SEIZURES AND EPILEPSIES

1. SEIZURES AND EPILEPSIES CONF.DR. INGRITH MIRON DR.ADRIANA MOCANU

2. SEIZURES and EPILEPSIES Definition Seizure- sudden episode, stereotyped, with changes in motor activity , behavior, sezitivo-sensory activity, emotional activity and often of consciousness,with abnormal electrochemical discharges in the brain. Epilepsyis a chronic disease of varied etiology of the central nervous system whose symptoms are seizures. Features: evolving nature , recurrence of seizures in the absence of tiggers at various intervals. The clinician must try to determine the underlying epileptic syndrome because this has profound implications for treatment and prognosis.

3. SEIZURES and EPILEPSIES Epilepsy etiology is multifactorial: → genetic factors and acquired factors: • structural brain lesions • birth defects • infections • vascular diseases • toxic • tumors • degenerative diseases → idiopathic character/symptomatic character → related with age

4. SEIZURES and EPILEPSIESthe etiology of seizures /epilepsy in relation to age Antenatal period • dysplasia and neuronal migration disorder • major brain malformations • intrauterine vascular accidents • intrauterine infection • maternal-fetal drug intoxications Neonatal period • neuroinfections • metabolic disorders (hypoglycemia, hypocalcemia) • anoxia or intracranial hemorrhage at birth • major brain malformations

5. SEIZURES and EPILEPSIESthe etiology of seizures /epilepsy in relation to age Small children • febrile seizures • hereditary metabolic diseases • neuroinfections • cortical dysplasia Older children / teens • genetic syndromes / idiopathic • degenerative diseases • tumors • traumatic brain injury • mesial temporal sclerosis

6. SEIZURES and EPILEPSIESClassification (ILAE 2010) Generalized seizures  • Tonic–clonic (in any combination)  • Absence   Typical   Atypical   Absence with special features   Myoclonic absence   Eyelid myoclonia

7. SEIZURES and EPILEPSIESClassification (ILAE 2010) • Myoclonic - Myoclonic - Myoclonicatonic - Myoclonic tonic  • Clonic • Tonic  • Atonic Focal seizures Unknown  Epileptic spasms

8. GENERALIZED TONIC CLONIC SEIZURES(grand mal seizure) Clinical manifestations: - occasionally:aura prior totheattack. - more oftentheattackbeginsabruptlywith a loss of consciousnessand tonic stiffening of allmuscles. - theremaybe a suddencry at thebeginning of theseizure, andcyanosismayoccurduringthe period of tonic contraction. - thisisfollowedbyclonicjerkingmovementsthat are maximal in thearms but involveallmusclegroups; - the individual islethargic or confusedandoftennoticesmusclesoreness

9. GENERALIZED TONIC CLONIC SEIZURES Clinical manifestations: • factorsthatmayleadto a lowering of theseizurethreshold:fatiguefromsleepdeprivation, stress, a febrile illness, and central nervoussystemstimulantssuch as theophylline, antihistamines, andamphetamines; • afterthepostictal period, thefindings on neurologic examination are usuallynormal; • occasionally:lacerations of thetongue,mucousmembranes of themouth, and on rare occasionstheremaybepointtenderness at the site of a vertebral body,compressionfracturethathasoccurredduringtheseizure.

10. GENERALIZED TONIC CLONIC SEIZURESEEG EEG (generalized seizure) : symmetric spikes firing at a rate to 10 CPS or more, followed by an irregular spike and slow wave discharge, and finally postictal slowing. EEG : symmetric spike, or spike-and-wave discharges, in both hemispheres synchronously. EEG -may be normal during the interictalperiod (even with a clear history of a seizure) The yield is increased by activation procedures: hyperventilation, photicstimulation and sleep deprivation. If the diagnosis remains in question: • repeat EEG or prolonged EEG recording may be necessary EEG is essential for distinguishing generalized seizures from partial seizures with secondary generalization.

11. GENERALIZED TONIC CLONIC SEIZURES Patients with syncopal episodes or with breath holding attacks may have brief periods of tonic, clonic, or a combination of tonic and clonic activity after the loss of consciousness. It is the precipitating factors that lead to a diagnosis of syncope or breath holding. If there has been an unwitnessed episode or a vague story in combination with a normal EEG, an appropriate approach is observation without making a specific diagnosis or starting any therapy.

12. GENERALIZED TONIC CLONIC SEIZURES Generalizedseizures are often familial or metabolic. Allpatientswithgeneralizedseizures: • bloodglucose • calciumlevels • electrolyteslevels(history of vomiting, diarrhea, or renal disease or signs of dehydration or hypertension,) • toxicologyscreen (toddlers or adolescents) • thyroidfunctiontests(signsof hyperthyroidism) • aminoaciduria and organic aciduria(childislessthan 1 year of ageandparticularlyifthereisanyevidenceofdevelopmentaldelay or retardation) • CT scanisusuallyhelpful.

13. GENERALIZED TONIC CLONIC SEIZURES Treatment after a single generalized seizure is somewhat controversial. - recurrent generalized seizures, treatment should be started with either Phenobarbital, Phenytoin, Carbamazepineor Valproic acid; - children under 4 years of age: Phenobarbital; • older children : first choice – Carbamazepine; • the dosage is pushed until there is either reasonable seizure control or toxicity; • use one drug at a maximal dose; • polypharmaceuticaltherapy is needed: maximum 2 drugs.

14. Absenceseizures (petit mal seizures) Absenceseizures: • 4 and 12 years of age; • history of staring spells(labeled as day-dreaming) • decrease in the quality of school performance; • no other history of neurologic problems. • head or eye turning and symmetric or asymmetric clonicactivity (unusual cases of complex absence seizures ); • typical absence seizures may be provoked by 2 to 4 minutes of hyperventilation, performed as part of the neurologic examination.; • there is often a family history of absence seizures.

15. Absenceseizures The diagnosis of absence attacks depends upon the EEG: - 3 cycle per second (CPS) spike and wave discharge, usually precipitated by hyperventilation; • background activity is generally normal; • occasional :variability in rates, with dischanges starting at 3 to 4 CPS and ending at 2 to 3 CPS; 3 CPS slow wave burst without spikes or episodes of polyspikes; • if the EEG is entirely normal, one should consider either day-dreaming or, if the episodes seem definitely epileptiform, partial seizures originating in the mesial temporal or basal frontal regions.

16. Absenceseizures Treatment: - ethosuximide and/or valproic acid ↔control of absence attacks; - start with ethosuximide(lower incidence of major side effects); - if absence attacks - not controlled with ethosuximide→valproic acid. - if neither drug is effective alone→a combination of ethosuximide and valproicacid→combination of ethosuximide or valproic acid with acetazolamide or clonazepam alone. Because absence attacks are generally easy to control, failure to establish reasonable control should lead to a reconsideration of the diagnosis or questions about drug compliance.

17. Absenceseizures The child who has absence without generalized tonic-clonic seizures has an excellent prognosis. There is a 90% remission rate for children who have pure absence attacks, at least normal intelligence, and a negative family history of other types of seizures. Remission rates are lower if there is a combination of absence and generalized tonic-clonic seizures.

18. PARTIAL SEIZURES Partial elementary seizures are characterized : • motor or sensory phenomena without loss of consciousness; • partial complex seizures may consist of staring, lip smacking, picking movements, hallucinations, laughter, fear or movements such as walking or running; • confusion and an alteration of consciousness are associated; • attacks are sudden, brief, and stereotypic and are followed by confusion; • findings on the neurologic examination are often normal; • focal seizures may be followed by Todd’s paralysis and a transient loss of function that clears within 24 hours.

19. PARTIAL SEIZURES EEG : diagnose and classify seizures. • the interictal EEG : focal sharp waves and spikes, often with an associated slow wave. • specific ictal patterns :initially slowly increase in amplitude and decrease in frequency and are followed by slow waves in the distribution of the discharge. If the focus is in the basal frontal or mesial temporal region, spike and sharp wave activity may not be apparent on routine EEG. The yield can be increased by sleep deprivation and by using nasopharyngeal leads in the older child who will tolerate this procedure; • focal spikes may be present in as many as 3% of normal children who have not and who will not have seizures in the future→abnormalEEG is not pathognomic of seizures.; • child with staring spells and EEG – normal/particularly : focal spikes, a diagnosis of partial seizures with involvement of the diencephalons can be made; • prolonged EEG monitoring may be necessary to determine the appropriate diagnosis in a child with repeated unusual episodes.

20. PARTIAL SEIZURES Benign focal epilepsy of childhood (rolandicseizures ) • familial; • start during school age (4 to 12 years); • not associated with any underlying central nervous system damage, and resolve during the teenage years in 85% of affected children.; • the typical rolandic seizures occurs during transitions from sleep to wakefulness and consists of focal motor activity involving the face and mouth, anarthria, and excessive salivation.; • the EEG obtained during sleep shows characteristic spike and slow wave discharge in the central temporal region.

21. PARTIAL SEIZURES 30 to 50% of the children with partial seizures, no etiology is apparent. Etiology: - perinatalasphxia or trauma; - postnatal meningitis or encephalitis; - head trauma and cerebrovasculardisease - intrauterine infection; - focal motor signs of cerebral palsy. CT should be carried out in all children with seizures: • confirm the occurrence of a previous vascular disease, infection, or trauma • arteriovenous malformations and neoplasms. Metabolic disturbances and neuronal storage diseases may present with focal seizures (developmental delay, abnormalities on neurologic examination, or growth disturbances) : additional metabolic assessment .

22. PARTIAL SEIZURES Treatment: First line drugs for partial seizures: - carbamazepine, - phenytoin, • phenobarbital. The are probably equally effective, the main differences being side effects. As first drugs we tend to use Phenobarbital for the child < 4 years of age and carbamazepine for older child.

23. Pediatric epilepsy syndromes Newborns Benign neonatal convulsions (fifth-day fits)  Familial benign neonatal convulsions  Early myoclonic encephalopathy  Severe idiopathic status epilepticus  Early infantile epileptic encephalopathy with suppression-burst

24. Pediatric epilepsy syndromes Infants Febrile convulsions  West’s syndrome: infantile spasms  Benign myoclonic epilepsy in infants  Severe myoclonic epilepsy in infants Myoclonic epilepsy (myoclonic status) in nonprogressiveencephalopathies  Epileptic seizures caused by inborn errors of metabolism Myoclonic-astatic epilepsy of early childhood  Lennox-Gastaut syndrome

25. Pediatric epilepsy syndromes Children Childhood absence epilepsy (pyknolepsy)  Epilepsy with myoclonic absences  Epilepsy with generalized convulsive seizures  Benign partial epilepsies Benign epilepsy with centrotemporal (rolandic) spikes  Benign psychomotor epilepsy Benign epilepsy with occipital spike-waves (BEOSW)  Other benign partial epilepsies  Benign partial epilepsy with extreme somatosensory-evoked potentials  Epilepsy with continuous spikes and waves during sleep  Epilepsy with photosensitivity  Eyelid myoclonia absences  Self-induced epilepsy

26. Pediatric epilepsy syndromes Older children and adolescents (juveniles) Juvenile absence epilepsy  Juvenile myoclonic epilepsy (JME)  Epilepsy with grand mal on awakening (GMA) Benign partial seizures of adolescence Kojewnikoff’s syndrome  Progressive myoclonus epilepsies - juvenile Gaucher’s - juvenile neuronal ceroidlipofuscinosis (NCL) - Lafora’ body disease Unverricht-Lundborg disease (Finnish or Baltic myoclonus epilepsy) - cherry-red spot myoclonus (neuraminidase deficiency) - dyssynergiacerebellarismyoclonica (Ramsay Hunt syndrome) - mitochondrial encephalopathy

27. Partial epilepsiesIdiopathic Benign epilepsy of childhood with centrotemporal spikes (BECTS, rolandic epilepsy) • common syndrome(1/4 of epilepsy cases in schoolagedchildren); • onset between ages 3 and 13; - the seizures have a simple partial onset, usually beginning in the face and variably generalizing to tonic-clonicseizures( almost always at night); - normal neurological examinations and no associated illnesses. -the EEG findings are classic : high-amplitude spikes and sharp waves in the central region, which are most frequent during light sleep. (MRI are unnecessary) • etiology is genetic, with an autosomal dominant inheritance reported for the EEG trait, but less than 25% of patients with the EEG pattern actually develop seizures. • a recent study demonstrated a link between chromosome 15q14 and families with BECTS. Prognosis is excellent: seizures are easily controlled with carbamazepine, phenytoin, or gabapentin and almost all children ↔without sequelae by age 15.

28. Partial epilepsiesIdiopathic Childhood epilepsy with occipital spikes • much less common; • characterized by daytime seizures consisting of visual experiences followed by complex partial seizures; • after the seizure, patients often have a headache. The EEG show bilateral high-amplitude spike-wave discharges in the occipital region; the course is benign.

29. Partial epilepsiesSymptomatic Symptomatic localization-related epilepsies: • the most common syndrome in adults; • many specific identificablecauses; • seizure types are limited to partial seizures that often, if untreated, progress to secondarily generalized tonic clonicseizures; The underlying pathology: - diffuse:anoxia, physical trauma or infections - multifocal: cerebrovascular disease (stroke, arteriovenous malformations, subarachnoid hemorrhage, venous thrombosis), brain tumors (astrocytomas, meningiomas, glioblastomas, metastatic tumors) and mesial temporal sclerosis.

30. Partial epilepsiesSymptomatic However, despite careful history-taking and the use of improved diagnostic techniques, in many cases the cause of the epilepsy cannot be determined. These are classified as cryptogenic. Consequently, epilepsy of undetermined origin or symptomatic cryptogenic is still the most common ,,syndrome” in this category. However, with high-resolution MRI scans, cortical heterotopias (migrational defects) are now being recognized in many patients with intractable cryptogenic epilepsy.

31. Generalized epilepsies and syndromes the generalized epilepsies are most common in the pediatric population. Idiopathic (genetic) syndromes have been well defined in the last few years, and indeed, gene foci have been mapped for some, cementing firmly the concept of a specific identifiable syndrome. 1.Idiopathic with age-related onset • Benign neonatal familial convulsions (rare) - generalized seizures occurring mostly during the first week of life; - must be differentiated from another symptomatic neonatal seizures and from benign myoclonic epilepsy in infancy (EEG with bursts of spike-and-wave discharges superimposed on an otherwise normal background); - family history ; seizures remit spontaneously after a few days; - deletion of chromosome 20q13.3 has been identified and DNA of this region encodes a potassium channel, thus providing a clear relationship between a gene product and clinical syndrome. • Childhood absence (pyknolepsy) – discust

32. Generalized epilepsies and syndromes • Juvenile myoclonic epilepsy (JME) - onset during the teenage years; - characteristic syndrome consisting of a triad of seizures (myoclonic, absence, and generalized tonic-clonic).; - myoclonicseizures usually occur in the morning and involve primarily the upper extremities; the most common complaint is clumsiness or jitters, which is exacerbated by stress and is often initially mistaken for adolescent behavior; • generalized tonic-clonic seizures develop, usually in the morning; absence seizures may be relatively difficult to detect. Not all persons have all three seizure types, but the EEG characteristics along with the history are usually diagnostic. It is important to differentiate this syndrome from localization-related epilepsies because treatment is highly specific; response to carbamazepine or phenytoin is usually poor, while valproate is very effective. A specific gene locus in chromosome 6p21.2-p11 has been proposed for this familial syndrome.

33. Generalized epilepsies and syndromes 2.Symptomatic and/or idiopathic generelized epilepsies - consists of a mixed set of clinical syndromes; their clinical manifestations are similar.; - some children in these groups have identifiable symptomatic causes, while in others the etiology is undetermined or cryptogenic. Infantile spasms (epileptic spasms, West’s syndrome or salaam seizures) - age of onset :4 and 12 months; - specific seizure type, a spasm that consists of flexion at the neck, waist, arms, and legs, with either abduction or adduction of the arms; these are quick, lasting only a second, hence the name ,,blitzkrampf”, or lightning seizure; - these seizures may occur hundreds of times a day; - infants with this syndrome usually develop normally until spasms occur, at which point there is arrest of psychomotor development.

34. Generalized epilepsies and syndromes Infantile spasms - approximately two thirds of patients have an EEG pattern described as hypsarrhythmia ( pattern : disorganized mixture of spikes and slow waves that are different in each hemisphere) and one third have large definable abnormalities. Current therapy : - adrenocorticotrophic hormone (ACTH) initiated within 1 month of the onset of spasms (5% mortality from complications of therapy, most often overwhelming infection); - ACTH and steroids are ineffective →conventional anticonvulsants , most often a benzodiazepine : clonazepam; - Vigabatrin has been reported to be particularly effective for control of seizures if West’s syndrome is caused by tuberous sclerosis.

35. Generalized epilepsies and syndromes Infantile spasms The prognosis in infantile spasms is related to the underlying brain disorder and to the therapy: - idiopathic infantile spasms who respond to optimal therapy have the best prognosis; - severe encephalopathic disorders have the worst prognosis; - among all patients with infantile spasms, 20% die before 5 years of age, and of the survivors between 75% and 93% are reported to be mentally retarded; - up to 50% have epilepsy later in life, and half of these develop the Lennox-Gastaut syndrome.

36. Generalized epilepsies and syndromes Lennox-Gastautsyndrome - has been designated to represent a combination of seizures – axial tonic attacks, tonic-clonic seizures, atypical absence seizures, and atonic or so called drop attacks – with mental subnormality and an EEG pattern of slow (< 2,5Hz) spike and wave; - onset is between 1 to 8 years. - difficult to treat: Valproate, benzodiazepines, and felbamate are most effective, but some of the other drugs sometimes actually worsen the akinetic and atypical absence seizures.

37. Generalized epilepsies and syndromes EPILEPSIES, UNDETERMINED AS TO FOCAL OR GENERALIZED In this category of epilepsies are a number of pediatric syndromes whose clinical natures have not yet been fully elucidated. Some patients may experience a mixture or focal and generalized EEG patterns and clinical seizures. This group includes a number of cases of myoclonic epilepsy with mental retardation. Special syndromes This category is designed to encompass conditions in which seizures do not occur spontaneously, but rather are related to specific stimuli. Thus, these patients probably have some predisposing CNS dysfunction. However, unlike the epileptic syndromes described above, treatment for these special conditions often consists of avoiding the specific stimuli, or treating only at the time of provocation. Also in this group are patients who have isolated seizures and may simply have a low seizure threshold.

38. FEBRILE SEIZURES

39. FEBRILE SEIZURES Definition and clinical manifestations: • febrile seizures occur in 2% to 4% of children; • they occur in febrile children from 3 months to 5 years of age who do not have a central nervous system infection; • apositive family history is common; • two types: - simple - complex → complex and simple febrile seizures differ in length, description and the number of seizures in 24 hours.

40. FEBRILE SEIZURES Simple febrile seizures:  generalized tonic-clonic seizures  no more than 15 minute duration • one seizure in 24 hours Complex febrile seizures: occur from 3 months to 5 years of age  no central nervous system infection  seizure more than 15 minutes or partial or more than 1 in 24 hours.

41. FEBRILE SEIZURES Etiology - important genetic predisposition to suggest that the disorder is inherited as an autosomal dominant trait / polygenic pattern; - when a child has a first degree relative with febrile seizures, the risk of febrile seizures : 10-15 %; - family history of febrile seizures was present in 8% to 22% of parents and in 9% to 17% of siblings of the patient; - factors that predict a first febrile seizure are: delayed neonatal hospital discharge, slow neurologic development ( judged by parents), a parent or sibling with febrile seizures, an uncle /aunt with FS and attendance at day care.

42. FEBRILE SEIZURES Evaluation of children with febrile seizures - routine blood work ; - EEG after a febrile seizure ? not seem justified - lumbar puncture: higher incidence of meningitis with complex febrile seizures than with simple febrile seizures; - neuroimaging, especially if a partial seizure occurs; assess for mesial temporal sclerosis and other structural lesions.

44. FEBRILE SEIZURES Treatment • controversial (most febrile seizures last only a few minutes ); many pediatric neurologists do not recommend chronic treatment for simple febrile seizures; • rectal diazepam (0,5mg/kg) or rectal lorazepam (0,1mg/kg) appear equally efficacious;diazepamper rectum is given when fever occurs to prevent febrile convulsions. • daily phenobarbital(dose of 4-5mg/kg/day as a single day dose) may be effective if compliance is excellent; the side effects of phenobarbital(mainly adverse behavior) : 40% of patients. • daily valproic acid (dose 15-20mg/kg/zi) maybeeffectivealthoughtherisk of toxic, fatal hepatitisappearshigh in thisagerange.

45. FEBRILE SEIZURES Simple febrile seizures • Risk of epilepsy: 2,4% by 25 years of age if the child is neurological normal. No evidence indicates that simple febrile seizures cause structural disease or that treatment prevents epilepsy. • Risk of recurrence: 50% if the first seizure is before 12 months of age; 30% if the first seizure is after 12 months of age; and 50% risk of recurrence thereafter. Complex febrile seizures Risk of temporal lobe epilepsy by 25 years of age is 49% if all three characteristics –prolonged, partial and flurry seazures– are present. The following two theories have been formulated for why the risk of epilepsy is so high: -the prolonged partial febrile seizure may cause mesial temporal sclerosis, leading to a focus for temporal lobe epilepsy -the patient has underlying mesial temporal sclerosis (possibly that is perinatal in origin), which acts as focus for complex febrile seizures and later for temporal lobe epilepsy.

46. Status epilepticus Definition: - recurrent seizures without a return of consciousness during the interictalperiod, - the episode lasts at least 30 minutes, - in this discussion we will consider only generalized tonic-clonic or grand mal status epilepticus. - history : seizures, compliance with anticonvulsant therapy, recent head trauma or febrile illness, drug use or exposure to toxins, and any underlying chronic illness.

47. Status epilepticus Examination : - check first the respiratory and cardiac condition (stabilize the patient if there are problems) ; - distribution of seizure activity; - skin : bruising, petechiae or needle marks; - eyes: papilledema or retinal hemorrhages; - abdomen: organomegalyor tenderness; - hypertoniaand upgoing plantar responses may be due to seizure activity and do not mean that the patient has definite underlying brain damage. Laboratory tests : complete blood count (CBC), glucose blood test, calcium, BUN, electrolyte levels and, if appropriate, anticonvulsant blood levels.

48. Status epilepticus Treatment - Diazepam (first choice ): 0,4mg/kg intravenously, repeating at 10 minutes intervals to a maximum of 3 doses as necessary to stop the seizures. - diazepam (brief duration of action :15 to 30 minutes), a second drug: phenytoin or phenobarbital; - phenytoin (possible head trauma→the ability to follow the mental status ) - both drugs can be given intravenously in increments of 10mg/kg. For both drugs, approximately 20mg/kg will be required for adequate loading. Use up to 30mg/kg of either drug in the first 60 minutes as necessary to control seizures. Give both drugs at a rate of 30mg/min; - the maximal dose is determined in part by the effect on seizures and in part by the side effects.; - side effects of phenobarbital : respiratory depression and hypotension; - the main side effects of phenytoin: cardiac conduction abnormalities and hypotension;

49. Status epilepticus Treatment - if after the first hour the initial drug has not been effective, switch to the second drug; if you being with phenytoin, use phenobarbital next. The second drug can then be pushed to a maximal dose over the next 60 minutes. - the combination of diazepam, phenytoin, and phenobarbital is not effective → paraldehyde a 4% solution by adding 10 ml of paraldehyde to 250ml of 5% dextrose in water; the loading dose is 0,1cc/kg, and maintenance is approximately 0.05cc/kg per hour; Make sure that the paraldehyde is not out of date (infrequently used drug). The bottle should be covered because the light causes paraldehyde to decompose to acetaldehyde. A glass bottle should be used because paraldehyde can bind to the plastic in intravenous bottles and tubing. Watch for acidosis and pulmonary hemorrhage. - alternate drug if there is no improvement is pentobarbital given at a loading dose of 3 to 5mg/kg and a maintenance dose of 1 to 2 mg/kg per hour.

50. Status epilepticus Treatment - supportive care is essential: intubatethe child at the first sign of respiratory suppression; blood gas levels are monitored (hypoxia and acidosis); maintain the blood pressure and treat hyperthermia ; Further work-up to determine the etiology depends upon the initial assessment: • the patient who has chronic seizures or an underlying chronic encephalopathy does not need additional neurodiagnostic testing ; • evidence of trauma : CT scan; • the child is febrile : lumbar punture ( as soon as possible) ; • if the cause of status epilepticus is not apparent from the initial history, examination or first laboratory data: combination of CT scanning, toxicologic screening of urine and blood and lumbar punture; • EEG should be monitored to confirm that seizure activity has stopped completely;onoccasion subclinical electrical status epilepticuscontinues (additions damage).