Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Seizures with focal onset may begin with a somatosensory, special sensory, visceral, or experiential aura in up to 83%, depending on the localization of the epileptic discharge and on the accuracy of documentation. Typically, an aura lasts seconds to minutes, is stereotyped, and evolves to other ictal clinical features, including loss of awareness. If an aura occurs in isolation, ie, is self-limited in time and without further progression, it is more appropriately called a focal-onset seizure without spread (“focal aware” seizures, according to the 2017 ILAE Classification of the Epilepsies). Rarely, such symptoms last hours to days (and rarely even years) and are then called “aura continua,” ie, represent a form of focal status epilepticus. As with epilepsia partialis continua, the motor counterpart to aura continua, the understanding of the nature of the aura continua in terms of exact pathophysiology awaits clarification. Animal experiments suggest that some neurochemical alterations, including galanin and other inhibitory peptides, might limit neuronal excitability in this peculiar epileptic manifestation.
• Aura continua is a rare phenomenon, difficult to diagnosis, and often occurring with other forms of seizures in the same individual.
• Therapeutic medication trials or specialized testing may be needed to firmly establish the diagnosis.
• Aura continua has varied clinical manifestations, depending on the cortical region of origin, and is often associated with an underlying focal cortical lesion.
• Treatment of aura continua is often difficult and complete seizure freedom is not always possible.
Galen enshrined the term "aura" into the medical terminology. In Book 3, Chapter 11, he deals with it, saying that "in epilepsy the head is sick, or sometimes the head in association with other organs. . . [epilepsy] can start from the stomachos...” Specifically, Galen coined the term aura (taken from the Greek and originally meaning "breeze") by describing a 13-year-old boy who explained that the condition "originated in the lower leg and then from here climbed upwards . . . as far as to the head; and as soon as it has touched the latter he was no longer able to follow.” Although the patient himself could not tell what exactly rose up, another youth, a better observer, said "that it was like a cold breeze" (35).
It is interesting to note that Alexander von Tralleis (6th century) recommended that in patients with such an aura, the therapy should also be directed to the organ affected by the aura. He described a patient in whom he had successfully treated his epilepsy by local application of capsicum to his involved foot (47).
John Hughlings Jackson (1835 to 1911) then described what was later called psychomotor attack by Gibbs and colleagues and Dämmerattacke (twilight attack) by Meyer-Mickeleit (37; 75). Jackson’s concept of "a particular variety of epilepsy" (56), the "uncinate fits," also had forerunners. In 1748, Robert Whyatt had described such a condition with gelastic seizures and olfactory aura (128). Anderson as well as Jackson and Beevor had noted the association of temporal lobe tumors with olfactory hallucinations and dreamy states (54; 04). However, it was the post mortem finding of a small cystic lesion restricted to the uncinate gyrus in a patient who had suffered from seizures with dreamy states, elaborated automatisms, and amnesia (55) that led Jackson and Stewart to the concept of "uncinate fits" with "origin of the discharge lesion . . . made up of some cells, not of the uncinate gyrus alone, but of some cells of different parts of a region of which this gyrus is part . .” (56).
The term "aura" is usually referred to that portion of a seizure experienced before loss of consciousness occurs and for which memory is retained. In the case of a focal aware seizure, the aura is the entire seizure; however, where consciousness is subsequently lost, the aura is, in fact, the first symptom of a focal impaired awareness seizure (28).
Scott and Masland first describe somatosensory hallucinations as a "continuous symptom" of an "aura continua” (102). The term "aura continua" can be found in Karbowski as a synonym for continuous psychomotor status (63; 137). Wolf used it as synonym for "status epilepticus of focal sensory seizures" or for hallucinosis (146; Wolf 1980; Wolf 1982).
The revised 2015 ILAE status epilepticus classification utilizes 4 axes: (1) seizure semiology, (2) etiology, (3) EEG correlates, and (4) age to classify status epilepticus (118). In this classification system, aura continua is listed in axis 1 under “Section B.2.b.a,” which includes seizures without prominent motor symptoms and without impairment of consciousness. Under this classification system, there is no specific minimum time duration for seizures to be considered status epilepticus. Instead, seizures are considered to be status epilepticus when there is “failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.” For focal status epilepticus with impaired consciousness, t1 (time when a seizure is likely to be prolonged leading to continuous seizure activity) is thought to occur at around 10 minutes. However, a t1 time duration has not been proposed specifically for focal seizures without impaired consciousness, including aura continua.
In the unified EEG terminology and criteria for nonconvulsive status epilepticus published in 2013, aura continua is classified as a form of nonconvulsive status epilepticus without coma or stupor with focal onset and without impairment of consciousness (10).
Long-lasting epileptic phenomena can be motor, nonmotor, or both (13). The term “aura continua” typically refers to those subjective feelings without visible motor phenomena. Thus, focal status epilepticus with motor phenomena or any other objective phenomena, such as aphasia, is not included. In the 2017 ILAE Classification of Seizure Types, aura continua is classified as a focal aware seizure type with nonmotor onset (33).
EEG may not reveal an ictal discharge during aura continua. However, working EEG criteria for nonconvulsive status epilepticus, including aura continua, includes epileptic discharges greater than 2.5 Hz or epileptic discharges less than 2.5 Hz or rhythmic delta/theta activity (greater than 0.5 Hz) AND one of the following: (1) EEG and clinical improvement after intravenous antiepileptic drugs or (2) subtle clinical ictal phenomena during the EEG patterns mentioned above or (3) typical spatiotemporal evolution (10).
From a clinical point of view, aura continua can be classified into 4 types: (1) somatosensory (ie, dysesthesia phenomena that involve the trunk, head and extremities); (2) aura continua that involve the special senses (ie, visual, auditory, vertiginous, gustatory and olfactory); (3) aura continua with predominantly autonomic symptoms; and (4) aura continua with psychic symptoms (122).
A special subtype in children, the so-called abdominal aura continua (abdominal epilepsy, recurring abdominal pain) has been described (100; 78; 90).
Pain as an epileptic aura (127), and painful epileptic seizures are likewise uncommon but are described (145; 147; 107). Direct evidence that long-lasting pain occurs as aura continua (ie, as a special form of focal status epilepticus) is also scanty, but this possibility should not be discarded. Indeed, Seshia and McLachlan report 2 patients with long-lasting aura continua and "pain" (103). The first patient was a 21-year-old with nose pain for 2 years and left temporal seizure origin. The symptom abolished after surgery, without pathology in the resected tissue. The second patient was a 43-year-old with epigastric pain and right temporal seizure origin; the symptom abolished after surgery. Certain forms of pain might be closely linked to epileptic basic phenomena (34), and the positive therapeutic effect of antiepileptic drugs in such circumstances is well-known.
Aura continua with elementary visual phenomena have been described by Gastaut, and prolonged complex visual hallucinations are described by Gastaut, and Sowa and Pituck (36; 111). Status epilepticus amauroticus is described by Barry and colleagues, and ictal visual hallucinations with reversible postictal hemianopia with anosognosia by Barry and colleagues, and Spatt and Mamoli (08; 112). Sheth and Riggs reported an unusual case of a clinically silent occipital electrographic status epilepticus persisting for more than 3 years in a 13-year-old girl (104). Hadjikoutis and Sawhney describe a case with occipital seizures presenting with bilateral visual loss (43).
Various medical conditions have been associated with epileptic visual hallucinations. Ghosh and colleagues reported a 34-year-old woman who developed simple partial seizures with ictal visual hallucinations and interictal right homonymous hemianopia due to left posterior quadrant seizures (41). These initially occurred 8 days after liver transplant surgery and occurred up to 22 times per day, with persistent interictal amaurosis. These continued for 1 week before EEG testing confirmed the epileptic etiology for her symptoms. The seizures ceased after levetiracetam treatment. In this case the etiology was not clear, as no lesion was seen on MRI, but it may have been related to immunosuppressive therapy. Donat and associates also described 2 men who developed visual hallucinations and hemianopia due to occipital seizures in the setting of nonketotic hyperglycemia (27). Kataoka and Ueno described a case of persistent headache and ictal palinopsia and polyopia in a 54-year-old woman with occipital lobe seizures (64). In this case as well, the MRI was normal. Gabapentin reduced the patient’s headaches and visual symptoms. Aura continua with visual allesthesia (visual images from one half of the visual field transposed to the other half) was reported in a 57-year-old man with a prior right parietal traumatic brain injury due to a gunshot wound (74). In this unusual case, the patient suffered from seizures during which images from his right visual field were transposed to his left. These symptoms eventually became continuous over an hour and correlated with seizures arising from the right parietal-temporal region on EEG. After treatment with lorazepam, levetiracetam, divalproex sodium, and gabapentin, his seizure frequency improved and he experienced occasional simple partial seizures on discharge from the hospital. Schiffter and Straschill as well as Wieser described aura continua musicalis (101; 130). Wieser’s patient was published under the heading psychomotor status epilepticus because, eventually, the aura continua with musical hallucinations (the patient experienced a song well-known and familiar to her) in "endless repetition" and with stereo-EEG documented restricted epileptiform discharges near Heschl gyrus spread to the ipsilateral mesiobasal limbic structures, accompanied by alteration of consciousness. The beginning of this electrical epileptiform status activity was accompanied by musical hallucinations only. Most cases with simple auditory hallucinations described in literature do not fulfill the criteria of an aura continua (88; 62). Blanke and colleagues describe a patient with epilepsy (secondary to left parieto-temporal brain damage) suffering from the paroxysmal unilateral experience of hearing a person in her near-extrapersonal space associated with a deficit in spatial auditory perception and other paroxysmal disorders of somatognosia (12).
Mesial temporal limbic status with olfactory symptoms has been documented (132). A "gustatory aura continua" occurred, with left hippocampal status activity in the depth EEG (138). It was also associated with subtle higher cognitive deficits detected with a tachistoscopically presented lexical decision task. Seshia and McLachlan report 1 patient with long-lasting metallic taste for 2 years (a 46-year-old with left temporal seizure origin; symptom abolished after surgery; oligodendroglioma) and another with foul taste for 5 years (a 34-year-old with right temporal seizure origin; symptom abolished after surgery; mesial temporal sclerosis) (103).
Hamasaki and colleagues reported a case of a 42-year-old man with a 12-year history of persistent olfactory auras that resolved after focal resection of the prepiriform cortex and focal amygdala resection, where an ictal discharge was seen on intracranial electrode monitoring (45). As in many other cases of aura, the scalp EEG showed no ictal change. The main clinical features of autonomic seizures are abdominal sensations, apnea, arrhythmias and bradyarrhythmias, chest pain, cyanosis, erythema, flushing, genital sensations and orgasm, hyperventilation, lacrimation, miosis, mydriasis, or hippus, palpitations, perspiration, pilomotor excitation ("gooseflesh"), tachycardia, urinary urgency and incontinence, and vomiting. Psychomotor partial seizures with autonomic symptoms as the leading feature are well known (143). Under the category nonconvulsive status epilepticus, Rabending and Fischer describe ictal bradycardia and asystole (94). For reference, though not a series of aura, another study evaluating focal epileptic seizures in 43 patients with refractory epilepsy found that 39% had rhythm and/or repolarization abnormalities on ictal ECG, including atrial fibrillation, supraventricular tachycardia, asystole, and other abnormalities (82). It is unclear how often aura continua causes cardiac abnormalities, though it is likely uncommon.
Autonomic seizures and autonomic status epilepticus have been best studied in Panayiotopoulus syndrome (84). In this syndrome with good prognosis, seizures start with autonomic symptoms, mainly emesis, while the child is fully conscious. Half of the seizures last longer than 30 minutes, constituting autonomic status epilepticus (85; 67). Although many patients have a relatively benign course, there are rare cases of more severe autonomic status epilepticus, including respiratory arrest requiring intubation (26).
Umbilical sensations in children (121), long-lasting borborygmi, widened pupils, pilomotor phenomena, goose-flesh or periodically shivering, etc. have been described (15; 129; 131; 133; 134; 135; 136; 131; 113). Certain peculiarities of personality and behavior are often associated with such conditions and, therefore, we describe such conditions in the context of "limbic dyscontrol syndrome" (38; 133). Autonomic phenomena may be associated with overt or subtle behavioral changes such as irritability, fear, panic, and sometimes, existential emptiness or some other form of pathological self-perception. One of Seshia and McLachlan’s patients suffered from epigastric fear for 8 years, which started after surgery (left temporal seizure origin; mesial temporal sclerosis) (103).
A particularly rare ictal or status symptom is aggression (23).
Limbic encephalitis might be associated with autonomic aura continua, and pilomotor status epilepticus has been reported in a case with voltage-gated potassium channel antibody: positive non-paraneoplastic limbic encephalitis (140).
Ictal depression and anxiety in temporal lobe epilepsy is far more frequent (125); Henriksen as well as McLachlan and Blume describe a status with fear as the outstanding clinical expression (48; 73). A large amount of literature exists on this topic (109; 117). Ictal laughter (79) is usually associated with hypothalamic pathology, mainly hamartoma, in which gelastic seizures are the hallmark.
A rare ictal phenomenon is "hemicrania epileptica" (51; 03), which may last longer than 30 minutes and, therefore, can then be labeled as a form of status epilepticus. For clarification, the diagnostic criteria for “hemicrania epileptica” as defined by the International Headache Society in 2004 are: (A) headache lasting seconds to minutes, with features of migraine, fulfilling criteria C and D; (B) the patient is having a partial epileptic seizure; (C) headache develops synchronously with the seizure and is ipsilateral to ictal discharge; (D) headache disappears immediately after the seizure. Thus, by this definition, it encompasses both short as well as long duration headaches associated with seizures and does not solely refer to conditions consistent with aura continua. The utility of this term is now disputed in the literature, as this condition could be considered 1 variant of “epileptic headache” (18; 65). In contrast, hemicrania continua is a primary headache disorder that is characterized by a continuous unilateral headache of moderate severity, exacerbations of severe pain, and complete responsiveness to indomethacin. In hemicrania continua, visual auras may precede or accompany the pain exacerbations (91; 17). However, due to the multiple clinical similarities between migraine with visual aura (including some cases of hemicrania continua) and occipital lobe seizures, it is possible that they share similar underlying electrophysiologic mechanisms (18).
Kim and colleagues evaluated headache as aura via video-EEG monitoring (65). They found that 6 (0.8%) of 775 patients with focal epilepsy reported a headache aura. The interval between headache onset and clinical seizure onset ranged from 1 to 35 seconds, with interval between headache onset and first EEG change ranging between -5 to 14 seconds. Four of these patients had right temporal seizures, and 2 had left sided onset (one temporal, one central). In contrast, 30.7% of the cohort of 775 focal epilepsy patients reported a postictal headache. These data suggest that headache aura is rare. However, as noted above, prolonged ictal headaches, a form of aura continua, may rarely occur. Psychic seizures were referred to by Jackson as so-called dreamy states, including déjà vu as well as ictal reminiscences (52; 54; 55; 56). He subsequently referred to such events as "psychical.” Gowers reported 25 patients with "psychical auras," with 10 having an "emotional aura"; all of these had fear (42). Penfield introduced the term "experiential" to describe such mental phenomena and divided the patients’ past experience into illusions and hallucinations, which could be predominantly visual, auditory, or both, or an "unclassified" experience such as a dream, a flashback, or a memory without further description. Lennox referred to 3 categories of "psychic seizures,” which are (1) dream states, feeling of unreality or illusions; (2) hallucinations; and (3) mild confusion or disorientation, a feeling of strangeness without loss of memory and consciousness. Experiential means that the mental phenomena have a relevance to the patient’s past; Gloor specified that they typically combine elements of perception, memory, and affect (39). A series of patients undergoing evaluation for epilepsy surgery reported that experiential auras were highly associated with a left hemisphere dominant seizure focus, with 11 out of 12 patients in that series having a left temporal seizure focus localization (49). In contrast, the investigators did not find that déjà vu was highly lateralized to 1 hemisphere versus the other. Mesial temporal lobe seizures may present as anxiety disorders (148). DiGiacomo and colleagues reported a case of a 60-year-old woman who was originally diagnosed with anxiety disorder and psychogenic nonepileptic seizures, but later diagnosed with aura continua with psychic symptoms consisting of “anxiety, motor agitation, fear and sensation of not being able to breathe” during intracranial EEG monitoring (25). This case highlights the multitude of difficulties that may arise in establishing this diagnosis when scalp EEG is negative.
The principal ictal "psychic phenomena" may be listed as follows (32):
• Perceptual hallucinations
- Déjà vu
- Change in reality
Aura continua appears to cause no lasting clinical negative sequelae. This contrasts with dyscognitive focal (psychomotor, complex partial) status where cognitive and other deficits may occur. Although most reported cases with psychomotor status have returned to baseline neurologic function (71; 20), several well-described patients have had prolonged memory deficits (30; 116). Patients with electrographic status epilepticus in the setting of serious medical illness have a poor prognosis, but this is due most often to the underlying serious cerebrovascular or other medical illnesses (59; 02).
A 50-year-old man with focal epilepsy presented to our epilepsy center with a history of seizures beginning at the age of 10 years. He had a history of (1) focal motor seizures causing tightening of the left lower extremity, at times spreading to cause whole body stiffening for 5 to 15 seconds; (2) rare secondarily generalized tonic-clonic seizures (only when antiepileptic medications were missed or changed); and (3) a continuous feeling of tingling in the left foot for years (consistent with aura continua). His convulsive seizures were completely controlled with antiepileptic medication. He underwent video-EEG monitoring, which revealed no ictal change during his focal motor seizures, though the video was consistent with an epileptic semiology. There was also no ictal pattern seen despite his continuous tingling foot sensation. However, his EEG did reveal rare spikes at Cz in wakefulness. His MRI brain was normal. At that time he had multiple focal motor seizures daily despite treatment trials with carbamazepine, lamotrigine, sodium valproate, and phenobarbital. Further trials of topiramate and levetiracetam were also ineffective in fully controlling his seizures. His seizures became milder after further medication changes, but he continued to experience the focal motor seizures affecting his foot once or twice daily and a continuous feeling of left foot tingling despite treatment with phenytoin and zonisamide. Eventually, his zonisamide was tapered and replaced with lacosamide. This caused complete resolution of his continuous foot tingling and a significant reduction in his focal motor seizures. Initially, after beginning lacosamide 200 mg/day (in addition to phenytoin), he had no seizures of any kind, including the aura continua, for 2 months. Now, at greater than 7 years’ follow-up, after further increases in lacosamide to 500 mg/day and tapering of the phenytoin, he experiences only rare and very mild focal motor seizures consisting of left foot tightening, the last occurring more than 1 year ago. Soon after beginning lacosamide, his aura continua resolved completely.
This case illustrates the complexity in confirming an epileptic origin for the aura continua, as there was no ictal change on his EEG during his symptoms of continuous left foot tingling (or even during his focal motor seizures). It also illustrates the longevity of symptoms that can occur in some cases of aura continua. Despite lack of ictal EEG confirmation, his clinical history of discrete focal motor seizures affecting the same foot, as well as rare focal to bilateral tonic-clonic seizures and spikes consistent with a seizure focus affecting his foot region strongly support an epileptic origin for the continuous symptoms as well. In his case, no SPECT or PET imaging was available during or after resolution of his aura continua. In many cases, such ancillary tests may be helpful diagnostically as ictal focal hyperperfusion on SPECT or hypermetabolism on PET could be supportive of the ictal mechanism for the symptoms. In this case, his clinical history was strongly supportive of aura continua and expensive ancillary confirmatory tests would likely not have altered his medical treatment because he also had focal motor seizures for which he underwent medication changes. Ultimately, the complete resolution of his foot tingling with antiepileptic medication changes strongly supports the diagnosis of aura continua.
• Aura continua appears to arise due to prolonged, long-lasting epileptic discharges arising from very localized cortical regions and possibly deep nuclei as well.
Theoretically, each part of the cortex, and probably deep nuclei as well (139), can give rise to long-lasting localized epileptiform discharges. According to their functional specialization, the epileptic dysfunction of a localized ganglionic structure of the brain may give rise to "positive" or "negative" symptoms of a particular quality.
The most common localization of sensory seizures that involve the trunk, head, and extremities (somatosensory) as well as the special senses (visual, auditory, vertiginous, gustatory and olfactory) are listed in Table 1 together with some references.
I. Somatosensory symptoms: contralateral
Localization: (post-) central
II. Somatosensory symptoms: bilateral, contralateral, or ipsilateral
Localization: Second sensory area localization (termination of the motor strip of the frontal parietal operculum), superior bank of the fronto-parietal Sylvian fissure
• often affects fingertips, feet, lips, or tongue (perioral region)
III. Macular and peripheral visual symptoms
Localization: Calcarine and pericalcarine occipital cortex
IV. Auditory symptoms
Localization: Auditory cortex, Heschl gyrus, tonotopical organization
Localization: Vestibular cortex in superior temporal gyrus rostral to auditory cortex
Localization: Parietal operculum near insula, anterior insula, probably the anterior mesial structures
Localization: Projection areas are:
- anterior perforate
VIII. Experiential phenomena
Localization: amygdala predominates; hippocampus, parahippocampal gyrus, temporal neocortex; possible left hemisphere dominance
An intriguing question is whether certain brain regions predispose more than others for such a circumscribed and long-lasting discharge behavior. By analogy with epilepsia partialis continua (137) and dyscognitive focal (psychomotor) or limbic status epilepticus (137), it is reasonable to assume that certain brain regions are, in fact, predisposed to this discharge behavior. From posttraumatic epilepsy, it is well known that the central and mesiotemporal lobe cortices are more seizure-prone than other cortices, but it is less clear whether region-specific differences exist to limit seizure discharges in time.
Aura continua occurs in many different medical conditions, as noted above. It is often associated with an underlying focal cortical abnormality but may occur in individuals without evidence of focal abnormalities on brain imaging. It has been described in patients with focal lesions, including brain tumors and traumatic brain injury, but has also been described during severe metabolic derangements and in individuals with chronic epilepsy. Any condition causing focal seizures could potentially cause aura continua.
An "aura continua" reflects the intrinsic epileptogenic properties of a discharging epileptogenic focus that remains "well controlled" with regard to spread. Obviously, in such a condition there is no further propagation of the epileptiform discharge and no further neuronal recruitment (ie, no relevant increase of the number of epileptically involved neurons). A hippocampal epileptic focus causing electrographic focal status epilepticus may be limited to a volume of less than 1 cm in diameter (138; 31). Metaphorically spoken, the "critical mass" necessary for the spread of the discharge is not reached. To a certain degree, however, waxing and waning occurs. The aura content is the product of the "interpretive cortex" (86) dealing with this discharging focus. Mechanistically, status epilepticus represents the failure of the natural seizure-suppressing mechanisms responsible for seizure termination (123). Proposed operational definitions of status epilepticus do not adequately reflect the underlying mechanisms involved in status epilepticus. As Engel rightly pointed out, mechanisms that prevent active inhibition, desynchronization of hypersynchronous discharges, and depolarization block have to be considered. In addition, progressive features that contribute to subsequent functional and structural brain disturbances and maturational factors may be important (29).
In a case series, several patients underwent selective amygdalohippocampectomy for drug-resistant mesial temporal lobe epilepsy, and for patients in whom this operation was successful with no further habitual full-blown seizures, they experienced persisting auras in the first months after this operation (132). Moreover, a few patients claimed that the feeling of an impending seizure would, with some fluctuation of its intensity, persist for hours or even days and, thus, mimic an “aura continua.” In such cases, it is likely to assume that the removal of amygdala and hippocampal formation led to a suppression of the full-blown psychomotor seizures, but that the temporal and insular neocortex were still epileptically disturbed and able to produce prolonged aura phenomena. The so-called "running down" phenomenon of such postoperatively persisting auras lends further support to the idea that, for the full expression of psychomotor seizures, both the mesial limbic and the neocortical cortices are necessary. Such a view differentiates between the epileptogenic zone and the seizure-onset zone with a further conceptual differentiation of the seizure-onset zone into an "actual" and "potential" seizure-onset zone (80).
From a clinical point of view, understanding of the nature of the aura continua in terms of exact pathophysiology awaits clarification. A modification of the electrographic characteristics of the focal status epilepticus by adequately addressed sensory stimuli has been documented in a long-lasting musical aura continua with circumscribed discharges in the right Heschl gyrus (130). Changes of antiepileptic drugs may play a role. A de novo right temporal nonconvulsive status epilepticus was reported during tiagabine adjunctive therapy in a 30-year-old woman with infantile-onset epilepsy due to left temporal gliotic area (50). Similar observations have been described with levetiracetam (06) and other antiepileptic drugs.
An analysis of patients diagnosed within a tertiary referral center as nonconvulsive status epilepticus (identifying 50 episodes of nonconvulsive status epilepticus in 45 patients over 4 years from a total of 1829 adult inpatient EEGs) revealed that approximately half of the patients with nonconvulsive status epilepticus had a previous diagnosis of epilepsy, and half had a history of generalized tonic-clonic seizures immediately before the onset of nonconvulsive status epilepticus (44). However, only 12% were alert, cooperative, able to respond to simple commands, and able to comply with the EEG procedure (14% were alert but unresponsive, 32% were confused with behavioral changes, 8% were drowsy, and 34% were semiconscious or unconscious). Unfortunately, this study gives no details on the symptoms of the "alert and cooperative" group. Concerning predictors of eventual morbidity in nonconvulsive status epilepticus, evidence exists that the level of consciousness during nonconvulsive status epilepticus is important (61; 105).
Although a detailed discussion regarding the pathophysiology of status epilepticus is beyond the scope of this article, GABAA, NMDA, and AMPA receptors appear to be involved, along with depletion of inhibitory peptides, including dynorphin and galanin (19). GABAA receptor-mediated inhibition is reduced in animal models of status epilepticus during status epilepticus (58). This reduced inhibition mediated by GABA receptors may be a basic mechanism underlying the self-sustaining and progressive nature of status epilepticus, including aura continua. In a mouse model of temporal lobe epilepsy (kainic acid injection into the dorsal hippocampus), distinct EEG patterns and selective neurochemical alterations in the contralateral hippocampus (including reduced calbindin-labeling of CA1 pyramidal cells, down-regulation of CCK-8, an up-regulation of NPY-labeling in mossy fibers, and a redistribution of galanin immunoreactivity binding) has been demonstrated (05). This might reflect long-ranging network alterations. The distinct alteration of specific neuromodulators in the contralateral hippocampus might be interpreted counteracting mechanisms to prevent the development of a mirror focus in this model and might give some hints to study the underlying pathophysiological mechanisms of "aura continua." Regulation of limbic status epilepticus by hippocampal galanin type 1 and type 2 receptors has been shown by Mazarati and Lu in a rat model of status epilepticus induced by electrical stimulation of perforant path. Galanin is a potent endogenous anticonvulsant peptide, and galanin receptors GalR1 and GalR2 mediate the anticonvulsant effects of galanin exhibiting differential effects on the initiation and the maintenance phases of status epilepticus. Activation of both galanin receptor subtypes exerts neuroprotective effects under conditions of excitotoxic injury (72).
Gap junctions, which couple adjacent cells, are also likely involved in aura continua and other forms of status epilepticus. Kinjo and colleagues found that gap junctions appear to be involved in epileptiform activity in the pilocarpine model of status epilepticus in the rat hippocampus, supporting prior work indicating the importance of gap junctions in prolonged epileptiform bursting (92; 66). Data also suggest that seizure propagation may also occur independently of synaptic transmission, gap junctions, or diffusion, and may occur via electrical field transmission (150).
Specialized imaging and cortical stimulation studies have helped to further refine the localization of specific symptoms of aura. Kovacs and associates reported a case of déjà vu occurring during deep brain stimulation only at specific stimulation parameters (68). SPECT imaging during the stimulated déjà vu showed increased perfusion in the right medial temporal regions. Similarly, Takeda and colleagues found that aura continua consisting of continuous déjà vu correlated with hyperperfusion in the entorhinal cortex in SPECT coregistered with MRI (114). Additionally, Bartolomei and associates found that stimulation of the entorhinal cortex in patients with epilepsy elicited déjà vu more readily than during stimulation of the hippocampus (09). However, their EEG data, which showed increased EEG signal correlation between several medial temporal lobe structures during déjà vu, suggested that déjà vu was likely caused by a transient cooperation between these various structures and not solely due to entorhinal cortex activation.
The incidence and prevalence of aura continua are unknown, as there are limited data regarding this condition, which is primarily reported via isolated case reports or small case series. It appears to be a relatively rare condition, but it may be underreported, as many patients and clinicians tend to focus on the treatment of discrete and more overt and disabling seizures.
Treatment of a patient’s chronic epilepsy may reduce the risk of developing aura continua. However, aura continua may occur in individuals without a clear diagnosis of epilepsy and, thus, may be difficult to diagnose in those cases. Vigilance regarding some of the unusual ictal manifestations that occur in aura continua could lead to earlier identification of auras and aura continua in patients at high risk for seizures. Early identification of auras may lead to antiepileptic medication treatment, which could reduce the risk for or mitigate the severity of aura continua.
An ongoing continuous or recurrent intermittent epileptic discharge might be suspected, and consequently proven, with EEG and response to antiepileptic drug treatment in an epileptic person with known focal pathology and prolonged aura symptoms consisting of phenomena that fit well with the localization of the epileptic discharge. However, in the absence of clear-cut EEG findings, an aura continua in particular (if expressing itself with strange and unusual phenomena) might be difficult to diagnose. Not infrequently, convincing ictal discharges cannot be detected without intracranial recordings. Such techniques, of course, are only justified in the context of surgical epilepsy therapy. Autonomic signs and symptoms occur in focal aware seizures and are frequent in focal with impaired awareness (psychomotor) seizures. Prolonged autonomic ictal features can mimic psychiatric, endocrine, cardiac, and gastrointestinal disorders (24). Cardiovascular and thoracic symptoms are not specific for temporal lobe seizures, but are also seen in frontal lobe seizures and probably more commonly so. Pupillary dilatation is thought by some authors to be a sign of hypothalamic seizure spread. Table 2 lists the most important differential diagnosis of autonomic phenomena.
Of importance is the differential diagnosis of limbic encephalitis, both paraneoplastic and non-paraneoplastic particularly.
Nonparaneoplastic limbic encephalitis has been associated with multiple antibody types. As noted in a review by Toledano and Pittock, there are several neural-specific autoantibodies targeting both intracellular and plasma membrane antigens that are associated with autoimmune epilepsy and limbic encephalitis (115). Status epilepticus, including nonconvulsive status epilepticus, can occur at presentation. A subacute onset of cryptogenic epilepsy, history of autoimmunity or viral prodrome, psychiatric or cognitive features of limbic encephalitis, or history of tumor are some of the clinical features that may raise suspicion for an autoimmune epilepsy. Furthermore, the opercular syndrome (also known by the eponym Foix-Chavany-Marie), and in particular the anterior (frontal) opercular syndrome, which comprises essentially difficulties in speech and swallowing due to the loss of voluntary control of the oro-facio-linguo-pharyngo-masticatory muscles, can be associated with seizures and even with focal status epilepticus (98; 11). Lingual epilepsia partialis continua with disabling dysarthria due to impairment of the left half of the tongue has been reported by Nayak and colleagues in a patient with suspected Rasmussen encephalitis (81).
Acute intermittent porphyria should not be forgotten (126) and can be checked for with analysis of porphyrinogens in blood, urine, and stool.
• Endocrine disorders
• Organic gastrointestinal disease
• Normal experiences
• Psychological disorders
- Panic attacks
• Hallucinations/illusions due to a loss of primary sense
• Metabolic disorder
- Recurrent drug abuse
• Acute CNS disorders, including limbic encephalitis
Aura continua might occur de novo, but in most instances it occurs in patients with known focal epilepsies, particular to temporal lobe epilepsy. Personal experience suggests that aura continua is more often seen in symptomatic focal epilepsies with evident morphological focal brain pathology. It might be that certain pathologies, such as certain tumors and focal cortical malformations, are more often associated with aura continua than other pathologies, but clear evidence from literature is missing. Olfactory or gustatory auras often are associated with tumors in the anterior temporal lobe (46).
As noted in the above section regarding visual aura continua, various medical conditions have been associated with this condition, even in the absence of an underlying focal lesion.
To be certain of the diagnosis of aura continua, 2 principal requirements have to be fulfilled: (1) long-lasting somatosensory, special sensory, visceral, or experiential symptom without visible motor component or impairment in level of consciousness; and (2) seizure activity on the EEG. However, as noted above, ictal EEG is often negative in probable aura continua. Polygraphic recordings, such as electrocardiography, respiration, and electrodermal skin responses are helpful for detecting and quantifying autonomic phenomena. If routine scalp EEG is nondiagnostic, ictal SPECT or PET may aid in the diagnosis. Finally, the prompt response to antiepileptic drugs might be important for the diagnosis. Because the majority of aura continua phenomena are associated with some kind of lesion, a thorough examination of the patient, including neurologic, neuropsychologic examinations, and MRI, PET, or SPECT in the ictal and interictal state is essential. Long-term video-EEG documentation may be useful, and, in epilepsy surgery cases, intracranial EEG recording may confirm the diagnosis. Symptom abolition of aura continua after surgery (103) or medication treatment may also support this diagnosis.
Therefore, it has been argued that the standard and widespread aggressive use of intravenous antiepileptic drugs is causing greater morbidity than it is sparing.
• As discussed above, no convincing evidence exists that aura continua will lead to significant irreversible neurologic deficits.
• Thus, the use of any treatment options must be tempered by the risk of adverse effects that may arise with overaggressive therapy.
With concurrent acute brain injury and aura continua, the situation might be different. Some experimental evidence can be found that ongoing discharges are synergistically harming the injured brain (14; 124; 57). Treatment, therefore, should find a balance that considers the potential neurologic morbidity due to ongoing focal discharges as well as the possible morbidity of IV antiepileptic drugs and polytherapy (60; 76).
Focal (partial) status epilepticus (106) is reported to be controlled by diazepam in 88% of 67 patients. Clobazam (21), midazolam, an imidazobenzodiazepine, and lorazepam (77) are considered antiepileptic drugs of first choice; midazolam is short acting and, therefore, can be well titrated on prolonged infusion if necessary. Paradoxical response to diazepam and midazolam in focal status epilepticus has been rarely observed (01). In children with Ohtahara-like syndromes and serial focal seizures associated with cortical dysplasia, pyridoxal phosphate showed good therapeutic efficacy (83). There was a recent report of sensory aura continua that responded to brivaracetam after failure of several other antiepileptic medications (99). Aura continua may respond to various antiepileptic medications, as exemplified by cases reported above. However, at times, aura continua may remain refractory to multiple antiepileptic medications, as in the case of visual allesthesia reported by Mendez and Chen (74). In such cases, treatment goals must take into account the risks of possible adverse medication side effects, which could outweigh potential benefits of treatment.
Nonparaneoplastic limbic encephalitis, particularly those with antibodies to plasma membrane proteins (in contrast to those with antibodies to intracellular targets), may respond favorably to immunosuppressive therapy utilizing intravenous steroids, intravenous immunoglobulins, plasmapheresis, and/or cyclophosphamide and other immunosuppressive agents (93; 22; 115). However, long-term immunosuppression may be necessary to prevent relapse and hippocampal sclerosis, and chronic epilepsy might evolve as sequelae of limbic encephalitis (140; 115; 07).
Treatment of seizures and status epilepticus in acute intermittent porphyria is a challenge. Gabapentin is considered a safe option. Other antiepileptic drugs (barbexaclon, barbiturates, carbamazepine, diazepam, phenytoin, valproate, etc.) can aggravate or trigger the symptoms of acute hepatic porphyria, or their safety is not known (110; 126). Case report data, as well as the lack of hepatic metabolism of levetiracetam, suggest that levetiracetam may also be safe in this condition (149).
There are limited data regarding outcome in aura continua because case reports and small case series constitute the bulk of the available data. Aura continua is often refractory to multiple antiepileptic medications. As noted above, the potential risks of treatment must be weighed against the benefits of treating the aura continua symptoms, which could vary in severity. Benzodiazepines and antiepileptic medication polytherapy are necessary to completely control aura continua in some cases. Oversedation, cognitive side effects, dizziness, and other common side effects of antiepileptic medications could occur in such cases. Thus, treatment of aura continua must balance the severity of the symptoms with quality of life.
Treatment in pregnancy is focused on use of the minimum dose and number of standard antiepileptic medication treatment(s) that is effective, with preference given to those antiepileptic medications associated with lower risk of fetal malformations, cognitive decline, and other potential adverse effects. Discussion of specific medications and treatment of epilepsy during pregnancy follows standard guidelines and is outside the scope of this article.
Maromi Nei MD
Dr. Nei of Sidney Kimmel Medical College of Thomas Jefferson University has no relevant relationships to disclose.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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Jan. 18, 2022
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