetic properties of hemozoin and blood makes SWI and ideal sequence. The areas of parasite sequestration and ring hemorrhages along the regions of the deep and superficial venous system have decreased signals which is a positive SWI finding [25]. Brain swelling with underlying vasogenic edema and positive DWI findings are typical features of CM and PRES [25].
3.4.3. Congenital toxoplasmosis
Nodular or curvilinear calcifications, or hydrocephalus are detected on CT or US of the brain [17].
3.4.4. Congenital cytomegalovirus
Neuroradiological findings are more helpful in identifying children at high risk for epilepsy than the clinical findings at birth. The common findings on neuro imaging are intracranial calcifications, ventricular dilations, migration disorder and white matter
29 abnormalities on CT or MRI. Ventricular dilations and migration disorders are highly associated with the development of epilepsy [18].
4.Autoimmune associated epilepsy
4.1. General description
Immune epilepsy refers to disorders in which seizures are the core symptom and it results directly from an immune disorder. Immune etiology is suspected when there is evidence of autoimmune mediated central nervous system inflammation [26]. The autoimmune process may be triggered by infection, underlying neoplasm or vaccine.
4.2. Etiology/pathophysiology
Intracellular neuronal antigens are targeted by onconeural autoantibodies in case of underlying tumor [27]. Certain heterogenous groups of encephalitic syndromes are associated with autoantibodies to the neuronal surface or synaptic antigens without an underlying tumor such as anti-LGI 1 encephalitis [27, 28].
Autoantigens of encephalitis associated with seizures and status epilepticus can be intracellular paraneoplastic antigens, cell surface or synaptic antigens, antigens of unclear clinical significance [26].
Anti –NMDAR encephalitis is mediated by antibodies against the NR1 subunit if the NMDAR. Initially NMDAR encephalitis was described as a paraneoplastic syndrome associated with ovarian teratoma, but studies have shown that it may occur in in men and children without any underlying tumor as well [29]. Anti-NMDAR encephalitis can be triggered by HSV encephalitis as well [27].
LGI1 is a secreted protein, that forms a trans-synaptic complex which interacts with the pre-synaptic VGKC through ADAM23. Autosomal dominant temporal lobe epilepsy is caused due to mutations of LGI1 [26].
Table 8. Cell-surface or synaptic antigens [26] Syndrome Clinical significance Location of epitopes Frequency of systemic tumor Response to immunother apy
30 NMDAR (NR1) Psychosis, dyskinesias, autonomic instability, hypoventilati on
High Extracellular Varies with age, gender and ethnicity Frequent LGI1 Limbic encephalitis, tonic seizures (faciobrachial dystonic seizures)
High Extracellular <10% Frequent
Caspr2 Encephalitis, Morvan’s syndrome, neuromyoton ia
High Extracellular ~40% Frequent
GABA(B) receptor Limbic encephalitis, early and prominent seizures
High Extracellular 70% Frequent
AMPAR (GluR1/2) Limbic encephalitis (frequent relapses)
High Extracellular 70% Frequent
mGluR5 Limbic
encephalitis
High Extracellular >90% Frequent
DPPX (subunit of Kv4.2 K+ channel Encephalitis, frequent relapses
N/A Extracellular N/A Frequent
GAD Limbic encephalitis, refractory epilepsy, stiff-person syndrome, cerebellar dysfunction High (may occur with cell-surface antibodies) Intracellular <5% Moderate
CRMP5: Collapsin response mediator protein-5; GAD: glutamic acid decarboxylase; NMDAR: N-methyl-D-Aspartate receptor, LGI1: leucine rich glioma inactivated protein 1, Caspr2: Contactin-associated protein-like 2, GABA(B) receptor: γ-Aminobutyric acid-B receptor, AMPAR: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor,
31 mGluR5: metabotropic glutamate receptor 5, DPPX: dipeptidyl-peptidase-like protein-6, N/A: not available, too early to assess significance.
Adapted from Davis R, Dalmau J. Autoimmunity, seizures, and status epilepticus. Epilepsia. 2013;54 Suppl 6(0 6):46–49. doi:10.1111/epi.12276
4.3. Clinical manifestations
4.3.1. NMDAR Encephalitis
NMDAr encephalitis is characterized by a progression of symptoms, initially viral like prodrome (malaise, fever, headaches and anorexia) followed by behavioral changes or psychosis progressing to temporal lobe dysfunctions with decreased level of consciousness, dyskinesias, catatonia, autonomic instability and frequent hypoventilation are seen [30, 26]. In pediatric population, the seizure phase is characterized by emotional and behavioral disturbances including apathy, fear, depression, delusion, hallucinations, psychosis, decreased cognitive skills, numbness in one or more extremities. Generalized tonic- clonic seizures may also be an initial symptom in children [31]. Seizures are often present in about 70% of patients. Children and teenagers are presented with seizures initially in about 30% of cases, and speech dysfunction is more prevalent in children [31, 26].
A positive serum or cerebro spinal fluid (CSF) sample screening for antibodies to the NMDA receptor subunit confirms the diagnosis of anti-NMDA receptor encephalitis. Patient with an acute onset of psychiatric symptoms with atypical features or unusual movements should be considered for screening [32].
Mild lymphocyctic pleocytosis, normally or mildly increased protein concentration, and CSF-specific oligoclonal bands are seen in 80 % of cases [32]. Non-specific slowing or slow continuous rhythmic activity during the catatonic phase of illness are typically seen in electroencephalograms (EEGs) and helps to distinguish between encephalitis and primary psychiatric disorders [32].
4.3.2. LGI1-AE
Limbic syndromes (mood changes, confusion, working memory deficits), hyponatremia and occasionally faciobrachial dystonic seizures are present [27].
32
4.4.1. NMDAR-Encephalitis
MRI: Initial presentation of NMDAr encephalitis is most likely to have normal brain MR imaging findings. In case of imaging abnormalities present, mild transient cortical enhancement are demonstrated by T2 FLAIR hyperintense locations [30]. Cortical and/or subcortical abnormalities, basal ganglia, infratentorial T2 hyperintensities with or without transient meningeal enhancement is seen [27].
4.4.2. LGI1-Encephalitis
MRI: Limbic encephalitis is demonstrated by increased T2/fluid-attenuated inversion recovery (FLAIR) signal in the mesial temporal lobe [27].
5. Post-traumatic epilepsy
5.1. Etiology
Traumatic brain injury is the most common cause of post traumatic seizures and epilepsy (PTE) [34]. The severity of brain injury is directly related to the prevalence of PTE. Non accidental trauma has a significant role as a cause of post traumatic epilepsy according to a study from a tertiary referral center [35].The factors associated with the origin of posttraumatic seizures is still unclear, however the most commonly accepted risk factors for delayed post traumatic seizures are depressed skull fractures, intracranial hematoma, prolonged unconsciousness, low Glasgow coma score and prolonged post traumatic amnesia [36].
In the acute phase after trauma, glutamate excitotoxicity leads to early onset seizures. Later, with course of time the secondary injury cascades stimulates mTOR activation and toll like receptor upregulation makes the transition towards PTE. In association with PTE, tauopathy develops and causes seizure generation enhancing chronic degeneration [37].
5.2. Clinical manifestations
Post-traumatic seizures can be classified according to the time of onset: 1) immediate PTS occurs within 24 hours after brain injury, 2) early PTS within a week post-injury, 3) late PTS occurring more than a week after injury.
Early seizures are most often generalized tonic-clonic type and focal onset is common in late seizures. Post traumatic epilepsy refers to recurrent and unprovoked PTS that occur at
33 least 1 week after TBI since the seizures present at first week after trauma are considered to be provoked by the head injury. Seizures that occur after 1 week after trauma are considered a manifestation of PTE [34].
The time interval from traumatic brain injury to the occurrence of the first seizure varies greatly. The occurrence of the first seizure is within a year post injury in 80% of PTE individuals, and more than 90% experience by the end of second year. The 2nd seizure is reported in 86% of patients within 2 years after the onset of first late seizure (>1 week from injury) [38].
5.3. Radiological findings
5.3.1. CT
In emergency situations, CT scan of the head would allow to visualize the underlying pathology such as intracranial hematoma or depressed fracture which needs urgent intervention. Focal hemorrhagic brain damage on CT scan is most important factor to predict early and late epilepsy [37].
5.3.2. MRI
MRI is the main choice of study in patients with PTE. MRI imaging with gadolinium and GRE sequence shows the presence of hemosiderin [39]. Frontal and temporal lobes are the most affected regions in TBI and PTE [39]. Seizure occurrence is demonstrated by the hemosiderin deposits on T2*- weighed imaging and gliotic scar formation around the hemosiderin. [36] MRI is more sensitive in detection of traumatic white matter abnormalities including the diffuse axonal injury than a CT scan [37].
In MRI-negative patients with potential temporal lobe epilepsy, hypometabolism on positron emission tomography (PET) may assist with diagnosis and surgical planning [39].
5.3.3.MT MRI
To detect the tissue characterization of diffuse axonal injury MT MR imaging is used. In case of diffuse axonal injury, the lesions are characterized by axonal disruption with Wallerian degeneration and gliosis. In the early stages after trauma, there is reactive swelling of axons, disintegration and fragmentation of myelin sheath occurs. Reactive gliosis
34 predominates in the later stages. The extent of gliosis is visualized better on T1-weighted MT images than conventional spin echo (SE) images [36].
6.Stroke and Epilepsy
6.1. Etiology
Stroke occurs in an estimated 3.8 per 100,000 children annually, and is an important causative factor of epilepsy and childhood brain injury.
Pediatric stroke can be ischemic or hemorrhagic. Children with acute seizures at the time of stroke are at particularly high risk [41]. Younger children experience seizures at the time of stroke more common than the older ones [42]. Post stroke epilepsy occurs in about 17% of children with hemorrhagic stroke and about 15-20 % with AIS [43]. Ischemia causes reversible or irreversible damage in the brain such as sudden disorganized electrical activity which leads to subsequent seizures [43]. Post stroke epilepsy has a latent phase, that follows an insult in which the brain undergoes epileptogenesis and potentiality for seizures. [44].
Epilepsy and remote symptomatic seizures are most common complication of pediatric stroke, and clinical factors such as age at the time of stroke, stroke type, location and number of infarct foci affect their risk. [43]
6.2. Clinical Manifestations
Two types of seizures can be distinguished after an ischemic stroke. Early post stroke seizures (EPSS) occurs up to 7 days and are consequences of local metabolic disturbances after areterial ischemic stroke (AIS) and late remote seizures occur between 7th day and one year after the onset of stoke. [43, 44]
The frequency of seizures and epilepsy after an ischemic stroke is higher in children than adult population. The incidence of a first remote seizure is 1 % per month, with a 13% cumulative incidence of active epilepsy by 1 year after childhood AIS [45]. Children with epilepsy complicating AIS have poorer cognitive outcomes and quality of life than those who do not [45].
Based on five risk factors, Galovic et al developed a multivariate model named “SeLECT” To evaluate the risk of late seizures within the first year after stroke. It includes the
35 severity of stroke, large-artery atherosclerotic etiology, early seizures, cortical involvement, and territory of middle cerebral artery involvement [43].
Kopyta et al demonstrated that focal seizures were present in all patients with PSS. About 40% were secondary generalized seizures. In a study by Pilarska and Lemka, EPSS which were tonic - clonic were present in about 7% of children with AIS and it was observed within the first 24hours after stroke [43].
Subtle or multifocal clonic seizures were present in a group of patients with neonatal AIS from Philadelphia. Focal seizure with or without secondary generalization was found in almost all patients in the group with childhood stroke, except one child who has infantile spasm [43]. Focal neurologic signs were most common presentation in both EPSS and LPSS, but was found to be more frequent in LPSS [46]. According to Hesdorffer et al, acute symptomatic seizures has a lowest risk of subsequent unprovoked seizures and hence cannot be recognized as epilepsy [43].
According to a Brazilian study of pediatric population, half of the children with stroke had early seizures and later evolved into epilepsy in about 30% of pediatric patients [48]. Breitweg et al demonstrated that early seizures were present in more than 20% of children with stroke and PSE in about 27% of patients [47]. In a study by Fox et al, remote seizures were present in about half of the children with arterial ischemic stroke (AIS) [47]. Early seizures evolved into epilepsy in about 30% of pediatric patients [47].
Post stroke epilepsy can be identified in a patient who had experienced at least 2 recurrent seizures, that were not provoked by any factors (toxic, metabolic, or any other) and occurred after the acute phase of stroke [43].
6.3. Radiological Findings
A recent meta-analysis has shown that cortical involvement is highly associated with increased risk of post stroke epilepsy in adults. Studies in children have shown association between cortical infarction and epilepsy but only a few reports have evaluated the relation using multivariate analyses [41]. The presence of multifocal infarction, focal cerebral arteriopathy and involvement of middle cerebral artery on neuroimaging is positively associated with PSE, and the prognosis is worse than single lesion [41,43].
Cortical lesions in the frontal lobe are associated with recurrent post stroke seizures [40].
36
7.Epilepsy associated with tumor
7.1. Etiology
Pediatric brain tumors are the leading cause of cancer mortality in children. Seizures are often associated with pediatric brain tumors. Factors that increase the risk of seizures include low grade, gray matter involvement, supratentorial location, and certain histological features - especially ganglioglioma, DNET and oligodendroglioma. [47]
The metabolic and neurotransmitter changes in the peritumoral brain may lead to the seizures. Seizures are also caused by the presence of peritumoral blood products, morphological changes such as malformations of cortical development, gliosis and necrosis [47].
Long term epilepsy associated tumors (LEAT) are low grade supratentorial tumors with a high propensity to develop seizures [49]. Dysembryoplastic neuroepithelial tumor (DNET), ganglioglioma and oligodendrogliomas are the most common LEAT [47].
7.2. Clinical Manifestations
7.2.1. Ganglioglioma
Seizures are the most frequent presenting symptom of gangliogliomas and they peak in adolescense. Focal seizures with dyscognitive features are often present, followed by focal motor and focal with secondary generalization. The frequency of seizures is variable from daily to monthly seizures [47]. The seizure control is good but recurrence remains a challenge [47].
7.2.2. Dysembryoplastic neuroepithelial tumor (DNET)
DNET’s are rare, but the most epileptogenic among primary pediatric tumors and seizures are present in all cases. They peak at age of 7-10 years. Seizures are focal with dyscognitive features. Secondarily generalized and primarily generalized tonic-clonic seizures are also often present. Papilledema, headache and other signs and symptoms of elevated intracranial pressure are rare at presentation or later in the course of the disease. Epilepsy with DNET is regularly disabling with often (daily to almost daily) seizures and is highly refractory to antiepileptic drugs. [47]
37 DNETs are highly resistant to antiepileptic drugs and bout 85% of cases are seizure free after surgical resection [47].
7.3. Radiological Findings
7.3.1. Gangliogliomas
MRI: Gangliogliomas occur most commonly in the tempero-pariental-occipital regions followed by the frontal lobes and posterior fossa. Gangliogliomas appear as an enhancing mass with partially cystic appearance in about 40% of cases. Calcifications can be seen in 40-50% of cases [47].
7.3.2. DNET
MRI: DNET appear as a well-circumscribed cystic mass most frequently centered in the cerebral cortex, particularly common in the temporal lobe [47]. It has a clear demarcated morphology with a cortical location, hypo or isointense T1 weighted images, hyperintense on T2 images and presence of cystic elements [48]. Atypical radiological findings such as infiltrative features, indistinct margins and mass effect localized in the medial temporal, frontal and occipital areas are also seen in some cases [48].
8.Hippocampal Sclerosis associated epilepsy
8.1 Etiology/pathophysiology
Hippocampal sclerosis (HS) is most commonly encountered in mesial temporal lobe epilepsy and is considered multifactorial in etiology. It can be acquired, secondary to postnatal injuries or genetically acquired [50, 51]. Prolonged febrile seizures in childhood, head trauma, seizures or infection at any age are also suspected causes of acquired temporal lobe epilepsy with HS [52].
Hippocampal scelerosis are associated with more severe cortical malformations, vascular malformations and low-grade glioneuronal tumors [50]. About 6.5% of pediatric TLE epilepsy patients are identified with HS surgically. The causal relationship between early HS and medically refracted pediatric epilepsy is still unclear [53].
38 The ILAE classified HS based on histological patterns into typical (type1) and atypical (type 2 and 3) groups [51]. The new ILAE system not only recognizes the severity of cell loss but also the pattern of cell loss [50].
The mechanism of neuronal damage in HS is due to the excitotoxicity caused by the neuronal death through activation of glutamate receptors. The excessive influx of calcium through the NMDA receptors and specific AMPA receptor subtypes and the metabotropic glutamate receptor activation results in reactions causing cell death [50].
8.2 Clinical Findings
Patients with mTLE-HS, often have a history of an ‘Initial precipitating injury’ before the age of 4, birth trauma, head injury or meningitis. Complex febrile seizures are most common. Seizures often begin by the end of first decade, although few studies show late onset, after 50 years. Seizures often includes auras with psychic, perceptual or dysamnestic phenomena [54]. Motor arrest with impaired awareness and responsiveness and blank starring appearance with dilation of the pupil are often present in the beginning of the seizure. Seizures cease at this stage or may be followed by semi volunteered coordinated movements [54]. Signs of hippocampal sclerosis are often associated with clinical intractable temporal lobe epilepsy in children [53].
Posturing of the upper extremity contralaterally indicates the involvement of the basal ganglia. Lateralizing signs such as ictal speech (nondominant TL), postictal dysphasia (dominant TL) and ictal anomia are present [54].
8.3 Radiological Findings
MRI: The most reliable signs of HS are reduced hippocampal volume, increased signal intensity and altered internal architecture [55]. The decreased hippocampal volume coordinates with the lower neuronal cell counts in the hippocampus and the increased T2 signal correlates with gliosis [55]. Additional signs include enlarged temporal horn, enlarged lateral ventricle, loss of dentate gyrus digitations [53].
‘Dual Pathology’ is defined as lesions associated outside the hippocampus or even outside the temporal lobe. Ipsilateral HS are seen in low grade tumors, malformations of cortical development, early ischemic lesions, hemiatrophy and vascular malformations. Bilateral HS are identified using automated or manual volumetry methods [55].
