24 Juvenile Myoclonic Epilepsy and Other Primary Generalized Epilepsies

Shahin Hakimian

Department of Neurology, UW Regional Epilepsy Center, University of Washington, Seattle, WA, USA

Introduction

Myoclonic, absence, and primary generalized tonic–clonic seizures (GTCSs) commonly occur in a group of overlapping epilepsy syndromes in otherwise neurologically intact patients. These constitute the idiopathic primary generalized epilepsies (IGEs), which in adults include juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and primary generalized tonic–clonic seizures upon awakening (PGTC, also known as idiopathic generalized epilepsy with pure grand mal) (see Chapters 2 and 21). In practice, symptoms and features among IGE syndromes overlap. IGEs can be distinguished from other forms of epilepsy based on history, neurological examination, and EEG. Recognizing IGEs affects treatment choices and helps with prognosis. The features of IGEs in adults and their differential diagnosis and treatment choices are discussed here.

Clinical features

Idiopathic primary generalized epilepsy syndromes in adults are common, representing 10–30% of new-onset epilepsy. Both genders are equally affected. “Idiopathic” in IGE implies a suspected genetic cause. A family history is frequently present (in up to 40%), but seizure manifestations may differ among family members. The genetic causes appear heterogeneous and polygenic. Autosomal dominant inheritance and autosomal recessive inheritance have been reported. In practice, a single causative genetic mutation is rarely identifiable.

SCIENCE REVISITED

Some of the identified genes in IGEs are widely distributed ion channels. This gives credence to the idea that their etiology is “general” cortical excitability.

Typically, seizures present in the teens to late 20s. However, age of onset can vary. Some 10–20% of children diagnosed with childhood absence epilepsy are later classified as having an adult IGE. Presentation after the third decade of life, while uncommon, is not entirely rare. Late presentation as the result of a GTCS may be the first recognized manifestation of an IGE whose earlier signs (e.g., jerks or absence) went unnoticed. Late presentation of a severe syndrome, however, should prompt consideration for other diagnoses such as symptomatic generalized epilepsy (SGE), particularly a progressive form. The bedside neurological examination is typically normal. Careful neuropsychological studies, however, have identified subtle frontal executive dysfunction in many patients with IGE.

The presence and relative frequency of absence, myoclonic, and GTCSs differ among patients and characterize the individual syndromes of JAE, JME, or PGTC. The seizures are typically stereotyped for an individual. Yet, occurrence and provocation of another generalized seizure type is possible.

Absence seizures (common in JAE but also seen in JME) show the typical brief interruptions of sensorium also found in classic childhood absence. Patients may report these as “losing time,” “spacing out,” dizziness, or light-headedness. These are sometimes reported as “auras,” which may mislead the practitioner. In adults, prolonged absence seizures (absence status) occur occasionally. During these, patients are somewhat interactive although they may appear forgetful, inattentive (spacey), or slow to respond.

CAUTION!

Absence seizures and absence status in adults can sometimes be subtle. Recognizing absence status can be particularly challenging in acute care settings.

Myoclonic seizures are most common in JME, although not every patient recognizes them. The jerks are brief, sudden muscle contractions occurring singly or repetitively in a burst. Myoclonus usually involves upper extremities, often synchronously and typically early in the morning upon awakening. Patients usually retain some awareness during brief bursts of myoclonus and can recall an experience of body jerks or “electrical jolts.” Involuntary twitches in arms disrupt activities such as writing, eating, applying makeup, shaving, and brushing teeth. The jerks are frequently dismissed as nervousness or clumsiness, however, until specifically exposed during medical history. Facial and vocal involvement is possible but uncommon. Lower limbs and torso may also suddenly contract, resulting in falls. Violent jerks are less common in IGE than SGE, although injuries can still occur from falls, dropping objects, mishandling motorized tools, etc. Bursts of myoclonus may “build up,” leading to a GTCS.

TIPS AND TRICKS

Carefully obtaining a history of myoclonus (and distinguishing it from benign sleep myoclonus) is a key to making a diagnosis of JME.

Generalized tonic–clonic seizures are the defining feature of PGTC but also commonly occur in JME and even JAE. Like the myoclonus, they preferentially occur early in the day. They are sometimes preceded by absence or myoclonic seizures. Lateralized semiology such as forced head version, unilateral tonic extension, or asymmetric myoclonus can occur in IGE, but stereotyped lateralization is less common. Injuries, falls, car accidents, and even unexpected death are possible with more severe seizures.

Differential diagnosis for idiopathic primary generalized epilepsy

The differential diagnosis for IGE is quite broad, encompassing precipitated seizures (such as alcohol-related seizures), focal epilepsy, and SGE syndromes. Some of these are discussed later in this chapter. Other nonepileptic causes are psychogenic events (see Chapter 6), subcortical myoclonus, syncope, narcolepsy, benign sleep myoclonus, and even periodic limb movement disorder. Nonepileptic causes can all be distinguished from IGE through a careful neurological history and examination confirmed by video–EEG recording.

Among focal onset epilepsies, frontal seizures may be mistaken for PGTC because both can present in the early-morning hours. The high-amplitude frontal discharges found on the EEG can be similar to the generalized spike-and-wave complexes found in IGE. If clinically warranted, the syndromes can be distinguished by careful EEG review and video–EEG monitoring to characterize semiology and ictal EEG. Focal motor seizures (including focal cortical myoclonus) may resemble myoclonus in JME. In focal motor seizures, epileptiform discharges are exclusively contralateral to the involved limb, and other typical IGE features are lacking. Multifocal epilepsy can be difficult to differentiate from IGE by history or interictal EEG alone. Ictal EEG patterns and semiology separate the two. Epileptogenic MRI abnormalities should be absent in IGE.

Symptomatic generalized epilepsies are defined as epilepsies caused by another neurological disorder. SGEs are distinguished from IGEs based on neurological history and an abnormal neurological examination. Multiple seizure types may be present.

Occasionally in adults, generalized seizures are an early manifestation of an SGE due to a neurodegenerative disorder. These are labeled progressive myoclonic epilepsies (PMEs). Because patients may initially appear neurologically intact, a PME may be misclassified as idiopathic. Over time PMEs more clearly resemble other SGEs: seizure becomes more severe; EEG shows background slowing; and neurological signs such as ataxia, cognitive impairment, dysarthria, tremors, and hearing loss develop. PMEs presenting in adults and teens include Unverricht–Lundborg disease, myoclonic epilepsy with ragged red fibers (MERRF), Lafora body disease, adult neuronal ceroid lipofuscinosis (type 4), dentatorubral–pallidoluysian atrophy (DRPLA), and Gaucher disease (subacute neuronopathic form, type 3). PME should be considered in the differential diagnosis of patients with unusual clinical findings who deteriorate or fail to respond to antiepileptic drugs (AEDs). Repeat diagnostic evaluation may be necessary, including MRI examination of the brain. The genetics of several of the PMEs are reviewed in Chapter 22.

EEG in primary generalized epilepsy

The classic EEG findings in JME are 3–5-Hz frontally maximum generalized spike-and-wave discharges (Figure 24.1). The discharges may be overtly symptomatic (associated with myoclonic seizures), subtle (associated with absence or subtle twitches), or without overt manifestations, even in the same patient at different times. Focal fragments of epileptiform discharges or some shifting asymmetry of discharges on EEG (Figure 24.1B) are expected and part of the syndrome. Other common findings are multispikes, generalized paroxysmal fast discharges, and photoparoxysmal responses. Figure 24.2 shows an ictal EEG recording for PGTC.

In practice, distinguishing generalized discharges and high-amplitude frontal spikes can be challenging. Therefore, frontal midline focal epilepsy should be considered in the differential diagnosis of IGE syndromes. Other EEG findings that overlap with IGE include multifocal discharges, benzodiazepine or alcohol withdrawal, and SGEs.

Imaging

Brain MRI appears normal in IGE. Nevertheless, imaging is recommended (e.g., by the American Academy of Neurology quality standards) for all cases of new onset of epilepsy in adults. The guidelines do not make a distinction between focal onset epilepsy and IGE. Prospective data for making an imaging exception for IGE solely based on history or EEG is lacking. Given the differential diagnosis, initial imaging with either CT or MRI is warranted in all patients. When there are atypical features, an abnormal neurological exam, seizures refractory to common AEDs, or evidence of progression, careful imaging with modern MRI scanners is necessary.

Treatment and prognosis

Fewer AED trials for IGE than for focal onset epilepsies have been performed. The data is particularly incomplete for the latest drugs and for myoclonic and absence seizures (Chapter 11). Valproate has clear efficacy for all three seizure types. Levetiracetam, lamotrigine, and topiramate have all shown efficacy primarily for GTCSs. Their efficacy for absence seizures is accepted but not supported by well-done trials. Lamotrigine in particular may paradoxically exacerbate myoclonus. Zonisamide has some incomplete evidence supporting its use. Benzodiazepines such as clonazepam (and probably clobazam) are helpful, particularly for eliminating myoclonic seizures and sometimes for GTCSs. Ethosuximide is a good choice for absence seizures but lacks efficacy for other seizure types seen in adults. Felbamate, phenobarbital, and primidone show efficacy but are best avoided as first- or second-line AEDs because of adverse effects.

By contrast, several drugs exacerbate absence and myoclonic seizures: carbamazepine, oxcarbazepine, vigabatrin, tiagabine, gabapentin, pregabalin, and probably eslicarbazepine acetate (Chapter 11). These should be avoided in IGE. These AEDs may change the manifestation of epilepsy. For example, carbamazepine may unmask absence seizures in PGTC epilepsy. Phenytoin, although effective for GTCSs, can also exacerbate absence or myoclonic seizures. Adequate data on lacosamide, rufinamide, and ezogabine are lacking. When there is uncertainty about the diagnosis, broad-spectrum AEDs should be favored over drugs that can exacerbate IGEs.

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