Clinical manifestations

Presentation and course

Atonic seizures may recognize a generalized or focal origin.

Generalized atonic seizures. The introduction of video polygraphic systems in the analysis of falling seizures has demonstrated that seizures characterized by pure diminution or loss of tone (atonic seizures) are distinctly rare, at variance with what was previously believed on the basis of only direct clinical observation. Only a few polygraphically documented atonic seizures are available in the literature: atonic seizures were present in 1 of 15 children studied by Ikeno and coworkers and in 9 of 45 patients with epileptic falls observed by Egli and coworkers (07; 19). Gastaut found atonic seizures in 3 of 2000 epileptic children followed at the Centre St. Paul pour Enfants Epileptiques in Marseille (12).

From clinical observation, two forms of atonic seizures have been recognized:

Polygraphic recording may reveal additional subtle clinical signs, such as bradycardia or brief arrest of respiration.

Partial focal atonic seizures. At least three types of ictal atonic phenomena may be seen in partial focal seizures:

Epileptic drop attacks (or falling seizures) may occur in the context of partial focal epilepsies, usually due to symmetric or asymmetric tonic stiffening caused by discharges involving the frontal lobe or supplementary motor areas (37; 39). More rarely, brief drop attacks are considered to result from atonic mechanisms, although video-polygraphic demonstration is available only in a few cases in the literature (34; 35).

Focal atonic seizures are partial focal seizures with ictal paresis or paralysis of one or more parts of the body, which must be distinguished from the more common postictal Todd paralysis. Several reports in the literature with video-EEG documentation of these seizures are now available (16) and have been reviewed (20). The ictal paralysis (usually hemiparesis) may be preceded or accompanied by a somatosensory aura.

Negative myoclonus is defined as an interruption of tonic muscular activity (50 to 400 msec in duration), time-locked to a spike or a sharp wave in the contralateral centro-parietal cortex on the EEG, without evidence of an antecedent myoclonia (38). Clinically, the negative myoclonus may be unilateral or bilateral and is manifest by brief lapses in tone that interfere with motor coordination, causing “instability” or, more often, dropping of objects from the hands, head nodding, or falls. Negative myoclonus may occur in a variety of extremely different epileptic conditions, including idiopathic and symptomatic entities. It is now classified as an autonomous epileptic seizure type (08).

Prognosis and complications

Whatever the origin and mechanisms of falling seizures in either generalized or partial focal epilepsies, their occurrence frequently represents an ominous sign because they are frequent, resistant to therapy, and physically dangerous, and they portend personality changes. In a series of 31 patients with epileptic drop attacks (of tonic or atonic origin) in partial epilepsy (mostly of frontal type), 74% of patients had a bad prognosis, and 45% were mentally retarded (39).

Biological basis

Localization

Because of the variety of seizures featuring atonia as the main clinical and polygraphic event, different mechanisms involving cortical and subcortical structures are likely implicated.

Gastaut and Broughton considered “epileptic drop attacks” related to very brief but intense inhibitory mechanisms, suggesting the importance of participation of the motor cortex (10). Data from electrical stimulation of human cerebral cortex reveal the existence of frontal regions whose activation produces inhibition of voluntary movement (27). These regions, defined as “negative motor areas,” have been localized in the superior bank of the Sylvian fissure near the rolandic representation of the face (“primary negative motor area”) (27) and in the rostral portion of the supplementary motor area in a region immediately anterior to the primary motor cortex (“supplementary negative motor area”) (25). The importance of these cortical inhibitory areas is well established in the genesis of focal atonic seizures and negative myoclonus but is only postulated in the origin of atonic falling seizures (34). An alternative explanation is that epileptic discharges in the primary sensorimotor cortex can produce negative motor phenomena via direct inhibition of the spinal motor neuron pool as suggested in humans by means of direct cortical stimulation through subdural electrodes (18) or ictal electrocorticogram (28).

The good results of callosotomy in the treatment of epileptic drop attacks in the context of partial epilepsies suggest that bilateral synchronization of the epileptic discharge via the corpus callosum is a crucial mechanism. Whether this may lead to bilateral activation of inhibitory cortical areas or cortical regions projecting downward to brainstem structures is not known. In the brainstem, the direct or indirect (via the corticoreticular efferents) activation of the pontine reticular formation, which is responsible for atonia or inability to move in REM sleep and in cataplexy, could produce a motor inhibition and underlie atonic seizures.

Pathophysiology

Generalized atonic seizures. Gastaut and colleagues studied the clinical features of the brief atonic seizures with video recording and found that the patients fall onto the ground in less than 1 second, with a typical sequence of events: (a) head drop (lasting for 250 msec), (b) trunk and legs drop (from 250 to 800 msec) (12). After an intermediate period of about 1 second, the patients resume a standing position in about 2 seconds. By examining the video-polygraphic features of 69 “atonic epileptic drop attacks” recorded in two patients with myoclonic-astatic atonic epilepsy, Oguni and colleagues observed that the clinical manifestations ranged from collapsing and landing on the buttocks to head nodding only (33). Detailed video analysis of the drop attacks with the patient in a standing position demonstrated the first manifestations to be flexion at the waist and knees, followed by further knee flexion, leading to falling straight down and landing on the buttocks.

The ictal EEG of atonic seizures discloses a generalized polyspike-wave discharge, with loss of tone usually being associated with the wave component of the spike-and-wave complexes.

Other ictal patterns include low- or high-voltage fast activity, flattening, or a burst of polyspikes followed by generalized spike-wave activity. Interictal EEGs are not specific to atonic seizures and consist of slow spike-wave activity or polyspike-wave complexes.

Partial atonic seizures. Epileptic drop attacks of atonic origin in the context of partial epilepsies have been studied in detail by Satow and colleagues in two patients, one with frontal lobe epilepsy and the other with parietal lobe epilepsy (34). Paroxysmal diminution of muscle tone mainly involved the axial muscles in both patients. The falls were slow, taking 2 to 5 seconds to fall down. Ictal EEG records showed low-voltage fast activity in the frontocentral area, followed by repetitive spikes at the midline frontocentral area in the patient with frontal lobe epilepsy and rhythmic spikes in the left central area in the patient with parietal lobe epilepsy. Interictal FDG-PET disclosed hypometabolic regions consistent with the clinical and EEG findings. Since this publication, at least nine additional case studies have reported similar findings, as reviewed by Kovac and Diehl (20).

Focal atonic seizures may have a long duration (longer than 30 minutes) and, therefore, may present as status epilepticus. Ictal EEG was recorded in 30 patients and showed spike-wave or slow-wave discharges (53%) or rhythmic ictal activity (47%) in frontal or centroparietal areas (63%), in the temporal lobe (20%), or distributed over a wide scalp region (17%) contralateral to the paralyzed limb (15).

In the only two patients with ictal electrocorticogram, the seizure discharges involved the mesial frontal or the primary sensorimotor cortices (31; 28).

Differential diagnosis

Confusing conditions

Because many seizure types and different mechanisms may be responsible for epileptic drops and falls, video-polygraphic monitoring is mandatory to achieve a correct diagnosis.

Aside from pure atonic seizures, epileptic drops and falls may be caused by myoclonic-astatic atonic seizures, myoclonic seizures, and (more frequently) tonic seizures (including axial spasms).

Myoclonic-atonic seizures are attacks in which the more or less pronounced loss of tone (usually leading to a sudden fall) is preceded by symmetrical myoclonic jerks of the arms or irregular twitching of the face. The ictal EEG shows generalized spike-wave discharges (at 2 to 3 Hz), with the spike usually associated with myoclonia and a brief period of attenuation and the slow wave with the ensuing atonia.

Myoclonic seizures causing sudden falls have been exceptionally recorded; in these cases, the jerks were associated with generalized spike-wave discharges at 3 to 3.5 Hz.

Tonic seizures represent the most common cause of sudden falls to the ground in children with Lennox-Gastaut syndrome. Tonic seizures may be axial, axial and proximal appendicular, or global and are characterized by sudden flexion of the neck and body, rising of arms in a semiflexed position, extension of the legs, contraction of facial muscles, rolling of the eyes, apnea, tachycardia or bradycardia, dilated pupils, enuresis, and facial flushing. Two types of “generalized” tonic seizures associated with falls have been described, namely short tonic seizures (or spasms) and prolonged tonic seizures.

Short tonic seizures, or axial spasms, resemble infantile spasms and are characterized by an abrupt and massive increase of tone, maximal in the neck and shoulder girdle. Polygraphic recordings demonstrate that these seizures often begin with a myoclonic jerk and, thus, are myoclonic-tonic seizures. The ictal EEG shows either generalized slow waves, no changes, or a slight attenuation.

Prolonged tonic seizures are characterized by an overt and sustained increase of tone over the axial and segmental muscles, over both agonist and antagonist muscles. The ictal EEG expression is either a run of low-voltage fast activity or a brief burst of generalized spike-wave or polyspike-wave activity.

Tonic posturing and stiffening are also responsible for the vast majority of epileptic falls occurring in partial epilepsies.

Video polygraphic monitoring may be needed to exclude drop attacks of nonepileptic origin. Meissner and colleagues analyzed the diagnosis in 108 consecutive patients with a history of drop attacks and found the following etiologies: unknown (64%), cardiac (12%), cerebrovascular insufficiency (8%), combined cardiac and cerebrovascular disease (7%), seizures (5%), vestibular (3%), and psychogenic (1%) (29). Other conditions in the differential diagnosis include cataplexy, syncopes, and breath-holding spells.

Associated and underlying disorders

Atonic seizures may occur in the context of generalized and partial focal epilepsies.

Epileptic falls and head nods of true atonic origin have been documented in the Lennox-Gastaut syndrome and myoclonic-astatic atonic epilepsy of early childhood (33), usually in combination with other seizure types.

In epilepsy with electrical status epilepticus during slow sleep, atypical absences with atonic components, epileptic falls, and negative myoclonus have been described in subgroups of patients (36), formerly reported under the heading of atypical benign epilepsy of childhood (01).

“Epileptic drop-attacks” are also described in partial focal epilepsies, particularly of frontal origin and with marked bilateral synchrony. In these cases, however, the falls are usually associated with tonic stiffening, or polygraphic documentation is scanty. Satow and colleagues reported pure atonic seizures in two patients with partial epilepsy (of frontal and parietal origin) studied by means of prolonged video-EEG monitoring (34).

Doose syndrome, or myoclonic-astatic epilepsy, is a rare childhood epileptic syndrome characterized by myoclonic-atonic seizures. The ketogenic diet has been found to be a successful treatment option for Doose syndrome.

Numerous gene mutations have been associated with atonic seizures, occurring in the context of distinct epilepsy syndromes of childhood. However, genetic heterogeneity in various syndromes and the phenotypic pleiotropy with most of the epilepsy-associated genes complicate the interpretation specifically to atonic seizures. Interestingly, ion-channel gene mutations do not appear to dominate the expression of atonic seizures. Mutations in transporter genes such as SLC2A1 (glucose transporter 1), SLC6A1 (GABA transporter), as well as ring chromosome 14 have been associated with atonic seizures, the first two in a Doose syndrome-like presentation.

Diagnostic workup

As stated before, video-polygraphic monitoring represents the only investigation capable of properly diagnosing atonic seizures. In fact, the definition of atonic seizures rests on the identification of the following neurophysiological features:

Therefore, video-polygraphy allows the recognition of epileptic or nonepileptic falls caused by different mechanisms and pathophysiology.

Ancillary diagnostic tools may be considered for specific purposes. MRI is needed in partial atonic seizures to disclose specific etiologies, such as cortical malformations (14). Stereo-EEG recording and ictal SPECT may be required in partial atonic seizures of symptomatic origin when surgical therapy is postulated.

Management

Medical treatment. The medical treatment of atonic seizures is usually disappointing and unsatisfactory because of the resistance to any conventional antiepileptic drug. Valproic acid associated with benzodiazepines is usually considered the treatment of choice. ACTH and hydrocortisone may have immediate and sometimes spectacular effects, but these are usually followed by relapse. Some of the newer antiseizure medications such as felbamate, lamotrigine, topiramate, rufinamide, and clobazam have shown efficacy in the treatment of drop attacks associated with the Lennox-Gastaut syndrome, in which the drop attacks may comprise of atonic as well as tonic seizures. A randomized, double-blind, placebo-controlled trial of rufinamide as adjunctive therapy in patients with Lennox-Gastaut syndrome showed a 42.5% median percentage reduction in drop attacks (13), whereas up to 77.6% reductions have been demonstrated with clobazam (30). Efficacy of cannabidiol for the treatment of refractory drop attacks associated with Lennox-Gastaut syndrome has been described (06).

Doose syndrome, or myoclonic-astatic epilepsy, is a rare childhood epileptic syndrome characterized by myoclonic-atonic seizures. One of the most successful treatment options for Doose syndrome is the ketogenic diet (03). Combination therapy of valproic acid and lamotrigine has been proposed as the treatment of choice for falling seizures in partial focal epilepsy.

Surgical treatment. Callosotomy is widely considered to be the surgical treatment of choice in patients with falling seizures who are not candidates for classical resective surgery. From a literature review, it appears that patients with tonic or atonic falls had a reduction of about 80% in seizure frequency after callosotomy in most instances. The aim of callosotomy is to limit the spread of convulsive discharges from one hemisphere to the other, and, therefore, patients with mainly lateralized foci with secondary generalization benefit the most (32). A meta-analysis suggests the superiority of callosotomy to vagus nerve stimulation for the treatment of atonic seizures (21). A review of 20 corpus callosotomy cases at the Children’s Hospital of Michigan found seven subjects who failed vagus nerve stimulator therapy responded with greater than 50% seizure reduction (26). They found corpus callosotomy to be an effective treatment for seizures leading to falls.