Seizures & Epilepsy MBBS IV Group C Tutor: Prof. V. Wong 16 th Feb 2004

Outline  Definitions  Pathophysiology  Aetiology  Classification  Video demonstration  Diagnostic approach  Treatment  Quiz

Definition  Seizure (Convulsion) Clinical manifestation of synchronised electrical discharges of neurons  Epilepsy Present when 2 or more unprovoked seizures occur at an interval greater than 24 hours apart

Definition  Provoked seizures  Seizures induced by somatic disorders originating outside the brain  E.g. fever, infection, syncope, head trauma, hypoxia, toxins, cardiac arrhythmias

Definition  Status epilepticus (SE)  Continuous convulsion lasting longer than 30 minutes OR occurrence of serial convulsions between which there is no return of consciousness  Idiopathic SE  Seizure develops in the absence of an underlying CNS lesion/insult  Symptomatic SE  Seizure occurs as a result of an underlying neurological disorder or a metabolic abnormality

Aetiology of seizures  Epileptic  Idiopathic (70-80%)  Cerebral tumor  Neurodegenerative disorders  Neurocutaneous syndromes  Secondary to  Cerebral damage: e.g. congenital infections, HIE, intraventricular hemorrhage  Cerebral dysgenesis/malformation: e.g. hydrocephalus

Aetiology of seizures  Non-epileptic  Febrile convulsions  Metabolic  Hypoglycemia  HypoCa, HypoMg, HyperNa, HypoNa  Head trauma  Meningitis  Encephalitis  Poisons/toxins

Aetiology of Status Epilepticus  Prolonged febrile seizure  Most common cause  Idiopathic status epilepticus  Non-compliance to anti-convulsants  Sudden withdrawal of anticonvulsants  Sleep deprivation  Intercurrent infection  Symptomatic status epilepticus  Anoxic encephalopathy  Encephalitis, meningitis  Congenital malformations of the brain  Electrolyte disturbances, drug/lead intoxication, extreme hyperpyrexia, brain tumor

Pathophysiology  Still unknown  Some proposals:  Excitatory glutamatergic synapses  Excitatory amino acid neurotransmitter (glutamate, aspartate)  Abnormal tissues — tumor, AVM, dead area  Genetic factors  Role of substantia nigra and GABA

Pathophysiology  Excitatory glutamatageric synapses  And, excitatory amino acid neurotransmitter (glutamate, aspartate)  These are for the neuronal excitation  In rodent models of acquired epilepsy and in human temporal lobe epilepsy, there is evidence for enhanced functional efficacy of ionotropic N-methyl-D-aspartate (NMDA) and metabotropic (Group I) receptors Chapman AG. Glutatmate and Epilepsy. J Nutr Apr; 130(4S Suppl): 1043S-5S

Pathophysiology  Abnormal tissues — tumor, AVM, dead area  These regions of the brain may promote development of novel hyperexcitable synapses that can cause seizures

Pathophysiology  Genetic factors  At least 20 %  Some examples  Benign neonatal convulsions--20q and 8q  Juvenile myoclonic epilepsy--6p  Progressive myoclonic epilepsy--21q22.3

Pathophysiology  Role of substantia nigra  Studies with 2-deoxyglucose indicate that a marked increase in metabolic activity in SN is a common feature of several types of generalized seizures; it is possible that some of this increased activity is associated with GABAergic nerve terminals that become activated in an attempt to suppress seizure spread.  Because GABA has been shown to inhibit nigral efferents, it is likely that GABA terminals inhibit nigral projections that are permissive or facilitative to seizure propagation From Gale K. Role of the substantia nigra in GABA- mediated anticonvulsant actions. Adv Neurol.1986;44:

Pathophysiology  Premature brain  It is more susceptible to specific seizures than is the brain in older children and adults  Kindling  Repeated subconvulsive stimulation (e.g. to the amygdala) will lead to generalized convulsion  This may explain the development of epilepsy after injury to the brain  One temporal lobe seizure -> contralateral lobe

Classification of seizures

Seizures Partial – Electrical discharges in a relatively small group of dysfunctional neurones in one cerebral hemisphere – Aura may reflect site of origin – + / - LOC Generalized – Diffuse abnormal electrical discharges from both hemispheres – Symmetrically involved – No warning – Always LOC

Simple Complex Partial Seizures 1. w/ motor signs 2. w/ somato- sensory symptoms 3. w/ autonomic symptoms 4. w/ psychic symptoms 1. simple partial --> loss of consciousnes s 2. w/ loss of consciousnes s at onset Secondary generalized 1. simple partial --> generalized 2. complex partial --> generalized 3. simple partial --> complex partial --> generalized

Simple partial seizures with motor signs  Focal motor w/o march  Focal motor w/ march  Versive  Postural  Phonatory

Simple partial seizures with motor signs  Sudden onset from sleep  Version of trunk  Postural  Left arm bent  Forcefully stretched fingers  Looks at watch  Note seizure

Simple partial seizures with sensory symptoms  Somato-sensory  Visual  Auditory  Olfactory  Gustatory  Vertiginous

Simple partial seizures with sensory symptoms  Vertiginous symptoms “Sudden sensation of falling forward as in empty space”  No LOC  Duration: 5 mins

Simple partial seizures with autonomic symptoms  Vomiting  Pallor  Flushing  Sweating  Pupil dilatation  Piloerection  Incontinence

Simple partial seizures with autonomic symptoms  Stiffness in L cheek  Difficulty in articulating  R side of mouth is dry  Salivating on the L side  Progresses to tongue and back of throat

Simple partial seizures with psychic symptoms  Dysphasia  Dysmnesic  Cognitive  Affective  Illusions  Structured hallucinations

Simple partial seizure with pyschic symptoms  Dysmnesic symptoms  “déjà-vu”  Affective symptoms  fear and panic  Cognitive  Structured hallucination  living through a scene of her former life again

Complex Partial Seizures  Simple partial onset followed by impaired consciousness  with or without automatism  With impairment of consciousness at onset  with impairment of consciousness only  with automatisms

Simple Partial Seizures followed by Complex Partial Seizures  Seizure starts from awake state  Impairment of consciousness  Automatisms  lip-smacking  right leg

Complex Partial Seizures with impairment of consciousness at onset  Suddenly sit up  Roll about with vehement movement

Partial Seizures evolving to Secondarily Generalised Seizures  Simple Partial Seizures to Generalised Seizures  Complex Partial Seizures to Generalised Seizures  Simple Partial Seizures to Complex Partial Seizures to Generalised Seizures

Simple Partial Seizures to Generalised Seizures  Turns to his R with upper body and bends his L arm  Stretches body  LOC  Tonic-clonic seizure  Relaxation phase  Postictal sleep

Simple Partial Seizures to Complex Partial Seizures to Generalised Seizures  Initially unable to communicate but understands  Automatism  Smacking  Hand-rubbing  Abolished communication  Generalised tonic- clonic seizure

Generalized seizures  Absence  Myoclonic  Clonic  Tonic  Tonic-clonic  Atonic

Absence seizures  Sudden onset  Interruption of ongoing activities  Blank stare  Brief upward rotation of eyes  Duration: a few seconds to 1/2 minute  Evaporates as rapidly as it started

Absence seizures  Stops hyperventilating  Mild eyelid clonus  Slight loss of neck muscle tone  Oral automatisms

Myoclonic seizures  Sudden, brief, shock-like  Predominantly around the hours of going to or awakening from sleep  May be exacerbated by volitional movement (action myoclonus)

Myoclonic seizures  Symmetrical myoclonic jerks

Clonic seizures  Repetitive biphasic jerky movements  Repetitive vocalisation synchronous with clonic movements of the chest (mechanical)  Venous injection of diazepam  Passes urine

Tonic seizures  Rigid violent muscle contraction  Limbs are fixed in strained position  patient stands in one place  bends forward with abducted arms  deep red face  noises - pressing air through a closed mouth

Tonic seizures  Elevates both hands  Extreme forward bending posture  Keeps walking without faling  Passes urine

Tonic-clonic seizures (grand mal) Tonic Phase  Sudden sharp tonic contraction of respiratory muscle: stridor / moan  Falls  Respiratory inhibition cyanosis  Tongue biting  Urinary incontinence Clonic Phase  Small gusts of grunting respiration  Frothing of saliva  Deep respiration  Muscle relaxation  Remains unconscious  Goes into deep sleep  Awakens feeling sore, headaches

Tonic-clonic seizures  Tonic stretching of arms and legs  Twitches in his face and body  Purses his lips and growls  Clonic phase

Atonic seizures  Sudden reduction in muscle tone  Atonic head drop

Epilepsy syndrome  Epilepsy syndromes may be classified according to:  Whether the associated seizures are partial or generalized  Whether the etiology is idiopathic or symptomatic/ cryptogenic  Several important pediatric syndromes can further be grouped according to age of onset and prognosis  EEG is helpful in making the diagnosis  Children with particular syndromes show signs of slow development and learning difficulties from an early age

CategoryLocalization-relatedGeneralized IdiopathicBenign epilepsy of childhood with centrotemporal spikes (benign rolandic epilepsy) Benign occipital epilepsy Benign myoclonic epilepsy in infancy Childhood absence epilepsy Juvenile absence epilepsy Juvenile myoclonic epilepsy Symptomatic (of underlying structural disease) Temporal lobe Frontal lobe Parietal lobe Occipital lobe Early myoclonic encephalopathy Cortical dysgenesis Metabolic abnormalities West syndrome Lennox-Gastaut syndrome CryptogenicAny occurrence of partial seizures without obvious pathology Epilepsy with myoclonic absences West syndrome (with unidentified pathology) Lennox-Gastaut syndrome (with unidentified pathology) Table 1. Modified ILAE Classification of Epilepsy Syndromes

Special syndromesFebrile convulsions Seizures occurring only with toxic or metabolic provoking factors Neonatal seizures of any etiology Acquired epileptic aphasia (Landau-Kleffner syndrome) Table 1. Modified ILAE Classification of Epilepsy Syndromes (cond’)

Three most common epilepsy syndromes: 1. Benign childhood epilepsy 2. Childhood absence epilepsy 3. Juvenile myoclonic epilepsy Three devastating catastrophic epileptic syndromes: 1. West syndrome 2. Lennox-Gastaut syndrome 3. Landau Kleffner Syndrome

Benign childhood epilepsy with centrotemporal spike (Benign Rolandic Epilepsy) 1. Typical seizure affects mouth, face, +/- arm. Speech arrest if dominant hemisphere, consciousness often preserved, may generalize especially when nocturnal, infrequent and easily controlled 2. Onset is around 3-13 years old, good respond to medication, always remits by mid-adolescence

Childhood absence epilepsy 1. School age ( 4-10 years ) with a peak age of onset at 6-7 years 2. Brief seizures, lasting between 4 and 20 seconds 3. 3Hz Spike and wave complexes is the typical EEG abnormality 3Hz Spike and wave complexes is the typical EEG abnormality 4. Sudden onset and interruption of ongoing activity, often with a blank stare. 5. Precipitated by a number of factors i.e. fear, embarrassment, anger and surprise. Hyperventilation will also bring on attacks. Juvenile myoclonic seizure 1. Around time of puberty 2. Myoclonic ( sudden spasm of muscles ) jerks → generalized tonic clonic seizure without loss of consciousness 3. Precipitated by sleep deprivation

West’s syndrome (infantile spasms) Triad: 1. infantile spasms 2. arrest of psychomotor development 3. hypsarrhythmia  Spasms may be flexor, extensor, lightning, nods, usually mixed. Peak onset 4-7 months, always before 1 year. Lennox-Gastaut syndrome Characterized by seizure, mental retardation and psychomotor slowing Three main type: 1. tonic 2. atonic 3. atypical absence Landau- Kleffner syndrome ( acquired aphasia )

Diagnosis in epilepsy  Aims:  Differentiate between events mimicking epileptic seizures  E.g. syncope, vertigo, migraine, psychogenic non-epileptic seizures (PNES)  Confirm the diagnosis of seizure (or possibly associated syndrome) and the underlying etiology

Diagnosis in epilepsy  Approach:  History (from patient and witness)  Physical examination  Investigations

History  Event  Localization  Temporal relationship  Factors  Nature  Associated features  Past medical history  Developmental history  Drug and immunization history  Family history  Social history

Physical Examination  General  esp. syndromal or non-syndromal dysmorphic features, neurocutaneous features  Neurological  Other system as indicated  E.g. Febrile convulsion, infantile spasm

Investigations  I. Exclusion of differentials:  Bedside: urinalysis  Haematological: CBP  Biochemical: U&Es, Calcium, glucose, ABGs  Radiological: CXR, CT head  Toxicological: screen  Microbiological: LP (Always used with justification)

Investigations  II. Confirmation of epilepsy:  Dynamic investigations : result changes with attacks  E.g. EEG  Static investigations : result same between and during attacks  E.g. Brain scan

Electroencephalography (EEG)  EEG indicated whenever epilepsy suspected  Uses of EEG in epilepsy  Diagnostic: support diagnosis, classify seizure, localize focus, quantify  Prognostic: adjust anti-epileptic treatment

International System of Electrode Placement in EEG

Electroencephalography (EEG)  EEG interpretation in epilepsy  Hemispheric or lobar asymmetries  Periodic (regular, recurring)  Background activity:  Slow or fast  Focal or generalized  Paroxysmal activity:  Epileptiform features – spikes, sharp waves  Interictal or ictal  Spontaneous or triggered

Electroencephalography (EEG)  Certain epilepsy syndromes have characteristic or suggestive features  E.g. Infantile spasmsHypsarrhythmia Childhood absence epilepsyGeneralized 3-Hz spike-wave Juvenile myoclonic epilepsyGeneralized/ multifocal 4-5 Hz spike- wave and polyphasic-wave Benign occipital epilepsyUnilateral/ bilateral occipital sharp/ sharp-slow activity that attenuates on eye opening Lennox-Gastaut syndromeGeneralized/ bianterior spike-wave activity at <2.5 Hz

Electroencephalography (EEG)  E.g. Brief absence seizure in an 18-year-old patient with primary generalized epilepsy

Electroencephalography (EEG)  Note:  Normal in 10-20% of epileptic patients  Background slowed by:  AED, diffuse cerebral process, postictal state  Artifact from:  Eye rolling, tremor, other movement, electrodes  Interpreted in the light of proximity to seizure

Neuroimaging  Structural neuroimaging  Functional neuroimaging

Structural Neuroimaging  Who should have a structural neuroimaging?  Status epilepticus or acute, severe epilepsy  Develop seizures when > 20 years old  Focal epilepsy (unless typical of benign focal epilepsy syndrome)  Refractory epilepsy  Evidence of neurocutaneous syndrome

Structural Neuroimaging  Modalities available:  Magnetic Resonance Imaging (MRI)  Computerized Tomography (CT)  What sort of structural scan?  MRI better than CT  CT usually adequate if to exclude large tumor  MRI not involve ionizing radiation  I.e. not affect fetus in pregnant women (but nevertheless avoided if possible)

Functional Neuroimaging  Principles in diagnosis of epilepsy:  When a region of brain generates seizure, its regional blood flow, metabolic rate and glucose utilization increase  After seizure, there is a decline to below the level of other brain regions throughout the interictal period

Functional Neuroimaging  Modalities available:  Positron Emission Tomography (PET)  Single Photon Emission Computerized Tomography (SPECT)  Functional Magnetic Resonance Imaging (fMRI)  Mostly used in:  Planning epilepsy surgery  Identifying epileptogenic region  Localizing brain function

Venn Diagram

Seizure Therapy AnticonvulsantSurgery Specific Treatments Reassurance and Education General Treatment Seizure

Education & Support  Information leaflets and information about support group  Avoidance of hazardous physical activities  Management of prolonged fits  Recovery position  Rectal diazepam  Side effects of anticonvulsants

Anticonvulsants  Suppress repetitive action potentials in epileptic foci in the brain  Sodium channel blockade  GABA-related targets  Calcium channel blockade  Others: neuronal membrane hyperpolarisation

Anticonvulsants Cabamazepine Phenytoin Valproic acid Tonic-clonic and partial Ethosuximide Valproic acid Clonazepam Absence seizures Valproic acid Clonazepam Myoclonic seizures Diazepam Lorazepam Short term control Phenytoin Phenobarbital Prolonged therapy Status Epilepticus Corticotropin Corticosteroids Infantile Spasms Drugs used in seizure disorders

Adverse Effects  Teratogenicity  Neural tube defects  Fetal hydantoin syndrome  Overdosage toxicity  Life-threatening toxicity  Hepatotoxicity  Stevens-Johnson syndrome  Abrupt withdrawal

Medical Intractability  No known universal definition  Risk factors  High seizure frequency  Early seizure onset  Organic brain damage  Established after adequate drug trials  Operability

Surgery  Curative  Catastrophic unilateral or secondary generalised epilepsies of infants and young children  Sturge-Weber syndrome  Large unilateral developmental abnormalities  Palliative  Vagal nerve stimulation

Surgical Outcome  Medical Intractability  A well-localised epileptogenic zone  EEG, MRI  Low risk of new post-operative deficits

References 1. Stedman’s Medical Dictionary. 2. MDConsult: Nelson’s textbook. 3. Illustrated Textbook of Pediatrics. 4. Video atlas of epileptic seizures – Classical examples, International League against epilepsy. 5. Guberman AH, Bruni J, 1999, Essentials of Clinical Epilepsy, 2 nd edn. Butterworth Heinemann. 6. Manford M, 2003, Practical Guide to Epilepsy, Butterworth Heinemann.