Clinical manifestations

Presentation and course

Experiential symptoms most frequently occur during seizures arising from temporal lobe regions (53; 18; 19; 07). This conclusion is robustly supported by multiple lines of evidence (17; 52). The most important evidence comes from intracranial EEG studies and electrical stimulations demonstrating that a dreamy state, including déjà vu and reminiscences, can arise from temporal lobe structures, in particular the perirhinal cortex and hippocampus (27). For instance, Bancaud studied patients with intracranial EEG and observed a temporal correlation between ictal EEG discharge and the appearance of experiential symptoms (04). Furthermore, the relationship between focal epilepsy and experiential phenomena is supported by functional brain mapping using electrical stimulation (06; 05). Penfield was the first to report that the “dreamy state” could be induced by electrical stimulation of the temporal lobe (48).

Temporal lobe areas integrate past and present experiences and encode them with appropriate emotion (38; 02). Seizures that arise from the occipital, parietal, and frontal lobes have not been strongly associated with experiential symptoms (46). One exception relates to seizures that originate in the frontal pole, which present with “forced thinking” (37). Penfield and Jasper observed this phenomenon but thought that it was substantially different from experiential symptoms. In addition, cortical stimulation during stereo-EEG recordings produced psychic phenomena in the posterior cingulum, precuneus, and inferior parietal lobule (03), although much less frequently than other somatosensory symptoms and with characteristics that appeared to be not too much more similar than those occurring when stimulating temporal lobe structures (28; 06; 05). The posterior cingulum and inferior parietal lobule are multimodal association cortical areas that have direct functional and anatomical connections to the temporal lobe; therefore, it is not surprising that seizures originating in these areas may also produce experiential phenomena. One study analyzed clinical, neuropsychological, imaging, and EEG (some with stereo-EEG) data in nine patients with ictal depersonalization (described as the sensation of being detached from one's body) and seven patients with derealization (described as the altered perception of the surroundings) (31). They found that ictal depersonalization originated in the dorsal premotor frontal cortex in seven of nine patients (77%) and in the mesial temporal lobe in the remaining two (23%). By contrast, all patients with ictal derealization had temporal lobe epilepsy seizure onset.

Experiential symptoms most frequently arise during the first portion of a larger seizure, such as a dyscognitive seizure or focal to bilateral tonic-clonic seizure. That is, patients describe experiential symptoms before they lose awareness and experience a focal seizure with impaired awareness or a generalized convulsion. Rarely, a patient may feel repetitive experiential symptoms lasting hours or days not leading to loss of awareness or automatisms (50), characterizing a nonconvulsive status epilepticus with focal aware cognitive seizures, previously called simple partial status epilepticus or aura continua (24; 23).

The most frequent type of experiential symptom described by patients with temporal lobe epilepsy is a sensation of visually experiencing an event multiple times, termed “dejà-vu” (from the French, “already saw”). The converse situation occurs when a patient reports a feeling of unfamiliarity associated with seeing familiar places or people, termed “jamais-vu” (from the French, “never seen”). These phenomena have also been reported in the auditory modality and termed “déjà-entendu” and “jamais-entendu” (from the French, “already heard” and “never heard”). One study showed that ictal fear was significantly associated with jamais-vu, déjà-vu, and derealization (16).

Patients with temporal lobe epilepsy sometimes report a feeling as if they are conscious and aware but not in control of their body, termed “depersonalization.” Others may report a visual illusion that they are looking at themselves from outside of their body, termed “autoscopy,” and a sensation that someone is standing beside them. Autoscopy appears to be more common in the nondominant hemisphere, sometimes associated with a sense of paralyzed limb (misoplegia) (41), but overall, experiential seizures do not have a preferential hemispheric lateralization (30; 17).

Prognosis and complications

If epileptic in origin, experiential phenomena most often occur in the context of temporal lobe epilepsy (07). The proportion of patients who become fully controlled using medical treatment follows the proportions outlined by Kwan and Brodie (34) in that approximately 60% to 70% of patients have their seizures controlled with medications. Most patients who become refractory to multiple antiepileptic medications become good candidates for epilepsy surgery and have a favorable prognosis (56).

Biological basis

Localization

From extensive autopsy studies, Hughlings Jackson concluded that patients who experienced “dreamy states” had lesions in the mesial temporal structures (32). Conversely, Wilder Penfield concluded from electrical stimulation of exposed lateral temporal neocortex during epilepsy surgery that experiential phenomena depended primarily on the lateral temporal neocortex (48). These divergent conclusions on the neuroanatomical origins of experiential symptoms by the founding fathers of epilepsy ushered in an era of strong controversy on this subject. Proponents of Jackson’s theory favored the mesial temporal region as the origin of experiential phenomena, arguing that a strong role in the processing of emotion and memory by this region made neuroanatomical sense. Furthermore, they argued that Penfield did not record the EEG from the mesial structures when stimulating the lateral temporal cortex. In contrast, proponents of Penfield’s theory were compelled by the vivid memories that were induced by stimulation of the lateral temporal neocortex.

Bancaud studied 20 patients with experiential symptoms using intracranial EEG (04). He concluded that “the dreamy state probably depends upon a neuronal network that engages both medial and lateral aspects of the temporal lobe, and that the anterior hippocampus, amygdala, and superior temporal gyrus have relatively privileged access to this circuit.” Further studies by Bancaud revealed that experiential symptoms of seizures did not occur unless mesial temporal structures were affected in some way (04). The lateral temporal neocortex was frequently involved but not essential. This was true for all sorts of experiential phenomena, which included emotions, activation of previous memories, or alteration of familiarity. Furthermore, Gloor found that stimulation of the amygdala resulted in the easiest elicitation of experiential phenomena. This conclusion was supported by Vignal, who concluded, based on intracranial EEG, that mesial temporal stimulation is enough to elucidate the “dreamy state” (55).

In contrast to studies using intracranial EEG, which localizes experiential symptoms to the mesial temporal lobe, postsurgical observations have offered different conclusions. A retrospective comparison of seizure semiology of mesial temporal and lateral temporal epilepsy suggests that experiential symptoms are much more common if the epileptic focus is located on the lateral surface of the temporal lobe (26). Nine out of 19 patients with neocortical-onset epilepsy reported experiential symptoms, compared to none out of 16 patients with mesial onset. Localization of experiential phenomena to the mesial or to the lateral temporal lobe probably should not be made. Moriarity and colleagues reported a patient in whom direct stimulation over the temporal neocortex elicited experiential phenomena, even after anterior temporal lobectomy and amygdalohippocampectomy (40).

Pathophysiology

Mechanisms by which seizures generate experiential symptoms are poorly understood (28). Hypothetical explanations center on whether experiential symptoms are secondary to “ictal activation” or to “ictal inhibition” of the cerebral cortex. Jackson speculated that experiential phenomena arise because regions of the cerebral cortex distant from the seizure focus are released from tonic inhibition. Penfield observed experiential symptoms during stimulation of the cerebral cortex and postulated that activation of stored memory traces produces experiential phenomena. Gloor provided an excellent observation noting that experiential symptoms are related to the normal function of the temporal lobe, which suggests that a seizure can activate normal temporal lobe functions such as memory or sense of familiarity (29). Gloor suggested that ictal activation results in disordered activation and disordered association of normal temporal lobe functions.

Accumulated experience from intracranial EEG recordings and electrical brain stimulation over 80 years demonstrates the role of inappropriate activation of the circuit involving the perirhinal cortex, parahippocampus, and hippocampus in the pathophysiology of ictal experiential phenomena (17; 27). Interestingly, electrical stimulation around the perirhinal cortex produces déjà vu more often and with a lower threshold than stimulation of the hippocampus (06).

A hypothesis of cortico-limbic networks proposes that déjà-vu results from an abnormal synchronization between rhinal cortices and the hippocampus, whereas focal seizures with dreamy state and reminiscences arise from hyperactivation between the hippocampus and a network of temporal neocortical areas associated with episodic memory (27).

Differential diagnosis

Confusing conditions

Patients who present with troubling experiential symptoms should be approached with a sensible differential diagnosis. Other than focal epilepsy arising from the temporal lobe, the differential should include normal mental states, psychiatric illness, manifestation of a generalized epilepsy syndrome, postictal phenomena, focal brain lesions, and migraine. Consideration of the duration of symptoms, associated features, risk factors, laboratory investigation, and response to treatment help to establish the diagnosis.

Experiential symptoms are frequently normal phenomena reported by people without any brain pathology. For instance, the experience of déjà-vu is common (12; 57). In these instances, the experiential symptoms are infrequent, brief, lasting several seconds, and isolated, never leading to unresponsiveness; frequently, the person lacks specific risk factors for epilepsy. In healthy subjects, déjà-vu occurs mostly in psychological states such as precognitive dreams or daydreams, indicating that the memory function is well preserved, whereas in people with epilepsy, déjà-vu is associated with dissociative experiences indicating an impairment of the visual-memory network (35).

A functional MRI (fMRI) study showed different neural responses of brain regions involved in memory and emotional processes in healthy subjects with versus without déjà-vu (42). Those with déjà-vu had a relatively reduced fMRI activation in the right parahippocampal, bilateral hippocampi, temporal middle gyri, superior frontal gyri, thalami, and caudate nuclei (42).

The differential diagnosis of experiential symptoms includes a variety of postictal phenomena. For instance, hyperfamiliarity for faces may be seen as postictal phenomena in temporal lobe epilepsy (13). In addition, postictal psychosis may present with features reminiscent of experiential phenomena, such as the experience of altered reality. The evaluation of refractory experiential phenomena should, therefore, include an attempt at temporal association of symptoms and the discharge on EEG (ie, whether the symptoms are associated with ictal or postictal phenomena). This is important as postictal psychosis frequently responds to antipsychotics (01).

Static lesions such as brain tumors or strokes can produce certain experiential symptoms such as delusions of misidentification (14), reduplicative paramnesia (36), and depersonalization (51). In instances in which experiential symptoms are of acute onset, are persistent, lasting days or weeks, and are not responsive to antiepileptic medications, a focal lesion should be considered, and a high-resolution MRI with an epilepsy protocol should be performed.

Experiential symptoms can occur as part of a migraine aura. The most significant distinction between symptoms of migraine aura and epilepsy is the duration of symptoms. Migraine aura lasts between 5 and 60 minutes and precedes a headache (49). In contrast, typical experiential auras associated with epilepsy last 20 to 40 seconds. Migraine can cause a variety of complex mental states generally before a migraine attack, including sensations of familiarity, sensations of depersonalization, or complex visual illusions such as mosaic vision (58).

Associated and underlying disorders

Temporal lobe epilepsy. Seizures with experiential symptoms have almost exclusively been reported in temporal lobe epilepsy. Most frequently, patients report experiential phenomena as the first part of a focal impaired awareness seizure. The duration of the experiential phenomena is generally in the order of 30 seconds to several minutes and is rarely longer. A comparison of semiology between mesial and lateral temporal lobe epilepsy suggests that experiential symptoms are most frequently encountered in patients who have seizures arising from the lateral temporal lobe (26; 07). These include autoscopic phenomena, sensations of déjà vu, and depersonalization. This has further been reported in cases of neocortical surgery in which experiential auras stopped following neocortical resection (10). Auditory auras and other experiential symptoms also occur in autosomal dominant familial lateral temporal lobe epilepsy with or without LGI1 mutation (54; 39). Experiential seizures have also been reported in other forms of benign familial temporal lobe epilepsy with normal MRI (25; 35).

Limbic encephalitis. Déjà-vu and other ictal experiential phenomena can occur in antibody-associated autoimmune encephalitis, particularly in those with glutamic acid decarboxylase and less frequently in N-methyl-D-aspartate receptor (NMDAR) antibodies (33). New-onset focal status with experiential symptoms and acute memory complaints is more frequent in NMDAR encephalitis (33).

Idiopathic generalized epilepsy. Experiential symptoms may appear in the context of idiopathic generalized epilepsy. Although rarely reported, complex visual illusions, negative and positive affective states, and distortions of time can occur in patients who present with absence status epilepticus (11; 47; 22). The importance of identifying idiopathic generalized epilepsy lies in differential response to antiepileptic medications; for instance, phenytoin or carbamazepine in absence status epilepticus is not effective and may exacerbate the conditions (44).

Diagnostic workup

Patients who present with troubling experiential symptoms should be evaluated to determine if the symptoms could be associated with neuropathology. MRI of the brain with thin, high-resolution coronal cuts focusing on the mesial temporal lobe is essential. Sleep-deprived EEG should be done with anterior temporal electrodes and should focus on finding evidence of epilepsy. Lumbar puncture and analysis of CSF are generally not indicated. The exception is when an inflammatory condition is suspected as the cause of the seizures, such as limbic encephalitis (09; 33). Video-EEG evaluation is indicated in cases in which the experiential symptoms persist despite treatment with antiepileptic medications. Scalp EEG usually does not detect focal aware seizures like experiential seizures unless it evolves to focal impaired aware or focal to bilateral tonic-clonic seizures (15).

Management

Treatment of experiential seizures should depend on the type of epileptic syndrome causing the symptoms. For instance, if focal epilepsy is suspected, appropriate first-line antiepileptic medications should be tried. It is important to note if experiential symptoms are followed by loss of awareness, which is the most frequent case. In these instances, appropriate precautions with regard to driving and employment should be taken. If experiential symptoms are seen in the course of medically refractory epilepsy, localization to the temporal lobe is generally favored. Surgery is the treatment of choice for patients with seizures refractory to medication (20).