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An Emergency Medicine–Focused Review of Seizure Mimics
The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–9, 2016 Published by Elsevier Inc. 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2016.11.002
Clinical Review AN EMERGENCY MEDICINE–FOCUSED REVIEW OF SEIZURE MIMICS James Webb, MD,* Brit Long, MD,† and Alex Koyfman, MD‡ *Department of Internal Medicine, San Antonio Military Medical Center, Fort Sam Houston, Texas, †Department of Emergency Medicine, San Antonio Military Medical Center, Fort Sam Houston, Texas, and ‡Department of Emergency Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas Reprint Address: Brit Long, MD, 3841 Roger Brooke Dr., Fort Sam Houston, TX 78234
, Abstract—Background: Seizures result in a change in motor, sensory, and behavioral symptoms caused by abnormal neurologic electrical activity. The symptoms share similar presentations of several other conditions, leading to difficulties in diagnosis and frequent improper management. Objective: This review evaluates adult patients with suspected seizure, signs and symptoms of seizure, mimics of seizure, and an approach to management of seizure mimics. Discussion: A seizure is caused by abnormal neurologic electrical activity resulting in altered motor, sensory, and behavioral symptoms. Other conditions may present similarly, causing a challenge in diagnosis. These conditions include syncope, psychogenic nonepileptic seizures, stroke or transient ischemic attack, sleep disorders, movement disorders, and migraines. Diagnosis of seizures in the emergency department (ED) is often clinical. Differentiation between seizures and other conditions can be difficult. Laboratories and imaging provide little benefit in definitive diagnosis in the emergency setting. For patients that have an apparent seizure, resuscitation and management is precedent while identifying any provoking factors and treatment of those factors. For adults recovering from suspected seizure, the combination of a focused history, physical examination, and additional studies can provide assistance in diagnosis. Conclusions: Patients with an apparent seizure should be resuscitated with identification of provoking factors. Many conditions can mimic seizures. A focused history, physical examination, and additional studies will assist in differentiating seizures from mimics. Published by Elsevier Inc.
INTRODUCTION Epilepsy affects approximately 2 million people in the United States (US), and approximately 150,000 US adults present every year with an unprovoked first seizure (1,2). Furthermore, 100,000–150,000 patients present in status epilepticus per year, and account for up to 55,000 annual deaths (3). Diagnosis of seizures can prove to be difficult, with social and financial implications to the patient. Identification of patients that would benefit from antiepileptic therapy is imperative (1–5). A seizure is caused by abnormal neurologic electrical activity resulting in altered motor, sensory, autonomic, or behavioral symptoms. A seizure can occur in both hemispheres (generalized) or within one hemisphere (focal), which can spread to the entire brain. Generalized seizures are more common and often have a genetic association. Tonic–clonic generalized seizures are the most frequent type of seizure that presents in an adult, consisting of a tonic phase with muscle stiffening, followed by a clonic phase with rhythmic muscle contractions (6,7). Focal seizures are more often due to an insult to the brain (7). The symptoms of the seizures depend on the location of the abnormal electrical activity in the cerebral cortex. Epilepsy occurs due to a predisposition to generate recurrent unprovoked seizures (6,8). Seizures can occur due to an identifiable insult (provoked seizures), which can be isolated to the brain or due to systemic disorder or illness. An unprovoked
, Keywords—seizure; epilepsy; status epilepticus; seizurelike; mimics; syncope
RECEIVED: 24 October 2016; ACCEPTED: 1 November 2016 1
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seizure occurs in the absence of these factors, and recurrence is seen in approximately half of these patients. Status epilepticus is defined by seizure lasting > 5 min or no return to baseline between seizures (1–3). DISCUSSION What Is the Cause of Seizures? Seizures are classified as provoked or unprovoked. Patients without a history of epilepsy presenting with seizure often have a provoking factor. Provoked seizures occur due to a variety of reasons, including systemic illness, brain trauma, central nervous system (CNS) infection (meningitis, encephalitis, brain abscess), anoxic injury, intracranial hemorrhage or surgery, metabolic disorders, illicit drugs or drug overdose (most commonly tricyclic antidepressants and isoniazid), or alcohol withdrawal, within 7 days of the trigger (9,10). Seizures with metabolic disorders are most commonly due to hypoglycemia or hyponatremia (9,10). These seizures might be dependent on how acutely the metabolic change occurs (11). Seizures associated with alcohol withdrawal, one of the most common causes, occur most often within 7–48 h of the last drink (9,12). Unprovoked seizures are those with no discernible cause or occurring > 7 days from a precipitating factor. Most causes of epilepsy are idiopathic. Those with identifiable etiology include trauma, brain neoplasm, CNS infection, stroke, degenerative or vascular disease, and congenital brain malformations (6,13). Special consideration should be made for pregnant patients with concern for eclampsia, children with febrile seizures, and patients presenting with head trauma. Signs of Seizure Acutely, seizures are often a clinical diagnosis. A clear history can be difficult to obtain from a patient directly, so obtaining information from a witness, if possible, is beneficial. Patients that have convulsions from tonic–clonic seizures, the most common presentation, often have a typical clinical sequence. First, there might
be an aura, such as de´ja` vu, a rising sensation in the abdomen, abnormal taste or smell, or autonomic changes. The ictal period frequently occurs for seconds to minutes (most lasting < 1 min), with a tonic phase with muscle stiffness, followed by a clonic phase with rhythmic movements. The postictal period occurs for minutes to hours with confusion, disorientation, and drowsiness (9,13,14). Incontinence is common, but not specific to convulsive seizures. Tongue biting is suggestive of seizure activity, with a lateral location most common. Table 1 presents findings suggestive of seizure. Of note, urinary incontinence is not helpful for differentiating seizure vs. mimic. Seizures associated with alcohol withdrawal occur with other symptoms of withdrawal, such as tachycardia, tremors, and diaphoresis (9,13,14). Focal seizures depend on the area of the cortex where the electrical activity occurs and can result in a variety of neurologically positive symptoms, such as limb movement, abnormal sensation, or hallucinations. Symptoms usually have an abrupt onset and can spread or march in accordance to progression of activity in the motor cortex. After the seizure occurs, focal neurologic deficits can occur (Todd’s paralysis), which typically resolves within 30 min. Focal seizures can progress into generalized seizures (6,7,14). Patients in status epilepticus have an extended period of seizure activity over 5 min, which is life-threatening. Status epilepticus can occur with generalized or focal seizures (3). Seizures are a clinical diagnosis based on history and examination; however, laboratory data can contribute to diagnosing metabolic disturbance, as well as assessment of damage due to prolonged seizure activity. The most common metabolic abnormalities include hypoglycemia and hyponatremia (10). Lactate has been shown to help differentiate seizures from psychogenic nonepileptic seizures (PNES) and syncope (sensitivity of 88%, specificity 87%) (18). Creatine kinase level elevation demonstrates a specificity ranging from 85% to 100% when differentiating seizure vs. PNES, although sensitivity ranges from 15% to 88% (19). The definitive diagnosis can be made with an abnormal electroencephalogram (EEG) during seizure activity (13).
Table 1. Findings in Seizure Sign/Symptom
Sensitivity, %
Specificity, %
Likelihood Ratio
Tongue biting (15) Urinary incontinence (16)* Observed head turning (17) Observed limb jerking (17) Postictal confusion (17)
33 38 43 69 94
96 57 97 88 69
8.167 (95% CI 2.969–22.461) 0.879 (95% CI 0.705–1.095) 13.481 (p < 0.001) 5.566 (p < 0.001) 3.031 (p < 0.001)
Data demonstrates typical signs often related to seizures in studies comparing seizures vs. syncope with sensitivity, specificity, and likelihood ratio. Urinary incontinence was statistically insignificant. * Statistics based on seizure vs. nonepileptic seizures and syncope.
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Table 2. Seizure Mimics Clinical Condition Syncope (23–30)
Cardiac disorders (23–25,29)
Diagnosis - Sudden loss of consciousness due to decreased cerebral perfusion, resulting in loss of postural tone, with rapid return to baseline. - Etiologies include cardiac, orthostatic, and neurocardiogenic (vasovagal). - More likely than seizure if: complete loss of consciousness, rapid onset and short duration, complete and spontaneous recovery. - Obtain history including identification of precipitating factors, position, and activity prior to event. - Short (seconds) period of convulsion may occur; myoclonic jerking in up to 90% of patients. - Cardiac: history and physical examination consistent with heart disease (see Cardiac Disorders below). - Orthostatic syncope: history suggestive of hypovolemia, bleeding, autonomic dysfunction, or medication-induced. - Neurocardiogenic: history of action causing increased vagal tone - cough, defecation, or carotid sinus hypersensitivity; often in young adults and non-exertional. - 12-lead electrocardiogram (ECG) to evaluate for dysrhythmias. - Orthostatic analysis if suspicious of orthostatic syncope: decrease in Systolic Blood Pressure $ 20 mmHg or Diastolic Blood Pressure $ 10 mmHg within 3 minutes of standing. - May obtain the following laboratory tests based on clinical suspicion: serum glucose level, complete blood count (CBC), serum electrolytes, cardiac biomarkers, and urinalysis. - Cardiac monitoring with echocardiogram and eventual cardiac stress test if evaluating cardiac source as indicated. - Consider referral for tilt-table test for neurocardiogenic source after ruling out life-threatening conditions. - Syncope due to cardiac dysrhythmia or mechanical (structural) disease. - Suggestive history includes: elderly patient, absence of prodrome, chest pain, loss of consciousness during exercise, supine position, and presence of palpitations before loss of consciousness. - Dysrhythmias include: supraventricular tachycardia, ventricular tachycardia, Mobitz type II second-degree or third-degree atrioventricular block, bundle branch blocks, Long QT Syndrome, Brugada Syndrome, WolffParkinson-White Syndrome, Right Ventricular Dysplasia, and pacemaker malfunction. - Mechanical disease includes: hypertrophic cardiomyopathy, aortic stenosis, mitral stenosis, atrial myxoma, aortic dissection, pulmonary embolism and pericardial tamponade. - Cardiac ischemia may also cause loss of consciousness. - Obtain ECG to evaluate for dysrhythmias.
Treatment - Cardiac syncope: see below. - Orthostatic syncope: volume repletion for hypovolemia, discontinue offending medication, avoidance of rapid upright position change, or compressive stockings. - Neurocardiogenic: avoidance of situations that induce syncope.
- Syncope due to cardiac dysrhythmia: antidysrhythmic medication or pacemaker placement. - Mechanical cardiac syncope: beta blocker or calcium channel blocker and referral for consideration of surgical correction.
(Continued )
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Table 2. Continued Clinical Condition
Psychogenic nonepileptic seizures (PNES) (31–35)
Metabolic disorders (9,10,13)
Stroke and transient ischemic attack (14,36,37)
Sleep disorders (38–41)
Diagnosis - Consider echocardiogram for structural disease. - Risk assessment to determine if requiring inpatient monitoring and treatment. - May refer for Holter monitoring or implantable loop recorder for outpatient monitoring. - Most commonly begins in ages 20–30 years. - 70% of patients have a psychiatric history; up to 40% of epilepsy patients have PNES. - Common comorbid illnesses: depression, posttraumatic stress disorder, and personality disorders. - Movements resembling epileptic seizures without abnormal neurologic electrical activity and may be uncontrollable. - Differ from seizure movements/more suggestive of PNES: asynchronous extremity movements, rapid head turning, pelvic thrusting, closed eyes, geotropic eye movements, absence of tongue biting, longer duration (>2 minutes), fluctuating course, memory recall, and crying. - Laboratory tests have limited, if any, benefit. - Consultation with neurologist and psychiatrist for evaluation and management. - Diagnosis with video EEG is gold standard; often not done in the ED. - No EEG changes observed before, during, or after event suggestive of PNES. - Metabolic disorders can result in provoked seizures. - Found in 2.4-8% of patients presenting with first generalized seizure. - Most often hypoglycemia or hyponatremia. - Others include hypernatremia, hyperglycemia, hypercalcemia and uremia. - Diagnosis with serum electrolytes and rapid assessment of glucose level. - Neurologic deficit with resolution due to cerebral ischemia. - Negative symptoms such as numbness, motor weakness, or vision changes, or dysarthria. - Obtain detailed history including risk factors and focused neurologic examination. - Evaluate for other etiologies with blood tests (glucose level, CBC, and serum electrolytes) along with additional tests based on history. - 12-lead ECG to evaluate for dysrhythmia as source. - Neurologic and cerebral vasculature imaging with computed tomography (CT). - Echocardiogram with cardiac monitoring for evaluation of cardiac source if clinically suspicious. - Narcolepsy with cataplexy may present similarly to seizures. - Narcolepsy occurs in about 1 in every 2000 people. It can occur with or without cataplexy. - Narcolepsy: excessive daytime sleepiness, lapses into sleep or multiple naps during the same day at least 3 times per week for 3 months.
Treatment
- Psychiatric evaluation. - If clinically suspicious, based on history and physical, avoid diagnosing patient with epileptic seizures until EEG is accessible. - Avoidance and discontinuation of inappropriate antiepileptic drugs which may worsen symptoms or cause adverse effects. - Psychiatric care: treating underline psychiatric distress.
- Treat the underline metabolic disorder based on laboratories. - Thiamine can be provided with glucose if hypoglycemic.
- Risk stratification and stroke prevention therapy warranted. - Thrombolytics may be warranted with negative head computed tomography and focal neurologic deficit(s) if the patient presents with three hours of symptom onset. - Blood pressure control may assist decreasing risk of future stroke.
- Sleep hygiene and maintaining a regular sleep schedule. - Treatment of additional sleep disorders. - Pharmacologic treatment for narcolepsy include Modafinil for mild-moderate, Methylphenidate, or Dextroamphetamine for severe. - Pharmacologic treatment for cataplexy include low-dose of antidepressants (venlafaxine, clomipramine) and sodium oxybate. (Continued )
Clinical Review of Seizure Mimics
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Table 2. Continued Clinical Condition
Movement disorders (42–45)
Migraine (14,46–48)
Diagnosis
Treatment
- Cataplexy: sudden loss of tone in response to emotion. - Recovery is rapid and complete with no loss of memory. - Related to other REM disorder symptoms of sleep paralysis and hypnagogic hallucinations. - Diagnosis with clinical history along with consulting a specialist for overnight polysomnography and multiple sleep latency test. - Dystonia involves sustained muscle contractions, repetitive twisting motions, or posturing. - Movements are often painful, sustained at its peak but may involve fluctuation at onset, and can involve a single (commonly the neck) or multiple parts of the body. - No alteration in mental status occurs. - May be genetic or secondary to a neurologic disease or medications such as antipsychotics and antiepileptics. - Toxins and ingestions may result in movement disorders, such as tetanus. - Recurrent headaches with or without aura (visual or sensory symptoms). - Symptoms include throbbing headache, nausea, vomiting, and sensitivity to light and sound. - Auras often involve positive visual symptoms including flashing lights or colors. - Diagnosis is based on history with at least two of the following symptoms: unilateral pain, throbbing pain, moderate-severe pain, and aggravated by physical activity; along with at least one symptom: nausea/vomiting or photo-/phonophobia. - Some migraines may have neurologic symptoms causing weakness or loss of consciousness. - Migraine with aura similar to certain focal seizures with visual symptoms (hallucinations) or seizure prodrome (aura).
- Treatment with medications is only warranted for primary care physicians.
- Stop offending medication. - Dystonia: treat with diphenhydramine or benztropine acutely. - Toxins or ingestions require treatment dependent on specific agent. - Referral to a movement disorder specialist for rehabilitation or pharmacological intervention.
- Avoidance of provoking factors. - Abortive medications include: selective serotonin receptor agonists, nonsteroidal anti-inflammatory drugs, antidopaminergic medications, steroids. - Consider prophylactic medications in association with primary care physician: tricyclic antidepressants, beta-blockers, antiepileptics.
EEG = electroencephalogram; REM = rapid eye movement; ED = emergency department.
Chameleon: Nonconvulsive Status Epilepticus Nonconvulsive status epilepticus (NCSE) is defined by persistent change (over 30 min) in behavior and mental processes from baseline without motor signs of seizure. Two main forms exist—absences and complex partial. NCSE occurs in up to 50% of patients with coma or convulsive status epilepticus (20,21). Those at risk include patients in coma, patients presenting with seizure, history of brain injury or epilepsy, and recent neurosurgical procedure (20,21). In the patient with status epilepticus without return to baseline with treatment or the patient who neurologically declines, NCSE should be considered. Positive symptoms include eye deviation, rhythmic eye jerking, and rhythmic twitching on muscle groups, while negative symptoms
include aphasia, mutism, amnesia, catatonia, and decreased responsiveness. Diagnosis requires EEG. Approximately 75% of patients will display decreased responsiveness only, and this condition is associated with a mortality rate of 50% (20,21). Seizure Mimics The diagnosis of seizure activity is difficult due to seizure mimics. Diagnosis is essentially clinical, and the motor, sensory, and behavioral changes that occur in other diseases, along with frequent change in the patient’s consciousness and inability to recall the event, creates difficulty in differentiating seizure and mimic (22). Approximately 20% of epileptic patients are misdiagnosed (22). The most common misdiagnoses are
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syncope and psychogenic nonepileptic seizures (5). The misdiagnosis can result in unnecessary, and usually unsuccessful, treatment with antiepileptic drugs. Inappropriate treatment can result in medication side effects, as well as affect patient employment and driving status (5). The mimics of seizures, which may present with similar symptoms and clinical history, can result in misdiagnosis. These conditions are described in Table 2, with diagnostic and treatment pearls. Emergency Medicine Approach Due to the risks associated with status epilepticus, patients who are concerning for currently having or presenting after a seizure should be assessed quickly. If a patient is currently seizing or in status epilepticus, rapid resuscitation is required. With high suspicion for continued seizure activity, aggressive treatment is required before consideration of seizure mimics. A definitive airway may be required with endotracheal intubation if the patient is unable to protect the airway, followed by assessment of breathing and circulatory status. Intravenous access should be obtained for treatment and diagnostic studies. If i.v. access is unobtainable, interosseous access is advised. Diagnostic laboratory studies that should be obtained include glucose level, electrolytes with calcium, serum lactate, pregnancy test for females, anticonvulsant level, and electrocardiogram (ECG). A focused neurologic examination, including mental status, motor, sensory, cranial nerves, reflexes, and cerebellar function, should be completed if possible. For an actively seizing patient, treatment includes benzodiazepines as first-line with at least two doses (such as lorazepam 0.1 mg/kg i.v. two doses), followed by second-line agents, such as phenytoin, fosphenytoin, levetiracetam, and valproic acid. Intubation with propofol or ketamine may be required for definitive seizure control (3,49–52). If the patient presents after resolution of a suspected seizure and return to baseline, i.v. access should be obtained for diagnostic studies. These include serum glucose level, serum electrolytes, calcium, pregnancy test if the patient is female (for concern for eclampsia), and additional blood tests if clinically indicated. If patient has a history of seizures, obtain an anticonvulsant drug level. An ECG is imperative to evaluate for dysrhythmia. Any metabolic derangement should be corrected (10,49,50,52). A focused history and physical examination should be completed in the hemodynamically stable patient who is not seizing with absence of neurologic deficit, with the consideration of seizure mimics. Important medical history factors to elicit include a history of trauma, stroke, brain surgery, cancer, infection, metabolic disorders,
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toxic ingestion, alcohol abuse, travel, and current pregnancy. If the patient has a history of seizures and is on antiepileptic therapy, consider causes that would lower the seizure threshold. If this is not the first generalized seizure, consider reasons for reoccurrence: compliance with antiepileptic medication, alcohol withdrawal, drug-use, systemic illness, or infection. Patients should be evaluated for tongue biting and any injury that could have occurred during a major fall. An ECG should be performed rapidly to evaluate for a cardiogenic source of collapse. Based on the history and physical, if a seizure mimic is suspected, proper diagnosis and treatment should be applied (2,4,13,49–53). Alcohol is a precipitating factor in one-third of seizures. The patient actively withdrawing requires treatment with i.v. benzodiazepines. Rapid assessment of blood glucose levels is required. If a patient is determined to be hypoglycemic, glucose and thiamine supplementation is warranted with evaluation for the cause of hypoglycemia (12,13,50,52). Neuroimaging is often completed in patients with concern for seizure. Approximately 6%–10% of head computed tomography (CT) scans are abnormal, despite the patient displaying no focal neurologic deficits on examination (13). CT is the most feasible test in the emergency department (ED). Magnetic resonance imaging (MRI) is preferable with a higher yield of determining abnormalities in the nonemergent setting, although this is often not warranted in the ED. First, determine whether an urgent CT is required. Indications include new focal deficits, head trauma, continued altered mental status, immunocompromised state, history of cancer, persistent fever, new focal seizures, history of stroke, or anticoagulation. Neuroimaging is recommended for all new-onset seizures, but this may be done as an outpatient for those with first time generalized tonic–clonic seizures without comorbidities and normal neurologic examination (13,50–54). Additional testing in the ED should be considered. A lumbar puncture should be done on patients who are immunocompromised or with suspicion for meningitis (50,54). EEG is not routinely available, but should be part of the definitive diagnosis as an outpatient. EEG should be considered if the patient is paralyzed, intubated, or in status epilepticus in the intensive care unit. Otherwise, EEG is not necessary in the ED (13). Admission for seizures or mimics may be required in several settings, including status epilepticus, cardiogenic syncope, persistent neurologic deficit, altered mental status, and poor social situation. The need for antiepileptic upon discharge for first-time seizures is based on laboratory testing, neuroimaging, and EEG, which are unlikely to be completed in the ED. Patients
Clinical Review of Seizure Mimics
with return to baseline, normal neurologic examination, normal laboratory results and imaging, and ability to follow-up as an outpatient can be discharged with outpatient follow-up, whether true seizure or mimic. If the patient has no comorbidities or structural brain disease, no antiepileptic medication is required upon discharge (13,54). CONCLUSIONS Seizures are caused by abnormal neurologic electrical activity resulting in altered motor, sensory, and behavioral symptoms. Resuscitation is the most important part of management in unstable patients or patients in status epilepticus. Obtaining i.v. access, airway management, and abortive seizure treatment should be done rapidly. Assessment and management of provoking factors of a seizure should be completed. For patients presenting after return to baseline, history and physical examination are important to differentiate between seizure and mimic. If a seizure is not suspected, syncope, psychogenic nonepileptic seizures, stroke or transient ischemic attack, sleep disorders, movement disorders, and migraines can be considered.
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ARTICLE SUMMARY 1. Why is this topic important? Seizures can frequently be misdiagnosed, leading to improper management. However, identifying seizure activity is important to detect an underline provoking factor, prevent reoccurrence, and avoid status epilepticus. 2. What does this review attempt to show? The review evaluates an adult patient with a suspected seizure, signs and symptoms of seizures, mimics of seizures, and an approach to management of seizure and seizure mimics. 3. What are the key findings? Seizures present with an alteration in motor, sensory, and behavioral changes. Other conditions may present similarly, causing a difficulty in differentiation. These conditions include syncope, psychogenic nonepileptic seizures, transient ischemic attack, sleep disorders, movement disorders, and migraines. All of these have different management and treatment requirements. A thorough history, physical examination, and proper additional studies will assist in differentiating seizures and mimics. For patients in status epilepticus and unstable patients, proper resuscitation and treatment is precedent while identifying any provoking factors and proper treatment of those factors. 4. How is patient care impacted? This review provides an evaluation of seizures and seizure mimics, signs and symptoms of seizures, and an approach to management of seizures and seizure mimics. Resuscitation of the actively seizing patient and consideration of mimics can improve patient care.
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http://dx.doi.org/10.1016/j.jemermed.2016.11.002
Clinical Review AN EMERGENCY MEDICINE–FOCUSED REVIEW OF SEIZURE MIMICS James Webb, MD,* Brit Long, MD,† and Alex Koyfman, MD‡ *Department of Internal Medicine, San Antonio Military Medical Center, Fort Sam Houston, Texas, †Department of Emergency Medicine, San Antonio Military Medical Center, Fort Sam Houston, Texas, and ‡Department of Emergency Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas Reprint Address: Brit Long, MD, 3841 Roger Brooke Dr., Fort Sam Houston, TX 78234
, Abstract—Background: Seizures result in a change in motor, sensory, and behavioral symptoms caused by abnormal neurologic electrical activity. The symptoms share similar presentations of several other conditions, leading to difficulties in diagnosis and frequent improper management. Objective: This review evaluates adult patients with suspected seizure, signs and symptoms of seizure, mimics of seizure, and an approach to management of seizure mimics. Discussion: A seizure is caused by abnormal neurologic electrical activity resulting in altered motor, sensory, and behavioral symptoms. Other conditions may present similarly, causing a challenge in diagnosis. These conditions include syncope, psychogenic nonepileptic seizures, stroke or transient ischemic attack, sleep disorders, movement disorders, and migraines. Diagnosis of seizures in the emergency department (ED) is often clinical. Differentiation between seizures and other conditions can be difficult. Laboratories and imaging provide little benefit in definitive diagnosis in the emergency setting. For patients that have an apparent seizure, resuscitation and management is precedent while identifying any provoking factors and treatment of those factors. For adults recovering from suspected seizure, the combination of a focused history, physical examination, and additional studies can provide assistance in diagnosis. Conclusions: Patients with an apparent seizure should be resuscitated with identification of provoking factors. Many conditions can mimic seizures. A focused history, physical examination, and additional studies will assist in differentiating seizures from mimics. Published by Elsevier Inc.
INTRODUCTION Epilepsy affects approximately 2 million people in the United States (US), and approximately 150,000 US adults present every year with an unprovoked first seizure (1,2). Furthermore, 100,000–150,000 patients present in status epilepticus per year, and account for up to 55,000 annual deaths (3). Diagnosis of seizures can prove to be difficult, with social and financial implications to the patient. Identification of patients that would benefit from antiepileptic therapy is imperative (1–5). A seizure is caused by abnormal neurologic electrical activity resulting in altered motor, sensory, autonomic, or behavioral symptoms. A seizure can occur in both hemispheres (generalized) or within one hemisphere (focal), which can spread to the entire brain. Generalized seizures are more common and often have a genetic association. Tonic–clonic generalized seizures are the most frequent type of seizure that presents in an adult, consisting of a tonic phase with muscle stiffening, followed by a clonic phase with rhythmic muscle contractions (6,7). Focal seizures are more often due to an insult to the brain (7). The symptoms of the seizures depend on the location of the abnormal electrical activity in the cerebral cortex. Epilepsy occurs due to a predisposition to generate recurrent unprovoked seizures (6,8). Seizures can occur due to an identifiable insult (provoked seizures), which can be isolated to the brain or due to systemic disorder or illness. An unprovoked
, Keywords—seizure; epilepsy; status epilepticus; seizurelike; mimics; syncope
RECEIVED: 24 October 2016; ACCEPTED: 1 November 2016 1
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seizure occurs in the absence of these factors, and recurrence is seen in approximately half of these patients. Status epilepticus is defined by seizure lasting > 5 min or no return to baseline between seizures (1–3). DISCUSSION What Is the Cause of Seizures? Seizures are classified as provoked or unprovoked. Patients without a history of epilepsy presenting with seizure often have a provoking factor. Provoked seizures occur due to a variety of reasons, including systemic illness, brain trauma, central nervous system (CNS) infection (meningitis, encephalitis, brain abscess), anoxic injury, intracranial hemorrhage or surgery, metabolic disorders, illicit drugs or drug overdose (most commonly tricyclic antidepressants and isoniazid), or alcohol withdrawal, within 7 days of the trigger (9,10). Seizures with metabolic disorders are most commonly due to hypoglycemia or hyponatremia (9,10). These seizures might be dependent on how acutely the metabolic change occurs (11). Seizures associated with alcohol withdrawal, one of the most common causes, occur most often within 7–48 h of the last drink (9,12). Unprovoked seizures are those with no discernible cause or occurring > 7 days from a precipitating factor. Most causes of epilepsy are idiopathic. Those with identifiable etiology include trauma, brain neoplasm, CNS infection, stroke, degenerative or vascular disease, and congenital brain malformations (6,13). Special consideration should be made for pregnant patients with concern for eclampsia, children with febrile seizures, and patients presenting with head trauma. Signs of Seizure Acutely, seizures are often a clinical diagnosis. A clear history can be difficult to obtain from a patient directly, so obtaining information from a witness, if possible, is beneficial. Patients that have convulsions from tonic–clonic seizures, the most common presentation, often have a typical clinical sequence. First, there might
be an aura, such as de´ja` vu, a rising sensation in the abdomen, abnormal taste or smell, or autonomic changes. The ictal period frequently occurs for seconds to minutes (most lasting < 1 min), with a tonic phase with muscle stiffness, followed by a clonic phase with rhythmic movements. The postictal period occurs for minutes to hours with confusion, disorientation, and drowsiness (9,13,14). Incontinence is common, but not specific to convulsive seizures. Tongue biting is suggestive of seizure activity, with a lateral location most common. Table 1 presents findings suggestive of seizure. Of note, urinary incontinence is not helpful for differentiating seizure vs. mimic. Seizures associated with alcohol withdrawal occur with other symptoms of withdrawal, such as tachycardia, tremors, and diaphoresis (9,13,14). Focal seizures depend on the area of the cortex where the electrical activity occurs and can result in a variety of neurologically positive symptoms, such as limb movement, abnormal sensation, or hallucinations. Symptoms usually have an abrupt onset and can spread or march in accordance to progression of activity in the motor cortex. After the seizure occurs, focal neurologic deficits can occur (Todd’s paralysis), which typically resolves within 30 min. Focal seizures can progress into generalized seizures (6,7,14). Patients in status epilepticus have an extended period of seizure activity over 5 min, which is life-threatening. Status epilepticus can occur with generalized or focal seizures (3). Seizures are a clinical diagnosis based on history and examination; however, laboratory data can contribute to diagnosing metabolic disturbance, as well as assessment of damage due to prolonged seizure activity. The most common metabolic abnormalities include hypoglycemia and hyponatremia (10). Lactate has been shown to help differentiate seizures from psychogenic nonepileptic seizures (PNES) and syncope (sensitivity of 88%, specificity 87%) (18). Creatine kinase level elevation demonstrates a specificity ranging from 85% to 100% when differentiating seizure vs. PNES, although sensitivity ranges from 15% to 88% (19). The definitive diagnosis can be made with an abnormal electroencephalogram (EEG) during seizure activity (13).
Table 1. Findings in Seizure Sign/Symptom
Sensitivity, %
Specificity, %
Likelihood Ratio
Tongue biting (15) Urinary incontinence (16)* Observed head turning (17) Observed limb jerking (17) Postictal confusion (17)
33 38 43 69 94
96 57 97 88 69
8.167 (95% CI 2.969–22.461) 0.879 (95% CI 0.705–1.095) 13.481 (p < 0.001) 5.566 (p < 0.001) 3.031 (p < 0.001)
Data demonstrates typical signs often related to seizures in studies comparing seizures vs. syncope with sensitivity, specificity, and likelihood ratio. Urinary incontinence was statistically insignificant. * Statistics based on seizure vs. nonepileptic seizures and syncope.
Clinical Review of Seizure Mimics
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Table 2. Seizure Mimics Clinical Condition Syncope (23–30)
Cardiac disorders (23–25,29)
Diagnosis - Sudden loss of consciousness due to decreased cerebral perfusion, resulting in loss of postural tone, with rapid return to baseline. - Etiologies include cardiac, orthostatic, and neurocardiogenic (vasovagal). - More likely than seizure if: complete loss of consciousness, rapid onset and short duration, complete and spontaneous recovery. - Obtain history including identification of precipitating factors, position, and activity prior to event. - Short (seconds) period of convulsion may occur; myoclonic jerking in up to 90% of patients. - Cardiac: history and physical examination consistent with heart disease (see Cardiac Disorders below). - Orthostatic syncope: history suggestive of hypovolemia, bleeding, autonomic dysfunction, or medication-induced. - Neurocardiogenic: history of action causing increased vagal tone - cough, defecation, or carotid sinus hypersensitivity; often in young adults and non-exertional. - 12-lead electrocardiogram (ECG) to evaluate for dysrhythmias. - Orthostatic analysis if suspicious of orthostatic syncope: decrease in Systolic Blood Pressure $ 20 mmHg or Diastolic Blood Pressure $ 10 mmHg within 3 minutes of standing. - May obtain the following laboratory tests based on clinical suspicion: serum glucose level, complete blood count (CBC), serum electrolytes, cardiac biomarkers, and urinalysis. - Cardiac monitoring with echocardiogram and eventual cardiac stress test if evaluating cardiac source as indicated. - Consider referral for tilt-table test for neurocardiogenic source after ruling out life-threatening conditions. - Syncope due to cardiac dysrhythmia or mechanical (structural) disease. - Suggestive history includes: elderly patient, absence of prodrome, chest pain, loss of consciousness during exercise, supine position, and presence of palpitations before loss of consciousness. - Dysrhythmias include: supraventricular tachycardia, ventricular tachycardia, Mobitz type II second-degree or third-degree atrioventricular block, bundle branch blocks, Long QT Syndrome, Brugada Syndrome, WolffParkinson-White Syndrome, Right Ventricular Dysplasia, and pacemaker malfunction. - Mechanical disease includes: hypertrophic cardiomyopathy, aortic stenosis, mitral stenosis, atrial myxoma, aortic dissection, pulmonary embolism and pericardial tamponade. - Cardiac ischemia may also cause loss of consciousness. - Obtain ECG to evaluate for dysrhythmias.
Treatment - Cardiac syncope: see below. - Orthostatic syncope: volume repletion for hypovolemia, discontinue offending medication, avoidance of rapid upright position change, or compressive stockings. - Neurocardiogenic: avoidance of situations that induce syncope.
- Syncope due to cardiac dysrhythmia: antidysrhythmic medication or pacemaker placement. - Mechanical cardiac syncope: beta blocker or calcium channel blocker and referral for consideration of surgical correction.
(Continued )
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Table 2. Continued Clinical Condition
Psychogenic nonepileptic seizures (PNES) (31–35)
Metabolic disorders (9,10,13)
Stroke and transient ischemic attack (14,36,37)
Sleep disorders (38–41)
Diagnosis - Consider echocardiogram for structural disease. - Risk assessment to determine if requiring inpatient monitoring and treatment. - May refer for Holter monitoring or implantable loop recorder for outpatient monitoring. - Most commonly begins in ages 20–30 years. - 70% of patients have a psychiatric history; up to 40% of epilepsy patients have PNES. - Common comorbid illnesses: depression, posttraumatic stress disorder, and personality disorders. - Movements resembling epileptic seizures without abnormal neurologic electrical activity and may be uncontrollable. - Differ from seizure movements/more suggestive of PNES: asynchronous extremity movements, rapid head turning, pelvic thrusting, closed eyes, geotropic eye movements, absence of tongue biting, longer duration (>2 minutes), fluctuating course, memory recall, and crying. - Laboratory tests have limited, if any, benefit. - Consultation with neurologist and psychiatrist for evaluation and management. - Diagnosis with video EEG is gold standard; often not done in the ED. - No EEG changes observed before, during, or after event suggestive of PNES. - Metabolic disorders can result in provoked seizures. - Found in 2.4-8% of patients presenting with first generalized seizure. - Most often hypoglycemia or hyponatremia. - Others include hypernatremia, hyperglycemia, hypercalcemia and uremia. - Diagnosis with serum electrolytes and rapid assessment of glucose level. - Neurologic deficit with resolution due to cerebral ischemia. - Negative symptoms such as numbness, motor weakness, or vision changes, or dysarthria. - Obtain detailed history including risk factors and focused neurologic examination. - Evaluate for other etiologies with blood tests (glucose level, CBC, and serum electrolytes) along with additional tests based on history. - 12-lead ECG to evaluate for dysrhythmia as source. - Neurologic and cerebral vasculature imaging with computed tomography (CT). - Echocardiogram with cardiac monitoring for evaluation of cardiac source if clinically suspicious. - Narcolepsy with cataplexy may present similarly to seizures. - Narcolepsy occurs in about 1 in every 2000 people. It can occur with or without cataplexy. - Narcolepsy: excessive daytime sleepiness, lapses into sleep or multiple naps during the same day at least 3 times per week for 3 months.
Treatment
- Psychiatric evaluation. - If clinically suspicious, based on history and physical, avoid diagnosing patient with epileptic seizures until EEG is accessible. - Avoidance and discontinuation of inappropriate antiepileptic drugs which may worsen symptoms or cause adverse effects. - Psychiatric care: treating underline psychiatric distress.
- Treat the underline metabolic disorder based on laboratories. - Thiamine can be provided with glucose if hypoglycemic.
- Risk stratification and stroke prevention therapy warranted. - Thrombolytics may be warranted with negative head computed tomography and focal neurologic deficit(s) if the patient presents with three hours of symptom onset. - Blood pressure control may assist decreasing risk of future stroke.
- Sleep hygiene and maintaining a regular sleep schedule. - Treatment of additional sleep disorders. - Pharmacologic treatment for narcolepsy include Modafinil for mild-moderate, Methylphenidate, or Dextroamphetamine for severe. - Pharmacologic treatment for cataplexy include low-dose of antidepressants (venlafaxine, clomipramine) and sodium oxybate. (Continued )
Clinical Review of Seizure Mimics
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Table 2. Continued Clinical Condition
Movement disorders (42–45)
Migraine (14,46–48)
Diagnosis
Treatment
- Cataplexy: sudden loss of tone in response to emotion. - Recovery is rapid and complete with no loss of memory. - Related to other REM disorder symptoms of sleep paralysis and hypnagogic hallucinations. - Diagnosis with clinical history along with consulting a specialist for overnight polysomnography and multiple sleep latency test. - Dystonia involves sustained muscle contractions, repetitive twisting motions, or posturing. - Movements are often painful, sustained at its peak but may involve fluctuation at onset, and can involve a single (commonly the neck) or multiple parts of the body. - No alteration in mental status occurs. - May be genetic or secondary to a neurologic disease or medications such as antipsychotics and antiepileptics. - Toxins and ingestions may result in movement disorders, such as tetanus. - Recurrent headaches with or without aura (visual or sensory symptoms). - Symptoms include throbbing headache, nausea, vomiting, and sensitivity to light and sound. - Auras often involve positive visual symptoms including flashing lights or colors. - Diagnosis is based on history with at least two of the following symptoms: unilateral pain, throbbing pain, moderate-severe pain, and aggravated by physical activity; along with at least one symptom: nausea/vomiting or photo-/phonophobia. - Some migraines may have neurologic symptoms causing weakness or loss of consciousness. - Migraine with aura similar to certain focal seizures with visual symptoms (hallucinations) or seizure prodrome (aura).
- Treatment with medications is only warranted for primary care physicians.
- Stop offending medication. - Dystonia: treat with diphenhydramine or benztropine acutely. - Toxins or ingestions require treatment dependent on specific agent. - Referral to a movement disorder specialist for rehabilitation or pharmacological intervention.
- Avoidance of provoking factors. - Abortive medications include: selective serotonin receptor agonists, nonsteroidal anti-inflammatory drugs, antidopaminergic medications, steroids. - Consider prophylactic medications in association with primary care physician: tricyclic antidepressants, beta-blockers, antiepileptics.
EEG = electroencephalogram; REM = rapid eye movement; ED = emergency department.
Chameleon: Nonconvulsive Status Epilepticus Nonconvulsive status epilepticus (NCSE) is defined by persistent change (over 30 min) in behavior and mental processes from baseline without motor signs of seizure. Two main forms exist—absences and complex partial. NCSE occurs in up to 50% of patients with coma or convulsive status epilepticus (20,21). Those at risk include patients in coma, patients presenting with seizure, history of brain injury or epilepsy, and recent neurosurgical procedure (20,21). In the patient with status epilepticus without return to baseline with treatment or the patient who neurologically declines, NCSE should be considered. Positive symptoms include eye deviation, rhythmic eye jerking, and rhythmic twitching on muscle groups, while negative symptoms
include aphasia, mutism, amnesia, catatonia, and decreased responsiveness. Diagnosis requires EEG. Approximately 75% of patients will display decreased responsiveness only, and this condition is associated with a mortality rate of 50% (20,21). Seizure Mimics The diagnosis of seizure activity is difficult due to seizure mimics. Diagnosis is essentially clinical, and the motor, sensory, and behavioral changes that occur in other diseases, along with frequent change in the patient’s consciousness and inability to recall the event, creates difficulty in differentiating seizure and mimic (22). Approximately 20% of epileptic patients are misdiagnosed (22). The most common misdiagnoses are
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syncope and psychogenic nonepileptic seizures (5). The misdiagnosis can result in unnecessary, and usually unsuccessful, treatment with antiepileptic drugs. Inappropriate treatment can result in medication side effects, as well as affect patient employment and driving status (5). The mimics of seizures, which may present with similar symptoms and clinical history, can result in misdiagnosis. These conditions are described in Table 2, with diagnostic and treatment pearls. Emergency Medicine Approach Due to the risks associated with status epilepticus, patients who are concerning for currently having or presenting after a seizure should be assessed quickly. If a patient is currently seizing or in status epilepticus, rapid resuscitation is required. With high suspicion for continued seizure activity, aggressive treatment is required before consideration of seizure mimics. A definitive airway may be required with endotracheal intubation if the patient is unable to protect the airway, followed by assessment of breathing and circulatory status. Intravenous access should be obtained for treatment and diagnostic studies. If i.v. access is unobtainable, interosseous access is advised. Diagnostic laboratory studies that should be obtained include glucose level, electrolytes with calcium, serum lactate, pregnancy test for females, anticonvulsant level, and electrocardiogram (ECG). A focused neurologic examination, including mental status, motor, sensory, cranial nerves, reflexes, and cerebellar function, should be completed if possible. For an actively seizing patient, treatment includes benzodiazepines as first-line with at least two doses (such as lorazepam 0.1 mg/kg i.v. two doses), followed by second-line agents, such as phenytoin, fosphenytoin, levetiracetam, and valproic acid. Intubation with propofol or ketamine may be required for definitive seizure control (3,49–52). If the patient presents after resolution of a suspected seizure and return to baseline, i.v. access should be obtained for diagnostic studies. These include serum glucose level, serum electrolytes, calcium, pregnancy test if the patient is female (for concern for eclampsia), and additional blood tests if clinically indicated. If patient has a history of seizures, obtain an anticonvulsant drug level. An ECG is imperative to evaluate for dysrhythmia. Any metabolic derangement should be corrected (10,49,50,52). A focused history and physical examination should be completed in the hemodynamically stable patient who is not seizing with absence of neurologic deficit, with the consideration of seizure mimics. Important medical history factors to elicit include a history of trauma, stroke, brain surgery, cancer, infection, metabolic disorders,
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toxic ingestion, alcohol abuse, travel, and current pregnancy. If the patient has a history of seizures and is on antiepileptic therapy, consider causes that would lower the seizure threshold. If this is not the first generalized seizure, consider reasons for reoccurrence: compliance with antiepileptic medication, alcohol withdrawal, drug-use, systemic illness, or infection. Patients should be evaluated for tongue biting and any injury that could have occurred during a major fall. An ECG should be performed rapidly to evaluate for a cardiogenic source of collapse. Based on the history and physical, if a seizure mimic is suspected, proper diagnosis and treatment should be applied (2,4,13,49–53). Alcohol is a precipitating factor in one-third of seizures. The patient actively withdrawing requires treatment with i.v. benzodiazepines. Rapid assessment of blood glucose levels is required. If a patient is determined to be hypoglycemic, glucose and thiamine supplementation is warranted with evaluation for the cause of hypoglycemia (12,13,50,52). Neuroimaging is often completed in patients with concern for seizure. Approximately 6%–10% of head computed tomography (CT) scans are abnormal, despite the patient displaying no focal neurologic deficits on examination (13). CT is the most feasible test in the emergency department (ED). Magnetic resonance imaging (MRI) is preferable with a higher yield of determining abnormalities in the nonemergent setting, although this is often not warranted in the ED. First, determine whether an urgent CT is required. Indications include new focal deficits, head trauma, continued altered mental status, immunocompromised state, history of cancer, persistent fever, new focal seizures, history of stroke, or anticoagulation. Neuroimaging is recommended for all new-onset seizures, but this may be done as an outpatient for those with first time generalized tonic–clonic seizures without comorbidities and normal neurologic examination (13,50–54). Additional testing in the ED should be considered. A lumbar puncture should be done on patients who are immunocompromised or with suspicion for meningitis (50,54). EEG is not routinely available, but should be part of the definitive diagnosis as an outpatient. EEG should be considered if the patient is paralyzed, intubated, or in status epilepticus in the intensive care unit. Otherwise, EEG is not necessary in the ED (13). Admission for seizures or mimics may be required in several settings, including status epilepticus, cardiogenic syncope, persistent neurologic deficit, altered mental status, and poor social situation. The need for antiepileptic upon discharge for first-time seizures is based on laboratory testing, neuroimaging, and EEG, which are unlikely to be completed in the ED. Patients
Clinical Review of Seizure Mimics
with return to baseline, normal neurologic examination, normal laboratory results and imaging, and ability to follow-up as an outpatient can be discharged with outpatient follow-up, whether true seizure or mimic. If the patient has no comorbidities or structural brain disease, no antiepileptic medication is required upon discharge (13,54). CONCLUSIONS Seizures are caused by abnormal neurologic electrical activity resulting in altered motor, sensory, and behavioral symptoms. Resuscitation is the most important part of management in unstable patients or patients in status epilepticus. Obtaining i.v. access, airway management, and abortive seizure treatment should be done rapidly. Assessment and management of provoking factors of a seizure should be completed. For patients presenting after return to baseline, history and physical examination are important to differentiate between seizure and mimic. If a seizure is not suspected, syncope, psychogenic nonepileptic seizures, stroke or transient ischemic attack, sleep disorders, movement disorders, and migraines can be considered.
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Clinical Review of Seizure Mimics
ARTICLE SUMMARY 1. Why is this topic important? Seizures can frequently be misdiagnosed, leading to improper management. However, identifying seizure activity is important to detect an underline provoking factor, prevent reoccurrence, and avoid status epilepticus. 2. What does this review attempt to show? The review evaluates an adult patient with a suspected seizure, signs and symptoms of seizures, mimics of seizures, and an approach to management of seizure and seizure mimics. 3. What are the key findings? Seizures present with an alteration in motor, sensory, and behavioral changes. Other conditions may present similarly, causing a difficulty in differentiation. These conditions include syncope, psychogenic nonepileptic seizures, transient ischemic attack, sleep disorders, movement disorders, and migraines. All of these have different management and treatment requirements. A thorough history, physical examination, and proper additional studies will assist in differentiating seizures and mimics. For patients in status epilepticus and unstable patients, proper resuscitation and treatment is precedent while identifying any provoking factors and proper treatment of those factors. 4. How is patient care impacted? This review provides an evaluation of seizures and seizure mimics, signs and symptoms of seizures, and an approach to management of seizures and seizure mimics. Resuscitation of the actively seizing patient and consideration of mimics can improve patient care.
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