Epilepsy

Epilepsy

I. Problem/Condition.

An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain, as defined by the task force of International League Against Epilepsy (ILAE) in 2005. ILAE has given the operational definition of epilepsy as –

• At least two unprovoked (or reflex) seizures occurring more than 24 hours apart;
• One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years;
• Diagnosis of an epilepsy syndrome

Epilepsy is seen in patients who have a seizure and whose brain has demonstrated a tendency towards having recurrent seizures. A seizure that is provoked by transient factors (after concussion, fever, hypoglycemia, alcohol withdrawal) on a normal brain should not be counted towards the diagnosis of epilepsy.

The risk of having recurrence of seizures after 2 unprovoked seizures is about 60-90%. Multiple review articles have demonstrated a prevalence of about 4-10 per 1000 individuals. Numerous studies have also shown a bimodal or U-shaped distribution, with children and the elderly being most frequently affected. Epilepsy is found in both developed and underdeveloped nations, however, there is slightly higher frequency of epilepsy in developed rather than developing nations. This is felt to be due to the decreased life expectancy of individuals in developing nations.

The ILAE commission has classified epilepsy as follows:

1. Generalized seizures – originates within one hemisphere and rapidly engages networks in both hemispheres

• Tonic-clonic

  Begins with bilateral myoclonic jerks, followed by tonic contraction of extremities and trunk resulting in extension of neck and extremities sustained for a short period of time.

  This is followed by clonic jerking of extremities.

  There can be emptying of bladder and bowels or tongue biting.

  After the seizure they are post-ictal and may take 15-60 minutes or longer to regain consciousness.

• Absence –

  Typical – Characterized by behavioral and mental arrest for few seconds and resume activity as if nothing happened. Characterized by a 3 hertz (Hz) spike and wave appearance on electroencephalogram (EEG) and can be induced in patients by using hyperventilation.

  Atypical – Seen in patients with developmental delay and the arrests last longer. They are less than 2.5 Hz on EEG.

  Absence with special features, myoclonic absence, and eyelid myoclonia.

• Myoclonic –

  Characterized by brief jerking of extremities and/or axial trunk muscles which are quick and irregular.

  Myoclonic, myoclonic atonic, and myoclonic tonic.

• Clonic – Involves rhythmic jerking of the muscles.
• Tonic – Classified by alteration in consciousness in addition to muscle rigidity.
• Atonic – Defined by a sudden loss of muscle tone. The patient may fall down.

2. Focal seizures – arises and is confined to area of one hemisphere. They can spread within the same hemisphere or sometimes to contralateral hemisphere and may even evolve to generalized seizure. May have aura (subjective alteration of experience), behavioural alterations, autonomic manifestations (brady/tachycardia, pallor, hypersalivation), and transient impairment of language or cognition. They are further classified as –

• Without impairment of consciousness or awareness (previously called simple partial seizure)
• With impairment of consciousness or awareness (previously called complex partial seizure)
• Evolving to a bilateral convulsive seizure (previously called secondary generalized seizure)

3. Unknown – Epileptic spasms seen usually in infants or children with gross structural lesions. It is characterized by tonic flexion of head, neck, and trunk with circumflexion of upper extremities.

4. Continuous seizure types – This is ongoing seizure activity for 30 minutes or more. Practically, it is a seizure lasting for more than 5 minutes.

• Generalized status epilepticus – generalized tonic-clonic status epilepticus, clonic status epilepticus, absence status epilepticus, tonic status epilepticus, and myoclonic status epilepticus
• Focal status epilepticus – epilepsia partialis continua of Kojevnikov, Aura continua, Limbic status epilepticus (psychomotor status), and hemiconvulsive status with hemiparesis

Epilepsy can be divided into multiple syndromes as well. Two of the more common syndromes encountered are Juvenile Myoclonic Epilepsy (JME) and Lennox-Gastaut.

• JME is composed of a myriad of seizure types and affects children in their early to late teens. It is characterized by myoclonic seizures, usually in the morning, absence seizures, and generalized tonic-clonic seizures. It has an EEG pattern that looks like a poly-spike and wave. The treatment for JME is lifelong.
• Lennox-Gastaut Syndrome is composed of a triad of tonic, atonic, and atypical absence seizures. It tends to affect younger children, and is usually more refractory to treatment than JME.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

The differential diagnosis for epilepsy is broad and includes physiologic as well as non-physiologic causes.

The physiologic causes include cardiac causes such as vasovagal syncope, Stokes-Adams Syndrome, or arrhythmias. Sleep disorders including parasomnias and cataplexy also need to be investigated. Neurologic causes include TIA, stroke, migraine headaches, transient global amnesia, hypnic jerks, movement disorders, hemifacial spasm, and dystonic reactions. Metabolic derangements such as hypoglycemia, hyponatremia, and hypomagnesemia must also be considered. Intoxications or withdrawals from alcohol or illicit drugs can lead to seizures as well.

Non physiologic causes include nonepileptic seizures and other psychiatric mimickers of epilepsy (ex: panic attacks).

B. Describe a diagnostic approach/method to the patient with this problem.

A high index of suspicion is the first step in identifying a seizure. Seizures should always be a consideration in any patient with an alteration of consciousness from baseline. This is especially critical in the geriatric population with multiple comorbidities and the change in state attributed to another cause. Seizures can be precipitated by an underlying infection, which in itself can result in alteration of consciousness.

An isolated or even repeated episodes of provoked seizure does not establish the diagnosis of epilepsy, and if identified correctly results in the patient not burdened by additional medications.

Further steps in evaluation can be done based on the degree of suspicion for a seizure.

1. Historical information important in the diagnosis of this problem.

• Age of onset.
• Seizure Semiology: Description of the events of the seizure itself: this is critical in identifying the origin of the seizure and has potential implications for treatment. Patients may have multiple seizure types and each type has to be identified correctly along with the frequency of each type.

  Was there an aura? Could the patient feel the event developing? Defining the aura can also localize the area of seizure onset.

  What happened first, second, third, etc.? The sequence of events during the seizure can also provide clues to the area of onset.

  Were the eyes open or closed? It has been shown with high sensitivity that patients have their eyes closed during non-epileptic seizures and can assist in diagnosing that difficult condition.

  Did the head turn? Which way?

  Which limb or limbs did it start in?

  Any loss of bowel or bladder control or any tongue biting?

  Frequency of seizures: Identifying the seizure burden helps in providing a guide for improvement with treatment as well as assessing and improving the patient quality of life.

  Duration of seizures

  Postictal period, including a description of the patient’s signs/symptoms and duration.

  Circumstances under which the seizure occurred: It provides the information about provoking and precipitating factors for seizures and may vary from patient to patient. A few examples are: Had the patient been up all night cramming for an examination? Had the patient been drinking, especially excessively? Had the patient been using other street drugs? Had the patient recently changed antiepileptic drugs (AEDs) or missed a dose?

  Were there witnesses for any of their seizures? Family members should ideally accompany the patient especially if they have witnessed the events as most patients do not recall the events during the seizure.

• Medication history:

  All current medications: certain antibiotics (Imipenem) or other agents used (ex: buproprion for smoking cessation) are well known to lower seizure threshold.

  Current antiepileptic drug (AED) regimen if any.

  All previously used AEDs and the maximal dosage achieved/tolerated.

  Why any particular medication was discontinued.

  Other medications: especially oral contraceptives, analgesics, any over the counter (OTC) medications or supplements used.

• Birth history

  Was the patient premature? And if so, by how many weeks?

  Any problems during the pregnancy or the birth?

  Vaginal or Caesarean section delivery?

• Did the patient have febrile seizures?
• Were all the developmental milestones achieved at the appropriate ages? Did the patient have any special education requirements? What is the highest level of education achieved?
• Was there any history of “daydreaming” as a child? Any history of head trauma with loss of consciousness?
• History of stroke/transient ischemic attack (TIA)?
• History of tumors?
• History of central nervous system (CNS) infections such as meningitis, neurocysticercosis, or herpes encephalitis?
• Any family history of seizures? If positive need to identify if maternal or paternal and trace as far back as possible.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

There are no special physical examination maneuvers for diagnosing epilepsy.

The examination of a patient suspected to have epilepsy or seizures should include a general medical examination followed by a complete neurologic examination.

The general examination should include searching for neurocutaneous syndromes with stigmata (ex: Tuberous sclerosis with adenoma sebaceum) as well as dysmorphic features (ex: microcephaly) in addition to routine system examinations.

The complete neurological examination should include a mental status examination assessing memory, language, cognition, concentration, right-left orientation and praxis. Testing of cranial nerves, the motor system, the sensory system, as well as reflexes, coordination, station and gait also need to be performed.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Multiple methods exist for evaluating seizures and epilepsy. One of the first to be considered after performing a careful, detailed history and physical examination should include an EEG.

The EEG acts not only to localize the area of electrical disturbance but has also been shown to be useful in the prediction of further seizures. A recent Quality Standards Subcommittee sponsored by the American Academy of Neurology and the American Epilepsy Society found level B evidence (Level B = probably helpful) for evaluation of a first seizure with an EEG. This is because of the initial EEG being positive in only about 23% patients with epilepsy; but if positive, adds credence to the clinical diagnosis. However, a negative EEG does not rule out the possibility of seizures or epilepsy.

Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain was also shown to be level B evidence for the evaluation of a first seizure as it was abnormal only in 10% of the patients. The choice of CT or MRI depends on the site of initial presentation of the patient. For a patient being evaluated in the emergency department (ED), CT is the imaging of choice because of the ease and speed of obtaining the study. However, all patients suspected of having seizures require an MRI of the brain with a specific seizure protocol. In those patients with other comorbidities and a high index of suspicion for infections or space-occupying lesions, a contrast-enhancing study maybe required.

Complete blood count (CBC), electrolyte panels, and blood glucose levels have not been shown to be useful for regular use in the evaluation of initial seizures (Level U evidence – the data are inadequate or conflicting). However, this is dependant on the initial presentation and the patient’s history. In a patient with history of diabetes mellitus and on hypoglycemic medications, blood glucose has to be checked prior anything else to rule out hypoglycemia as the cause of the seizure.

Lumbar puncture in the evaluation of a first seizure also has a level U evidence, unless the patient is febrile or there is a high index of suspicion for infection (ex: the immunocompromised patient).

Toxicology screens may also not be needed in the routine evaluation of seizures, once again unless there is any index of suspicion.

PET-CT (positron emission tomography-CT), single-photon emission computed tomography (SPECT) scans and MEG (magnetoencephalography) scans have been shown to be useful to localize the epileptic focus, when being evaluated for epilepsy surgery. These are not performed routinely.

C. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

When combined with a good history and physical examination associated with a high index of suspicion of seizures, any of the mentioned tests can be appropriate. However, the reverse can be true especially if the history is incomplete, and precious resources are wasted requesting unnecessary tests.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Epilepsy.

Management of epilepsy differs depending on the setting and if the diagnosis of epilepsy has already been established.

The first step is to take a detailed history and to perform a complete neurological examination of the patient.

In evaluating someone with a seizure, the first thing to consider is if this event represents a seizure or one of the many varied conditions in the differential diagnosis, such as syncope.

If it is a seizure, then it needs to be confirmed that it truly is a first seizure: studies have shown that on detailed history 50% of patients report a prior seizure, although not definitely recognised or diagnosed.

In a patient with history of epilepsy, the history will provide the reason for the current episode.

Identifying provoking or precipitating factors are critical: ex: check blood glucose to rule out hypoglycemia.

If there is any history of head trauma, brain tumor, or suspicion for other acute neurological emergencies obtain diagnostic imaging of the brain and as mentioned previously, in the ED setting a CT head is ideal.

Consider serum laboratory tests, alcohol and toxicology screens if supported by the history.

Check AED levels if the patient is taking any antiepileptic medications. If the head CT or lab results are abnormal or the patient has focal neurological deficits, a neurology or neurosurgery consult is appropriate.

If the above results and physical examination are normal, and the patient has returned to baseline, discharge can be considered with close neurology follow up.

In a patient with an established diagnosis of epilepsy, correction of the precipitating or provoking factor is usually the key. Patient education to prevent such episodes in the future are critical.

There is some debate among epilepsy experts on whether or not to treat the first seizure. This depends on multiple factors such the circumstances under which the seizure occurred, the certainty that the event represents a seizure, the patient’s job, i.e., the risks versus benefits of treatment of the first seizure. It has been generally accepted to treat after the second unprovoked seizure.

Convulsive Status Epilepticus

(For management of Nonconvulsive status epilepticus, please see that chapter.)

Although the textbook definition of convulsive status epilepticus (CSE) is when a patient has a seizure lasting for more than 30 minutes or a series of seizures lasting for 30 minutes without return to baseline in between events, for practical purposes any seizure that lasts as much as 5 minutes needs immediate treatment and is the accepted working definition.

There are several algorithms for managing status epilepticus and as with all medical emergencies, start with the airway, breathing, circulation, disability (ABCDs).

Within the first 5 minutes of onset, benzodiazepines are administered. One of the first line options – (i) intramuscular midazolam (10 milligram (mg) for >40 kilogram (kg) and 5 mg for 13-40 kg), (ii) intravenous (IV) lorazepam (0.1 mg/kg/dose), or (iii) intravenous diazepam (0.15-0.2 mg/kg/dose) should be chosen. With lorazepam and diazepam 1 dose can be repeated at 2 minute intervals. Repeated doses can be given while the initial AED is being administered to control ongoing seizures.

This should be followed by an AED such as fosphenytoin at 20 mg/kg (1500 mg max dose) given at up to 150 mg/minute.

Other AEDs include valproic acid at 20-40 mg/kg (3000 mg max dose) or leviteracetam at 60 mg/kg (4500 mg max dose): these agents can be considered as first or second-line agents, depending on availability.

If the seizure does not resolve within 30 minutes, consider administering a third epileptic drug or anesthetic inducing medications such as propofol or midazolam.

The patient should be intubated and propofol started at 20 microgram (mcg)/kg/min and maintained at 30-200 mcg/kg/min. Midazolam can be started at 0.2 mg/kg and maintained at up to 0.05-2 mg/kg per hour.

If seizures do not resolve, consider transferring the patient to a tertiary medical center with availability of a neurologist and/or epileptologist and capabilities for further evaluation, monitoring and treatment of refractory CSE.

The patient should be placed on 24 hour EEG monitoring at this time. If seizures do not resolve with the measures outlined above by 48 hours after the onset, consider adding barbiturates such as pentobarbital or thiopental. The goal at this time should be to attain burst suppression or electrographic seizure suppression on EEG.

Difficult to treat/refractory status epilepticus has additional agents that have been shown to be helpful in limited case series or case reports: such as ketamine, isoflurane, magnesium, and ketogenic diet.

Correction of any underlying metabolic derangements have to be done from the outset.

Outpatient management

It involves multiple issues, including patient education and compliance.

The first major issue that needs to be considered is that of patient safety. Seizure precautions should be reviewed with the patient and caregiver at each visit, including the following:

• Driving restrictions – which vary by state
• Utilizing heavy machinery
• Heights, ladders, and working underground
• Working around water, including the danger of taking baths or swimming
• Hot stoves or open flames

Other issues that need to be addressed include: medications and their potential side-effects, interactions with other medications, need for compliance, changing from brand to generic antiepileptic medications, suicidal potential, bone health issues.

Special consideration needs given to the care of women with seizures. There are multiple issues unique to women such as catamenial epilepsy (seizures related to monthly periods), contraception, pregnancy, and teratogenicity that require a skilled neurologist or epileptologist to be an integral part of their health management.

Another issue to be addressed is the psychiatric comorbidities commonly associated with epilepsy: primarily depression, as well as anxiety, and panic disorder.

If the patient has non-epileptic seizures, they need further counseling and long-term psychiatric follow-up.

For absence seizures ethosuximide is preferred. If there is association of other seizure types along with absence seizures either valproic acid, lamotrigine, or topiramate can be used. Tonic or atonic seizures (as seen in Lennox-Gastaut syndrome) require either valproic acid, lamotrigine, or topiramate.

For myoclonic seizures again consider valproic acid, lamotrigine, or topiramate. For juvenile myoclonic epilepsy, levetiracetam and zonisamide have been approved.

For generalized seizures, valproic acid has been recommended as first choice as per SANAD trial. Other treatment options include phenytoin, topiramate, and lamotrigine. Risk versus benefit analysis for use of valproic acid in women of childbearing age or pregnant women should be carefully done. Levetiracetam can be used in pregnant women, and as per study by Shallcross et al., it did not show any increased incidence adverse effects in children exposed to it in utero versus those who were not exposed.

For focal seizures there are a wide variety of drugs with indication for monotherapy – phenytoin, phenobarbital, carbamazepine, lacosamide, lamotrigine, oxcarbazepine, and topiramate. Efficacies are similar.

Vagal nerve stimulators (VNS) have been used in refractory epilepsy. A VNS is a device about the size of a pacemaker that is implanted in the chest. Wires lead from the generator unit to the vagus nerve and pass a small current through that nerve. A decrease in the number of required AEDs needed to treat an individual has been shown to be associated with this device, but it may take as long as 12 months to start to achieve the maximum benefit. Cough, dyspnea, and hoarseness have been seen as side effects but usually decrease over time. It is a good choice in some patients who has refractory epilepsy and are not candidates for epilepsy surgery.

Various other devices are currently in development that assist in detecting and treating seizures and are expected to be available soon.

Epilepsy surgery is also a consideration for intractable disease. Multiple studies have shown up to a 70-90% seizure free rate with appropriate surgical therapy, particularly with mesial temporal lobe seizures. It is recommended that after an appropriate trial of at least two antiepileptic agents (maximum doses without side-effects and tolerated by the patient for at least 2 years) surgery should be considered.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

With status epilepticus in particular, many of the medications used can cause hypotension, arrhythmia or respiratory depression.

Some of the common AEDs and their side effects include:

1. Phenytoin: 20 mg/kg IVx 1 at a maximum of 50 mg/minute. It is known to cause purple glove syndrome with extravasation, in addition to hypotension, osteomalacia, and arrhythmia. It is also less pH balanced than fosphenytoin, which has the same loading dose, but can be given at a rate of up to 150 mg/minute. Hence, fosphenytoin is preferred over phenytoin for intravenous infusion.

2. Valproic Acid: has been associated with hepatotoxicity and carries a black box warning in association with pancreatitis. It can also cause thrombocytopenia and hyperammonemia.

3. Phenobarbital: has been associated with sedation, lethargy, and respiratory depression.

4. Lamotrigine: has been associated with rash and Stevens-Johnson Syndrome.

5. Topiramate: has been known to cause weight loss as well as nephrolithiasis and acute-angle narrow glaucoma. Cognitive changes have also been reported.

6. Felbamate: has been associated with aplastic anemia and liver failure.

7. Carbamazepine: has been associated with balance problems, dizziness, visual problems as well as hyponatremia. It has also been rarely been associated with arrhythmia and heart block.

8. Oxcarbazepine: has been known to cause nausea/emesis, headache, and Stevens-Johnson Syndrome.

9. Levetiracetam: has been associated with agitation and hostility and drowsiness.

In addition, AEDs may need to be adjusted due to oral contraceptive pills or other hormonal birth control methods in women.

IV. What’s the Evidence?

Fisher, RS. “ILAE official report: a practical clinical definition of epilepsy”. Epilepsia. vol. 55. 2014 Apr. pp. 475-82.

Glauser. “Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society”. Epilepsy Currents. vol. 16. 2016 Jan-Feb. pp. 48-61.

Vespa. “Guidelines for the evaluation and management of status epilepticus”. Neurocritical Care. vol. 17. 2012 Aug. pp. 3-23.

Krumholz, A. “Practice parameter: Evaluating an apparent unprovoked first seizure in adults (an evidence based review). Report of the quality standards subcommittee of the American Academy of Neurology and the American Epilepsy Society”. Neurology. vol. 69. 2007 Nov. pp. 1996-2007.

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