Neurology: Seizures and Epilepsy

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Epilepsy and other Seizure Disorders 06

Dr. Arman Oronce SHIFTING tuxedokamen

Friday, July 03, 2015 FIRST

OUTLINE: I. Epilepsy and other seizure Disorders II. International Classification of Epilepsy

a. GENERALIZED SEIZURES (bilateral, symmetric and without focal onset)

b. PARTIAL OR FOCAL SEIZURES (seizures beginning locally)

c. SPECIAL EPILEPTIC SYNDROMES III. Generalized Seizures

a. Grand Mal b. Absence, Petit Mal

IV. Absence or Petit Mal: Variants a. Lennox-Gestaut Syndrome

V. Myoclonus and Myoclonic Seizures a. Juvenile Myoclonic Epilepsy

VI. Partial or Focal Seizure a. FRONTAL LOBE PARTIAL SEIZURES

(Focal Motor and Jacksonian Seizures) VII. Somatosensory, Visual, and other Ssensory

Seizure VIII. Complex Partial Sezire

a. Amnesic Seizures: b. Behavioral and Psychiatric Disorders

IX. Special Epileptic Syndrome a. Benign Childhood Epilepsy b. Infantile Spasm c. Febrile Seizure d. Febrile Seizure (Complicated) e. Reflex Epilepsy f. Epileptia Partia Continua g. Hysterical Seizure

X. The Nature of Dicharging Leison XI. The Seizure Event XII. The Pathology of Epilepsy XIII. Laboratory Abnormalities in Seizure XIV. Role of Hereditary Seizure XV. The Probable Cause of Seizure (Age Periods)

a. Neonatal Seizures b. Infantile Seizures c. Early Childhood Seizures d. Later Childhood and Adolescent e. Adult Life f. Late Adult Life g. Seizure in Pregnancy

XVI. Treatment XVII. Status Epilepticus

a. Treatment EPILEPSY AND OTHER SEIZURE DISORDERS In contemporary society, the frequency and importance of epilepsy can hardly be overstated Approximately 1% of persons in the U.S. will have epilepsy by age 20 Over 2/3 of all epileptic seizures begin in childhood (most in the 1

st year of life); the incidence increases again slightly

after age 60

EPILEPSY: an intermittent derangement of the nervous system due to “an excessive and disorderly discharge of cerebral nervous tissue on muscles.”

The discharge may result in an almost instantaneous loss of consciousness or impairment of psychic function, convulsive movements, disturbance of sensation or some combination thereof

CONVULSION: an intense paroxysm of involuntary repetitive muscular contractions

INTERNATIONAL CLASSIFICATION OF EPILEPSY

I. GENERALIZED SEIZURES (bilateral, symmetric and without focal onset)

a. Tonic, clonic, or tonic-clonic (grand mal)

b. Absence (petit mal) i. With loss of consciousness

only ii. Complex – with brief tonic,

clonic, or automatic movements

c. Lennox-Gestaut syndrome d. Juvenile myoclonic epilepsy e. Infantile spasms (West syndrome) f. Atonic seizures

II. PARTIAL OR FOCAL SEIZURES (seizures

beginning locally) a. Simple (without loss of consciousness

or alteration in psychic function) i. Motor – frontal lobe origin

(tonic, clonic, tonic-clonic, jacksonian, benign rolandic epilepsy, epileptia partialis continua)

ii. Somatosensory or special sensory (visual, auditory, olfactory, gustatory, vertiginous

iii. Autonomic Pure psychic b. Complex (with impaired

consciousness) i. Beginning with simple partial

seizures and progressing to impairment of consciousness

ii. With impairment of consciousness at onset

III. SPECIAL EPILEPTIC SYNDROMES 1. Myoclonus and myoclonic seizures 2. Reflex epilepsy 3. Acquired aphasia with convulsive

disorder 4. Febrile and other seizures of infancy

and childhood

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5. Hysterical seizures GENERALIZED SEIZURES GENERALIZED TONIC-CLONIC SEIZURES (Grand Mal)

Prodrome

Apathetic, depressed, irritable, or rarely, ecstatic

One or more myoclonic jerks of the trunk or limbs

Abdominal pains or cramps; sinking, rising, or gripping feeling in the epigastrium

Pallor or redness of the face; throbbing headache, constipation or diarrhea

Tonic Phase

Seizures strike out of the blue, without warning; with a sudden loss of consciousness and fall to the ground

Initial motor signs are brief flexion of the trunk, opening of mouth and eyelids, and upward deviation of the eyes

Arms are elevated and abducted, elbows semi-flexed and the hands pronated

Followed by a more protracted extension

Piercing cry as the whole musculature is seized in a spasm and air is forcibly emitted through the closed vocal chords

Breathing is suspended; skin and mucous membranes become cyanotic

Pupils are dilated and unreactive to light

Bladder may empty at this stage

Lasts for 10 to 20 seconds Clonic Phase

At first, mild generalized tremor which rapidly gives way to brief flexion spasms that come in rhythmic salvos and agitate the entire body

Face is violaceous and contorted by a series of grimaces; tongue is bitten

Autonomic signs: rapid pulse, increased blood pressure, dilated pupils, salivation and sweating

Remain apneic until the end of the clonic phase

30 seconds

In the terminal phase of the seizure, all movements have ended and the patient is still and limp Patient wakes up, begins to look about, bewildered and confused May awaken with a pulsatile headache Has no memory of any part of the spell but knows that something has happened because of the strange surroundings (ambulance or hospital), sore bitten tongue and aching muscles from the violent contractions

Clinical states that simulate a grand mal convulsion: Clonic jerking of the extended limb with

vasodepressor syncope Basilar artery occlusion (ischemia of the

corticospinal tract in the pons) Limb-shaking TIAs Hysterical psychogenic seizures Panic attacks Breath-holding spells in infants

IDIOPATHIC NONCONVULSIVE SEIZURES (Absence, Petit Mal)

Notable for their brevity and the paucity of motor activity

Resembles a moment of absentmindedness or daydreaming

Attack comes without warning: sudden interruption of consciousness; patient stares and briefly stops talking or ceases to respond

Attack may have a brief burst of fine clonic movements of the eyelids, facial muscles, or fingers or synchronous movements of the arms

Minor automatisms: o lip-smacking, chewing o fumbling movements of the fingers

Mild vasomotor disorder

As a rule, o patients do not fall; after 2-10 secs o they reestablish full contact with the

environment o resume their preseizure activity

The most characteristic epilepsy of childhood; rare before 4 years old or after puberty

As many as several hundred may occur in a single day

Frequency decreases in adolescence and often disappear, only to be replaced by major generalized seizures

Responds well to valproate and ethosuximide

EEG: o 3-per second-spike and wave pattern

ABSENCE OR PETIT MAL VARIANTS

Lennox-Gestaut Syndrome

o Between 2-6 years old o Characterized by atonic or astatic seizures (i.e., falling

attacks) o Often succeeded by various combinations of minor

motor, tonic-clonic, and partial seizures o With intellectual impairment o EEG:

o 1-2 hz spike and wave pattern o Often preceded in earlier life by infantile spasms, a

characteristic EEG picture (“hypsarrythmia”) and an arrest in mental development : West syndrome

o Grave implication of a serious neurologic disease

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o Prematurity, perinatal injury and metabolic diseases of infancy are the most common underlying conditions

o Persists into adult life; one of the most difficult to treat

MYOCLONUS AND MYOCLONIC SEIZURES

Brisque, brief muscular contractions (50-100 ms); some are so small as to involve only one muscle or part of the muscle

Others are so large to implicate a limb on one or both sides of the body or the entire trunk musculature

May be part of absence seizures and as isolated events in GTCs

Benign and respond well to medication

vs Disseminated myoclonus: o onset in childhood, suspicious of acute viral

encephalitis, lithium or drug toxicity or subacute sclerosing panencephalitis

Juvenile Myoclonic Epilepsy

The most common form of idiopathic generalized epilepsy

Begins in adolescence: age 15

Generalized seizure, often upon awakening or less often, myoclonic jerks

Myoclonic jerks of the arm and upper trunk, prominent with fatigue, during early stages of sleep or after alcohol ingestion

Does not impair intelligence; not progressive

EEG: o 4-6 hz irregular polyspike and wave activity

Valproic acid effective in eliminating the seizures and the myoclonus

PARTIAL OR FOCAL SEIZURES FRONTAL LOBE PARTIAL SEIZURES (Focal Motor and Jacksonian Seizures)

Most common type: turning movement of the head and eyes to the side opposite the irritative focus with tonic contraction of the trunk and limbs on that side (focus on the supplementary motor area)

Major generalized convulsion without an initial turning of the head and the eyes:

o lesion in one frontal lobe

Contraversive deviation of the head and the eyes: o focus on the superolateral frontal region

(area 8)

Jacksonian seizure: o tonic contraction of the fingers of one

hand, the face on one side, or the muscles of the foot

Jacksonian seizure: clonic movements in these parts analogous to that in GTCs

Classic Jacksonian form: o hand, up the arm, to the face and down the

leg; or if the first movement is in the foot, the seizure marches up the leg, down the arm and to the face

Consciousness is not lost if the sensorimotor symptoms remain confined to one side

Disease process or focus of excitation is usually in or near the rolandic cortex; if there is a sensory accompaniment, focus is in the postrolandic convolution

Seizure discharges from the cortical language areas: brief aphasic disturbance (ictal aphasia) or vocal arrest

SOMATOSENSORY, VISUAL, AND OTHER SENSORY SEIZURES

Focal or marching: o focus in or near the post rolandic

convolution of the opposite cerebral hemisphere

o Numbness, tingling, “pins and needles”, sensation of crawling, electricity, or movement of the part; lips, fingers and toes

Visual seizures: o focus in or near the striate cortex of the

occipital lobe o Elemental visual sensations of darkness or

sparks and flashes of light, stationary or moving and colorless or colored (red: most frequent)

o Only one eye is affected, the one opposite the lesion

Auditory seizures: o focus in the superior temporal convolution

(buzzing or roaring in the ears) o Human voice, sometimes repeating

unrecognizable words: more posterior part of the temporal lobe

Vertiginous seizures: o focus in the superoposterior temporal

region (sensation of vertigo, giddiness, light headedness)

Olfactory hallucinations: o inferomedial parts of the temporal lobe

(disagreeable or foul odor)

Gustatory hallucinations: o focus in the temporal lobe (salivation and

sensation of thirst) COMPLEX PARTIAL SEIZURES

Psychomotor seizures; temporal lobe seizures

Aura (initial event in the seizure) may either be a focal seizure or a perceptual illusion

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There is a period of altered behavior and consciousness for which the patient is later found to be amnesic

Illusions, hallucinations, dyscognitive states and affective experiences

Sensory illusions and distortion of ongoing perceptions are the most common

Objects or persons may shrink or recede into the distance (micropsia) or may enlarge (macropsia)

Hallucinations, most often visual and auditory: formed or unformed visual images, sounds and voice

Dyscognitive state:

o feelings of increased reality or familiarity (déjà vu) or of strangeness or unfamiliarity (jamais vu) or a stated depersonalization

o Fragments of certain old memories or scenes insert themselves into the patient’s mind; abrupt interruption of memory

o Epigastric and other abdominal sensations

Emotional experiences: o sadness, loneliness. anger, happiness,

sexual excitement, fear and anxiety (most common), rage

o Each of these psychic experiences may constitute the entire seizure (simple partial seizure)

o Some combination may occur and proceed to a period of unresponsiveness

Motor components (automatisms):

o lip smacking, chewing or swallowing movements, salivation, fumbling of the hands, shuffling of the feet

o May work around in a daze or act inappropriately (undressing in public or speaking incoherently)

o Patient is out of contact with surroundings, may have no response at all or may look at the examiner in a perplexed way

Violence and aggression:

o nondirected oppositional resistance in response to restraint during the period of automatic behavior

o Rarely, laughter (gelastic epilepsy) is the most striking feature of automatism

Volvular epilepsy:

o walking repetitively in circles o Running (epilepsia procursiva); aimless

wandering (paromania) o Dystonic posturing of the arm and leg

contralateral to the seizure focus

Any type of complex partial seizures may proceed to other forms of secondary generalized seizures

Psychomotor Triad: o motor changes (45%) o automatic behavior (32%) o alterations in psychic function (25%)

Increased incidence in adolescence and the adult years

About 1/3 of cases traced to severe febrile convulsions in early life; 5% of patients with febrile seizures continue to have seizures during adolescence and adult life

Neonatal convulsions, head trauma and various other nonprogressive perinatal neurologic disorders are factors that face the child at risk to develop complex partial seizures

2/3 of patients with complex partial seizures also have generalized tonic-clonic seizures which may lead to ischemic damage to the hippocampal portions of the temporal lobe

MRI may disclose loss of volume in the hippocampus and adjacent gyri on one or both sides – medial temporal sclerosis

Post-ictal behavior: o global and nonfluent aphasia, prolonged

disorientation to time and place, automatisms, Todd’s paralysis (postictal posturing and paresis of an arm), aphasia, postictal nose wiping

Versus Absence seizures: o instantaneous return of full consciousness

after the attack Amnesic Seizures:

Brief, recurrent attacks of transient amnesia as the only manifestations of complex partial seizures

Some resemblance to transient global amnesia

Brief and frequent, occurs on awakening, impaired performance on complex cognitive tasks

Behavioral and Psychiatric Disorders

About 1/3 with history of major depressive illness, anxiety; psychotic symptoms in 10%

Post-ictal state of complex partial seizures may take the form of a protracted paranoid-delusional state or amnesic psychosis

SPECIAL EPILEPTIC SYNDROMES BENIGN CHILDHOOD EPILEPSY

Rolandic epilepsy with centrotemporal spikes or with occipital spikes

Self-limited; autosomal dominant; 5-9 yrs old

Announces itself by nocturnal tonic-clonic seizure with focal onset

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Thereafter, chronic contractions of one side of the face, arm and leg

Easily controlled by a single anticonvulsant drug; disappears during adolescence

A similar type of benign epilepsy with no intellectual deterioration and cessation of seizure during adolescence is associated with spike activity over the occipital lobe

INFANTILE SPASMS

Infancy and early childhood; 1st

year of life

Recurrent, gross flexion movements of the trunk and limbs and, less frequently, by extension movements: salaam or jacknife seizures

Severe EEG abnormalities: continuous multifocal spikes and slow waves of large amplitude (hypsarrythmia)

Seizures diminish and disappear by age 4-5; patients are left mentally impaired

Respond dramatically to adrenocorticotrophic hormone (ACTH), steroids and clonazepam

MRI and CT scans: normal or cortical dysgenesis FEBRILE SEIZURES

Benign; strong tendency to be inherited

6 months – 5 years (peak: 9-20 months)

Single, generalized motor seizure as the temperature reaches its peak

Recovery is complete

Risk of developing epilepsy in later life is only slightly greater than that of the general population (2-4%)

EEG is normal FEBRILE SEIZURES (COMPLICATED)

An acute encephalitic or encephalopathic state presents as a febrile illness with focal or prolonged seizures

With generalized or focal EEG abnormalities; repeated episodes of febrile convulsions with the same or different illnesses

Fever and convulsions with structural brain disease (bacterial meningitis, head and birth trauma)

Later on, with increased risk of developing complex partial seizures (70%) in patients with medial temporal sclerosis

Risk of developing complex forms of seizure in later life is 8-49%

REFLEX EPILEPSY

Seizures evoked by discrete physiologic or psychologic stimuli

Myoclonic jerks, absence or tonic clonic

Responds to clonazepam, valproate, carbamazepine, phenytoin

Types (5): 1. Visual: flickering light, visual patterns, colors

(red): rapid blinking or eye closure 2. Auditory: startle, specific sounds, musical

themes and voices 3. Somatosensory: brisk or unexpected tap or

sudden movement after sitting or lying still 4. Writing or reading of words or numbers 5. Eating

EPILEPTIA PARTIALIS CONTINUA

Focal motor epilepsy with persistent rhythmic clonic movements of one muscle group (face, arm or leg)

Repeated at fairly regular intervals; continue for days, weeks, or months without spreading to other parts of the body (focal motor status epilepticus)

Not abolished during sleep

Causes: developmental anomalies, encephalitis, demyelinative diseases, brain tumors, degenerative diseases

Responds poorly or not at all to anticonvulsants HYSTERICAL SEIZURES

Psychogenic; nonepileptic in nature

Sham seizures; pseudoseizures

Occur in the presence of other people, highly emotional states

BREAK TIME!

THE NATURE OF THE DISCHARGING LESION

Physiologically, seizure is defined as a: o Sudden alteration of central nervous system

(CNS) function resulting from a paroxysmal high-frequency

o synchronous low-frequency, high-voltage electrical discharge

The discharge arises from excitable neurons in any part of the cerebral cortex and possibly in any secondarily involved structures as well

A seizure discharge can be initiated in an entirely normal cerebral cortex:

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o ingestion or injection of drugs, withdrawal from alcohol or other sedative drugs, or by repeated stimulation with subconvulsive electrical impulses (“kindling phenomenon’)

Why the neurons in or near a focal cortical lesion discharge abnormally is not fully understood

Neurons are said to be deafferented; they are known to be hyperexcitable and may remain so chronically in a state of partial depolarization

Their cytoplasmic membranes appear to have an increased ionic permeability, rendering them more susceptible to activation by hyperthermia, hypoxia, hypoglycemia, hypocalcemia and hyponatremia

Epileptic foci are characterized by spontaneous interictal discharges, during which the neurons of the discharging focus exhibit large Ca-mediated paroxysmal depolarizing shifts (PDSs), followed by prolonged after hyperpolarizations (AHPs)

AHPs are also due in part to Ca-dependent K currents but are better explained by enhanced synaptic inhibition

The PDSs occur synchronously and summate to produce surface-recorded interictal EEG spikes

The AHPs correspond to the slow wave of the EEG spike-and-wave complex

Neurons surrounding the epileptogenic focus are hyperpolarized from the beginning and are mainly GABEergic, thereby inhibiting the neurons within the focus

Seizure spread depends on any factor or agent that activates neurons in the focus or inhibits those surrounding it

BIOCHEMICAL STUDIES OF NEURONS IN A SEIZURE FOCUS

a. Elevated levels of extracellular K in glial

scars near epileptic foci b. Defect in voltage-sensitive Ca channels c. Increased sensitivity to acetylcholine d. Decreased GABA, decreased taurine,

increased glycine, either increased or decreased glutamic acid

But whether these changes are the cause or result of seizure activity has not been determined THE SEIZURE EVENT

Firing of the involved neurons in the cortical focus begins (EEG: periodic spike discharges that increase in amplitude and frequency)

Once the intensity of the seizure discharges exceeds a certain point, it overcomes the inhibitory influence of surrounding neurons

Spread to neighboring cortical regions via short corticocortical synaptic connections

If the abnormal discharge remains confined to the cortical focus and the immediate surrounding cortex, there are probably no clinical signs and symptoms of seizure

If unchecked, cortical excitation spreads to the adjacent cortex, to the contralateral cortex and to subcortical nuclei (basal ganglia, thalamic and brainstem reticular nuclei)

It is then that the first clinical manifestations of the seizure begins, depending upon the portion of the brain from which the seizure originates

The excitatory activity from the subcortical nuclei is fed back to the original focus, a mechanism that serves to amplify their excitatory activity (EEG: high-voltage polyspike discharges)

Propagation downward to spinal neurons via the corticospinal and reticulospinal tracts, yielding a generalized tonic-clonic convulsion

The spread of excitation to the subcortical, thalamic and brainstem centers correspond to the tonic phase and loss of consciousness and signs of ANS overactivity (salivation, mydriasis, tachycardia, increase in blood pressure)

The development of unconsciousness and generalized tonic contraction of muscles are represented in the EEG as diffuse, high-voltage discharge pattern appearing simultaneously over the cerebral cortex

Soon after the spread of excitation, a diencephalocortical inhibition begins and intermittently interrupts the seizure discharge

The discharge changes from the persistent discharge of the tonic phase to the intermittent bursts of the clonic phase (EEG: from a continuous polyspike to a spike-and-wave pattern)

The intermittent clonic bursts become less and less frequent and finally cease together, leaving in their wake an “exhaustion” of the neurons in the epileptogenic focus and a regional increase in the permeability of the blood-brain barrier

An overshoot of these inhibitory mechanisms is the basis of:

Todd’s paralysis postictal stupor sensory loss aphasia hemiparesis headaches diffuse slow waves in the EEG regional edema in MR images

The paralysis that follows might be due to neuronal depletion of glucose and increase in lactic acid

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In absence attack, a strong element of inhibition is present diffusely throughout the attack

This inhibition accounts for the failure of excitation to spread to lower brainstem and spinal structures

However, the absence seizure can also at times activate the mechanism for rhythmic myoclonus, probably at an upper brainstem level

Both the tonic or tonic-clonic and absence seizures are generated in the neocortex and enhanced by the synchronizing influences of subcortical structures

The generalization of the clinical and electrical manifestations depends upon activation of a deep, centrally located physiologic mechanism

This includes the midbrain reticular formation and its diencephalic extension, the intralaminar and the nonspecific thalamic projection systems

No evidence, however, that seizure activity originates in these deep activating structures

The Seizure Event: COMPLEX PARTIAL SEIZURES

Almost always of temporal lobe origin, arising in foci in the medial temporal lobe, amygdaloid nuclei and hippocampus

Electrical stimulation in these areas reproduces feelings of:

o Depersonalization o Emotionality o Automatic behavior

Automatic behaviors are due to the direct effect of the temporal lobe discharge or a post excitatory or inhibitory effects in others

Loss of memory is due to the paralytic effect of the discharge in neurons of the hippocampus

In most autopsied cases of primary generalized epilepsy, the brains are grossly and microscopically normal

o No visible lesions in the seizure states complicating drug intoxication and withdrawal, transient hyper-and hyponatremia, and hyper-and hypoglycemia

With secondary epilepsies: o zones of neuronal loss o gliosis (scar)

and other signs of tissue loss: o porencephaly o dysgenetic cortex o heterotropias o vascular malformations o tumors

Most common histologic findings in the brains of epileptics is a bilateral loss of neurons of the pyramidal cell layer of the hippocampus

LABORATORY ABNORMALITIES IN SEIZURES MRI

Mesial temporal sclerosis, glial scars, porencephaly, heterotropias and other disorders of neuronal migration

Subtle cortical swelling CT SCAN

Atrophy, calcifications and malformations

May be abnormal in GTCs, and absence (10%), Lennox-Gestaut (52%), West syndrome (77%), complex partial seizures (63%)

POSITRON EMISSION TOMOGRAPHY (PET) AND SINGLE PHOTON EMISSION TOMOGRAPHY (SPECT)

Areas of hypometabolism and hypoperfusion CSF

Small number of WBCs; slight increase in protein ROLE OF HEREDITY IN SEIZURES

A genetic factor is operative in the primary generalized tonic-clonic seizures (familial incidence in 5-10%)

Primary idiopathic epilepsies:

60% for monozygotic twins

13% for dizygotics

Idiopathic epileptic syndromes of proven inherited pattern:

a. Benign neonatal familial convulsions (autosomal dominant)

b. Benign myoclonic epilepsy of childhood (autosomal recessive)

c. Absence epilepsy and benign rolandic epilespy (autosomal dominant)

d. Juvenile myoclonic epilepsy e. Simple febrile convulsions

THE PROBABLE CAUSES OF SEIZURES (AGE PERIODS) NEONATAL SEIZURES

First days of postnatal life

Abrupt movement or posturing of a limb, stiffening of the body, rolling up of the eyes, a pause in respiration, lip smacking, chewing or bicycling movement of the legs

24-48 h: anoxic encephalopathy

Several days or weeks after birth: acquired hereditary metabolic disease (hypoglycemia- most frequent), hypocalcemia, hereditary pyridoxine deficiency, biotidinase deficiency

Benign neonatal convulsion: day 3-day 7, without specific EEG changes, remit, autosomal dominant

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INFANTILE SEIZURES (1 month – 2 years)

Most characteristic pattern is the massive myoclonic jerk of head and arms leading to flexion or less often, to extension of the body (infantile spasms, salaam spasms)

Tiberous sclerosis, phenylketonuria, Sturge-Weber angiomatosis

When the myoclonus begins with fever and unilateral or bilateral clonic seizures or with partial seizures that are followed by focal neurologic abnormalities, there is a likelihood of developmental delay

Replaced by partial or generalized seizures after the 5

th year

EARLY CHILDHOOD (5-6 YEARS)

May take the form of status epilepticus or as a focal myoclonus, atypical absence, or GTCs

The more typical absence begins in this age period and carries a good prognosis

Partial epilepsies may appear for the first time during this age period: good prognosis, unimpaired neurologic and intellectual capacities, between 3-13 years old, familial

Rasmussen encephalitis: o intractable focal epilepsy with

progressive hemiparesis; 3-15 years old; more girls than boys; extensive destruction of the cortex of the white matter with intense gliosis; with antibodies to glutamate receptors (autommune), responds to steroids

LATER CHILDHOOD AND ADOLESCENCE

Most common epileptic problem in general practice

Most likely a GTC and often marks the beginning of a juvenile myoclonic epilepsy

If there had been some type of seizure at an earlier period, consider a developmental disorder, hypoxic encephalopathy, hereditary metabolic diseases as cause

Complex partial seizures when long-standing and associated with mental backwardness, scholastic failure and inadequacy of social adjustment

Nearly half of febrile seizures end up as temporal lobe epilepsies (CPS) with borderline or subnormal intelligence

ADULT LIFE (Secondary to Medical Disease)

1. Primary and metastatic brain tumors 2. Withdrawal seizure - alcohol or benzodiazepine

sedative drugs 3. Infections

a. Bacterial meningitis (more so in children)

b. Herpes simplex encephalitis – myoclonic jerks

c. Viral, treponemal, parasitic encephalitis, subacute sclerosing panencephalitis, lipid storage diseases

d. Neurocysticercosis, tuberculous granuloma

4. Endogenous metabolic encephalopathies a. Uremia: twitch-convulsive syndrome b. Hyponatremia, hypernatremia,

hyperosmolar state, hypoglycemia, hyperglycemia, thyrotoxic storm, hypomagnesemia, hypocalcemia

c. Lead in children; mercury in children and in adults

d. Generalized seizures, with or without twitching: hypertensive encephalopathy, sepsis, hepatic stupor, congestive heart failure

5. Medications: a. imipenem and penicillin congeners b. cefapime c. tricyclic antidepressants d. lithium e. lidocaine f. aminophylline

6. Global arrest of circulation and cerebrovascular diseases

a. cardiac arrest b. suffocation or respiratory failure c. CO poisoning d. hypoxic-ischemic encephalopathies e. cortical stroke f. embolic infarction g. cortical venous thrombosis with

ischemia h. ruptured saccular aneurysm

LATE ADULT LIFE

o Focal or generalized o Primary or secondary tumor or an infarct that

had not declared itself clinically o Previous infarcts are by far the most common

lesions underlying status epilepticus in later life o Cortical and subcortical encephalomalacia, the

result of previous traumatic contusions are other causes; brain abscess, inflammatory and infectious illnesses less common

o Administer AEDs for 6-12 months in an adult with a first unexplained seizure; MRI and EEG

o Risk of recurrence greatest in the first 24 months SEIZURES IN PREGNANCY 2 Types of problem:

1. The woman with epilepsy who becomes pregnant: no change in frequency in 50%, increased seizure frequency in 25%, decreased seizure frequency in 25%

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2. The woman who has her first seizure during pregnancy

Slight increase in the number of stillbirths and a doubling in the incidence of mental retardation and non-febrile seizures in the offspring

Potential teratogenic effects of anti-epileptic drugs (AEDs):

o cleft lip o cleft palate o subtle facial dysmorphism (“fetal

anticonvulsant syndrome”)

Risk of congenital defects is 2-3%; increases to 4-5% in women taking anticonvulsants

AEDs generally safe during breastfeeding o Carbamazepine o Valproate o Phenytoin

TREATMENT FOUR PARTS

1. The use of antiepileptic drugs 2. Surgical excision of epileptic foci 3. Removal of causative and precipitating factors 4. Regulation of physical and mental activity

ANTIEPILEPTIC DRUGS

GENERAL PRINCIPLES

Most important facet of treatment

In approximately 70%, seizures are controlled completely or almost completely; in 20-25%, attacks are significantly reduced in frequency and severity

It is useful to be familiar with half-lives, effective blood levels and dosages, serum-protein binding characteristics, interactions among these drugs and between antiepileptic and other drugs

HALF-LIFE OF COMMONLY USED AEDs

Valproate 6-15 h

Phenytoin 12-36

Carbamazepine 14-25

Phenobarbital 40-120

Lamotriine 15-60

Topiramate 20-30

Gabapentin 5-7

Primidone 6-18

Ethosuximide 20-60

Clonazepam 18-50

Levetiracetam 6-8

Zonisamide 63

GENERAL PRINCIPLES

Phenytoin, phenobarbital and ethosuximide have long half-lives and may therefore be given once daily

Valproate and carbamazepine have short half-lives

Certain drugs are more effective in one type of seizure than in another

Initially, only one drug (monotherapy) should be used and the dosage increased until sustained therapeutic levels have been assumed

If seizures are not controlled by the first drug, a different drug should be tried but frequent shifting of drugs is not advisable (give adequate trials before shifting)

GENERAL PRINCIPLES

In changing medication, the dosage of the new drug should be increased gradually to an optimum level while the dosage of the old drug is gradually decreased

Sudden withdrawal of a drug may lead to an increase in seizure frequency or status epilepticus

If seizures are still not controlled, a second drug can then be added; make an effort to succeed with one drug and with no more than two

The therapeutic dose must be determined, to some extent by trial and error and by measurement of serum levels

EFFECTIVE BLOOD LEVELS OF AEDs (ug/ml)

Valproate 50-100

Phenytoin 10-20

Carbamazepine 4-12

Phenobarbital 15-40

Primidone 5-12

Ethosuximide 50-100

Clonazepam 0.01-0.07

Levetiracetam

Zonizamide 2- 5

GENERAL PRICIPLES

Blood for serum levels ideally drawn in the morning before breakfast and the first ingestion of anticonvulsants

In general, higher serum concentrations of drugs are necessary for the control of simple or complex partial seizures than for the control of generalized tonic-clonic seizures

Blood level is not a precise measure of the amount of drug entering the brain because the larger proportion of the drug is bound to albumin and does not penetrate the blood-brain barrier

Certain anticonvulsants also have metabolites that may produce toxicity but are not measured

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by ordinary methods that determine serum concentration

GENERAL PRINCIPLES Always consider possible interactions with other drugs o Chloramphenicol

o causes the accumulation of phenytoin and phenobarbital

o Erythromycin o causes the accumulation of carbamazepine

o Antacids o reduce the blood phenytoin concentration

o Valproate o leads to the accumulation of phenytoin and

phenobarbital o Warfarin levels

o are decreased by phenobarbital and carbamazepine and increased by phenytoin

o Phenytoin, carbamazepine and barbiturates o can increase the chance of breakthrough

menstrual bleeding in women taking oral contraceptives

GENERAL PRINCIPLES

No AEDs are given after the occurrence of a single generalized seizure in an otherwise normal child or adult with normal EEG and MRI; no family history of seizures

AEDs may be discontinued in patients seizure-free for 2 years, although 1/3 may relapse

Relapse rate is less in patients with absence and GTCs than in those with complex partial seizures and secondary generalization

Patients with juvenile myoclonic epilepsy should probably continue with medication lifelong

Epilepsy caused by brain wounds are reduced in frequency or disappear in 20-30 years, no longer requiring treatment

SPECIFIC TREATMENT

Phenytoin, carbamazepine and valproate are o effective in both GTCs and partial

seizures; valproate less effective in complex partial seizures

Carbamazepine and phenobarbital are o preferable to phenytoin in children

In general, phenobarbital is o used for seizure control in infancy

Gabapentin o is effective in partial seizures and

secondary generalized seizures; vigabatrin is effective in partial seizures

Ethosuximide and valproate are o equally effective in absence seizures;

valproate is given in children over 4 years

Felbamate o is used as an adjunctive form in GTCs,

complex partial seizures, Lennox-Gestaut syndrome

In Lennox-Gestatut syndrome (the most difficult to treat),

o valproate decreases the frequency of seizures in 50%

o lamotrigine, topiramate and vigabatrine are beneficial in 25%

In seizure states with myoclonus as a major element (absence, juvenile myoclonic epilepsy): valproate

In infantile spasms: o ACTH o Steroids

In post anoxic intention myoclonus: o Clonazepan o Valproate

Lamotrigine may be effective as a first line of drug

SIDE EFFECTS AND TOXICITY

Overdose with phenytoin: o Ataxia o Diplopia and stupor o Prolonged use causes coarse facial

features, gum hypertrophy, breast enlargement

Phenobarbital: o Drowsiness o Mental dulling o Nystagmus and Staggering gait; o Behavioral problems in retarded

children o Hyperactivity

Carbamazepine: o Leukopenia o Pancytopenia o Hyponatremia o Diabetes insipidus (rare)

Valproate: o occasionally hepatotoxic

Lamotrigine: o less risk of teratogenic effects

Felbamate: o bone marrow depression, liver failure

MECHANISMS OF ACTION

Blockage of voltage-dependent Na channels resulting in decreased release of excitatory neurotransmitters, preventing abnormal neuronal firing and seizure spread: phenytoin, carbamzepine, lamotrigine, valproic acid, zonizamide

Amplification of the GABA-mediated inhibitory synaptic responses/transmission: phenobarbital,

NEUROLOGY LEC




valproic acid, gabapentin, vigabatrin, clonazepam

Inhibition of Ca flux through thalamic T-type Ca channels which mediate thalamic neuronal burst firing activity during sleep: ethosuximide

STATUS EPILEPTICUS

Recurrent generalized convulsions at a frequency that prevents the regaining of consciousness

Most serious therapeutic problem; 20-30% overall mortality

Rising temperature, acidosis, hypotension and renal failure from myoglobinuria may be encountered

Carries a risk of serious neurologic sequelae (“epileptic encephalopathy”)

MRI shows signal abnormalities in the hippocampus (most often reversible)

From time to time, pulmonary edema is encountered

TREATMENT

IV diazepam at a rate of 2 mg/min until the seizure stops or a total of 20 mg has been given or Lorazepam 0.1 mg/kg, given by IV push at a rate not to exceed 2 mg/min Load dose of phenytoin (15 to 18 mg/kg) by IV, at less than 50 mg/min IV Phenobarbital at 100 mg/min until the seizures stop or a total dose of 20 mg/kg or Midazolam (0.2 mg/kg loading dose, followed by an infusion of 0.1 to 0.4 mg/kg/h) If none of these controls the seizures, discontinue all medications, except phenytoin Pentobarbital (5 mg/kg) or propolol (2 mg/kg), Isoflurane, Halothane

Approximately 25% of all patients with epilepsy (simple and complex partial) are candidates for surgery and half of these may benefit

Most favorable candidates: complex partial seizures and a unilateral temporal lobe focus (rates of cure and significant improvement approach 90%)

Other surgical procedures are section of the corpus callosum (partial and secondarily generalized seizures, atonic drop attacks) and hemispherectomy (in young children, and with intractable unilateral motor seizures and hemiplegia, Rasmussen encephalitis, Sturge-Weber disease and large porencephalic cysts)

Surgical or endovascular reduction of AV malformations reduce the frequency of associated seizures

REGULATION OF PHYSICAL AND MENTAL ACTIVITY

Maintain regular hours of sleep

Use of alcohol in moderation

Moderate amount of physical exercise

With incompletely controlled epilepsy (never drive an automobile, operate unguarded machinery, climb ladders or take tub baths behind locked doors)

Simple advise and reassurance

Ketogenic diet: o Starve for a day or 2 to induce

ketosis followed by a diet in which 80-90% of calories are derived from fat

o Abandoned by about 1/3 of children and their families

END OF TRANS

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Neurology: Seizures and Epilepsy

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