o Seizure—single, mostly self-limited episode of neuronal hyperactivity leading to a clinical manifestation o Epilepsy—disorder defined by either Two or more unprovoked seizures One unprovoked seizure accompanied by features suggesting a high risk of recurrence o Genetic Epilepsy Syndromes Seizure activity is only part of a broad neurologic presentation where a diagnosis can be made by diagnostic criteria and even genetic testing More commonly seen in kids than adults o Provoked vs. Unprovoked Unprovoked implies it occurred in the absence of an identifiable, removable, and/or avoidable trigger Very commonly, people with alcohol abuse with recurrent withdrawal seizures do not have epilepsy. If a patient never drank again or continued drinking without stopping, they wouldn't get these seizures Seizure Mimickers o “Not all that shakes is a seizure.” “Not all seizures shake.” o 10% patients or more referred with “refractory seizure disorder” are evaluated and discharged with a diagnosis other than seizure disorder. Most common others Psychogenic/Non-Epileptic Convulsive Syncope o There are a lot of factors you must take into account. It often requires neurology input: Duration Eye closure during event Motor activity Bodily injury Vocalization Incontinence Autonomic features Post ictal phase Sleep onset End organ effects Diagnostic studies o Psychogenic Seizure Mimickers These used to be called pseudo seizures Felt to be a conversion disorder This is opposed to the former thought of malingering or faking for secondary gain Up to 30% have a history of epilepsy and may be on numerous anticonvulsants Hallmark: patient with previous seizure disorder that fails to respond to multiple anti- convulsant courses Suggestive features Prolonged duration o Most of the time when someone gets to 2-3 minutes in a seizure, central inhibitory pathways kick in to try to suppress your endogenous epileptic source or someone administered an abortive med such as a benzo o Prolonged duration may be a hint of something that is not an epileptic seizure Type of movement o Asynchronous o Unusual movements EX: no pelvic thrusting or head thrusting o Fluctuating amplitude o Note: Generalized tonic clonic seizures tend to be synchronous, do not fluctuate in amplitude (rather decrease overtime), and do not tend to have unusual movements during event. Eye closure and vocalization o Would expect upper pharyngeal, intercostals, and diaphragm to behave the same way. If someone has prolonged constant vocalization or phonation suggests it is a psychogenic, nonepileptic seizure. Recovery phase o Most true generalized seizures are followed by a prolonged bout of relative unresponsiveness because of the endogenous inhibitory systems that try to suppress seizure activity in the first place o People who abruptly come around may not have had true epilepsy Relative lack of end-organ injury o No biochemical or physical evidence of muscle or tissue injury goes along with psychogenic, nonepileptic seizures Diagnosis Gold standard diagnostic test: video EEG o If a patient has an event without EEG registering electrical instability, that is the gold standard. Serum prolactin 10-20 minutes after the event and 6 hours later can help distinguish these from true seizures o However, it is only 60% sensitive for generalized seizures do cannot be used alone o Specificity is also a problem. There are lots of causes of hyperprolactinemia other that seizure activity. o Must immediately and then hours later to hopefully see it rapidly decline. o Convulsive Syncope Syncope related to transient cerebral hypoperfusion Similar to arrhythmias in heart with coronary ischemia May have transient myolonic activity as reperfusion occurs Can be the end-result of syncope from any cause Patients often have a prodromal phase Typically described as nausea, dizziness, and fading/tunneling of vision These are negative symptoms related to hypoperfusion This is NOT the aura. Aura are positive symptoms related to neuronal hyperactivity just prior to the shaking event. o EX: visual or olfactory hallucinations o Aura is NOT prodrome. Features Skin changes o Cyanosis: true seizure o Pallor: convulsive syncope Urinary incontinence may be present o People can have this with syncope just like with a seizure o Fecal incontinence is more specific for a true seizure, but even then it is not 100% Recovery is rapid and bodily injury is minimal to none Event itself is that of brief (seconds) of shaking, likely related to neuronal firing from hypoperfusion o Other Mimickers Severe movement disorder Some people get such severe chorea, dystonia, tremors, etc. that can almost appear as seizure activity Hallucinations Migraine Sleep disorders Cerebrovascular event Transient global amnesia Toxic/metabolic encephalopathy Others Treating the First Seizure o Up to 10% of all people may have a seizure sometime in their lives but only 1-2% have epilepsy. Because of this and the potential risk of anticonvulsant drugs, not all patients should be treated. o Three Considerations in Diagnosing Epilepsy Two or more unprovoked seizures One unprovoked seizure accompanied by clinical features suggestive of increased risk of recurrence Genetic epilepsy syndrome o Three Important Aspects Risk of recurrence Low if it is a treatable process Higher if CNS is structurally or functionally abnormal Consequence of recurrence Role of Anticonvulsants Risks Benefits o Average Risk of Recurrence: 30-50% at 2 years Risk is highest in the presence of focality and type/certain epilepsy syndromes. Advanced age and family history can also play a role Focality History o Aura Might imply some local set of neurons began activating and then led to generalized instability o Actual Event Unilateral arm shaking rapidly progressing to generalized shaking implies focality o Post Ictal Finding Neurons that started to original hyperactive episode are now sort of blunted EX: Todd’s paralysis This can last a day or two Transient hemiparesis after seizure ends indicating a focal origin of instability that led to generalized activity Examination o Looking for asymmetries and focality Imaging Modalities o Especially by MRI in adults EEG Testing o Keep in mind many people with a first-time seizure have a normal initial EEG o We check EEG in the interictal setting IE not having an event o In adults with new onset seizure activity, the most common area of origin is deep in the white matter, which may be a little too deep for cutaneous scalp electrodes to pick up Type Some syndromes (mostly the ones seen in kids) have such a high rate of recurrence you are stuck treating for life Epilepsy syndromes with the highest risk for recurrences include (but are not limited to) o Juvenile Myoclonic Epilepsy o Absence Seizures Beware. The risk of recurrence is so high you treat for kife. o Other Electroclinical Syndromes o Consequences of Recurrence Occupational EX: air traffic controller Recreational Psychological Furthermore, if the initial presentation was status epilepticus, there is a high risk for an adverse outcome should the seizure recur. o Risks and Benefits of AEDs Prevention of Recurrence Starting drugs after one event does not eliminate recurrences. May reduce by up to 50% o This is why literature does not support treating every single person who has a seizure Adverse Effects General Drug Specific Classification of Seizures o May guide therapy, prognosis, and even genetic counseling o Prior approaches focused on clinical presentation Partial Simple: consciousness intact o Motor o Sensory o Autonomic o Psychic Complex: consciousness altered o Early vs. eventual o Automatisms Generalized Primary o More likely diagnosed in childhood o Convulsive Tonic Clonic Tonic-clonic o Nonconvulsive Myoclonic Atonic Absence Secondary o Can result from a partial seizure Implies something that began on a partial bases led to secondary generalization o Most common type in adults o Newer Approach calls for considering three factors What is the mode of onset? Focal Generalized What is the etiology? Genetic Structural Toxic/metabolic Unknown Is there an electroclinical syndrome? Age of Onset Seizure Phenotype EEG/Imaging Findings Electrical Clinical syndromes o Almost all are genetic, and the majority begin in childhood o Clinical/radiologic/electrical features that suggest certain syndromes are associated with very high risk of seizure recurrences Regarding “focal seizures,” the terms “simple partial” and “complex partial” have somewhat fallen out of favor. More appropriate is a detailed description of the event Examples: o With changes in consciousness/awareness o Without changes in consciousness/awareness o With or without sensory/psychic phenomena o Secondary generalization An epileptic aura is now thought of as a focal seizure Juvenile Myoclonic Epilepsy 5% of all adults with epilepsy Absence myoclonic jerks generalized seizure Onset in late adolescence/early adulthood Prominent genetic component Many cases begin with absence seizures in early teens followed by recurrent myoclonic activity that may lead to generalized o Myoclonus is in the morning and is often provoked by Sleep deprivation Alcohol Flickering lights o Since it tends to be in the early morning, patient may not be aware of it and be mislabeled as generalized epilepsy EEG with classic 4-6 Hz discharge pattern Treatment issues o Very responsive to therapy Valproic acid Lamotrigine o Worsened by certain drugs Phenytoin Carbamazepine This is a big distinguishing factor with these classic antiepileptic drugs o Requires lifelong therapy as 75-100% recur if attempts to taper are made o Prolonged unresponsiveness after convulsion? Post Ictal State Brain stops seizing, patient stops shaking, little bit of unresponsiveness, meaning neuro inhibitory transmitters have gained control of epileptic activity and the person will come around Drug Induced Benzo to stop the ongoing seizure are still acting on the brain and eventually the drug will wear off Disease Progression Progression of meningoencephalitis Progression of brain tumor Trauma Intraparenchymal or subarachnoid hemorrhage Status Epilepticus May have evolved from convulsive status to nonconvulsive status Status Epilepticus o This is a true neurologic emergency. o Diagnostic criteria vary but must be considered in patients with continuous seizure activity greater than 30 minutes or with frequent seizures and failure to regain consciousness between bouts. Given the high- risk for bad outcome however status epilepticus must be assumed to occur if seizures are occurring beyond five minutes. o Considerations when a patient with a seizure stops convulsing Seizure has ended – post ictal Medication side effect Causative disease process is probably progressing Progression into nonconvulsive status epilepticus o Risk factors include Not inherence to anticonvulsant regimen This is the number one cause This has the best prognosis Withdrawal from neurotrophic drugs Acute or remote brain injury Certain epilepsy syndrome Metabolic disturbances Certain drugs – may lower threshold o Any type of seizure can progress to status epilepticus. It is simply prolonged or uncontrolled electrical hyperactivity. It is an electrical event not always a phenotypic one EX: prolonged olfactory hallucinations When the seizure is generalized, there is a greater risk of significant in organ injury o Mortality is 20%, they’ll hire if inciting insult was in toxic brain injury or if the event was severe enough to warrant induction of coma. Biggest predictor of death is closely related to what caused status epilepticus in the first place. o Diagnosis makes it difficult if the patient has progress to nonconvulsive status epilepticus. Therefore, continuous EEG monitoring is essential a diagnosis is being considered in a patient who is stop convulsing but remains and responsive. o Treatment Source Control Sourcing symptom control must occur rapidly and at the same time. Bring in neurosurgeon High dose steroids in setting cerebral edema Broad spectrum antimicrobial if expect infectious cause Patient Stabilization ABCs Control hemodynamics and airway Control Electrical Hyperactivity Beyond supportive care (ABCs, etc.), initial pharmacologic therapy should be via separate IV catheters: benzodiazepine and loading of phenytoin, fastening talent, or valproic acid o Lorazepam 0.1 mg/kg or diazepam 0.15 mg/kg o Phenytoin or fosphenytoin 20mg/kg o Valproic acid 20-40 mg/kg 30% of patients have refractory status epilepticus and therapeutic consideration include o Phenobarbital o Pentoparbital o Propofol o Midazolam o Complications Cardiopulmonary complications Aspiration pneumonitis +/- acute lung injury/ARDS Neurogenic pulmonary edema Mechanical/electrical cardiac events Metabolic complications of massive cell death Rhabdomyolysis o Elevated muscle enzymes, hyperkalemia, hyperphosphatemia, renal failure, etc. Progression of the causative factor Neurologic impairment in survivors High risk of future recurrences Pregnancy and Epilepsy o Almost all pregnancies have a good outcome in epileptic patients o Selected issues to address in pre-conception phase Oral contraceptives and drug interactions OCPs may become ineffective when co-administered with agents that induce cytochrome P450 activity o Phenytoin o Carbamazepine o Phenobarbital o Oxcarbazepine o Topiramate This is the only newer generation one that does this. It requires a high dose. Anti-Epileptic Regimen Seizure control optimized prior to conception o If possible, regimen should be simplified several months before conception. Valproic acid should generally be avoided o This is the most teratogenic one Folate supplementation should be added in childbearing age o Selected Issues in Pregnancy Teratogenicity Baseline risk in general population is 1-2% Structures affected o Neural tube Normally closes by the 2nd or 3rd week so patient may not yet know she is pregnant o Cardiovascular, genitourinary, and midline facial features may also be affected Risk factors o Overall 4-8% of epileptic patients taking medications o Valproic acid: highest risk Also associated with autism and decreased IQ o Combination regimen, especially If involving 1st generation agents Monitoring o Start at weeks 16-18 o Serum AFP Amniotic fluid AFP acceptable as well o Ultrasound Prevention o Role of folic acid o If pregnancy is already established, it is not recommended that regimen changes be made to prevent teratogenicity as any breakthrough seizures could be catastrophic Issues with Pharmacokinetics Altered volume of distribution, altered renal and/or hepatic metabolism, and altered plasma protein binding could alter the pharmacokinetics of anticonvulsants Plasma free drug levels may need to be followed as pregnancy progresses Drugs that induce the cytochrome P450 system may also increase vitamin K catabolism o K supplementation is recommended in late stages of pregnancy to prevent hemorrhagic complications Anticonvulsant Therapy o Consideration in Choosing AED therapy Seizure type Side effect profile Some do not want say cutaneous side effects Patient preference Drug once a day Other medications End-organ functions Liver, renal, thyroid all must be considered Potential pregnancy o In general, all anticonvulsants are equally efficacious though there are differences in adverse effects and effectiveness across various epilepsy syndromes. o Two basic factors leading to treatment failure Disease related Seizure mimicker o If people fail therapy, think potentially of this Intrinsic risk seizure recurrence o Some clinical scenarios have a higher risk of true seizure recurrence even if proper therapy is given Drug Related Beyond failure to attain therapeutic levels Adverse effects may outweigh benefit Chosen agent may worsen patient’s seizure type o Monotherapy is preferred as evidence for benefit of combination therapy is conflicting. If the first agent fails, it is suggested that a second agent should be started and once it reaches a steady state, tapering of the first agent should be done Many people with abnormal substrate in the brain fail even a second agent If the second agent fails, two options are Start a third agent and taper the second Start a third agent and combine with the second o Not all epileptics need life-long AED therapy and if the patient remains seizure free for at least two years, gradual withdrawal from AED can be attempted Risk for recurrence is 30-50% over two years, most likely in the first several months after tapering is complete More likely in certain epilepsy syndromes, in patients that were difficult to control, and in the presence of neuroanatomic focality (IE focal CNS lesions and such) Consideration should be given to driving restrictions during tapering and other aspects of quality of life o First Generation Agents Phenytoin Carbamazepine Phenobarbital Valproic acid Ethosuximide o Second Generation Agents Gabapentin Pregabalin Lamotrigine Topiramate Levetiracetam Oxcarbazepine Zonisamide Felbamate Lacosamide Tiagabine Vigabatrine o Notes on the Drugs Valproic acid, lamotrigine, levetiracetam, zonisamide, and topiramate are considered “broad- spectrum” AEDs with proven efficacy across various epilepsy syndromes. These five are generally effective Others are more effective in refractory cases or in combination with other drugs Ethosuximide is only used for absence seizures Carbamazepine and phenytoin may worsened the course of some generalized electroclinical syndromes, such as juvenile myoclonic epilepsy and absence seizures. o Adverse Effects Many adverse effects have been described and may be considered in terms of General o Seen in numerous agents o Systemic o Neurologic Medication specific o Limited to 1-2 agent Selected General Adverse Effects Gastrointestinal discomfort Abnormal liver enzymes Weight change (especially weight gain with older agent) Mucocutaneous: various types of eruptions o Risk of SJS/TEN greater with all first-generation agents as well as lamotrigine (main) and oxcarbazepine o Most serious skin lesions develop in the first three months of therapy o Certain HLA haplotypes carry a higher risk of SJS/TEN with carbamazepine and may have to be tested Bone Marrow Failure o These drugs all alter folate metabolism Drug Interactions Mostly induction of cytochrome P450 3A4 system leading to o Loss of efficacy of other drugs o The increase in generation of a toxic metabolite Phenytoin Carbamazepine Oxcarbazepine Phenobarbital Topiramate o Require high doses to produce this effect. Metabolic bone disease and various hematologic problems (mostly bone marrow suppression or immune mediated peripheral destruction) are possible, especially with the older agents Selected General Neurologic Effects Headache Tremor Dizziness Vision changes Cognitive dysfunction Sedation These are to be expected because the real goal of AED is to suppress firing and action potential generation of unstable neurons. o We cannot pick what receptors are targeted. Hyperactive and normal neurons affected similarly. Selected Medication Specific Adverse Effects Phenytoin o Cosmetic IE gingival hyperplasia o Drug fever o Pseudolymphoma o Toxic effects: ataxia, nystagmus, dysarthria, confusion, and seizures Carbamazepine and Oxcarbazepine o Diplopia o Hyponatremia It causes SIADH Valproic Acid o Pancreatitis o Menstrual irregularities o Elevated serum ammonia o Hair loss Phenobarbital o Dependence Topiramate o Nephrolithiasis o Metabolic acidosis o Angle closure glaucoma o Weight loss Gabapentin and Pregabalin o Edema Role of Following AED Levels A level is considered toxic when there is associated clinical evidence of toxicity o Note that people can develop toxicity with normal drug levels EX: Normal level phenytoin is 10-20 total. If a patient develops hypoalbuminemia for whatever reason, then more of that level is free. Free level is what has all the effects. Hypoalbuminemia can be toxic at a level of 17-18. o Level is toxic when patient has toxic symptoms. It is NOT based on a drug level. A level is therapeutic when seizures are controlled without evidence of toxicity General considerations o Evaluating toxicity o Evaluating possible treatment failure o Ongoing or anticipated pharmacokinetic changes Pregnancy Change in protein binding Concentration Other medication Thus, monitor with FREE drug level not total. Drug interactions End organ disease Need proper liver and renal clearance o Evaluating adherence to therapy o Early in treatment to establish therapeutic levels When you start drug and reach steady state 4-5 plasma half lives o