OBJECTIVES 1. 2. 3. 4. 5. 6.
Seizures and Epilepsy
Understand the definitions of seizure, epilepsy, and other terms related to this topic. Discuss the demography/epidemiology of seizures and epilepsy. Understand the different types of seizures: A. Recognize the key features distinguishing partial from generalized seizures B. Understand how these differences impact choice of treatment. Recognize the cardinal of features of key epileptic syndromes. Understand the diagnostic approach to seizures. Understand the basics of treatment of epilepsy.
Seizures represent the most common neurologic disturbance affecting humans other than headache (which you could argue is often not really neurological). Up to almost 10% of the population will experience at least one seizure in their lifespan. Of these, nearly half will be subject to recurrent seizures (epilepsy). Seizures and epilepsy are particularly troublesome for patients because of their unpredictable occurrence and the associated abrupt loss of competence. This often results in severe social and personal morbidity with attendant loss of selfconfidence, personal safety, financial and recreational independence. Treatment, however, is generally very successful and promising new modalities of treatment are rapidly being developed or refined.
I. Definitions: Seizure: (from Gk, to be seized from forces without) generally refers to a disturbance of usual neurological functioning of relatively abrupt onset that is due to transient disturbance of CNS activity. Other more or less synonymous terms include: attack, fit, spell. Epileptic seizure: a seizure caused by recurrent, sudden, synchronous (paroxysmal) firing of a group of cortical neurons; in other words, a seizure due to a paroxysmal electrical disturbance of brain signaling. Epilepsy: condition in which an individual suffers from recurrent epileptic seizures which is not temporary. Convulsion: The overt, major motor manifestations of a seizure (rhythmic jerking of the limbs). Aura: subjective disturbance of perception that represents the start of certain seizures (actually represents a focal electrical disturbance at the start of the seizure). Ictus or ictal phase: the seizure itself; the part of the event where the convulsion occurs or when the brain activity consists of paroxysmal firing of brain neurons. Post-ictal phase: the period after the convulsion or actual seizure where the “brain is tired� and the individual is sleepy, confused, disoriented or experiences temporary neurological dysfunction. Interictal: between seizures.
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II. Background: • About 1-2% prevalence of seizure disorders in the US. • Cumulative lifetime incidence of epilepsy is about 3-4%; Cumulative lifetime incidence of a seizure is about 9%. • Onset of epilepsy is most common in the young (children) and the elderly. • About 40% of epileptics have a generalized epilepsy syndrome (see below) • About 50 % of children have a generalized epilepsy syndrome compared to about 20 % of adults. • III. Pathophysiology (for the complete idiot) • An epileptic seizure represents the abnormal (pathological) paroxysmal, synchronous firing of a group of (usually) cortical neurons. This group of neurons is referred to as the seizure focus. • Disturbance in the normal balance between inhibition and excitation a) Neuronal depolarization vs. repolarization b) Propagation vs. limitation of inter-neuronal transmission c) Glutamate vs. GABA Examples: 1. Pyridoxine is co-factor for synthesis of GABA. Depletion of pyridoxine by isoniazid (drug for TB) causes uncontrolled seizures. (too little inhibition!!!) 2. Glycine is co-agonist at NMDA (excitatory) receptor. Non-ketotic hyperglycinemia is a condition in which excess glycine accumulates. It is associated with uncontrolled epileptic seizures. (too much excitation!!!).
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New developments: In some inherited, familial epileptic syndromes, ion channel defects have been discovered which are presumably responsible for the disturbance in neuronal excitability. Example: Benign neonatal familial convulsions (BFNC): defect in a neuronal K+ channel; discovered here at Uof U.
IV. Etiology • Primary vs. Secondary Epilepsy (more or less equal to idiopathic vs. symptomatic) • Primary (idiopathic): not due to a localized or diffuse brain lesion, injury, structural abnormality or identified disease (such as infection). Many idiopathic cases are familial, and may be related to gene defects (e.g., such as BFNC as noted above). Many idiopathic cases are relatively benign, self-limited and occur more often in children. • Secondary (symptomatic): caused by a brain disease, injury, focal disturbance etc... For example, brain infections, tumors, scarring from strokes, drugs, etc... • Overall, cause of seizure disorders is unknown (idiopathic) in about 70% of cases; Proportion of idiopathic cases is highest in middle-aged children (5-12) and lowest in neonates and adults over 20. V. Classification Scheme of Seizures/Epilepsy (see figure) A. THE SEIZURE IS THE SYMPTOM; EPILEPSY IS THE DISEASE. Seems confusing?!? Just remember then: the seizure is what you see or what the family, patient, police officer, 2
EMT etc.. tells you they saw. The epilepsy syndrome is what you as a physician diagnose (if you can) Example: child aged 6 has recurrent, early morning convulsions before awakening observed by the parents (these are the seizures). There is a history of similar events in other children. After evaluation, you find the EEG abnormality is typical. You diagnose Benign Rolandic Epilepsy (this is the disease or epilepsy syndrome). From this epilepsy diagnosis alone you can reassure the family about prognosis and provide appropriate advice and treatment!
B. A Simpleton’s Seizure Classification: see figure: 1. Generalized vs. Partial a. Generalized: • The “whole brain” is affected at once; both hemispheres electrically disturbed. • The key (essential) clinical feature is LOSS OF CONSCIOUSNESS! b. Partial (focal): • Only part of the brain (the focus) is affected. • Consciousness is not lost (in some it can be impaired... see below) The only tricky part is that a seizure can start as a partial (focal) seizure and spread (generalize). This is known as the process of secondary generalization. If you are not able to observe or otherwise define the onset of a given generalized seizure, you may not be able to tell if it is a primary generalized seizure (one that begins abruptly as generalized) or a secondarily generalized seizure (one that begins as a focal seizure and spreads). The importance of the difference between these two will become evident.
2. Both Generalized and Partial seizure types can each be divided into two groups: a. Generalized Seizures: • inter-ictal EEG feature: generalized spike and wave discharges 1. Generalized convulsive (“grand mal” or generalized tonic-clonic): • sudden, immediate loss of consciousness without warning • initial generalized tonic contraction and posture (causing fall and epileptic cry) • then, generalized, bisynchronous rhythmic forceful jerking movements • slowing of the frequency of the convulsive movements • typically lasts 1-3 minutes • post-ictal exhaustion, sleep, disorientation 2. Absence: • sudden, immediate loss of consciousness without warning • no loss of postural tone • no or minimal motor manifestations (only minor twitching of eyelids or other)
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interrupts activity or function typically lasts less than 15 seconds no post-ictal phase
b. Partial (focal) Seizures: • inter-ictal EEG correlate: focal epileptiform discharges. 1. Simple partial • only one part of one hemisphere of the cerebral cortex affected; pretty much any part can be so affected. • Hence, CONSCIOUSNESS IS NOT AFFECTED. • symptoms depend on the part affected: motor, sensory, auditory, visual etc... • duration is variable: seconds to minutes to hours or even days; usually seconds to minutes.
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There is no post-ictal alteration of consciousness (but there can be post-ictal motor impairment: e.g., after a prolonged focal seizure affecting the right arm, the right arm could be weak or paralyzed; this is known as a post-ictal Todd’s paralysis).
2. Complex partial (appropriately, given their name, these are the most complicated seizures to understand, so bear with me and hang in there!!!) • again, only one part of one hemisphere of the cerebral cortex affected initially. • However, there is greater spread of the discharge to allow impairment of consciousness • Hence, there is ALTERATION of consciousness during part of the seizure • The seizure often starts as a focal seizure (if this affects perception, this is known as an aura). • Spread or extension of the discharge results in alteration of consciousness • Normal behavior is affected and patients often manifest automatisms: lip-smacking movements, fumbling, non-sensical hand movements, fidgeting, stereoptypic repetitive behaviors, or even fairly complex patterns of non-willed, non-sensical behavior. Some functional interaction with the environment is often possible. • Duration is usually more than 30 seconds; can last many minutes. • There is post-ictal confusion, disorientation or fatigue and sometimes agitation or combativeness. Amnesia for some portion of the ictus occurs. • If there is sufficient spread (generalization), there can be secondary generalization to a generalized tonic-clonic convulsion. Other important considerations regarding Complex-partial seizures: • Often referred to as “psychomotor” seizures because of the prominent disturbance of psychological or behavioral function • Also often referred to as “Temporal lobe seizures” due to the frequent origin in the mesial (medial) temporal lobes or posterior frontal lobes. • Due to the proximity of the discharge to medial temporal lobes and olfactory pathways the aura often consists of an olfactory hallucination, fleeting memory percept, or other ineffable sensation (often a “rising epigastric sensation”) • There is often a significant overlap with psychiatric disturbances (both in terms of clinical manifestations of the seizures as well as with inter-ictal behavioral function) So, to remember the key elements of complex-partial seizures, remember the 4 “A”s Aura Alteration of consciousness Automatisms Amnesia 3. Other generalized seizure types: Unfortunately, the above simple classification scheme has to be expanded a little bit to include a few other “generalized” seizure types (there is sometimes argument that these are not always generalized, but we will ignore that for now).
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a. Myoclonic: • sudden, usually generalized, single body jerk, often throwing individual to the ground. • can affect single body part (in this case, not a generalized seizure) • so brief, cannot really know if consciousness is affected • can occur one after another repetitively or in clusters b. Astatic (sometimes called atonic) • sudden loss of postural tone with a collapse to the ground (“drop attack”) • if more restricted, can just involve nuchal and head muscles: head nod • can often be intermixed with other seizure types (atypical absence, myoclonic) • often causes injury c. Atypical absence • an absence seizure that is usually longer than typical duration (>15 sec) • often occur back to back or in clusters • often intermixed with drop attacks (astatic seizures) or myoclonic seizures • associated with a “slow spike and wave EEG” (see Lennox-Gastaut Syndrome, below). d. Infantile spasms: • clusters of generalized myoclonic seizures which occur in infancy • usually there is an underlying severe brain disease • associated with a typical EEG pattern: high amplitude, disorganized, chaotic, multifocal spikes and spike and wave discharges (hypsarrhythmia) • often has poor prognosis • treatment with ACTH VI. Important Epilepsy Syndromes: you must remember the ones identified by ***. The others are for your future reference or edification. ***A. Benign Rolandic Epilepsy (Epilepsy with centro-temporal spikes). The most common seizure disorder of childhood. Seizure type: partial or secondarily generalized sensory-motor seizures occurring at the transitions between wakefulness and sleep. usually affect oral-motor function particularly. infrequent (weekly or less) Etiology: unknown (idiopathic). often familial. presumed ion channel? Age: childhood (5-12years) EEG: focal, centrotemporal (Rolandic) spikes (i.e., located over the rolandic cortex... yes, you got it, where the sensory-motor strip is found) Treatment: no treatment or carbamazepine. Prognosis: excellent. easy seizure control. remission in 95%. no long term sequellae. ***B. Childhood absence epilepsy. The next most common seizure disorder of childhood. Seizure type: simple absence seizures. 1/3 or less will also have at least one generalized tonic-clonic seizure. Often frequent (many per day). 6
Etiology: unknown (idiopathic). often familial. presumed ion channel? Age: childhood (5-12years) EEG: generalized 3/sec spike and wave discharges. Treatment: ethosuximide or valproic acid. Prognosis: excellent. easy seizure control. remission in 70% or more. few with long term sequellae. C. Idiopathic Generalized tonic-clonic epilepsy. More variable and later onset. Seizure type: generalized tonic-clonic seizures. Often in early AM or after nap. No warning, or non-specific feeling before seizure hits. Etiology: unknown (idiopathic). Age: later childhood, early adulthood: 10-25 years EEG: normal or generalized less well defined spike and wave discharges. Treatment: carbamazepine, valproic acid or phenytoin. Prognosis: good. fairly easy seizure control in about 75%. remission more variable than the above. D. Juvenile myoclonic epilepsy. A rarer syndrome with onset in adolescence. Seizure type: early morning myoclonic seizures (single or multiple myoclonic jerks). absence seizures. generalized tonic-clonic seizures. Etiology: unknown (idiopathic). often familial. presumed ion channel? Age: childhood (10-16years); female predominance. EEG: generalized fast spike and wave discharges (4 to 6 cycles/sec) often with photosensitivity. Treatment: valproic acid. Prognosis: generally excellent seizure control possible but remission is rare.
***E. West syndrome (infantile spasms). The most typical recognizable specific pattern of infancy. Represents a specific seizure pattern with very variable etiologies and generally poor outcome. Seizure type: infantile spasms (usually at least one cluster per day or more). usually associated with decline in behavioral function. Etiology: variable: any bad brain condition in infancy can cause this: tuberous sclerosis accounts for about 15% of cases; others, brain damage from perinatal hypoxic-ischemic injury, infection, trauma, metabolic disorders, you name it! Age: infancy: peak age 6 months. EEG: hypsarrhythmia: see above. Treatment: ACTH; vigabatrin (only available in civilized countries, not the US) Prognosis: very poor; although some, if treated early and no cause evident, can do well. F. Lennox-Gastaut syndrome. The most characteristic malignant seizure disorder of childhood. Involves frequent, mixed seizures that are hard to control usually associated with severe developmental decline. Seizure types: mixed seizures with absence, atypical absence, myoclonic, astatic and generalized tonic-clonic. Nocturnal generalized tonic seizures are common. Usually associated with decline in behavioral and cognitive function, often leading to intellectual impairment and/or autistic features. Etiology: variable: sometimes due to the same conditions causing infantile spasms at a younger age (e.g., tuberous sclerosis). Can evolve from infantile spasms. However, often appears in otherwise completely normal children and no cause can be discovered. Age: 2-10 years (peak is 3-5). EEG: “slow� generalized spike and wave discharges (2 to 2.5 cycles per second). Treatment: often frustratingly unsuccessful: valproic acid, benzodiazepines, felbamate. 7
Prognosis: very poor; although some can undergo unexpected remission or improvement.
VII. Evaluation and management of seizures and epilepsy: A. Evaluation: 1. Epilepsy is generally a clinical diagnosis arrived at by a careful history. 2. Since the patient’s consciousness is often impaired, the history must be expanded by interviewing witnesses: family, friends, EMT personnel, police officers, mistresses, fellow criminals, accomplices etc... 3. The details are important! Very carefully define the circumstances leading up to the event (illness or not, lack of sleep, time of day, fever, drug use, alcohol etc...). What is the individual’s recollection of the event? Was there an “aura?” What exactly happened during the event? Do not be satisfied by medical terms used by non-medical or even other medical personnel. Clarify for yourself exactly what happened. Was there a post-ictal phase etc...? For all this use the mnemonic: Aura, Cry, Fall, Fit Tonic, Clonic, Urine, Sh-4. The clinical exam is usually normal or simply reflects the individual’s underlying disease. Look for clues: cutaneous stigmata of inherited diseases (tuberous sclerosis), tongue or oral mucous membrane laceration, bruises or rug burns sustained in fall, neurological impairments indicating that a neurological disease exists which could lead to seizures. 5. “Routine laboratory tests”: nothing is ever “routine” but usually one obtains CBC, electrolytes, calcium, magnesium, glucose, urine and serum “toxic substance” screen (ie, screen for drugs of abuse). 6. EEG: a. usually one obtains an “inter-ictal” EEG (an EEG in between seizures). 30 to 40% of the time this can be normal. Typical patterns, however, can be very helpful (e.g., 3 per second spike and wave, centro-temporal spikes, focal epileptiform discharges). b. In some complex cases (uncertain diagnosis or seizures not responding to treatment) EEG monitoring to try to capture an event is helpful. 7. Neuroimaging: looking for lesion in the brain. Usually MRI preferable to CT scan (exceptions: small infants, suspicion of blood). 8. Keep in mind the conditions which mimic epileptic seizures (see table): Vasovagal syncope Cardiac arrhythmia Transient Ischemic Attack
Hypoglycemia Migraine Drug reactions
Panic attack Breatholding spells Non-epileptic paroxysmal event (pseudoseizure)
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1. When to treat? a. overall, the risk of recurrence after a single seizure is about 30%, but many clinical factors affect this risk. b. Treatment is indicated when 1) recurrence is likely, AND 2) the individual seizures are either dangerous, occur during the day or are otherwise disturbing, AND 3) they occur often enough. (Example: children with benign rolandic epilepsy may have recurrence weekly, but the seizures occur in bed during sleep, do not put the child at risk, do not result in social stigmatization, and hence may not demand treatment.)
c. Treatment after a single seizure: usually, one does not treat with an anticonvulsant (antiepileptic drug, AED) after a single seizure unless there is an obvious risk of recurrence or the first seizure was prolonged (status epilepticus). An obvious risk of recurrence typically exists if one of the following is present: i) abnormal (epileptiform EEG), ii) structural lesion or disease which is a focus for the seizure (tumor, stroke etc...), iii) close relative with epilepsy of the same type who has required treatment. d. Treatment after a recurrent seizure: usually, one does treat with an anticonvulsant (antiepileptic drug, AED) after the second or subsequent seizure unless there is a clear contraindication to treatment or treatment is unnecessary (see reasons as above). 2. How to treat? Choice of anticonvulsant: (this is basically the subject of entire courses. For this lecture you should remember the names of the five major drugs and their clinical indications. Most importantly, remember which is the drug of choice for what (underlined). The rest of the stuff is in there for your future use or to ignore completely (had to satisfy my obsessive-compulsive tendencies). a. The Meat of the Matter: The five BIG ones: 1. PHENOBARBITAL indications: almost only for children under 2 years of age; Drug of choice for neonates dose: 5 mg/kg/day; adult: 90-180 mg/day half-life: approx 24 hrs dosing: daily or twice a day. important side effects: cognitive blunting, behavioral, allergic skin reactions serum monitoring: none 2. VALPROIC ACID (VPA; depakene, depakote) indications: all idiopathic generalized seizures; also partial seizures. Drug of choice for idiopathic generalized seizures of all types including absence seizures. dose: 20-60 mg/kg/day; adult: 750 -1500 mg/day half-life: approx 8 hrs 9
dosing: twice or three times daily unless use sustained release preparation. important side effects: hyperactivity, tremor, thrombocytopenia, hair loss, liver damage can be fatal), pancreas damage (can be fatal). serum monitoring: CBC, ALT. 3. PHENYTOIN (PHT; dilantin; fosphenytoin=cerebyx) indications: generally not used in children except for status epilepticus; commonly used in adults for partial seizures (all types) and some generalized dose: 5-8mg/kg/day; adult: 300-400 mg/day half-life: approx 24 hrs dosing: daily or twice a day. important side effects: cognitive blunting, depression, gingival hyperplasia (thickening of the gums), coarsening of facial features, excess hair growth (hypertrichosis), allergic skin reactions serum monitoring: none, or CBC sometimes. 4. ETHOSUXIMIDE (ESM; Zarontin) indications: only good for absence epilepsy (one of the drugs of choice for absence epilepsy) dose: 15-40mg/kg/day; adult: 750-1000 mg/day half-life: approx 12 hrs dosing: twice a day. important side effects: abdominal distress, macrocytic anemia, allergic skin reactions serum monitoring: none, or CBC sometimes. 5. CARBAMAZEPINE (CBZ; tegretol, carbatrol) indications: probably drug of choice for partial seizures and some generalized tonic-clonic dose: 15-30mg/kg/day; adult: 1000-1400 mg/day half-life: approx 8 hrs dosing: three times daily unless sustained release preparation important side effects: rare behavioral side effects, tiredness, sleepiness, allergic skin reactions, very rare severe blood dyscrasias (agranulocytosis) serum monitoring: CBC, ALT. b. “Newer medications:� (you should recognize these names but the details are not in scope of this lecture) Felbamate: restricted use due to high risk of hepatotoxicity and bone marrow toxicity. Topiramate: primarily as adjunct for partial seizures. Gabapentin: primarily as adjunct for partial seizures ; pretty weak anticonvulsant. Lamotrigene: primarily as adjunct for partial seizures. Levetiracetam: primarily as adjunct for partial seizures. 10
Zonisamide: primarily as adjunct for partial seizures, but promise for primary generalized seizures as well. Oxcarbazepine: similar to carbamazepine but may have fewer side-effects. If this pans out, may replace carbamazepine as drug of choice for partial seizures.
c. General rules: 1. begin with single agent and use drug of choice (not the most fancy, newest marketed, the one for which you have samples etc...) 2. if seizures not controlled, increase dose gradually until control is achieved or side effects occur; serum levels are useful but of secondary importance. 3. If first choice not effective, try a second sensible option; overlap the two medications, but attempt to quickly discontinue the first (ineffective) medication. 4. avoid polypharmacy if possible: polypharmacy generally results in more toxicity and often in drug interactions that make management more challenging. 5. If must use more than one medication to achieve success, use “rational polypharmacy:” a grossly overrated term referring to use of medications that may have synergistic mechanisms of action; in my humble opinion, clinical experience gets you farther than “rational polypharmacy.” d. How long to treat? In general, one treats for two seizure-free years. Once that is achieved, if all is auspicious, one can safely attempt to withdraw the medication (usually gradually over 1 month). In general, if one is dealing with idiopathic epilepsy in children who have a normal neurological examination, have a normal EEG and a favorable family history, the chance of remission overall is 70%. e. Other: 1. seizure precautions: NO bathing or swimming alone (includes bathtub!), driving restrictions, other sensible but not excessive precautions, avoid sleep-deprivation and in some cases (photosensitive epilepsies) certain video-games, discos, flashing lights etc... 2. Social issues surrounding the care of individuals with epilepsy are critical, often overwhelming and require a great deal of attention and time. Frequently the help of other persons and professionals must be enlisted. ***This section that follows is for your future reference; you will not be responsible for this material for purposes of the Clinical Neurology course. VIII. Status Epilepticus A. Definition: recurrent epileptic seizures without full recovery of consciousness before next seizure begins, or more or less continuous seizure activity lasting greater than 30 minutes. This is serious! B. Types: 1. Generalized convulsive status epilepticus: The most common; just like it sounds. 11
2. “Non-convulsive status:” the person is in fact conscious but in an altered state (“Encephalopathic” or “spacey”). Usually response time is delayed, there is often confusion and disorientation, and minor twitching or “myoclonic movements” are often present. This can be either continuous absence seizures (absence status) or continuous complex partial seizures (complex-partial status). 3. Epilepsia partialis continua: continuos focal seizures; consciousness usually preserved. C. Settings where status epilepticus occurs: 1. Severe metabolic disorders: hyponatremia, pyridoxine deficiency 2. Infection: herpes encephalitis, severe meningoencephalitis 3. Severe, diffuse head trauma. 4. subarachnoid hemorrhage; other acute hemorrhages. 5. abrupt withdrawal of anticonvulsants 6. treatment of absence epilepsy with carbamazepine: can precipitate absence status. 7. sometimes first febrile seizure in a child consists of status epilepticus. D. Mortality: 5 -15% or less; nevertheless, can have serious morbidity. E. Convulsive status epilepticus: 1. Characteristics: • more or less generalized convulsions without cessation • imbalance between high energy demand in Brain and poor energy substrate delivery to brain: the longer this lasts the worse the potential consequences. • as time progresses can result respiratory insufficiency, hypoxia, hypotension, hyperthermia, eventual brain ischemia and rhabdomyolysis (muscle breakdown due to excessive contraction) • represents a medical emergency 2. Management: • identify cause • stabilize patient (ABCs = Airway, Breathing, Circulation) • immediate labs: CBC, electrolytes, calcium, glucose, toxic screen imaging if needed) • treatment with anticonvulsants which have rapid onset of action and can be safely and effectively delivered parenterally: a) lorazepam (ativan) 0.05-0.1 mg/kg/dose IV or diazepam (valium) 0.2 to 0.3 mg/kg/dose IV b) fosphenytoin 18-20 PEs /kg/dose IV; PE stands for phenytoin equivalents which is how doses of this phenytoin prodrug are calculated. c) phenobarbital 15-20 mg/kg/dose IV. F. Absence status: • not as dire an emergency • treatment is with IV lorazepam or diazepam 12
• discontinue offending agent (carbamazepine or phenytoin) if present • IV or enteral valproic acid G. Complex partial status: • difficult to recognize • variable presentation • altered consciousness, spaciness, “twilight state” with ongoing automatisms; can mimic some psychiatric diseases (catatonic states, etc...) • again, not as much of a dire emergency • treatment: recognition (often requires EEG monitoring) and medications as in convulsive status epilepticus above. F. Epilepsia partialis continua: • usually focal clonic movements of limited portion of the body (i.e., just the hand, just the finger, corner of the mouth etc...) • often refractory to treatment • benzodiazepines (lorazepam and diazepam) effective at high dose but they wear off quickly and have significant sedative side effects. • phenytoin, phenobarbital can be used. • often a focal lesion or a metabolic disease (mitochondrial encephalopathy) is present. a special case is Rasmussen’s Encephalitis (rare condition of children in which there is progressive unilateral cortical atrophy and intractable focal seizures of unknown cause-- possibly autoimmune antibody-mediated reaction to glutamate receptors.
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