Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Frontal lobe seizures can have bizarre manifestations; however, they are easily recognizable if the clinician is well aware of the clinical presentation. Frontal lobe seizures are typically brief, nocturnal, and without loss of consciousness. Focal clonic seizures, asymmetric tonic seizures, hyperkinetic seizures, absence type seizures, and masticatory seizures originate in different subregions of the frontal lobes. Treatment includes medical as well as surgical options.
• Focal clonic seizures originate in the primary motor area; asymmetric tonic seizures involve the supplementary motor area; and prefrontal seizures often manifest as hyperactive seizures.
• Frontal lobe seizures may have bizarre manifestations with hyperactive behavior and preserved consciousness.
• Frontal lobe seizures can be misdiagnosed as psychiatric disease or sleep disorders.
• Frontal lobe seizures are brief and nocturnal and occur in clusters.
The first detailed description of focal clonic seizures, a type of seizure originating in the posterior frontal lobes, was published by JF Bravais in 1827 (16). Hughlings Jackson, in 1867, related clonic seizures to electric discharges in the contralateral prerolandic region (105). He described seizures with a “march of spasm” and wrote: “We may first see movement of the index-finger, then of the hand, then the whole arm, then of the face, leg, then of bilateral muscles” (63). The Commission on Classification and Terminology of the International League Against Epilepsy still classified these seizures as “Jacksonian seizures” in 1989 (03). In later classifications by the International League Against Epilepsy, those seizures are listed as “focal clonic seizure (without spread)” and “Jacksonian march seizures (with local spread)” (30; 31). They are also referred to as “focal motor seizures with elementary clonic motor signs” (30; 31), “clonic seizures” (64), “simple motor seizures,” or “somatomotor seizures.” If they involve the entire hemibody they are termed “hemiclonic seizures” (30). If focal clonic seizures persist for a prolonged time the term “epilepsia partialis continua” is applied (31).
Penfield and Welch performed stimulation experiments of the human and monkey cortex. They defined the supplementary motor area (Brodmann area 6) as a region of the brain that mediates speech and behavioral arrest, vocalization, and asymmetric contralateral posturing when stimulated (78). They described supplementary motor area seizures as seizures with speech arrest, unilateral arm posturing, and head or eye deviation, later referred to as "fencing posture" (77; 76). In a detailed study of pharmacologically induced seizures, Ajmone-Marsan created the term "M2e" to describe tonic abduction and external rotation of the shoulder with flexion of the elbow with or without head turning. He described supplementary motor involvement if M2e posturing occurred without loss of consciousness and without progression into a secondarily generalized tonic-clonic seizure (02). With the introduction of intracranial long-term EEG recordings, supplementary motor area seizures again became the focus of scientific interest in the late 1980s and early 1990s and were described in greater detail (26; 70; 69; 37; 108; 61; 23; 86; 08; 46; 35). The terms “adversive seizure” and “supplementary sensorimotor seizures” were also used to describe supplementary motor area seizures (02; 01). They were also listed as “focal (asymmetrical) tonic seizures” by previous publications (30; 31).
Focal unaware seizures of frontal lobe origin with bizarre automatisms were initially recognized by Tharp, who described three patients that were misdiagnosed as having psychogenic attacks (107). Using stereoencephalography, Geier, Bancaud, and Talairach defined frontal lobe automatisms further (40; Geier et al 1977), and detailed descriptions of focal impaired awareness seizures of frontal lobe origin followed (115; 111). The term "hypermotor seizure" was proposed for this type of seizure (64). These seizures are also termed "frontal lobe seizures with hypermotor automatisms," "frontal lobe seizures with frenetic automatisms," "complex partial seizures frontal lobe type," "frontal lobe seizures with agitated behavior," or "seizures with hyperactive automatisms" (113). They were also termed “hyperkinetic seizures” or “focal motor seizures with hyperkinetic automatisms” in some classification publications (30; 31).
In a later report of the International League Against Epilepsy (ILAE) on revised terminology and concepts for organization of seizures and epilepsy, frontal lobe seizures are classified as “focal seizures” with further descriptors such as “with or without impairment of consciousness” or “with or without observable motor components” (11). The latest iteration outlines the ILAE operational classification of seizure types with focal seizures described as either aware or with impaired awareness (34). Frontal lobe seizures with secondary generalization are now described as focal seizures evolving to bilateral tonic-clonic.
The frontal lobes contain 40% of the entire cerebral cortex. Epileptiform activity may arise in various areas of the large cortical surface, and several different seizure types are associated with subregions of the frontal cortex. These include focal clonic seizures, asymmetric tonic seizures, hyperkinetic seizures, frontal lobe absence seizures, and masticatory seizures. These seizure types are discussed below.
Frontal lobe seizures are the second most common type of seizures seen at epilepsy centers during presurgical evaluation for medication resistant epilepsy (09). The average age of onset of patients with intractable seizures of the anterior neocortex usually is in late childhood or early adolescence (53). Men and women are equally affected.
General characteristics of frontal lobe seizures. Frontal lobe seizures are significantly shorter in duration than seizures originating in the temporal lobes (52). Nighttime preponderance and association with sleep-wake cycle has been reported (115; Niedermeyer 1998; 53). Seizures may occur in nightly clusters of as many 70 in a row (36). Convulsive and nonconvulsive status epilepticus is frequently observed in frontal lobe epilepsy (114; 113).
No specific type of aura has been linked to frontal lobe seizures (53). Patients report an unspecific, unexplainable feeling, often localized to the head (“cephalic aura”) (53). However, a prospective series could not confirm that this aura distinguishes between seizures of frontal and temporal origin. Asymmetric tonic seizures originating in the supplementary motor area are often preceded by a somatosensory aura (69; 21). Autonomic auras like nausea or palpitations as well as emotional auras such as fear are also reported (53).
It was long assumed that frontal lobe seizures generalize rapidly and frequently in frontal lobe seizures (83). However, systematic analysis did not confirm that secondarily generalized seizures occur more frequently than in other localization-related epilepsies (21; 53). The notion that seizures of the anterior neocortex frequently generalize may stem from the observation that asymmetric tonic seizures share some clinical similarities with secondarily generalized tonic clonic seizures.
Consciousness is often preserved, even when there is bilateral motor involvement. If consciousness is impaired, these seizures typically are followed by minimal, if any, postictal confusion. If seizures of frontal lobe onset spread to the temporal lobes, postictal confusion, as typical for temporal lobe seizures, can be observed. Patients with frontal lobe epilepsy may have cognitive impairments. These may include verbal, executive function deficits. Theory of mind impairments have been described as a salient feature of frontal lobe epilepsy (41).
Specific seizure types.
Focal clonic motor seizures. Focal clonic seizures consist of unilateral clonic movements of the extremities, trunk, or face. Consciousness is preserved. The clonic activity occurs contralateral to the epileptic discharge. Clonic movements may be restricted to specific muscle groups such as the face or hand (focal clonic seizure without march), or they may spread following the somatotopic organization of the motor cortex (Jacksonian seizure, focal clonic seizure with march). Clonic movements can be multifocal involving several unrelated muscle groups. Focal clonic seizures do not have a daytime preponderance but have a tendency to continue for hours, days, or even months (epilepsia partialis continua). In addition to the clonic movements of the extremity, there may also be a dystonic component with, for example, cramping of the affected hand or foot.
Focal clonic seizures are often seen with diffuse unilateral hemispheric damage, but they are also associated with small circumscribed lesions in the primary motor cortex (Brodmann area 4) (22). Epilepsia partialis continua is characteristic of Rasmussen syndrome. In Rasmussen syndrome, focal clonic seizures are often multifocal with different muscle groups exhibiting differing frequencies and timing. In addition, epilepsia partialis continua can be associated with focal lesions, most commonly tumors, or inborn errors of metabolism (31).
Although a focal clonic motor seizure clearly implies seizure activity in the primary motor area, it does not equate with seizure origin there. Seizures beginning practically anywhere else in the brain can have a focal clonic component. Even when focal clonic motor activity is the sole clinical manifestation of the seizure, origin can be in clinical silent areas of the brain both anterior and posterior to the primary motor cortex.
Asymmetric tonic seizures. During seizures originating in the supplementary motor area, patients typically assume a sudden tonic posture of the extremities. Although tonic posturing is usually asymmetric (69), it can be very symmetric with few if any lateralizing features. Classically, there is tonic arm extension and elevation with forced head deviation to the side of the extended arm with the patient appearing to be looking at his upraised hand, referred to as fencing posture (13; 73). The tonic arm may also be flexed at the elbow, externally rotated and abducted, a posture previously termed M2e over 50 years ago by Ajmone-Marsan (02). If one arm is tonically extended the other is often flexed. Fingers of the abducted arm are often spread apart. The opposite hand is often clenched to a fist. Asymmetric tonic posture is more pronounced in the upper extremities but can also be observed in the lower extremities. During the fencing posture the patient may exhibit cycling or stepping movements of the legs. Although typical postures have been described as above, in practice, there are probably no clearly consistent patterns but a wide variety of different tonic manifestations. Individual patients, however, exhibit very stereotyped patterns. Consciousness is often preserved. Speech arrest occurs, but vocalization with the patient crying out for help is also possible (113). Tonic posturing may be followed by some brief clonic jerking, often bilateral (21). If seizures do not secondarily generalize, patients usually have no postictal confusion and rapidly return to normal. There is often nocturnal preponderance of brief, frequent seizures. These seizures can be distinguished from secondarily generalized seizures by the tonic postures, preservation of consciousness, paucity of clonic movements, and rapid postictal clearing. Asymmetric tonic seizures, however, can secondarily generalize. Careful attention to initial clinical seizure manifestations will often suggest the correct diagnosis but, in some cases, it can prove very difficult.
Asymmetrical tonic seizures are associated with seizure origin in the supplementary motor area but may also be observed with seizure origin in other areas of the anterior neocortex (13; 53; 113; 45; 85). Asymmetric tonic signs have lateralizing value to localize the seizure onset zone (14). Because many cortical areas of the anterior neocortex are clinically silent in terms of clinical seizure activity, analogous to focal clonic motor seizures, asymmetric tonic posturing can result from spread to the supplementary motor area from other cortical regions (01). Finally, these types of seizures can occur with seizure origin outside the anterior neocortex and may involve spread to the supplementary motor area from the posterior mesial neocortex (112).
When supplementary area seizures present with typical characteristics, they can be identified on the basis of these characteristics alone. However, because EEG findings in patients with asymmetrical tonic seizures are often normal or nonspecific, familiarity with the clinical characteristics is essential to avoid diagnostic error.
Patients with probable asymmetric tonic seizures were diagnosed with a specific parasomnia termed "paroxysmal nocturnal dystonia," an entity that is now recognized as a type of frontal lobe epilepsy (93; 82).
Hyperkinetic seizures. These seizures begin suddenly, sometimes explosively, with the onset of complex behavioral automatisms (107; 114; 111). Patients may jump around, thrash, rock to-and-fro, pound on objects, or rock back and forth. They may jump out of bed and run around in circles. Bicycling movements or stepping movements are frequently described. More subtle seizures consist of awakening and scrambling about the bed. Automatisms with sexual content are also reported (genital manipulation, pelvic thrusting), but sexual sensations are not (100). Motor manifestations are often accompanied by vocalization, such as screaming, yelling, shouting, humming, grunting, laughing, or barking. The patient may swear and produce understandable speech. Because of the prominent motor features these automatisms, which are distinctly different than the automatisms seen in temporal lobe seizures, have been called "hypermotor automatisms" (64). Consciousness is often preserved, and the patient clears rapidly after the seizure. The patient may be unable to speak during the seizure but will recall test phrases afterwards. The automatisms often have a nocturnal preponderance with flurries of many brief seizures per night. If consciousness is not impaired initially during a cluster of seizures, it does become clouded with an increasing number of seizures. The patient may go several days without seizures until the next flurry. These seizures are often bizarre in appearance and, when coupled with a paucity of EEG findings, are frequently misdiagnosed as psychogenic attacks.
These hyperactive seizures are associated with seizure origin in various parts of the anterior neocortex (53; 113). Although some authors proposed that bizarre hyperactive seizures are associated with origin in the orbitofrontal (107) or anterior cingulate areas, they are also observed with frontopolar, mesial frontal, and dorsal frontal origin (53). Hyperkinetic seizures are mainly associated with frontal lobe seizure onset (36). However, there are some case reports of hyperkinetic seizures with insular onset (88; Ryvlin et al 2008).
Absence type seizures (frontal lobe absence, frontal absence). Absence type seizures with altered consciousness and minimal motor involvement have been described in association with origin in the frontal lobes (05; 98; 53). The patient loses contact with his environment. He may still respond to his surroundings to some degree but in a slow and inappropriate way. These seizures can be brief and distinct, but they may also last hours or even days. These episodes, when prolonged, are a type of nonconvulsive status epilepticus. Although this condition has also been called "spike-wave stupor," this term is somewhat misleading because of the great variability in the level of altered consciousness from a barely perceptible change to bland unresponsiveness. For example, during prolonged episodes of this type of nonconvulsive status, patients may seem normal but complain of being mildly confused. They may also be partially or completely amnestic for events occurring during the episode despite appearing alert. The ictal EEG pattern consists of generalized disorganized spike-wave activity, a pattern similar to that described for absence status in adults. It is, therefore, important to differentiate this type of frontal lobes seizure from idiopathic generalized absence seizures, as they may be clinically and electrographically similar.
Masticatory seizures (opercular seizures). Masticatory seizures are characterized by prominent mastication, swallowing, and excessive salivation (05; 12). Consciousness is preserved. If the seizures originate in the dominant hemisphere, they are accompanied by expressive aphasia. They have been localized to the opercular region of the frontal lobes.
Frontal lobe seizures manifesting with typical temporal lobe symptomatology. Seizures may originate in the frontal lobes but present as temporal lobe seizures. Due to the close anatomic relationship of the medial, posterior orbitofrontal cortex to the mesial temporal structures, seizures originating in the orbitofrontal cortex may present clinically as temporal lobe seizures (53). They may begin with olfactory hallucinations followed by an altered state of consciousness with the typical oroalimentary and manual automatisms (05). These seizures can be clinically indistinguishable from mesial temporal lobe seizures, and only further diagnostic studies such as neuroimaging, intracranial EEG recording, or both can correctly identify extratemporal seizure origin.
Combined seizure types. Although the various types of frontal lobe seizures may appear as relatively typical examples, it is not uncommon for them to present as mixed forms. For example, an asymmetric tonic seizure may include some hypermotor automatisms or a seizure can begin with hypermotor automatisms and then evolve into a temporal lobe seizure.
Bonini and colleagues proposed an alternate categorization of frontal lobe seizures in terms of semiology with an anatomical correlate along the rostrocaudal axis based on 54 patients implanted with stereoencephalography (SEEG) (15). Group 1 clinically had elemental motor signs involving precentral and premotor regions, group 2 was characterized by elemental motor and gestural motor behavior corresponding to premotor and prefrontal involvement, group 3 had integrated gestural motor behavior with distal stereotypies corresponding to anterior lateral and medial prefrontal regions, and group 4 had fearful behavior implicating the ventromedial prefrontal cortex.
The true percentage of patients with seizures originating in the anterior neocortex is not known because many patients may respond well to medications. Some patients remain intractable despite optimal management with antiseizure medications. If epilepsy surgery is performed, reported success rates for a good or seizure-free outcome vary between 26% and 80% (115; 111; 18; 57; 90; 08; 97; 98; 104; 53; 95; 47; 58). If patients are seizure-free two years after surgery, their likelihood of remaining seizure-free is 86% (29). Epilepsy surgery can be effective in lesional and MRI-negative patients (96; 67; 58).
A 41-year-old woman had seizures since the age of seven years. Her seizures were initially infrequent and consisted of leg tingling and left arm elevation. Despite multiple antiepileptic medications, she had a seizure about once per month. At 40 years of age, after a failed pregnancy, her seizures increased in frequency and occurred every night. She did not lose consciousness during her seizures. Her seizures were brief and only lasted 10 to 20 seconds but were associated with left arm and leg elevation. She underwent video-EEG monitoring; however, there were only minimal EEG changes during the seizures.
She did not have any interictal epileptiform abnormalities.
Her MRI showed a right mesial frontal lesion.
She underwent an intracranial EEG study that localized the seizure onset zone to the right supplementary motor area. She underwent a resection of the mesial frontal cortex. Pathology confirmed cortical dysplasia. She was seizure-free at last followup, more than seven years after surgery.
Because large areas of the anterior neocortex, such as the prefrontal cortex, may be clinically silent in terms of clinical seizure manifestations, the first clinical sign may be the result of propagation to areas remote from the region of seizure origin. As a result, clinical presentation may not correlate with seizure onset. However, there are some typical locations that are associated with certain seizure types.
Focal clonic seizures indicate involvement of the primary motor cortex, but isolated lesions of the primary motor cortex are relatively uncommon. Focal clonic seizures are most commonly seen with diffuse contralateral hemispheric lesions (22).
Asymmetric tonic seizures are associated with seizure origin in the supplementary motor area; however, as explained above, they may also be the result of secondary spread to the supplementary motor area. Seizures may spread to the supplementary motor area from the prefrontal cortex, often the fronto-polar area, or from the parietal cortex (13; 113). Asymmetrical tonic posturing or a fencing posture is a fairly reliable sign to distinguish frontal lobe seizures from temporal lobe seizures (73).
In asymmetric tonic seizures, the predominant and sometimes exclusive tonic posturing is contralateral to the side of seizure origin (70; 53). The lateralizing value of forced head turning with asymmetric tonic posturing has been discussed extensively in the literature. It occurs more commonly contralateral to the side of seizure origin, but not invariably (87; 74; 116; 14). If forced head turning occurs shortly before generalization, it is more consistently contralateral to the side of seizure origin (117). Head and eye deviation has been described to be more commonly associated with dorsolateral frontal seizure onset, involving the frontal eye-fields, but is definitely also a common sign of seizures originating in the supplementary motor area (53; 27).
Hyperactive seizures seem to localize nonspecifically to the anterior neocortex (115). They have been suspected to originate in the orbitofrontal (107; 65; 20), mesial frontal (111), anterior cingulate (05), frontopolar area, and frontal dorsal convexity (83). There is no conclusive evidence that any of these locations is more commonly associated with this type of seizure. Hypermotor automatisms could also represent a frontal release phenomenon (53; 113). Hyperactive seizures with rocking and agitated automatisms are thought to originate anterior to the motor areas of the frontal lobes, whereas tonic and dystonic features suggest onset in supplementary motor area (84). Due to seizure propagation, seizures originating in the insula can present as hyperactive seizures and mimic nocturnal frontal lobe epilepsy (88).
Absence type seizures were reported to originate at the medial surface of the frontal lobes (05), but have also been observed with frontopolar and frontal convexity seizure onset (53).
Masticatory seizures are associated with onset in the frontal operculum (05; 12; 53).
As discussed above, seizures originating in the orbitofrontal region can present with typical hyperactive automatisms, or they can clinically mimic seizures originating in the temporal lobes (Munari and Bancaud 1992; 71; 53). It has been proposed that the orbitofrontal area may remain clinically silent, and clinical manifestations are just a manifestation of seizure spread. It has also been proposed that the major clinical manifestations are autonomic in nature and not easily recognized (71). The close neural connections between the frontobasal region and the temporal lobe can also result in hyperkinetic manifestations of temporal lobe seizures (109).
The same principles associated with the causes of human epilepsy apply to frontal lobe seizures. These have been summarized by Engel and include nonspecific predisposing factors, specific epileptogenic disturbances, and precipitating factors (32). The causes are variable and include amongst others genetic disorders, postanoxic brain injury, neoplastic brain disorders, infections including neurocysticercosis, disorders of cortical development, and inflammatory and immune mediated disorders.
The basic pathophysiology of frontal lobe seizures is the same as for other focal seizures, which is thought to be a localized breakdown of the balance of electrical inhibition and excitation. The striking tendency of certain types of anterior neocortical seizures to occur in nocturnal clusters of frequent, brief seizures with little or no postictal confusion, the preservation of consciousness during some complicated seizures with documented bilateral brain involvement, and the propensity of anterior neocortical seizures of all types to evolve into episodes of status epilepticus would strongly suggest that some special, as yet unknown, pathophysiological mechanisms exist. Liu and colleagues have described early lipofuscin accumulation as a separate novel pathology distinct from focal cortical dysplasia (62).
Frontal lobe seizures have the same underlying pathologic substrate as other types of focal epilepsies. Cortical dysplasias and other malformations of cortical development are a common substrate. Tumors, vascular malformations, and posttraumatic encephalomalacia are other etiologies. A significant number of patients with frontal lobe seizures have no identifiable lesion on imaging and, therefore, the underlying etiology often remains unclear. Autosomal dominant nocturnal frontal lobe epilepsy is a channelopathy of the nicotinic acetylcholine receptor that is widely distributed throughout the frontal lobes (66).
There are scan studies specifically addressing the epidemiology of frontal lobe seizures. The general principles are addressed by Téllez-Zenteno and Hernández-Ronquillo, who reviewed the epidemiology of temporal lobe seizures (106). Focal seizures including frontal lobe seizures are estimated to represent 60% of patients with epilepsy. The prevalence in epilepsy ranges from four cases per 1000 in the developed world to 57 cases per 1000 persons in developing countries, especially those afflicted by neurocysticercosis. The median incidence of epilepsy in developed countries ranges from 25 to 50 per 100,000 person-years and is as high as 115 per 100,000 person-years in developing countries. The incidence is highest in early adulthood in the developing world as opposed to children and the elderly in developed countries.
Seizure precautions are the same as in any other seizure disorders. The general principles of prevention that are applicable to focal epilepsy are relevant to frontal lobe seizures. Prevention strategies are also dependent on the etiology, which commonly includes structural abnormalities.
Differential diagnosis includes generalized epilepsy (absence), psychogenic nonepileptic seizures, parasomnias (REM behavior disorder, periodic limb movement disorder, somnambulism), and other focal epilepsies (parietal, temporal).
Despite increased recognition and understanding of frontal lobe seizures, the potential for diagnostic error remains high (115; 05; 18; 54). For example, hyperactive seizures coupled with loud vocalization or asymmetric tonic seizures can have a bizarre appearance. They can easily be mistaken as nonepileptic psychogenic seizures (54). Ictal and interictal EEG in frontal lobe seizures can be uninformative and without any definite epileptiform changes, which accounts for diagnostic errors. Frontal lobe seizures can be misdiagnosed as parasomnias; however, interactive behavior, indistinct onset, and failure to wake after the event point to parasomnias (24).
Familiarity with the condition is of primary importance. For example, if a patient gives a history of frequent nocturnal episodes consisting of stiffening of one side of the body more than the other or of multiple nocturnal episodes of awakening, scrambling about the bed, and shouting with at least partial preservation of consciousness, the diagnosis should be strongly suggested based on history alone.
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). This is a disorder that usually manifests itself in childhood with clusters of brief, nocturnal seizures (94). These may have the appearance of bizarre hyperactive seizures or asymmetric tonic seizures without loss of consciousness. Seizures occur in clusters, exclusively at night and more commonly in stage 2 sleep. Patients with this syndrome are cognitively and neurologically intact. However, neuropsychological impairment and more severe forms with psychiatric manifestations have been reported (24; 81). Imaging studies do not reveal any structural abnormalities and the seizures usually respond well to standard antiepileptic medications (92). Missense mutations of the gene for the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) have been shown to be responsible for the syndrome (102). The gene has been mapped to chromosome 20q13.2 and 15q24 (103) and has been shown in Australian, British, Canadian, Spanish, Japanese, and Norwegian families (72). A gene locus on chromosome 1 encoding the beta2 subunit of the nicotinic receptor (CHRNB2) has been reported in Italian and Scottish families (38; 79). In an Italian family, a missense mutation of the alpha2 subunit (CHRNA2) has been described, which indicates that autosomal dominant frontal lobe epilepsy is a heterogeneous disorder (66). Six mutations have been identified and further specified by Hoda and colleagues (Hoda et al 2008). Potassium channel KCNT1 mutations have been identified in families with ADNFLE with intellectual disabilities and psychiatric features by Heron and associates (43). ADNFLE has been associated with the corticotrophin release hormone (CRH) gene as well as with DEPDC5 mutations (91; 80). Nocturnal frontal lobe epilepsy may also be caused by a mutation in the GATOR1 complex gene NPRL3 (55). Separately, DEPDC5 mutations are associated with familial focal epilepsy with variable foci (FFEVF), an autosomal dominant disorder as described by Dibbens and colleagues (25). Baulac and associates have reviewed the spectrum of DEPDC5 mutations that includes both nonlesional focal epilepsy and focal epilepsy associated with malformations (07). A review by Baldassari and colleagues tried to define the phenotypical and mutational spectrum of epilepsies associated with DEPDC5, NPRL2, and NPRL3 genes (GATOR1 complex is a negative regulator of the mTORC1 pathway) in 73 probands. Fifty percent had hypermotor/frontal lobe seizures. Sudden unexplained death in epilepsy (SUDEP) occurred in 10% of the families (04).
Autosomal dominant frontal lobe epilepsy usually responds well to standard antiseizure medications. Carbamazepine is effective in these patients (66). Interestingly, autosomal dominant nocturnal frontal lobe epilepsy seems to improve with nicotine (17).
Rasmussen syndrome. Focal clonic seizures and especially epilepsia partialis continua are associated with Rasmussen syndrome, which is characterized by the development of epilepsia partialis continua, slowly progressive hemiparesis, progressive cognitive deficits, and progressive atrophy of the affected hemisphere (99). Seizures are often unresponsive to standard antiseizure medications and functional hemispherectomy should be considered if there is no improvement. Diagnosis is made by the typical clinical picture and histopathologic findings (42). There typically is microglial proliferation, micronodules, and perivascular infiltrations with cuffing and neuronophagia (99). Because of the underlying inflammatory process, immunosuppressive therapy and treatment with immunoglobulin has been shown to be effective.
Benign childhood epilepsy with centrotemporal spikes. This disorder is characterized by partial seizures with or without generalization occurring during childhood with typical centrotemporal spikes. There is a genetic predisposition, no cognitive impairment, and usually good response to standard antiseizure medications. Remission during the second decade of life is the rule. Seizures may present as typical focal clonic seizures with unilateral involvement of face, lips, and tongue or as masticatory seizures with drooling and speech arrest (60). Consciousness is often preserved. Benign childhood epilepsy with centrotemporal spikes is considered a benign syndrome as seizures frequently remit in adulthood. Seizures usually respond well to treatment with antiepileptic medications. Fejerman and colleagues describe a variant with difficult-to-treat seizures but with good prognosis (33).
An accurate and complete clinical history and neurologic exam is essential to diagnose frontal lobe seizures. Neuroimaging should be performed to search for intracerebral lesions. MRI imaging should include FLAIR imaging to assess for cortical dysplasia. MRI at 3 Tesla is preferred to identify subtle abnormalities of cortical development. Interictal EEG is often of limited use for the diagnosis and is frequently normal. Even long-term interictal EEG recordings may be completely normal. If interictal spikes are observed, they can be helpful to establish the diagnosis of epilepsy. However, the location of interictal spikes can be falsely localizing. For example, patients with orbitofrontal seizure origin may have anterior temporal spikes on EEG. Interictal midline theta activity has been identified to be a reliable indicator of frontal lobe seizure onset, but a negative interictal EEG does not rule out frontal lobe seizures (10).
Video and EEG monitoring is often required to establish a definite diagnosis by recording clinical seizures and ictal EEG. As previously noted, in a certain percentage of patients even ictal scalp EEG findings may not show definite epileptiform activity, and diagnosis has to rely on clinical seizure characteristics. In addition, ictal EEG is often obscured by artifact. Neuropsychological testing may show cognitive deficits that correlate with frontal lobe dysfunction. Impairment of executive function, response inhibition, and social cognition are associated with frontal lobe epilepsy (51).
Reformatted MRI and ictal SPECT studies can be helpful to localize seizure origin but are usually only performed in specialized epilepsy centers (59). Interictal FDG-PET can be helpful in seizure onset localization. Magnetoencephalography (MEG) or EEG source imaging can be helpful to localize interictal spikes to certain subregions of the frontal lobes (39; 75). If epilepsy surgery is considered and the MRI is normal, intracranial video and EEG monitoring with subdural or depth electrodes or both is usually mandatory. Functional mapping may be necessary to identify functionally important regions of the brain such as language areas and the primary motor cortex.
Other currently investigational diagnostic methods like recording EEG and coregistering it with fMRI (EEG-fMRI) and advanced MRI methods may help to localize the seizure onset zone to subregions of the frontal lobes.
Seizures of the anterior neocortex respond to standard antiepileptic medications. Levetiracetam, lamotrigine, carbamazepine, phenytoin, valproic acid, zonisamide, and oxcarbazepine are well-established antiepileptic medications routinely used for frontal lobe seizures. Newer antiepileptic medications, such as lacosamide and perampanel, may be helpful in intractable seizures (101). Eslicarbazepine and brivaracetam are also newer options (28; 89). Cenobamate has been approved as adjunct antiseizure therapy in adults with focal epilepsy (56). The choice of the antiseizure medication should be guided by the side-effect profile of the particular agent. Unfortunately, a patient’s economic situation also influences the choice of antiseizure medication (49). If patients are not responsive to monotherapy, polytherapy should be considered.
If medical therapy fails, resective surgery should be considered and the patient should be referred to a specialized epilepsy center for epilepsy surgery. If monotherapy trial of 2 standard antiseizure medications at therapeutic doses fails to control seizures, surgical referral should be considered. If resective surgery is not possible, callosotomy to prevent generalization or vagus nerve stimulation are other surgical options (48). Responsive neurostimulation has been available since 2013, with a median reduction of seizures of 70% at 6.1 years for frontal and parietal seizures (50). Deep brain stimulation targeting the anterior nucleus of the thalamus is also available for the treatment of focal seizures (68). Centromedian stimulation of the thalamus is not approved, but has been used in patients with Lennox-Gastaut and generalized seizures involving the frontal lobes (110).
Autosomal dominant frontal lobe epilepsy usually responds well to standard antiepileptic medications. Carbamazepine is effective in these patients (66).
Consideration is similar to any other patients with focal seizures and includes the risk of teratogenesis from antiseizure drugs (06).
Anesthetic considerations are similar to any other patients 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 (19).
Dawn Eliashiv MD
Dr. Eliashiv of the David Geffen School of Medicine at the University of California, Los Angeles, received honorariums from Eisai, Greenwich, Cyberonics (LivaNova Inc), Medtronic, Neuropace, SK Lifescience, Sunovion, and UCB for consulting work.See Profile
Jerome Engel Jr MD PhD
Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, received honorariums from Cerebel for advisory committee membership.See Profile
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Nov. 08, 2021
Epilepsy & Seizures
The cardinal symptom of absence status epilepticus is the altered state of consciousness while the patient is usually fully alert and partially responsive. It is characterized by a prolonged, generalized absence seizure that typically lasts for hours but can last for days. It may be typical, occurring in patients with idiopathic generalized epilepsy, or atypical, or may appear de novo. Medication nonadherence is a common trigger.
Oct. 23, 2021
Epilepsy & Seizures
Experiential symptoms are illusions or hallucinations that result in erroneous interpretations of the present experience, including déjà-vu, jamais-vu, hyperfamiliarity, sensory and memory illusions, and out-of-body experiences termed autoscopy. They can occur in focal epilepsy arising from the temporal lobe, as well as during the aura phase of migraine headache, in the context of psychiatric disease, or in association with mass lesions or inflammatory conditions of the temporal lobe.
Oct. 18, 2021
Epilepsy & Seizures
West syndrome presents in infants with spasms, hypsarrhythmia on EEG, and psychomotor delay. Infantile spasms are characterized by synchronous, bilateral, brief, and sudden contractions of the axial muscle groups. It is one of the most recognized types of epileptic encephalopathy.
Oct. 17, 2021