Annals of Internal Medicineᮋ

In the Clinic® Diagnosis

Epilepsy Prevention

n epileptic is defined by the Inter- Treatment national League Against (ILAE) Aas “a transient occurrence of signs and/or symptoms due to abnormal excessive or syn- Further Considerations chronous neuronal activity in the brain” (1). In 2014, the ILAE provided an operational (practi- cal) clinical definition of epilepsy as a disease of the brain defined as any of the following condi- tions: at least 2 unprovoked [or reflex] occurring more than 24 hours apart; 1 unpro- voked [or reflex] seizure and a probability of further seizures similar to the general recur- rence risk [at least 60%] after 2 unprovoked sei- zures, occurring over the next 10 years; [and/or] a diagnosis of an epilepsy syndrome (2).

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Physician Writer doi:10.7326/AITC201602020 Kaarkuzhali B. Krishnamurthy, MD CME Objective: To review current evidence for diagnosis, prevention, treatment, and further considerations of epilepsy. Funding Source: American College of Physicians. Disclosures: Dr. Krishnamurthy, ACP Contributing Author, has disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=M15-2484. With the assistance of additional physician writers, the editors of Annals of Internal Medicine develop In the Clinic using MKSAP and other resources of the American College of Physicians. In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical guidelines, please go to https://www.acponline.org/clinical_information/guidelines/. © 2016 American College of Physicians

Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 A seizure can cause isolated or fection (6). Because a first seizure combined sensory, motor, cogni- can lead to other events, an elec- tive, or emotional symptoms. The troencephalogram (EEG) is also ILAE defines reflex seizures as recommended at the time of initial those “that are objectively and presentation as identification of consistently demonstrated to be interictal abnormalities increases evoked by a specific afferent the risk for a second seizure, which stimulus or by activity of the pa- 1. Fisher RS, van Emde Boas may or may not lead to a diagnosis W, Blume W, Elger C, tient” (3). Epilepsy is a chronic of epilepsy (4). Genton P, Lee P, et al. Epileptic seizures and disorder that can have long- epilepsy: definitions pro- standing medical, psychological, The causes of epilepsy vary and posed by the International are identified in only about 30% League Against Epilepsy and social sequelae. (ILAE) and the Interna- of people with the disorder (see tional Bureau for Epilepsy Isolated seizures are common; (IBE). Epilepsia. 2005;46: the Box: Seizure Evaluation). 470-2. [PMID: 15816939] they are believed to occur in 1 in Common risk factors include pre- 2. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, 10 persons over a lifetime. An iso- mature birth; complicated febrile Cross JH, Elger CE, et al. lated seizure should not be con- seizures; infections, such as men- ILAE official report: a prac- tical clinical definition of fused with epilepsy. The preva- ingitis or encephalitis, at any age; epilepsy. Epilepsia. 2014; lence of recurrent, unprovoked 55:475-82. [PMID: head trauma, which may be mi- 24730690] seizures, or epilepsy, is believed to nor, particularly if it is recurrent; 3. Illingworth JL, Ring H. Conceptual distinctions be 5–8 per 1000 persons in devel- and/or a family history of epi- between reflex and nonre- oped countries; higher (10/1000 flex precipitated seizures lepsy or neurologic illnesses. in the : a sys- persons) in developing countries; Causes of epilepsy may include tematic review of defini- and higher still in rural areas, due tions employed in the structural lesions related to dis- research literature. Epilep- in part to infectious and traumatic turbances in intrauterine devel- sia. 2013;54:2036-47. [PMID: 24032405] causes (4). In low- and middle- opment, such as TORCH (toxo- 4. Moshe´ SL, Perucca E, income countries, other factors, Ryvlin P, Tomson T. Epi- plasmosis, other [syphilis, lepsy: new advances. including age and sex, can influ- varicella-zoster, parvovirus B19], Lancet. 2015;385:884-98. ence morbidity and mortality re- [PMID: 25260236] rubella, cytomegalovirus, and 5. Wagner RG, Bottomley C, lated to epilepsy (5). Ngugi AK, Ibinda F, herpes) infections, abnormalities Go´mez-Olive´ FX, Kahn K, of neuronal migration, and fetal et al; SEEDS Writing Causes of isolated seizures can Group. Incidence, remis- include such toxic, metabolic, intracranial hemorrhage. Prema- sion and mortality of con- ture birth can lead to white mat- vulsive epilepsy in rural structural, and infectious factors northeast South Africa. as alcohol intoxication and with- ter and cortical damage in the PLoS One. 2015;10: e0129097. [PMID: drawal, hypoglycemia and hyper- developing brain, producing an 26053071] environment that is conducive to 6. Krumholz A, Wiebe S, glycemia, acute stroke, and me- Gronseth G, Shinnar S, ningoencephalitis. Thus, the the initiation and propagation of Levisohn P, Ting T, et al; seizures (7). Other acquired le- Quality Standards Sub- algorithm for evaluation of a first committee of the Ameri- seizure includes a thorough his- sions can serve as seizure foci, can Academy of Neurol- ogy. Practice parameter: tory and physical examination, a including benign and malignant evaluating an apparent intracranial or extra-axial tumors, unprovoked first seizure in blood glucose test, electrolyte adults (an evidence-based panels, a blood count, toxicology abscesses, cysts, hemorrhagic review): report of the Quality Standards Sub- screening, brain imaging (com- lesions, or strokes. Genetic causes committee of the Ameri- puted tomography [CT] or mag- have been identified for some id- can Academy of and the American Epilepsy netic resonance imaging [MRI]), iopathic , and Society. Neurology. 2007; systemic illnesses, such as HIV in- 69:1996-2007. [PMID: and spinal fluid analysis in pa- 18025394] tients with fever or other symp- fection and malaria, can also lead 7. Robinson S. Systemic prenatal insults disrupt toms or signs of intracranial in- to chronic epilepsy (8). telencephalon develop- ment: implications for potential interventions. Epilepsy Behav. 2005;7: 345-63. [PMID: Diagnosis 16061421] What are the symptoms of 8. Bhalla D, Godet B, Druet- tingling, pain, or isolated motor Cabanac M, Preux PM. epilepsy? symptoms) or twitching, jerking, Etiologies of epilepsy: a comprehensive review. Symptoms of seizures vary or rhythmic or semirhythmic un- Expert Rev Neurother. widely. They can be isolated controlled movements. They can 2011;11:861-76. [PMID: 21651333] sensory symptoms (numbness, be purely psychic symptoms,

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Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 such as fear, sadness, elation, or creased intracranial pressure. laughing. Awareness may be al- Hemiatrophy of a limb or digit Seizure Evaluation tered, leading to an inability to suggests incomplete contralateral First seizure: interact normally. Although pa- cerebral development, such as tients may seem to be conscious, can be seen in patients who may Thorough history and physical difficulty responding verbally to have had intrauterine insults. examination questions and difficulty integrating Bloodwork: Serum glucose Several causes of altered behav- new memories, as well as auto- level, chemistry panel (so- ior should be considered in the matic behaviors such as lip smack- dium, calcium, phosphorus, differential diagnosis of pre- ing, chewing, or swallowing, can magnesium,) liver function sumed epilepsy (9). Syncope is a tests, blood urea nitrogen/ be signs of a seizure. Patients with commonly misidentified event that creatinine, pregnancy test for focal-onset epilepsy (in which the can occur with vascular insuffi- women, complete blood electrical disturbance spreads to ciency, cardiac dysrhythmias, hy- count, toxicology, alcohol involve wider areas of the cerebral povolemia, anemia, and auto- level cortex) may have other visible mo- nomic dysfunction. Sleep Lumbar puncture if febrile, tor manifestations, including stiff- disturbances; metabolic derange- nuchal rigidity, immune ening, jerking, or twitching on one ments, such as hypoglycemia; compromise or both sides of the body. Loss of movement disorders; and mi- tone, incontinence, and tongue Electroencephalogram graine can also lead to repetitive biting may occur. Confusion and Computed tomography or or stereotyped movements, al- disorientation may be seen for sev- magnetic resonance imaging tered awareness, and impaired Consider HIV test eral minutes afterward and, con- cognitive function. Altered aware- cordant with the duration of the ness in the context of delirium or Breakthrough seizure: seizure, resolution to normal cog- dementia can also be mistaken for History and examination nitive function may take hours or seizure activity, although the coin- days. Patients with absence sei- Bloodwork: As above, add in cidence of seizures in these medi- trough levels zures may stare or blink repeti- cal conditions can be high. Finally, No need for neuroimaging tively with little else in the way of psychiatric and psychological con- unless new seizure type, motor manifestations, and they ditions, including panic attacks, may not be aware that a seizure change in seizure semiology posttraumatic stress disorder, and or frequency has occurred unless they are told. nonepileptic events (also known as However, lack of recall does not pseudoseizures), may be difficult Electroencephalogram if patient does not return to distinguish absence seizures from to distinguish from epileptic sei- baseline complex partial seizures because zures and may require further some patients with the latter also testing. may be unaware that an event has occurred. What tests should be done to diagnose epilepsy? In patients with epilepsy, in addi- In addition to the bloodwork tion to obtaining a detailed history noted earlier, more specific test- with special emphasis on the pa- ing in patients with epilepsy tient's description of seizure onset should focus on identifying 2 fac- (“How do you know that a seizure tors: confirmation that the events is going to occur? What's the first are epileptic, and identification thing that happens? Then what? of the cause. For confirmation, an Do you have any other intermittent EEG should be offered. In a rou- movements or feelings that occur tine EEG, a short period (typically without an apparent cause?”), a 20–60 minutes) of brain wave thorough physical examination activity is recorded. Although the should be performed to look for likelihood of capturing a clinical focal findings that indicate the event is small, identification of presence of an intracranial struc- interictal discharges, such as tural disturbance. A finding of sharp waves and spikes, in- 9. Benbadis S. The differen- blurred disc margins on an ocular creases the evidence supporting tial diagnosis of epilepsy: examination could indicate an in- the event as epileptic in nature. If a critical review. Epilepsy Behav. 2009;15:15-21. tracranial mass lesion causing in- the patient's symptoms occur [PMID: 19236946]

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Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 relatively frequently or can be sions, such as malignant or meta- provoked by certain reproduc- static tumors, subdural or epidu- ible situations, ambulatory outpa- ral hematomas, or empyemas, tient or inpatient EEG monitoring may require acute surgical inter- may be helpful. This involves vention. Other focal findings, placing electrodes on the pa- such as migrational disorders or tient's scalp that capture data vascular lesions, may serve as that are then processed through evidence supporting focal onset computer software with detec- for a patient's presentation. tion algorithms, such as auto- Do patients with epilepsy have mated spike detection and sei- zure detection programs. The related comorbidities? subsequent recording, including Once a definitive diagnosis of video if available, is reviewed epilepsy is made, consideration and interpreted by a trained elec- of and ongoing monitoring for troencephalographer. Extended comorbidities should occur. Epi- recording typically occurs for lepsy is not protective against days at a time and more readily common medical conditions, identifies electrical disturbances such as hypertension, hypercho- that may be seen only in certain lesterolemia, or diabetes, so phy- sleep states. In addition to the sicians must screen patients with automated detection features, epilepsy as they would any other the patient can activate a push- patient. In addition, some anti- button that saves a portion of the convulsants have such adverse recording preceding and follow- effects as disturbances of calcium ing the patient's clinical signal. For homeostasis or appetite en- patients who have identified situa- hancement or suppression, tions or conditions that provoke which can exacerbate concomi- events, continuous EEG recording tant medical conditions. It is im- may be a perfect mechanism for portant for physicians, including diagnosis because the recording primary care providers, to be can occur while the patient per- aware of these potential effects forms the provocative maneuver. and to monitor for them.

Cardiac testing may also be of- Epidemiologic studies have identi- fered as part of a diagnostic eval- fied other medical conditions, uation. Routine electrocardiogra- such as pneumonia, asthma, and phy and ambulatory cardiac upper gastrointestinal bleeding, monitoring can be used to look that seem to be more prevalent in for evidence of dysrhythmias patients with epilepsy than in the leading to altered awareness or general population (10). The loss of consciousness. Echocardi- mechanisms for this are not clear ography can show evidence of but can include acute and chronic cardiac wall dysfunction as an adverse effects of indicator of prior cardiac isch- as well as shared risk factors (10). emia. Similarly, focal wall hypoki- nesis or valvular disease could be Other concomitant medical mechanisms to generate clots problems may include hormonal that could be transferred via the imbalances, which are known to bloodstream to the brain, caus- occur in both women and men ing recurrent strokes. with epilepsy at rates higher than those of the general public and 10. Gaitatzis A, Sisodiya SM, Sander JW. The somatic Neuroimaging is mandatory for in patients with other neurologic comorbidity of epilepsy: patients with epilepsy, particu- conditions. Reproductive endo- a weighty but often un- recognized burden. larly if it is newly diagnosed, to crine disorders, such as polycys- Epilepsia. 2012;53: look for focal lesions as a cause. tic ovarian syndrome, occur more 1282-93. [PMID: 22691064] Focal or space-occupying le- than twice as often in women

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Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 with epilepsy than in those in the epilepsy than in the general pop- general population (11). In sus- ulation (16). These can occur as ceptible women, the relative epi- primary medical conditions but leptogenic potential of serum also as consequences of anticon- estradiol can lead to perimen- vulsant therapy and should be strual or periovulatory seizures or watched for closely for the dura- seizures that occur during the tion of the patient's medical entire second half of the men- treatment. Suicide is more com- strual cycle (12). The effect of mon in patients with epilepsy menopause on seizures and epi- than in the general population, lepsy syndromes is not well- and because the disorder carries 11. Herzog AG. Disorders of understood, particularly because a high burden of stigma, patients reproduction in patients factors that are commonly seen in with epilepsy: primary may be reluctant to seek help for neurological mecha- the perimenopausal period, such a coexistent mood disorder. Like- nisms. Seizure. 2008; 17:101-10. [PMID: as sleep disturbances, can also wise, fear of having a seizure in 18165118] affect seizures (13). Men with epi- public can lead to social isola- 12. Herzog AG, Klein P, Ransil BJ. Three patterns lepsy, even those who are not re- tion, diminished opportunities to of catamenial epilepsy. ceiving anticonvulsant therapy, Epilepsia. 1997;38: develop friendships, and de- 1082-8. [PMID: can have low sexual function, and creased social support (17). The 9579954] 13. Sveinsson O, Tomson T. those receiving enzyme-inducing prohibition against driving for Epilepsy and meno- anticonvulsants, such as phenytoin people with active seizures can pause: potential implica- tions for pharmacother- and , may have de- also diminish quality of life, given apy. Drugs Aging. 2014; creased testosterone bioactivity (14). 31:671-5. [PMID: that many communities do not 25079452] have sufficient public transporta- 14. Devinsky O. Neurologist- Cognitive impairment can occur induced sexual dysfunc- tion options to allow for commut- in patients with epilepsy (15). tion: enzyme-inducing ing to work or social events (18). antiepileptic drugs [Edi- This may be seen before the on- torial]. Neurology. 2005; Endogenous depression seems 65:980-1. [PMID: set of seizures, as in patients with to be more common in patients 16217046] cerebral lesions, which may also 15. Witt JA, Helmstaedter C. with temporal lobe epilepsy than Cognition in the early be the cause of the epilepsy. Fre- stages of adult epilepsy. in those with focal epilepsy origi- quent or prolonged seizures can Seizure. 2015;26:65-8. nating in other brain regions and [PMID: 25799904] lead to disturbances of cortical 16. Schmidt D, Schachter SC. in patients with primary general- Drug treatment of epi- function during and after a sei- ized epilepsy (19). Some anticon- lepsy in adults. BMJ. zure, as can transient or more 2014;348:g254. [PMID: vulsants can cause mood distur- 24583319] consistent metabolic or hypoxic 17. McCagh J, Fisk JE, Baker bances, including suicidality, GA. Epilepsy, psychoso- derangements that may occur as whereas anticonvulsants with cial and cognitive func- a consequence of the seizures. tioning. Epilepsy Res. mood-stabilizing properties, such 2009;86:1-14. [PMID: Anticonvulsants themselves may as and , may 19616921] cause cognitive dysfunction, 18. Naik PA, Fleming ME, lead to depression if the dosage is Bhatia P, Harden CL. Do which may be particularly notice- drivers with epilepsy decreased or the medication is have higher rates of able in patients using combina- withdrawn (16). The coincidence motor vehicle accidents tion therapy (16). than those without epi- of epilepsy and mood disorders lepsy? Epilepsy Behav. 2015;47:111-4. [PMID: Patients with temporal lobe epi- may also increase risk for recurrent 25960422] or breakthrough seizures (20). 19. Garcia CS. Depression in lepsy may have associated cogni- temporal lobe epilepsy: tive deficits related to the lateral- a review of prevalence, A retrospective cohort study identified people clinical features, and ity of the seizure focus; for who submitted insurance claims for anticon- management consider- example, language deficits may ations. Epilepsy Res vulsant medications and reviewed subsequent Treat. 2012;2012:1-12. be seen in patients with temporal claims to determine whether they visited an 20. Shcherbakova N, Rascati K, Brown C, Lawson K, lobe epilepsy arising in the domi- emergency department, used an ambulance, Novak S, Richards KM, nant hemisphere for language. or were hospitalized for seizure treatment. A et al. Factors associated with seizure recurrence These deficits may be seen even total of 5.3% of patients receiving mono- in epilepsy patients if the epilepsy is well-controlled. therapy required 1 of the 3 outcomes in the treated with antiepileptic monotherapy: a retro- first year of follow-up. Preexisting mental spective observational Finally, mood disorders, such as health disorders, such as depression, anxiety, cohort study using US administrative insurance depression and anxiety, occur substance abuse, or schizophrenia, further in- claims. CNS Drugs. more frequently in patients with creased risk (20). 2014;28:1047-58. [PMID: 25086640]

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Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 Diagnosis... Epilepsy is best identified by a careful history and physical examination. Proper neuroimaging with MRI may identify causal factors. Ambulatory or continuous EEG monitoring may be especially helpful in the differential diagnosis, even if seizures are not captured. Many co- morbidities are associated with epilepsy, either from the etiologic cause or from treatments for the condition. Proper identification and manage- ment of these may lead to improved functioning and quality of life.

CLINICAL BOTTOM LINE

Prevention How can epilepsy be come more evident. For many prevented? patients, insufficient sleep or al- There are no consistent mecha- cohol use can trigger seizures. nisms to prevent the develop- Initial and recurrent counseling ment of epilepsy. Avoidance of on ways to improve sleep dura- risk factors may not be possible tion and quality may help to pre- given that most do not require vent further occurrences, particu- recurrent exposure; mild head larly for adolescents, elderly injury, such as a concussion, may patients, and those with newborn be the exception because emerg- children. Likewise, assisting pa- ing data suggest that recurrent tients in identifying alternative mild head injuries can lead to epi- strategies to avoid or limit alco- lepsy. Few if any randomized, con- hol use in social situations may trolled trials have been done to help to allow them to maintain determine whether early introduc- normal or age-appropriate social tion of anticonvulsant therapy in, interactions, thereby reducing the for example, patients with viral en- stigma of epilepsy. Providing cephalitides alters subsequent thoughtful alternatives, such as development of seizures (21). After limiting alcohol intake to 1 or 2 a significant head injury, the use of drinks on a weekend night rather anticonvulsant therapy versus pla- than prohibiting all alcohol intake, cebo does not seem to reduce the not only allows patients to feel risk for early or late posttraumatic comfortable asking for help and seizures (22). support from their physicians but also provides reasonable modifi- Although there may be no effec- cations that patients are likely to tive mechanisms to prevent the adopt. development of epilepsy, there may be ways to prevent seizures Finally, some patients are at risk in patients who are prone to the for recurrent seizures. These can disorder. For example, for pa- occur in situations where normal 21. Pandey S, Rathore C, Michael BD. Antiepileptic tients with clear reflex epilepsy, absorption of seizure medica- drugs for the primary identification of situations or tions can be impaired, such as and secondary preven- tion of seizures in viral events that can trigger seizures with comorbid gastrointestinal encephalitis. Cochrane Database Syst Rev. 2014; may be clear, whereas triggers illness or during colonoscopy 10:CD010247. [PMID: for those with nonreflex forms of preparation. Other patients show 25300175] 22. Thompson K, Pohlmann- epilepsy may become apparent a clustering pattern of seizures as Eden B, Campbell LA, Abel H. Pharmacological only after several seizures have a feature of their particular epi- treatments for prevent- occurred. Encouraging patients lepsy syndrome. For these pa- ing epilepsy following traumatic head injury. to keep a record of events occur- tients and for those who may be Cochrane Database Syst ring over the 24 hours after each at risk for recurrent seizures, in- Rev. 2015;8:CD009900. [PMID: 26259048] seizure may allow patterns to be- termittent use of short-term ben-

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Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 zodiazepine therapy may prevent An emergency-use study in San Francisco, Cal- progression into status epilepti- ifornia, allowed paramedics to administer 1 of cus (23). Patients must be care- 3 randomly assigned intravenous medications fully counseled to ensure that the to adult patients with prolonged or repetitive rescue medication is used only in convulsive seizures (status epilepticus): 5 mg emergency situations, with due of diazepam, 2 mg of lorazepam, or placebo, with a second injection given if seizures did consideration given to the ad- not resolve. Status epilepticus resolved in verse effects of . 59.1% of patients who received lorazepam and Patients should also be advised 42.6% of those who received diazepam com- that if seizures persist despite 1–2 pared with 21.1% of those who received pla- doses of benzodiazepine treat- cebo. Of note, the rate of respiratory or circula- ment, they may require emer- tory problems in patients who received gency transport to a hospital for was approximately 10% ver- further treatment (24). sus 22.5% in the placebo group (24).

Prevention... There are no proven strategies to prevent epilepsy. How- ever, taking a careful history may identify avoidable seizure triggers, such as sleep deprivation, alcohol use, and planned or inadvertent non- adherence to medication. Providing patients with a small quantity of low-dose oral benzodiazepines may decrease risk for recurrent seizures in the setting of intercurrent illness.

CLINICAL BOTTOM LINE 23. Lowenstein DH. Treat- ment options for status epilepticus. Curr Opin Pharmacol. 2005;5: 334-9. [PMID: 15907922] 24. Alldredge BK, Gelb AM, Treatment Isaacs SM, Corry MD, How should epilepsy be treated of adults with epilepsy. Head-to- Allen F, Ulrich S, et al. A comparison of loraz- initially? head comparisons of these medi- epam, diazepam, and placebo for the treatment The risk for seizure recurrence in cations have not been done; of out-of-hospital status adults with an unprovoked first however, trials that have com- epilepticus. N Engl J Med. 2001;345:631-7. seizure is 21%–45% in the first 2 pared specific drug regimens [PMID: 11547716] 25. Krumholz A, Wiebe S, years; initiation of treatment after have not found clear evidence Gronseth GS, Gloss DS, the first event reduces risk over supporting the use of a specific Sanchez AM, Kabir AA, et al. Evidence-based the next 2 years but does not medication over another in cir- guideline: management cumstances where both medica- of an unprovoked first seem to improve the chances of seizure in adults: report long-term remission (25). Thus, tions have proven efficacy in a of the Guideline Devel- opment Subcommittee introduction of therapy after a particular epilepsy syndrome or of the American Acad- seizure type (26). emy of Neurology and single seizure requires careful the American Epilepsy discussion between the patient Society. Neurology. Thus, after an initial filtering pro- 2015;84:1705-13. and the health care provider. [PMID: 25901057] cess to identify the set of anticon- 26. French JA, Kanner AM, A second seizure typically results vulsants with efficacy in the pa- Bautista J, Abou-Khalil B, Browne T, Harden CL, in the initiation of treatment. Al- tient's type of epilepsy, further et al; Therapeutics and Technology Assessment though there are several meth- consideration must be given to Subcommittee of the ods to treat epilepsy, including potential adverse effects; interac- American Academy of Neurology. Efficacy and medications and devices ap- tions with other medical condi- tolerability of the new antiepileptic drugs I: proved by the U.S. Food and tions or medications; time to treatment of new onset Drug Administration (FDA), surgi- reach optimal dosing; plans for epilepsy: report of the Therapeutics and Tech- cal options, and hormonal inter- childbearing; and other lifestyle nology Assessment Sub- factors, including the patient's committee and Quality ventions, pharmacotherapy is Standards Subcommittee typically offered as the initial preferences with respect to the of the American Acad- emy of Neurology and treatment. More than 2 dozen dosing schedule. Although some the American Epilepsy anticonvulsants have been ap- patients may have to consider Society. Neurology. 2004;62:1252-60. proved by the FDA for treatment cost or affordability of the anti- [PMID: 15111659]

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Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 convulsant, this may be mitigated medications have chemical prop- by patient-assistance programs erties or specific formulations provided by most of the pharma- that enable them to be taken ceutical companies that manufac- once daily. For patients who use ture anticonvulsant medications smartphones or computer apps in the United States. Drugs used for scheduling, programming to treat epilepsy in the United daily reminders can improve States are listed in the Appendix adherence. Table (available at www.annals .org). Medications differ in how they can be introduced and in- Before any medication is intro- creased. Thus, it is important to duced, a period of counseling is determine the likelihood of an- warranted to educate patients on other event before the medica- the need for consistency with re- tion reaches an effective serum spect to anticonvulsant therapy. concentration. If the likelihood is Seizure medications are not ef- high, introducing a medication fective unless they are taken reg- that can be increased quickly ularly and in accordance with would be better than initiating guidelines that render a consis- treatment with a medication that tent serum concentration that is might take weeks or months to individualized for the patient. reach a reasonable effective se- Some patients may achieve sei- rum concentration. zure freedom with serum concen- trations that are above or below One of the strongest predictors the listed therapeutic blood lev- of favorable long-term outcomes els; for those patients, increasing for patients with epilepsy is a or decreasing dosing to achieve positive response to the first anti- a level within the therapeutic convulsant (27). Furthermore, the range is not indicated because likelihood of seizure freedom this may cause toxicity if the dose decreases “proportionately with 27. Mohanraj R, Brodie MJ. is too high or lack of efficacy if the number of other antiepileptic Early predictors of out- come in newly diag- the dose is too low. Once an effi- drugs unsuccessfully tried” (4). nosed epilepsy. Seizure. Although there are no significant 2013;22:333-44. [PMID: cacious dose is established, it 23583115] may be helpful to document a differences in patients' self- 28. Jacoby A, Sudell M, Tudur Smith C, Crossley serum concentration so that if reported quality of life with differ- J, Marson AG, Baker GA; problems occur, such as clinical ent initial anticonvulsant agents, SANAD Study Group. Quality-of-life outcomes signs of overmedication or adverse effects and break- of initiating treatment with standard and newer breakthrough seizures, one can through seizures affect quality of antiepileptic drugs in ascertain whether they are re- life (28). Thus, for patients who adults with new-onset epilepsy: findings from lated to a change in serum con- do not respond to the first agent the SANAD trial. Epilep- or who have unacceptable ad- sia. 2015;56:460-72. centration or whether other fac- [PMID: 25630353] tors, such as lack of adherence or verse effects, use of a second 29. French JA, Kanner AM, Bautista J, Abou-Khalil B, duplicate dosing, may have agent is indicated, either as an Browne T, Harden CL, caused the problem. Many newly adjunct to the first or with plans et al; Therapeutics and Technology Assessment diagnosed patients with epilepsy for a cross-taper to allow for re- Subcommittee of the sultant monotherapy. All of the American Academy of are young and may not be habit- Neurology. Efficacy and ually taking other daily medi- newer anticonvulsant agents are tolerability of the new antiepileptic drugs II: cines. Thus, suggestions and appropriate for adjunctive treat- treatment of refractory guidance on strategies to re- ment of refractory partial sei- epilepsy: report of the Therapeutics and Tech- member to take medications zures, the most common type in nology Assessment Sub- committee and Quality at a specific time may improve adults (29). Standards Subcommittee adherence. of the American Acad- Seizure medications work by sta- emy of Neurology and the American Epilepsy Patients are more likely to adhere bilizing cellular mechanisms that Society. Neurology. to once-daily treatment regi- prevent spontaneous neuronal 2004;62:1261-73. [PMID: 15111660] mens, and many anticonvulsant depolarization. The exact mecha-

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Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 nisms by which various medica- idiosyncratic or non–dose- tions influence this function in- dependent adverse effects that clude interaction through may not be amenable to modifi- sodium, calcium, or potassium cation and can lead to intoler- channels and/or effects on ance by patients. such neurotransmitters as ␥-aminobutyric acid or gluta- One controversial effect that the mate. Some anticonvulsants in- FDA found to be common to all volve several mechanisms of ac- anticonvulsant medications is an tion, but the exact mechanism increased tendency to suicidality, has not been identified for oth- which can be seen as early as 1 ers. Recognition of the mecha- week after initiation of treatment nism may be particularly impor- (32). Although other studies have tant for patients in whom initial not found an increased risk for anticonvulsant therapy fails be- suicidality in patients using anti- cause use of a second agent with convulsants, the FDA warning a different mechanism of action is requires that physicians warn pa- more likely to be effective (30). tients of the risk for suicidality Because the first or second pre- and screen for depression or sui- scribed medication fails in up to cidality at regular intervals during one third of patients with epi- dose escalation (33). lepsy, it is important to consider Are there devices to treat 30. Margolis JM, Chu BC, additional strategies to choose epilepsy? Wang ZJ, Copher R, subsequent medications or com- Cavazos JE. Effectiveness Two FDA-approved devices are of antiepileptic drug binations of medications that used to treat epilepsy. The vagus combination therapy for may improve outcomes (31). partial-onset seizures nerve stimulator is approved for based on mechanisms of adjunctive use in adult patients action. JAMA Neurol. If a patient continues to have sei- 2014;71:985-93. [PMID: with partial-onset seizures that 24911669] zures while receiving 2 anticon- 31. Divino V, Petrilla AA, vulsants at adequate dosages, are refractory to anticonvulsant Bollu V, Velez F, Ettinger treatment. Of note, this device A, Makin C. Clinical and referral to a neurologist or a spe- economic burden of cialty center is indicated, both to has been approved by the FDA breakthrough seizures. for adjunctive treatment of Epilepsy Behav. 2015; ensure accuracy of the diagnosis 51:40-7. [PMID: chronic or recurrent depression, 26255884] and to offer additional treatment 32. U.S. Food and Drug options, including implantable and data support mood improve- Administration. Suicidal ment in patients with epilepsy Behavior and Ideation devices and surgery. and Antiepileptic Drugs. (34). The device consists of a Silver Spring, MD: U.S. What are the adverse effects of Food and Drug Adminis- generator implanted subcutane- tration; 2014. Accessed epilepsy treatment? ously in the anterior chest wall or at www.fda.gov/Drugs /DrugSafety/Postmarket- Many of the common adverse axilla and a lead threaded subcu- DrugSafetyInformation- effects of anticonvulsant therapy taneously from the generator to forPatientsandProviders /ucm100190.htm on 10 are linked more to escalation the left vagus nerve. It can be December 2015. 33. Rissanen I, Ja¨a¨skela¨inen rates and absolute quantities of programmed to provide regular E, Isohanni M, Koponen medications given than to spe- electrical impulses every few min- H, Ansakorpi H, Miet- tunen J. Use of antiepi- cific mechanisms of action. For utes and can also be triggered to leptic or benzodiazepine example, all seizure medications deliver a train of impulses medication and suicidal ideation—The Northern can cause fatigue, dizziness, through use of an external hand- Finland Birth Cohort 1966. Epilepsy Behav. blurred vision, incoordination, held magnet. The second feature 2015;46:198-204. and gait imbalance. These tend can be used to treat seizures [PMID: 25935512] 34. Morris GL 3rd, Gloss D, to be dose-dependent rather when a patient is aware that an Buchhalter J, Mack KJ, than idiosyncratic and can some- event is occurring or may be Nickels K, Harden C. Evidence-based guide- times be alleviated by using a used by health care providers in line update: vagus nerve stimulation for the treat- slower dose-escalation plan or an attempt to decrease the ment of epilepsy: report administering the medication on length of an event after it has of the Guideline Devel- opment Subcommittee a full stomach rather than ran- started. In addition to the surgical of the American Acad- domly during the day. However, risks of pain and infection, emy of Neurology. Neu- rology. 2013;81:1453-9. each anticonvulsant also has hoarseness can occur through [PMID: 23986299]

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Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 disruption of the recurrent laryn- tions have decreased over the geal nerve in the neck. This may past 30 years, possibly because be transient or permanent and of improvements in operative can recur during stimulation techniques or in perioperative periods. care (36). Nevertheless, patients must understand the magnitude The second FDA-approved de- and significance of these residual vice is the responsive neuro- risks when considering elective stimulation system for epilepsy, surgery. which consists of a stimulator sur- gically implanted in the skull, To evaluate surgical complication rates over with leads extending from the time, Tebo and colleagues performed a litera- generator to the surface of the ture search of articles that included at least 2 brain or into the brain paren- patients and discussed complications of intra- cranial epilepsy surgery. They found 61 arti- chyma and placed where sei- cles, which included a total of 5623 patients, zures are believed to originate. and divided them into those published be- After a period of recording and tween 1980 and 1995 and those published identifying seizure patterns, the between 1996 and 2012. In a comparison of device can be programmed to patients who had temporal lobectomies dur- respond to seizures directly, ing these time frames, the occurrence of neu- sending electrical impulses into rologic deficits decreased from 41.8% to 5.2%, the seizure focus or foci to abort persistent neurologic deficits decreased from seizure propagation (35). 9.7% to 0.8%, and wound infections and/or meningitis decreased from 2.5% to 1.1%. Sim- What is the role of surgery? ilar findings were seen in patients who under- For patients in whom adequate went extratemporal or multilobar resections quantities of 2 or more anticon- (36). vulsants have failed or who have 35. Morrell MJ; RNS System Many patients have a transient in Epilepsy Study Group. intolerable adverse effects, Responsive cortical stim- period of psychiatric disturbance ulation for the treatment surgery—the only existing cure for in the postsurgical period; this of medically intractable epilepsy—should be offered. If partial epilepsy. Neurol- risk is higher for patients with a ogy. 2011;77:1295-304. the focal area of the brain from preexisting mood disorder. [PMID: 21917777] which a patient's seizures origi- 36. Tebo CC, Evins AI, Chris- Proper screening and postopera- tos PJ, Kwon J, Schwartz nate can be identified, removal TH. Evolution of cranial tive monitoring can help to mini- epilepsy surgery compli- of this area would, in theory, pre- cation rates: a 32-year mize the consequences. systematic review and vent the onset of seizures. How- meta-analysis. J Neuro- ever, the evaluation process is Current recommendations state surg. 2014;120:1415- 27. [PMID: 24559222] complex and requires not only that anticonvulsants may be re- 37. Engel J Jr, Wiebe S, electrographic identification of French J, Sperling M, duced or withdrawn in patients Williamson P, Spencer D, the seizure source but also ascer- who become seizure-free after et al; Quality Standards Subcommittee of the tainment of the potential deficits surgery, but the risk for subse- American Academy of that could occur if the focal re- quent relapse is higher in those Neurology. Practice pa- rameter: temporal lobe gion of the brain were resected. for whom all anticonvulsant ther- and localized neocortical resections for epilepsy: At this point, referral to an epi- apy is stopped. Approximately report of the Quality lepsy center is indicated because two thirds of patients with spe- Standards Subcommittee of the American Acad- the evaluation process for surgi- cific types of resections, such as emy of Neurology, in cal consideration is best per- anterior temporal lobectomies, association with the American Epilepsy Soci- formed in the center where sur- may become free of all but sim- ety and the American Association of Neurologi- gery may be done. ple partial seizures (37). cal Surgeons. Neurology. 2003;60:538-47. [PMID: Several risks are associated with Several minimally invasive surgi- 12601090] 38. Quigg M, Harden C. intracranial surgery for the treat- cal techniques are being investi- Minimally invasive tech- niques for epilepsy sur- ment of epilepsy. These can in- gated, including stereotactic ra- gery: stereotactic radio- clude wound infections and diosurgery, laser-induced surgery and other technologies. J Neuro- meningitis, hemorrhagic compli- thermal ablation and thermoco- surg. 2014;121 Suppl: cations, and persistent neuro- agulation, and ultrasound abla- 232-40. [PMID: 25434958] logic deficits. These complica- tion (38). Preliminary results

஽ 2016 American College of Physicians ITC26 In the Clinic Annals of Internal Medicine 2 February 2016

Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 seem promising in terms of pre- events. In women with a 3-fold or venting some complications of greater increase in seizures open-brain surgery, but the around the time of menses, allo- larger volume of epileptogenic pregnanolone (a reduced- tissue capable of propagating progesterone metabolite) was seizures may make the more fo- shown to reduce seizure fre- cused approach less effective quency (39). This approach to overall. treatment requires extensive re- Is there a role for hormonal cordkeeping to identify a cata- treatment of epilepsy? menial pattern of events along Another treatment method for with serial blood work to identify women who have hormonally hormonal changes, but it can sensitive seizures is exogenously provide improvement in seizure administered hormonal treat- control in a subset of women with ment to mitigate the hormonal epilepsy without additional anti- oscillations that can trigger convulsant therapy.

Treatment... Many anticonvulsants are available for initial treatment of seizures. Should 2 or more fail in a patient, referral to a neurologist or epilepsy center is warranted to consider further treatment options, such as implantable devices; resective or minimally invasive surgery; or, for women with catamenial epilepsy, hormonal manipulation.

CLINICAL BOTTOM LINE

Further Considerations What additional measures Injuries can be caused directly by should be taken to prevent seizures or indirectly through morbidity and mortality from confused behavior in the postic- seizures? tal state. Patients should be coun- In addition to the obvious need seled to avoid situations that can for treatment to prevent further result in injury both at the time of seizures, several ancillary difficul- initial diagnosis and at annual visits for reinforcement. For ex- ties affect people with epilepsy ample, suggesting that patients and require comprehensive and use elevators instead of escala- coordinated care between all tors or use crosswalks when pos- members of a patient's treatment sible instead of jaywalking can team. The first such matter in- diminish the risk for injury should volves patient safety (see the a patient have a seizure in these Box: Safety and General Health situations. Use of harnesses and Counseling for Patients With Epi- rigging while rock climbing or lepsy). People with epilepsy have hiking in mountainous terrain 39. Herzog AG, Frye CA; a standardized mortality rate that Progesterone Trial Study should be recommended if Group. Allopregnanolone is up to 10 times higher than that levels and seizure fre- avoidance of these activities is of age-matched controls, with quency in progesterone- not possible. treated women with 40% of the deaths related to such epilepsy. Neurology. 2014;83:345-8. [PMID: factors as accidents during sei- Urging patients to confine swim- 24944264] 40. Te´llez-Zenteno JF, Ron- zures (for example, drowning, ming to locations where a life- quillo LH, Wiebe S. Sud- trauma, choking, or burns), sui- guard is on duty at poolside or den unexpected death in epilepsy: evidence-based cide, status epilepticus, and sud- beachside can improve the analysis of incidence and den unexpected death in epi- chances of rescue should a pa- risk factors. Epilepsy Res. 2005;65:101-15. [PMID: lepsy (SUDEP) (40). tient have a seizure in the water. 16005188]

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Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 For open-water swimming or raft- or elderly adults may be at risk. Safety and General Health ing, use of a life jacket can keep a Even so, for patients who are no Counseling for Patients With patient's head above water if he longer legally able to drive due Epilepsy or she loses awareness. Patients to recent seizures, physicians Identify/avoid seizure triggers: should be counseled to avoid should properly document Sleep deprivation, missed swimming or engaging in water medications, alcohol, whether they counseled the pa- menstrual period sports alone. tient on the driving restriction Injury prevention: Use of safety/ and how long it will be in place. Water safety in the home should protective equipment for For patients who lose their li- also be discussed. Patients who sports (life vests for water censes, state-specific require- sports, helmets for biking, have seizures and lose con- ments for license reinstatement skating, skiing) sciousness in the shower or bath- are in place. For the practitioner, General health: Calcium/vitamin tub can drown in as little as 2 it is important to stay abreast of D supplementation, inches of water. Use of a water encourage daily walking for the ever-changing driving restric- intake cutoff device, available at weight-bearing exercise, folic tions, particularly as they pertain hardware stores, can help pre- acid supplementation for to reporting to government women, contraception, vent accumulation of water if a agencies. If available, referral to family planning patient has a seizure in a bathtub, social service agencies that may Home safety: Turn down water and adjusting the water tempera- be able to assist with transporta- temperature, purchase/ ture on the hot water reservoir install overflow valves, pad tion can increase the likelihood could prevent burns. hard surfaces; avoid that patients with recent seizures stairs/escalators, use crosswalks and cross with Additional safety measures to be will adhere to the driving lights, keep identification at discussed include use of helmets restrictions. all times while biking or skiing. If patients Consider prescription for rescue have young children in the home, Stress has been identified as a medication (lorazepam, counseling on parenting safety risk factor for seizures in many diazepam) for use during (such as proper securing of guns patients with epilepsy. Use of illness or other high-risk stress modification techniques, period and doors) should be offered. Proper storage and monitored such as yoga, meditation, or reg- administration of seizure medica- ular exercise, can be helpful, and tion should also be discussed, referral for counseling should especially for young children and also be considered. adolescents because they may Many general medical consider- inadvertently or purposely take ations should be discussed with incorrect quantities of anticonvul- patients with newly diagnosed sant therapy (41). epilepsy. Because some anticon- Researchers in the United Kingdom reviewed a vulsants have been shown to in- database of primary care records to identify co- terfere with proper bone metab- horts of persons aged 1 to 24 years with and olism, recommendations for without epilepsy. Subsequent medical records appropriate calcium and vitamin were reviewed for a median of 2.6 years. Peo- D supplementation should be ple with epilepsy had an 18% increased risk given, along with appropriate for fracture, a 49% increased risk for burns, counseling for weight-bearing and 2.5 times the risk for poisoning from med- exercise. Regular bone densi- ications (41). tometry should be arranged to Medicolegal considerations for monitor for osteopenia or osteo- patients with epilepsy include porosis for these patients, with proper counseling and docu- treatment as indicated. For fe- mentation around driving restric- male patients with childbearing tions, which vary among states. potential, folic acid should be

41. Prasad V, Kendrick D, Most states do not require physi- prescribed and patients should Sayal K, Thomas SL, West cians to report patients who vio- be educated about the need for J. Injury among children and young adults with late the state-specific driving reg- regular use of this vitamin sup- epilepsy. Pediatrics. ulations; the exception is under plement throughout the child- 2014;133:827-35. [PMID: 24733872] circumstances in which children bearing years, regardless of

஽ 2016 American College of Physicians ITC28 In the Clinic Annals of Internal Medicine 2 February 2016

Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 whether the patient has an active azepine and oxcarbazepine have 42. Harden CL, Pennell PB, desire to conceive (42). been associated with hyponatre- Koppel BS, Hovinga CA, mia, and and zoni- Gidal B, Meador KJ, For women with epilepsy during et al; American Academy samide have been associated of Neurology. Practice the childbearing years, offering parameter update: man- with renal stones (45). These agement issues for advice and information about the acute and chronic adverse effects women with epilepsy— risks and benefits of using anti- focus on pregnancy (an are rare, but if they occur, practi- evidence-based review): convulsant therapy during preg- vitamin K, folic acid, tioners must recognize that they nancy, including the possible blood levels, and breast- are related to the specific anti- feeding: report of the need for upward adjustment of Quality Standards Sub- convulsant so that appropriate committee and Thera- dosing, is important and should treatment adjustments can be peutics and Technology be done before conception Assessment Subcommit- made. tee of the American to prevent inadvertent self- Academy of Neurology and American Epilepsy discontinuation of medication Are patients with epilepsy Society. Neurology. (43). Avoidance of valproate and stigmatized? 2009;73:142-9. [PMID: 19398680] polypharmacy can reduce the Patients with epilepsy frequently 43. Harden CL, Hopp J, Ting TY, Pennell PB, French risk for major congenital malfor- encounter social and workplace JA, Hauser WA, et al; mations in women with epilepsy discrimination. Patients are more American Academy of Neurology. Practice pa- (44). likely to self-report stigma if they rameter update: man- are single or have poor quality of agement issues for Patients with epilepsy could ben- women with epilepsy— life or decreased health literacy, focus on pregnancy (an efit from regular screening for evidence-based review): mood disorders, not only at the whereas married patients have obstetrical complications better self-reported quality of life and change in seizure onset of therapy but annually as a frequency: report of the (46, 47). This has been seen in Quality Standards Sub- feature of ongoing care. Depres- committee and Thera- sion and anxiety symptoms may many cultures and ethnicities and peutics and Technology may be influenced by beliefs Assessment Subcommit- be ictal phenomena, can be reac- tee of the American about the causes of epilepsy, Academy of Neurology tive to the disorder (particularly and American Epilepsy at times of breakthrough sei- which is believed to be due to Society. Neurology. witchcraft or other supernatural 2009;73:126-32. [PMID: zures), and can be secondary to 19398682] causes in some communities 44. Harden CL, Meador KJ, anticonvulsant use. Treatment Pennell PB, Hauser WA, may involve counseling or may (48, 49). Gronseth GS, French JA, et al; American Academy require intervention with phar- Patients also report stigma re- of Neurology. Practice macotherapy. Because some an- parameter update: man- lated to employment status (50). agement issues for ticonvulsants also affect mood, it Unemployment and underem- women with epilepsy— may be helpful to review ongo- focus on pregnancy (an ployment are common among evidence-based review): ing anticonvulsant choices to see teratogenesis and peri- patients, and early referrals natal outcomes: report of whether they may be causing a should be offered for access to the Quality Standards mood disturbance. Similarly, if Subcommittee and Ther- resources, including job training. apeutics and Technology treatment of a mood disorder Assessment Subcommit- Patients with epilepsy who are seems warranted, use of an anti- tee of the American referred for vocational rehabilita- Academy of Neurology convulsant with mood-stabilizing and American Epilepsy tion services are more likely to Society. Neurology. properties may preclude the 2009;73:133-41. [PMID: find employment than those who need for independent medica- 19398681] are not (51). For patients who 45. Gaitatzis A, Sander JW. tion for the mood disorder itself. The long-term safety of may have a seizure at work, phy- antiepileptic drugs. CNS Drugs. 2013;27:435-55. Many idiosyncratic acute and sicians are commonly asked to [PMID: 23673774] complete paperwork attesting to 46. Bautista RE, Shapovalov chronic toxicities occur with D, Shoraka AR. Factors greater-than-expected frequency the patient's ability to return to associated with increased felt stigma among indi- when particular anticonvulsants work safely. Practitioners need to viduals with epilepsy. are used. For example, valproate be careful in their responses be- Seizure. 2015;30:106- 12. [PMID: 26216694] has been associated with poly- cause employers may misinter- 47. Zou X, Hong Z, Chen J, Zhou D. Is antiepileptic cystic ovarian syndrome, pancre- pret them, causing patients to be drug withdrawal status atitis, and nonalcoholic fatty liver, wrongly fired. If patients recog- related to quality of life in seizure-free adult among other systemic effects. nize that discrimination is occur- patients with epilepsy? Phenytoin has been associated ring, referral to nonprofit agen- Epilepsy Behav. 2014; 31:129-35. [PMID: with pseudolymphoma, carbam- cies designed to help and 24407247]

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Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 support people with disabilities with a family history of sudden can be helpful. death unrelated to epilepsy, re- ferral to a cardiologist for screen- What is SUDEP, and how can it ing for such disorders as long QT be prevented? syndrome or to a sleep specialist 48. Lim YJ, Chan SY, Ko Y. An important topic patients for evaluation of obstructive Stigma and health- related quality of life in should be counseled on is sleep apnea may address comor- Asian adults with epi- SUDEP. This refers to death in a bidities that could increase risk lepsy. Epilepsy Res. 2009;87:107-19. [PMID: patient with known epilepsy that for SUDEP (55, 56). However, 19782536] is “not due to trauma, drowning, 49. Winkler AS, Mayer M, most of the risk factors believed Schnaitmann S, Ombay status epilepticus, or other to be associated with SUDEP are M, Mathias B, Schmut- zhard E, et al. Belief known causes, but for which not modifiable because they systems of epilepsy and there is often evidence of an as- probably represent the presence attitudes toward people living with epilepsy in a sociated seizure” (52). of a more severe form of epi- rural community of northern Tanzania. Epi- lepsy. However, to the extent that lepsy Behav. 2010;19: The incidence of sudden death is poorly controlled epilepsy relates 596-601. [PMID: estimated to be 20 times higher 20965788] to poor adherence to anticonvul- 50. Smith G, Ferguson PL, in patients with epilepsy than in sant use, discussion of this as a Saunders LL, Wagner JL, the general population. In the Wannamaker BB, risk factor may provide patients Selassie AW. Psychoso- United States, approximately cial factors associated with additional impetus to look with stigma in adults 5000 people die of SUDEP each for ways to be more involved in with epilepsy. Epilepsy year (53). Although the precise Behav. 2009;16:484-90. their self-management (57). With [PMID: 19782005] mechanisms are not well- the ready availability of online 51. Sung C, Muller V, Jones understood, there is evidence to JE, Chan F. Vocational resources for health-related infor- rehabilitation service support seizure-related auto- patterns and employ- mation, many patients and fami- ment outcomes of peo- nomic dysfunction, cardiac dys- lies are aware of this condition ple with epilepsy. Epi- rhythmias, and respiratory dys- lepsy Res. 2014;108: and should be given an opportu- 1469-79. [PMID: function (54). Several risk factors nity for discussion and support, 25048309] have been identified, including 52. Devinsky O. Sudden, despite the general reluctance of unexpected death in poorly controlled convulsive sei- epilepsy. N Engl J Med. health care providers to address 2011;365:1801-11. zures, long-term exposure to an- this topic. Referrals for psycho- [PMID: 22070477] ticonvulsant therapy, and need 53. Jehi L, Schuele S. Sud- therapy and counseling should den death in epilepsy: for polypharmacy. For patients also be offered. where is the “heart” of the problem? [Editorial]. Neurology. 2015;85: 208-9. [PMID: 26092913] Further Considerations... Patients with epilepsy are at risk for social 54. Shorvon S, Tomson T. Sudden unexpected isolation, workplace discrimination, and increased morbidity and mor- death in epilepsy. Lancet. tality. Early intervention to identify causal factors and to identify support 2011;378:2028-38. [PMID: 21737136] and resources may diminish the effect of stigma on patients with epi- 55. Massey CA, Sowers LP, lepsy. Proper counseling and identification and treatment of modifiable Dlouhy BJ, Richerson GB. risk factors may help to decrease the occurrence of injury and/or death Mechanisms of sudden unexpected death in in people with epilepsy. epilepsy: the pathway to prevention. Nat Rev Neurol. 2014;10:271- 82. [PMID: 24752120] CLINICAL BOTTOM LINE 56. Lamberts RJ, Blom MT, Wassenaar M, Bardai A, Leijten FS, de Haan GJ, et al. Sudden cardiac arrest in people with epilepsy in the commu- nity: circumstances and risk factors. Neurology. 2015;85:212-8. [PMID: 26092917] 57. Shankar R, Cox D, Jalihal V, Brown S, Hanna J, McLean B. Sudden unex- pected death in epilepsy (SUDEP): development of a safety checklist. Seizure. 2013;22:812-7. [PMID: 23962523] doi:10 .1016/j.seizure.2013.07 .014

஽ 2016 American College of Physicians ITC30 Annals of Internal Medicine 2 February 2016

Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 In the Clinic Patient Information www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm Brochures and fact sheets that can be printed and given to patients and links to other related resources, including Tool Kit some in Spanish. www.cdc.gov/epilepsy/family-and-friends.htm Information for family and friends of people with epilepsy. Epilepsy www.cdc.gov/epilepsy/basics/index.htm http://patient.info/health/epilepsy-a-general -introduction www.aan.com/Guidelines/home/GetGuidelineContent /689 Patient summaries of epilepsy guidelines from the American Academy of Neurology. Clinical Guidelines www.aesnet.org/clinical_resources/guidelines American Epilepsy Society. www.aan.com/Guidelines/home/ByTopic?topicId=23 American Academy of Neurology. www.nice.org.uk/guidance/cg137 National Institute for Health and Care Excellence. In the Clinic

2 February 2016 Annals of Internal Medicine ITC31 ஽ 2016 American College of Physicians

Downloaded From: http://annals.org/ by a University of Arkansas User on 09/02/2017 In the Clinic WHAT YOU SHOULD Annals of Internal Medicine KNOW ABOUT EPILEPSY

What Is Epilepsy? Epilepsy is a brain disorder that causes seizures. Seizures occur when there is abnormal electrical activity in your brain cells. People with epilepsy have had 2 or more seizures in their lifetime. The cause of epilepsy is not always known. Your risk increases if you: • Have a family history of epilepsy • Were born prematurely • Had unexplained fevers as a child • Have had infections, such as meningitis • Have had a head injury What Are the Warning Signs? • Surgery to remove the damaged part of your Seizures are the main symptoms. Signs can differ brain that is causing the seizures depending on the type of seizure. They can in- • Hormone medicines in women if seizures are clude changes in mental status, such as: related to hormone changes • Unexplained fear, sadness, or laughing • Feeling unusual or different from normal Questions for My Doctor • Losing awareness or passing out • What is causing my seizures? • Trouble responding to questions • How can I tell if I will have another seizure? • Feeling confused and disoriented • What are the side effects of the medicines? • Stiffening, jerking, or twitching • Is it safe for me to drive? • Numbness, tingling, or pain • Can I still do the things I enjoy? • Tongue biting • Could my seizures cause long-term damage? • Loss of bladder control • Should I wear a medic alert bracelet? • Are there other lifestyle changes I need to How Is It Diagnosed? make because of my epilepsy? Your doctor will first need to rule out all other pos- sible causes of your seizures. You will be asked Bottom Line about your medical history, your symptoms, and • Epilepsy is a disorder in which too much what happens when you have a seizure. Your electrical activity in the brain causes seizures. doctor will then complete a physical examina- The cause of epilepsy is not always known. tion. Testing may be needed, including: • The symptoms of a seizure vary and can differ • A test that measures brain waves, called an EEG for everyone. Signs can include unexplained • Imaging tests, such as an MRI fear or sadness, loss of awareness, trouble responding to questions, and confusion. How Is It Treated? Physical signs can include jerking and twitching, numbness and tingling, tongue Medicines called anticonvulsants are usually used biting, passing out, or loss of bladder control. to reduce or stop seizures. It is important to take • To diagnose epilepsy, your doctor will ask you these medicines as directed. It is also important questions about your medical history and to avoid seizure “triggers,” such as lack of sleep what happens when you have a seizure. Your and drug or alcohol use. If these treatments do doctor will give you a physical examination not help with your symptoms, your doctor may and may run other tests. refer you to a specialist to explore other options. • Medicines called anticonvulsants are used to These may include: help limit seizures. If these medicines do not • An electrical device implanted in your chest to help, you may be referred to a specialist to help reduce seizures discuss other treatment options. For More Information

MedlinePlus www.nlm.nih.gov/medlineplus/epilepsy.html National Institute of Neurological Disorders and Stroke www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm Patient Information

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Anticonvulsant† Dosing Side Effects Precautions *Carbamazepine Initial dose: 200 mg bid. Hepatic, CV adverse events, Serious hematologic and (Carbatrol, Tegretol, Usual dose: 800–1200 ocular adverse events, dermatologic reactions. Tegretol-XR, Epitol) mg total daily dose, hyponatremia Caution with Asian patients. dosed tid–qid for Consider dose reduction with regular-release or bid hepatic disease. Caution with: for extended-release. cardiac disease, glaucoma, Monitor serum sunlight. Complex drug concentrations interactions Oxcarbazepine (Trileptal) Initially, 300 mg bid. Hyponatremia, visual impairment Caution with severe hepatic (first-line agent) Usual dose 1200 mg disease. If CrCl<30, decrease bid dose by half. Inhibitor of CYP2C19, inducer of CYP3A4 Topiramate (Topamax) Initially, 25 mg bid. Usual Weight loss, metabolic acidosis, Caution with: hepatic disease, dose 200 mg bid oligohidrosis ocular disease. If CrCl<70, decrease dose by half. CYP3A4 inducer and CYP2C19 inhibitor. Caution with CYP3A4 inducer *Lamotrigine (first-line Immediate-release: Start Weight loss, abdominal pain, Serious dermatologic reactions. agent) (Lamictal, at 50 mg qd. Usual diarrhea, blurred vision, Decrease dose by 25%–50% Lamictal XR, Lamictal dose 250 mg bid. dysmenorrhea, hyponatremia, with moderate-severe hepatic ODT) Extended-release: Start aseptic meningitis disease and by >50% with at 50 mg qd. Usual concomitant valproic acid. dose 250–500 mg qd. Consider decreased dose with Dose varies with CKD. Caution with cardiac concomitant disease. Clearance is lower in anticonvulsants nonwhites *Valproic acid (first-line Initially, 10–15 mg/kg Alopecia, elevated blood Hepatotoxicity, teratogenicity, agent) (Stavzor, total daily dose, dosed ammonia, thrombocytopenia, pancreatitis. Avoid with: Depakene) bid–tid (bid for menstrual disturbances hepatic disease, pregnancy. *Divalproex sodium delayed-release, qd for Caution with CKD. Monitor (Depakote, Depakote Depakote ER). Usual platelet counts and ER) dose is below 60 coagulation. Metabolized via mg/kg daily CYPs 2C19 and 2C9. Inhibits CYP2C9 Gabapentin (Neurontin) Immediate-release: Peripheral edema, weight gain, Decrease dose if CrCl<60. Does Initially, 300 mg tid. diplopia, blurred vision, not interact with other Usual dose 300–800 anticonvulsants mg tid (Keppra, IV or PO Immediate- Infection, anorexia behavioral Decrease dose if CrCl<80. Few Keppra XR) release: Initially, 500 symptoms drug interactions, possibly mg bid. Usual dose carbamazepine 1500mgbid. Extended-release: 1000 mg qd, up to 3000mgqd Pregabalin (Lyrica) Initially, 150 mg total Peripheral neuropathy, amnesia, Decrease dose if CrCl<60. Few daily dose, dosed xerostomia, myoclonus, drug interactions. Caution with bid–tid. Maximum 600 peripheral edema, weight HF mg total daily dose, gain, angioedema, diplopia, dosed bid–tid thrombocytopenia, dependence, creatine kinase elevation Tiagabine (Gabitril) Initially, 4 mg qd. Usual Diarrhea, pharyngitis, serious Caution with hepatic disease. 32–56 mg total daily rash Substrate of CYP3A4 dose, dosed bid–qid Zonisamide (Zonegran) Initially, 100 mg qd. Severe rash, metabolic acidosis, Avoid with sulfonamide Usual dose 100–400 azotemia, diplopia, dysgeusia, hypersensitivity. Caution with: mg qd psychosis, weight loss hepatic disease, CKD. Metabolized by CYP3A4

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஽ 2016 American College of Physicians Annals of Internal Medicine 2 February 2016

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Anticonvulsant† Dosing Side Effects Precautions Lacosamide (Vimpat) PO or IV: Initially, 50 mg Diplopia, blurred vision, AV Avoid with severe hepatic bid. Usual dose block, PR prolongation, DRESS, disease. Maximum dose 150 100–200 mg bid dependence mg bid with: mild–moderate hepatic disease, CKD. Substrate and inhibitor of CYP2C19 (first-line Initially, 250 mg bid. Weight loss, elevated hepatic Caution with: hepatic disease, agent) (Zarontin) Usual dose 20–40 enzymes, Stevens-Johnson CKD. Monitor: LFTs, CBC. mg/kg total daily dose, syndrome, hematologic Substrate for CYP3A4 dosed bid. Maximum reactions, nephrotic syndrome total daily dose 1.5 g *Felbamate (Felbatol) Initially, 1200 mg total Dermatologic reactions Serious hematologic reactions, daily dose, dosed hepatotoxicity. Avoid with tid–qid. Usual total hepatic disease. Decrease daily dose 2400 mg. dose by half with CKD. Maximum total daily Inhibitor of CYP2C19, inducer dose 3600 mg of CYP3A4 Rufinamide (Banzel) 200–400 mg bid. Usual Shortened QT interval, status Avoid with severe hepatic dose 1600 mg bid epilepticus, diplopia, blurred disease. Consider decreased vision, anemia, leukopenia dose with mild–moderate hepatic disease. Weak inducer of CYP3A4, weak inhibitor of CYP2E1 *Phenytoin (Dilantin, IV or PO immediate- Gingival hyperplasia, peripheral CV risk with rapid infusion. Avoid Phenytek) release: 4–7 mg/kg neuropathy, hirsutism, with pregnancy. Caution with: total daily dose, given hematologic reactions, serious hepatic disease, CrCl<10, in divided doses. dermatologic reactions, severe diabetes, thyroid disease, Administer hypersensitivity reactions, arrhythmias. Inducer of CYPs sustained-release qd. lymphadenopathy, CV adverse 3A4, 2C9, 2C19. Substrate of Monitor serum levels events, blurred vision, CYPs 2C9, 2C19. Highly decreased bone mineral protein bound density with long-term use Phenobarbital IV or PO: 1–3 mg/kg total Long-term use: megaloblastic Avoid with: pregnancy, severe daily dose, dosed anemia, osteopenia, hepatic disease, acute pain. qd–bid. For status osteomalacia, miosis, Caution with: elderly, CKD. If epilepticus: loading dependence IV: respiratory CrCl<10, avoid chronic use. dose 10 mg/kg IV, depression, bronchospasm, Inducer of CYPs 2C, 3A, 1A2 followed by 5 mg/kg IV hypotension in 30–60 min. Maximum loading dose 25–30 mg/kg

AV = atrioventricular; bid = twice daily; CBC = complete blood count; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P450 isoenzyme; DRESS = Drug Reaction with Eosinophilia and Systemic Symptoms; GI = gastrointestinal; HF = heart failure; IM = intramuscular; IV = intravenous; LFT = liver function test; PO = oral; q12hr = every 12 hours; qd = once daily; qid = 4 times daily; SC = subcutaneous; SCr = serum creatinine; tid = three times daily. * = Black box warning. † All anticonvulsants have CNS side effects (drowsiness, dizziness, headache, insomnia, anxiety, asthenia, tremor, others), hyper- sensitivity reactions, nausea, vomiting, depression. Avoid abrupt discontinuation. Caution with: elderly, pregnancy. Monitor for depression. Complex drug interactions between anticonvulsants.

2 February 2016 Annals of Internal Medicine ஽ 2016 American College of Physicians

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