Clinical manifestations

Presentation and course

Asymmetric tonic seizures are usually defined as having multiple discrete episodes lasting less than 1 minute, usually with a nocturnal predominance. Patients do not typically lose consciousness at the beginning but may lose consciousness later. The seizures occur in clusters (19). Patients exhibit very sudden arm movements or extension, which maybe unilateral or bilateral. If occurring unilaterally, the extended arm is contralateral to the ictal-onset zone. There can also be associated forced head turning, more frequently contralateral to the ictal-onset zone. The tonic motor activity is often followed by clonic movements. Tonic arm or leg extension can be bilateral and symmetric. Stepping automatisms of the legs may be associated with the seizure. Patients usually return to baseline very quickly without postictal aphasia, confusion, or changes in their tone (17). However, seizures may go on to be secondarily generalized with more tonic-clonic activity and loss of consciousness. Some patients demonstrate an aura, usually somatosensory in nature, such as numbness, tingling, a pulsating sensation, or heaviness. In many patients, seizures start suddenly and without any preceding signs.

Interestingly, patients with asymmetric tonic seizures have been noted to have less postictal stertorous respirations and briefer postictal generalized suppression of EEG as compared to bilateral symmetric seizures (07). Furthermore, asymmetry has also been reported in generalized seizures. As per a systematic review, the key focal signs reported in generalized-onset tonic-clonic seizures include early head version, figure of four sign, asymmetric seizure termination, auras, and automatisms (09). Asymmetry in clonic phase, asymmetrical seizure termination, figure of four sign, side-to-side axial movements, index finger pointing, and fanning posture of the hand were found to be significantly associated with focal to bilateral tonic-clonic seizures when compared with generalized-onset tonic-clonic seizures.

The seizure type is not known to manifest in any specific age group. Research studies include patients from 2 to 50 years of age. Both sexes appear to be affected equally. However, among the frontal lobe seizures, asymmetric or lateralized motor signs, such as dystonic posturing and figure of four, were reported to become more common with increasing age in a retrospective cohort of 122 patients (15).

Prognosis and complications

Like other focal epilepsies, 80% of patients respond to medication management. No specific medications are designed for the control of this seizure type, and no documented data show that localization helps influence the probability of the medication response (01).

Intractable forms may require surgical intervention or optimal control of their seizures (see Management section). Asymmetric tonic seizures associated with epileptic encephalopathies, such as Lennox-Gastaut syndrome, have a poor prognosis.

There is a higher risk of seizure recurrence as compared with those with generalized seizures (25). Loss of consciousness, although less common, can cause trauma, aspiration, burns, and accidents. Psychosocial issues add to significant morbidity. SUDEP is more common in patients with drug-resistant epilepsies, especially Lennox-Gastaut syndrome.

Clinical vignette

This 20-year-old right-handed female started having seizures at 7 years of age, manifested by tonic posturing of her right arm followed by tonic-clonic activity. Seizures were mainly nocturnal and occurred one to three times every night. Seizures were intractable to multiple medications. She underwent vagus nerve stimulator placement at 17 years of age--at that time failing medical management with oxcarbazepine, levetiracetam, zonisamide, and clonazepam. At the time of presentation to the level 4 epilepsy center, the patient seemed cognitively slow, was on carbamazepine and valproic acid, and had a normal examination.

Her seizures were recorded with video-EEG and consisted of asymmetric tonic extension of all four extremities lasting 20 to 40 seconds with impairment of consciousness.

Her EEG was unremarkable despite major motor activity, and even over the vertex there was minimal reflection of her seizure on EEG. Her MRI was unrevealing and did not show any clear abnormality. Further work-up, including investigation with intracranial EEG electrodes, proved seizure onset in the left supplementary motor area. The patient had a resection of her left supplementary motor area, and her seizures ceased. Pathology revealed cortical dysplasia. Her cognition improved significantly despite no changes in her antiseizure medication, which was most likely due to improved sleep. The patient is now attending college and has remained seizure-free for more than 4 years.

Biological basis

Localization

Asymmetric tonic seizures are thought to originate in the supplementary motor area, which is located on the mesial surface of the frontal lobes, just anterior to the primary motor area on the medial surface of the brain. Using deep brain electrodes to stimulate the region of the supplementary motor area in the dominant hemisphere, Lim and colleagues demonstrated that they could elicit predominately tonic movements (28). Many early investigators correlated asymmetric tonic activity with the supplementary motor area (34; 31; 03). Forced head deviation and limb extension is usually contralateral to the seizure-onset zone. If tonic posturing is asymmetric, it occurs contralateral to the seizure-onset zone. Hintz and colleagues studied 122 patients with frontal lobe epilepsy including those with asymmetric tonic seizures and noted that asymmetric tonic posturing and unilateral features may develop over time in patients with bilateral symmetric tonic seizures (15).

Asymmetric tonic seizures can also be a result of propagation to the supplementary motor area. Parietal lobe seizures and occipital lobe seizures can propagate anteriorly and have the identical appearance of supplementary motor area seizures (03; 26; 33; 17). Brief asymmetric tonic posturing has been associated with seizures originating in the precuneus region in the mesial parietal region, as well as the posterior cingulate region (11; 21). Seizures originating in the fronto-polar areas as well as those originating anterior to the actual supplementary motor area can propagate to the supplementary motor area and be indistinguishable from supplementary motor area seizures (16). Ikeda and colleagues demonstrated that although analysis of the epileptogenic zone with modalities including video-EEG monitoring, MRI, and neuroimaging with radioisotopes demonstrated involvement of the supplementary motor area, of the four patients enrolled only one demonstrated a true primary focus of their seizures in the supplementary motor area with chronically implanted subdural electrodes. Three of the four patients were found to have epileptogenic zones around the supplementary motor area, and resection with preservation of the supplementary motor area demonstrated good seizure control (16).

Etiology and pathogenesis

Some causes of asymmetric tonic seizures include the following (25):

Pathophysiology

Seizures are thought to be caused by neuronal excitation, which becomes synchronized with changes in the modulatory effect of interneurons (14; 36). From an initial seizure-onset zone, seizures may propagate to various other areas of the brain and lead to clinical symptoms. Subcortical structures may also play a major role in generating tonic and clonic activity, but this needs further investigation. The role of glutamate as a mediator of cellular hyperexcitability is also well established. AMPA receptors have been found to play a predominant role in mediating the degeneration and spread of seizure activities (36).

The supplementary motor area is closely connected to other areas, and seizure activity may propagate rapidly out of the supplementary motor area. As a consequence, asymmetric tonic seizures can be easily mistaken as originating elsewhere. Baumgartner and colleagues demonstrated rapid spread from the supplementary motor area to the primary motor cortex (03; 01). Using ictal SPECT, Laich and colleagues demonstrated that the bilateral basal ganglia were involved and there was a connection of the supplementary motor area to the cerebellum (26). A statistical analysis of transcallosal propagation of spikes recorded from subdural electrodes demonstrated that a propagation of spikes arises from the mesial frontal region via myelinated fibers to the contralateral nasofrontal region (37). In a retrospective analysis of 123 patients with supplementary motor epilepsy and bilateral asymmetric tonic seizures treated with resective epilepsy surgery, earlier contralateral abduction, and unilateral extension, especially in the upper limb, had the most localizing value (06).

There are many underlying causes for focal epilepsy and asymmetric tonic seizures. They include, but are not limited to neoplasm or malignancy, vascular insults, trauma, malformations of cortical development, inflammatory diseases, infections, systemic causes, and inborn errors of metabolism.

Epidemiology

There are very few specific epidemiological studies of asymmetric tonic seizures. It is generally accepted that in developed countries, the incidence of epilepsy is around 50 per 100, 000 per year. In resource-poor countries, the incidence is likely to be higher. Prevalence of active epilepsy is in the range of 5 to 10 per 1000 in most locations, although it might be higher in some isolates. Age-specific incidence rates have changed, with a decrease in younger age groups and an increase in persons older than 60 years. Nearly 30% of patients with focal epilepsy have seizures arising from the frontal lobe (25).

Prevention

Seizure precautions are the same as in any other seizure disorder. The general principles of prevention that are applicable to focal epilepsy are relevant to asymmetric seizures. Prevention strategies are also dependent on the etiology, which commonly includes structural abnormalities.

Differential diagnosis

Confusing conditions

Because patients generally are alert during these seizures, with short tonic posturing, asymmetric tonic seizures can easily be mistaken for nonepileptic events. Asymmetric tonic seizures can appear as psychogenic nonepileptic seizures, as consciousness may be preserved. A distinguishing feature is that epileptic seizures are extremely stereotyped and brief.

Because there is a nighttime predominance, parasomnias as well as nocturnal paroxysmal dystonias need to be considered in the differential diagnosis.

Additionally, dyskinesias, motor dystonias, tics, Tourette syndrome, chorea, and ballism should also be considered in the differential diagnosis (17).

Associated and underlying disorders

Asymmetric tonic seizures are associated with the syndrome of supplementary motor area epilepsy. Patients with supplementary motor area epilepsy have short, nocturnal seizures as described above. Frequently, the syndrome is caused by a clear lesion in the supplementary motor area, such as a mass lesion or cortical dysplasia. Seizure onset occurs usually in childhood in the case of cortical malformations or later if associated with mass lesions. Intellectual development and cognitive function are usually normal.

Autosomal dominant sleep-related hypermotor (hyperkinetic)/SHE epilepsy is characterized by seizures that occur in clusters. They are brief, usually occur at night, and have predominantly motor manifestations with tonic or hyperkinetic activity. Age of onset is usually within the first or second decade of life. Interictal EEG is usually normal and ictal EEG may show a sharp, strong spike followed by slow-wave discharge predominantly in the frontal regions. Seizures may persist throughout adult life but usually respond well to antiepileptic medications. Several genes coding for alpha 4 nicotinic acetylcholine receptor (nAChr) and ion channels like KCNT1 have been found to be associated with this epileptic syndrome (39; 30).

Patients with Dravet syndrome, an electroclinical syndrome associated with SCN1A mutations, may also be associated with asymmetric tonic seizures. In a series, five of eight patients had asymmetric tonic seizures (22).

There is also an association of asymmetric tonic seizures with the spectrum of seizures in patients with developmental/epileptic encephalopathies, such as Lennox-Gastaut syndrome. Asymmetric tonic seizures can be one of the seizure types in addition to generalized tonic-clonic seizures, atypical absences, or drop attacks. This severe form of epilepsy usually begins before 4 years of age, with a variety of seizure types including tonic, atonic, and atypical absence as well as myoclonic activity. There is also an association with impaired intellectual functioning, developmental delay, and behavioral problems.

Diagnostic workup

Initially when characterizing a seizure, a routine 20- to 30-minute scalp electroencephalogram is usually one of the first diagnostic tests performed. This test is not very sensitive to this particular type of seizure due to the deep location of the supplementary motor area. There is usually no disturbance in background rhythm, and interictal sharp waves are rare or absent in this patient population (31). An MRI of the brain should be performed to assess for structural lesions as well as subtle lesions, such as cortical dysplasias.

Some patients will require evaluation with video-EEG to establish a final diagnosis and characterize the seizures. Prolonged video-EEG may show interictal abnormalities in the midline. Background rhythm is usually normal. Video-EEG is helpful in characterizing the events based on semiology. Ictal EEG is often obscured by movement artifacts and can be entirely normal. Ictal sharp waves, if present, are seen near the midline (31). It is important to demonstrate that seizures are stereotyped. Nighttime predominance and association with sleep can be easily demonstrated.

If epilepsy surgery is considered, patients can further be evaluated with PET scan, ictal and interictal SPECT imaging. Ictal SPECT may demonstrate hyperperfusion in the region of the supplementary motor area and associated areas in the ictal phase (26). Laich and colleagues classified characteristic blood-flow patterns in the following two groups:

Wong and colleagues also characterized hyperperfusion of the supplementary sensory motor area ipsilateral to the epileptogenic region with the more typical asymmetric seizure with head version (38). If bilateral supplementary motor area hyperperfusion was observed, seizures were more likely to present with hypermotor automatisms.

Interictal PET scanning and magnetoencephalography (MEG) may also be helpful to identify the seizure-onset zone. Interictal PET, albeit not very sensitive, may show hypoperfusion on the mesial frontal surface of the brain, and MEG can localize magnetic and electrical dipoles to the appropriate brain region.

Management

No single specific antiseizure medication has been shown to be superior in frontal lobe epilepsy or asymmetric tonic seizures. Typical medications used in these patients include, but are not limited to, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, topiramate, zonisamide, valproic acid, levetiracetam (19), lacosamide, and perampanel. Perampanel has been shown to be especially effective in a subgroup of secondarily generalized seizures (24). Similarly, a study looking at the subgroup of patients with secondarily generalized seizures pooled data from the pivotal phase III studies (32). Brivaracetam greater than 50 mg/day was shown to result in 30.4% of patients achieving seizure freedom during the 12-week therapy phase. Medication side-effect profile should be considered in each individual patient. Due to the teratogenic effect of valproic acid, it should be avoided in women in their reproductive years. Comorbidities should also be considered in choosing the appropriate antiseizure medications. For example, topiramate may be helpful in patients with comorbid migraines. Levetiracetam and perampanel may worsen preexisting depression or psychiatric disease. In a practice guideline update summary, level A evidence was shown with pregabalin and perampanel for adult drug-resistant focal epilepsy (20). Cenobamate is an approved carbamate derivative with demonstrated efficacy for focal epilepsy (23). Ketogenic diet may also be considered for children with drug-resistant epilepsy when two or more antiseizure medications are ineffective (10).

Intractable seizures may respond to surgery. An anterior callosotomy can also be considered for patients refractory to medication management (18). Usually, a failure of monotherapy of two medications at appropriate doses is sufficient to refer the patient to a level 4 epilepsy center for surgical consideration (12). Surgical evaluation may include intracranial EEG evaluation.

Success rate after supplementary motor area resection ranges between 20% and 80%. Most studies report 50% to 70% favorable seizure outcomes (27). Epilepsy surgery can also be successful in patients who have a normal MRI.

The goal of epilepsy surgery should address psychosocial functioning, including employment (27).

Surgical resection of the unilateral supplementary motor area has been studied and found to be well tolerated. In a study of 28 patients, unilateral resection of the dominant and nondominant supplementary motor area for epilepsy was performed. Postoperatively, patients were found to have reversible contralateral weakness or dysphasia without cognitive impairments. These symptoms were found to last for a mean of 11 days, with a range of 3 to 42 days. Symptoms frequently resolve; this is a well-recognized syndrome that occurs after resection of the supplementary motor area without long term consequences (40).

Special considerations

Pregnancy

Consideration is similar to any other patient with focal seizures and includes the risk of teratogenesis from antiseizure drugs (02).

Anesthesia

Anesthetic considerations are similar to any other patient with focal seizures and are dependent on underlying etiology. Direct cortical stimulations to localize the motor strip during surgical resection of lesions in proximity to primary somatosensory cortex may necessitate the avoidance of muscle relaxants (08).