Introduction to Epilepsy Care

Definitions

Epilepsy is a chronic condition characterized by a predisposition to experience multiple unprovoked epileptic seizures, along with the psychosocial and other effects such a condition brings.

An epileptic seizure is a paroxysmal and transient phenomenon in which there is excessive synchronous electrical activity in the brain along with corresponding clinical changes.

Epilepsy is clinically defined as the occurrence of two or more unprovoked epileptic seizures at least 24 hours apart; or one seizure with a probability of recurrence (as determined by diagnostic testing) of 60% or greater; or one seizure but sufficient history or testing to indicate a known epilepsy syndrome.

Seizures versus Epilepsy

Epileptic seizures can occur without entailing the condition of epilepsy. Febrile seizures (FS), which occur in up to 3–5% of children, are associated with spiking fevers and are not considered a form of epilepsy (although a tendency to FS can be inherited, and lifetime risk of epilepsy is slightly elevated).

Acute symptomatic seizures are seizures which are precipitated by some insult that acutely lowers the seizure threshold. Seizures caused by hypoglycemia, or so-called early posttraumatic seizures occurring within seven days of a traumatic brain injury are examples. Seizures due to drug toxicity or withdrawal also qualify.

Although events which can precipitate acute symptomatic seizures may also increase a patient’s risk of epilepsy (such as head injury), the diagnosis of epilepsy still requires a reasonable probability that future unprovoked seizures will occur.

How to diagnose a seizure

First a note: as seizures are defined as abnormal neuronal firing states it is entirely possible for a seizure to have, especially at onset, no clinical signs. If caught on EEG, this would be termed an electrographic (as opposed to electroclinical) seizure. In practical terms, clinically silent seizures can only be known to occur via EEG.

Clinical seizures have several requisite characteristics. They are paroxysmal; they are transient; they involve some change in neurologic function;

We roughly partition the life of a PWE into interictal and ictal periods. Naturally even for patients who have multiple daily seizures the ictal periods cumulatively amass only a small fraction of the patient’s time.

It seems sensible to reserve the term seizure for spells which are strongly suggested by the evidence to be caused by abnormal neuronal synchronous firing. The words spell, attack, paroxysm, or even fit may suffice if there is uncertainty. EEG evidence is not always necessary. In any case, the most likely EEG evidence is interictal epileptiform activity rather than electrographic recording of the seizure itself (unless admitted to the EMU). Be mindful that patients and even many physicians will use the term seizure much more broadly. It’s even common for patients who have been definitively diagnosed not to have seizures, and repeatedly apprised of such, to nonetheless continue to talk about their spells as seizures.

The term postictal deserves care. You may hear it used willy-nilly to refer to a disoriented state following a patient’s spell, whether the spell is a seizure or no. The term means no more than an indeterminate time or state immediately following a seizure. When first investigating a patient’s spells, when their nature is not yet definite, it is more appropriate to simply describe the patient’s state following the spell than to hand-wave it away as postictal. Some seizures produce little to no recognizable postictal state (ie, the patient bounces back as if nothing had happened). A given patient may be irritable, or even psychotic, rather than merely somnolent and disoriented. They may have no neuropsychiatric or neurasthenic symptoms but nonetheless have postictal monoparesis or aphasia.

Semiology

In neurology our diagnostic workflow revolves around localization. The history and physical exam define one or more segments of the neuraxis where the lesion might lie, and the localization leads to the differential diagnosis. This is much the same for epilepsy. But in our case we need to reconstruct the sequence of symptoms and signs that occurs during a seizure and use those to trace the portion of the cortex involved. This sequence is known as the semiology of the seizure.

Neuroanatomy of Epilepsy

There are several conceptual zones or areas of cortex involved in epilepsy. The epileptogenic zone or EZ is the theoretical cortical area whose extirpation would lead to cure of the patient’s epilepsy. The seizure onset zone or SOZ is the area in which seizures can first be seen to arise on EEG. The symptomatogenic zone or SZ is that area whose involvement by seizure leads to the patient’s clinical semiology. In some cases the SZ is nearly identical to the SOZ and in other cases they are distinct. The irritative zone or IZ is the area over which interictal discharges occur. It is usually a bit broader than the EZ and SOZ and may enlarge in different states such as NREM sleep.

Epilepsy is essentially understood as a cortical phenomenon but there are some subcortical structures which are probably important. The thalamus, especially its reticular nucleus, appears to be important in some forms of generalized epilepsy. Brainstem structures are probably involved in the alteration of awareness that occurs with some focal seizures.

Types of seizures

Causes of epilepsy

Neonatal–Infancy

HIE, perinatal stroke, hydrocephalus, malformations of cortical development (MCD), congenital or heritable metabolic disorders, mitochondrial disorders, benign infantile convulsions, benign neonatal convulsions, fifth-day fits, cerebral hemorrhage (esp. periventricular), trauma,West syndrome, tuberous sclerosis, Sturge-Weber, Ohtahara syndrome, severe myoclonic epilepsy of infancy (Dravet syndrome), GEFS+, meningitis-encephalitis.

Childhood

BCECTS, childhood absence epilepsy, trauma, congenital/heritable metabolic disorders, mitochondrial disorders, lysosomal storage disease, meningitis-encephalitis, hypoxia, childhood cerebral tumors, ADFLE, malformations of cortical development (MCD)

Adolescence

JME, JAE, EGMA, MTLEHS, trauma, infection, ADFLE.

Young Adults

MTLEHS, JME, EGMA, trauma, vascular malformations

Middle age

Trauma, brain tumors (primary or secondary), cerebral hemorrhage, infarcts, neurodegeneration, vascular malformations, anoxia.

Elderly

Brain tumors, vascular malformations, hemorrhages, infarcts, neurodegeneration, trauma, infection (herpes encephalitis, abscesses, etc), anoxia.

Treatment

Goals of Treatment

  1. Abolish all seizures permanently with fewest number of anticonvulsants giving lowest burden of adverse effects.
  2. Failing that, reduce seizures as much as possible, and to only non-disabling seizures (ie, auras) if possible, using fewest number of anticonvulsants with lowest burden of adverse effects.
  3. Failing that, balance medication adverse effect profile and efficacy with meaningful reduction in seizure frequency and intensity.
  4. In rare circumstances, eg super-refractory status epilepticus, treatment may be entirely palliative.

Treatment

Anticonvulsants: mainstay of treatment; reduce neuronal firing rate or synchronicity by various mechanisms.

Surgery: in pharmacoresistant patients, seizure focus may be identified and resected if non-eloquent.

Neural Stimulation: vagus nerve stimulation is oldest; reactive neurostimulation has recently been approved. These methods deliver intermittent electrical current to the CNS and have widespread modulatory effects.

Ketogenic diet: carbohydrate-restricted diet causes ketosis, which has anticonvulsant effect.

Anticonvulsant Use

  1. Start small and titrate slowly to goal dose.
  2. Always wean off slowly; never stop abruptly.
  3. Adverse effects usually increase with dosage.
  4. Common adverse effects: somnolence, bradyphrenia, memory problems.
  5. Second- and third-generation drugs generally better tolerated.
  6. With some exceptions, no drug has been consistently proven to be more efficacious than any other drug.
  7. Generalized epilepsies are treated with a distinct subset of agents.
  8. Flattest serum concentration of drug is the most desirable.
  9. Common risks to be discussed: teratogenic potential, depression/suicide, bone mineral density, drug-drug interactions (incl. OCs), folate supplementation (esp. with PHT and women of childbearing age).

Numbers

Special Groups

Women

Women of childbearing potential (WCP) face several risks that male PWEs do not. All anticonvulsants are teratogenic to different potentials. Anticonvulsants may interfere with hormonal contraception. During pregnancy, uncontrolled seizures can lead to spontaneous miscarriage or stillbirth. Finally, eclampsia is a major cause of epileptic seizures that are not considered to constitute epilepsy.

Of the anticonvulsants, the safest in terms of excess risk of major congenital malformations (MCMs) appear to be lamotrigine, levetiracetam, and gabapentin. The baseline risk of MCMs is approximately 1%; these drugs raise the risk up to 3% or so. First-generation drugs are among those with the greatest teratogenic potential, with valproate raising the risk of MCMs to 9%, among them neural tube defects of various kinds and an increased incidence of intellectual disability and autism.

WCPs should be counseled to use contraception if not planning a pregnancy. If there are possible interactions with her anticonvulsant, she may be counseled to consult with her OB/GYN for a higher-dose estrogen-containing oral contraceptive, or for other options. She should also be counseled to take folic acid at least 1 mg/d. Some authorities suggest as much as 4 mg/d, especially in women about to be pregnant or already pregnant.

Lamotrigine levels are known to fall during pregnancy and should be tracked and compared to a known baseline. Increases of dose of up to two or three times their normal daily intake sometimes occur. Levetiracetam levels may also change but this is less well-established.

The optimal strategy for pregnancy is to wait until the woman is seizure-free and on a minimal therapeutic dose of a single agent. If the agent has a high teratogenic potential, it should be switched to one with a low potential unless contraindicated. The risks of harm and possibilities of benefit have to be weighed at each step. In general, it is helpful to note that the risk to the fetus of anticonvulsants is probably highest during the first trimester, while the risk due to seizures is lowest in that same time-frame. These trends flip towards the later part of pregnancy.

When pregnant, frequent visits are advised to optimize treatment. If possible, she should see a high-risk OB or MFM specialist.

Elderly

Incidence of epilepsy is highest in patients over 65 y. The most common cause is stroke, which can cause both acute symptomatic seizures (within 48 h for ischaemic stroke; within a few hours for subarachnoid hemorrhage) and epilepsy. Positive predictors for epilepsy include early seizures and additional strokes. Between 4–9% of patients with strokes have seizures.

Elderly PWEs with epilepsy are also at increased risk of stroke and should have their vascular risk factors evaluated.

Neoplasms

Tumoral epilepsy is usually induced by a brain neoplasm’s various effects on surrounding brain tissue rather than by the tumor itself. (The notable exception are hypothalamic hamartomas, which directly cause ictal activity and are associated with gelastic seizures.)

Epilepsy occurs more commonly with low-grade gliomas than high-grade gliomas. It is the presenting symptom of the tumor in 30–50% of cases.

If the patient is controlled with medication, there may be no need to do anything further if a surgical resection or debulking is contemplated. In pharmacoresistant patients, however, the tumoral resection should optimally involve an epileptologist and proceed essentially as a plan for epileptogenic zone resection along with tumor resection, which may include the use of electrocorticography and cortical mapping.

Be aware there may be drug interactions between anticonvulsants and chemotherapeutic drugs.

Epilepsy Clinic

New Patient Visits

  1. Document seizure onset, seizure semiologies (if more than one), triggers, frequency of seizures, current AEDs, past AEDs and reasons for quitting.
  2. Document age- and patient-appropriate risk factors. Include developmental history in younger patients.
  3. Document comorbidities including traumatic injuries, social problems, mood or anxiety problems.
  4. Document results of MRIs, EEGs, EMU evaluations, PET scans, ECoG, and other tests.
  5. Document blood monitoring results, if any.
  6. Counsel on seizure safety; driving law; suicide and AEDs; common and idiosyncratic adverse effects; pregnancy and teratogenesis; depression/anxiety; SUDEP.

Patient Return Visits

  1. Document any interim seizures, their semiologies, and any provoking factors.
  2. Document current medications, deviations from documented medications, and adherence.
  3. Document adverse effects.
  4. Screen for depression (NDDI-E).
  5. Document women of childbearing age are abstinent or using contraception; and that they are taking folate at least 1 mg/d.
  6. Refill as needed.

Tips/Tricks

Biopsychosocial

Epilepsy has been called “the quintessential neuropsychiatric disease.”

PWEs are more likely to have mood disorders and more likely to be in poverty than the general population. Screening for depression and suicidality should occur at every visit.

As neurologists we have ample experience with psychotropic drugs to be able to treat mild to moderate depression and other psychiatric diseases. Although the SSRIs as a class have a warning about increased seizures, drugs like (es)citalopram, sertraline, and fluoxetine have only a marginally increased risk of seizures and are usually appropriate to use for mood disorders or anxiety. Be sure to tell patients about SSRI discontinuation syndrome, as it can be a nasty surprise.

In general try to avoid antidepressant doses of tricyclics and definitely avoid imipramine. Amytriptyline and nortryptiline are OK, especially in headache prophylaxis doses.

Bupropion should probably be avoided although evidence of seizure exacerbation implicates larger (300 mg) doses.

Use of benzodiazepines for anxiety can be helpful but the main caveat is that chronic benzodiazepine therapy may have irreversible deleterious effects on cognition. In a PWE whose thinking may be muddled by the disease as well as by medications, keeping cognitive reserve is important. It’s better to choose long-acting benzodiazepines such as clonazepam, lorazepam, or diazepam. Avoid alprazolam. Warn against discontinuation.

Neuroleptics, or antipsychotics, should be avoided where possible. Sometimes PWEs who have intellectual disability have behavioral problems and may require some risperidone. In general, “typical” or older neuroleptics have a worse effect on seizures than newer ones. Clozapine should be avoided as it demonstrably can exacerbate seizures at doses of 150 mg/d or so.

Many of the worst effects of epilepsy are on a person’s social standing. The loss of a job may come about because patients absolutely cannot satisfy the job requirements because of their disease but it is also common for patients to be let go for “liability reasons” which amount to pure discrimination. The will to fight unlawful termination is often extinguished by the demoralization of the diagnosis.

The loss of driving that comes with uncontrolled epilepsy is also a major determinant of morbidity. In most cities in the US public mass transit is difficult to navigate. Patients may become isolated because of inability to travel. They may lose out on work. Patients with any history of epilepsy are essentially barred from

The disease still carries a stigma and this too has a deleterious effect on many patients.

Poverty is itself a risk factor for chronic disease and poverty can prevent PWEs from getting needed care. They may not be able to afford medications or copays. At present the Medicaid expansion in many states has extended health insurance coverage to millions of patients, but not all states have expanded Medicaid and there is uncertainty about its future.

PWEs need an income. Physicians can help by providing letters to employers, by setting clear guidelines about which job duties patients can undertake, by referring patients to advocacy groups like the Epilepsy Foundation of Michigan, and when necessary to provide documentation for disability insurance. Without an income PWEs have many worse problems than their epilepsy and will do more poorly.

One aspect of improving mental health is also advocating for more socialization.

Drug Abbreviations

Drug name Abbrev.
phenytoin PHT, DPH
carbamazepine CBZ
phenobarbital PB
ethosuximide ETX,ESX
valproate, divalproex VPA
vigabatrin VGB
levetiracetam LEV, LVT
lamotrigine LTG, LMG
oxcarbazepine OXC, OXZ
topiramate TPM
zonisamide ZNS
lacosamide LCM, LAC
rufinamide RUF
retigabine, ezogabine RTG, EZG
perampanel PER
clobazam CLB
fosphenytoin fPHT
primidone PMD, PRM
acetazolamide ACTZ, ACZ, AZM
stiripentol STP
tiagabine TGB
gabapentin GBP
pregabalin PGB
pentobarbital PTB
midazolam MDZ
diazepam DZP
lorazepam LRZ
clonazepam CLZ
felbamate FBM
eslicarbazepine acetate ESL
brivaracetam BRV
propofol PRO, PRF
cannabidiol CBD