Frontal Lobe Epilepsy: A Primer for Psychiatrists and a Systematic Review of Psychiatric Manifestations.

BACKGROUND: Frontal lobe epilepsy (FLE) can masquerade as a primary psychiatric condition, be misdiagnosed in-lieu of a true psychiatric disorder, or may be comorbid with psychiatric illness. OBJECTIVES: To (1) qualitatively review psychiatric manifestations of FLE and (2) to systematically review the cases/case series of psychiatric manifestations of FLE presented in the literature to date. METHODS: A systematic review of the literature was performed following the PRISMA guidelines and using PubMed/Medline, PsychInfo, and Cochrane database of systematic reviews to identify cases and case series of psychiatric manifestations of FLE. RESULTS: A total of 35 separate articles were identified. Further, 17 patients primarily presented with psychosis, 33 with affective symptoms, and 16 with personality changes. Also, 62% of cases were males and 38% were females. Ages ranged from 2-83 years with the average age of 32.7. Prior psychiatric history was reported in 27.3% of cases. Causes of seizure were known in 53%, with the most common causes being dysplasia and tumor. Only 6 cases (<10%) did not have electroencephalographic correlations. Psychiatric manifestations were primarily ictal in 74.3% of the cases. Associated manifestations included motor (63.6%), cognitive (34.8%), and medical (9.0%) findings. Surgery was required in 31.8% of the cases, whereas others were treated with medications alone. All, but 3, patients were seizure free and saw an improvement in symptoms with treatment. CONCLUSIONS: Given the complexity and multifunctionality of the frontal lobes, FLE can present with complex, psychiatric manifestations, with associated motor, cognitive, and medical changes; thus, psychiatrists should keep FLE on the differential diagnosis of complex neuropsychiatric cases.

Multimodal Assessment Reveals Late-Onset Hemispheric Shift of Language in a Child with Meningocerebral Dysplasia.

We report on a girl with progressive left frontal tissue destruction starting at the age of almost 8 years. She manifested acutely with epileptic seizures accompanied by Broca aphasia as well as transient right hemiparesis. Due to refractory epilepsy developing over the next years, which originated from the left frontal lobe, the decision was made to proceed to epilepsy surgery. By then, her language functions had recovered despite progressive left frontal tissue-destruction, raising the possibility of a hemispheric shift of language. Clinical functional magnetic resonance imaging (fMRI) was conducted to localize brain regions involved in language production. A complex pattern of clear right-hemispheric dominance, but with some left-sided contribution was found. However, a Wada test suggested the left hemisphere to be critical, seemingly contradicting fMRI. Invasive electroencephalogram recordings could reconcile these results by identifying the fMRI-detected, residual left-sided activation as being relevant for speech production. Only by combining the localizing information from fMRI with the information obtained by two invasive procedures could the unusual pattern of late-onset language reorganization be uncovered. This allowed for extensive left frontal resection, with histology confirming meningocerebral angiodysplasia. Postoperatively, language functions were preserved and seizure outcome was excellent. The implications of our findings for presurgical assessments in children are discussed.

[Clinicopathologic study of intractable epilepsy-related encephalitis].

OBJECTIVE: To investigate the clinicopathologic features of intractable epilepsy related encephalitis. METHODS: The clinical and pathologic findings of 15 cases of intractable epilepsy after functional neurosurgical treatment were reviewed and analyzed retrospectively. RESULTS: All patients, including four male and 11 female, had medically intractable epilepsy. The mean age of onset for seizure was 5.3 years (1-15 years) and the disease duration was 4.7 years (0.5-15 years). A definite past history was identified in 11 patients, including viral encephalitis in nine patients, anoxia in utero and head trauma in one patient respectively. The extent and sites of involvement were different, including single cerebral hemisphere diffusely in five cases, multiple lobes in seven cases, and single lobe in three cases. Temporal lobe was involved in 13 cases, frontal lobe in eight, parietal lobe in eight, occipital lobe in seven, and insular lobe in four. Microscopically, all cases were characterized by perivascular inflammatory cells infiltration in the subarachnoid space. The focal cerebral cortex showed obvious atrophy with various degrees of the neuronal loss and glial proliferation, eventually leading to glial scar formation. In addition, microglia nodules, lymphatic cuff and neuronophagia were also observed. Seven cases of focal cortical dysplasia were identified among the 11 cases with adequate perilesional cerebral cortex. Hippocampus sclerosis was found in two cases. Intranuclear inclusions were seen in six cases, and these were immunopositive of cytomegalovirus-late antigen, and three cases also showed multinucleated giant cells and calcifications. CONCLUSION: Encephalitis is one of the common causes of refractory epilepsy, and may result in refractory epilepsy as a sequel.

Multifactorial etiology of interictal behavior in frontal and temporal lobe epilepsy.

PURPOSE: Based on discussions on the so called "epileptic personality" in patients with epilepsy, interictal behavioral impairments in frontal and temporal lobe epilepsies were examined in a multivariate approach that took demographic, clinical, and neuropsychological determinants into consideration. METHODS: A total of 428 patients with epilepsies originating from the temporal (TLE; 84%) or frontal (FLE; 16%) lobes were examined in regard to personality (Fragebogen zur Persönlichkeit bei zerebralen Erkrankungen [FPZ], a clinical personality questionnaire) and mood (Beck Depression Inventory [BDI I]). Prevalence of impaired behavioral domains was determined. Etiologically relevant determinants of behavioral problems were identified via multiple regression analyses. KEY FINDINGS: Elevated depression scores (BDI) were evident in 42% of the patients, and not different in TLE and FLE. In regard to personality, introversion together with low mood, sociability, and self-determination, as well as problems with interpersonal communication were frequent. The TLE group tended to show greater neuroticism and introversion, while FLE appeared more associated with behavioral aspects of an organic psychosyndrome. Multivariate analyses revealed demographic characteristics (age, gender, education), clinical aspects (psychiatric history, affected hemisphere, mesial pathology, seizure frequency, cognitive functions), and treatment (antiepileptic drug treatment) as relevant determinants, explaining up to 30% of the behavior. SIGNIFICANCE: Behavioral abnormalities in patients with frontal or temporal lobe epilepsy are common but on the average mostly mild. Within a multivariate etiological model, localization (mesial yes/no) and lateralization (left > right) dependent behavioral problems in TLE and FLE seem to be overshadowed by other variables, of which patients' and their families' psychiatric history, patient characteristics and pharmacological treatment appear of major importance. Better education and cognitive capabilities may be discussed as protective features.

Adversive seizures associated with periodic lateralised epileptiform discharges (PLEDs) after left orbital contusion.

We report a patient who presented with adversive seizures associated with periodic lateralised epileptiform discharges (PLEDs), a month after head trauma. The PLEDs predominantly involving the left frontal contacts became more frequent at the onset of adversive seizures during EEG. Brain MRI demonstrated a contusion scar in the left orbital cortex with reduced diffusion, not only around this orbital lesion but also in the ipsilateral anteromedial thalamus. Single photon emission computed tomography revealed focal cerebral hyperperfusion in the left medial orbitofrontal region, basal ganglia, and thalamus. The abnormal metabolism involving the thalamus and striatum could be associated with the ipsilateral orbital contusion and might have been caused by cortical-subcortical, trans-synaptic hyperactivity. Further studies are warranted to determine the role of subcortical structures in the generation of PLEDs and adversive seizures. [Published with video sequences].

Cingulate epileptogenesis in hypothalamic hamartoma.

Hypothalamic hamartoma (HH) is a relatively rare cause of epilepsy, mainly affecting children. Nearly all patients develop gelastic seizures, often followed by other focal seizure types. Our case illustrates the mechanisms of epileptogenesis in HH. The patient developed gelastic attacks as a baby, and secondarily generalized seizures and drop attacks at 9 years of age. Magnetic resonance imaging (MRI) confirmed the presence of a HH. Presurgical assessment with intracranial electroencephalography (EEG) monitoring recorded gelastic seizures with generalized epileptiform activity. Functional stimulation of the hamartoma provoked gelastic attacks. Single pulse electrical stimulation (SPES) was used to identify epileptogenic cortex. SPES of the left cingular cortex provoked generalized responses similar to the spontaneous generalized discharges. Our results suggest that long-standing history of epilepsy in patients with HH may be related to additional sources of epileptogenic activity. Electrical stimulation performed in this patient provided additional data to favor the hypothesis of secondarily epileptogenesis in the cingulate gyrus independently from the primary origin in the HH.

Different faces of frontal lobe epilepsy: The clinical, electrophysiologic, and imaging experience of a tertiary center.

OBJECTIVE: Frontal lobe epilepsy (FLE) is the second most common epilepsy among drug-resistant focal epilepsies. Semiologic and electrophysiologic features of FLE present some difficulties because frontal lobe seizures are brief, accompanied by complex motor activities and emotional signs. The rich connectivity of the frontal lobe with other areas leads to the rapid and widespread propagation of seizure activity, which contribute to the difficulty of evaluating the semiologic and EEG patterns of the seizure. In this study, we investigated semiologic, interictal, ictal, and postictal EEG characteristics; the imaging data of patients with FLE and the possible contribution of these data to localization and lateralization of seizures. MATERIALS AND METHODS: The medical records of patients who were diagnosed as having FLE between 2010 and 2019 in our clinic were evaluated retrospectively. The diagnosis of FLE was considered either when patients had a structural lesion in the frontal region or seizure semiology and EEG characteristics were compatible with FLE. Clinical, electrophysiologic, and imaging features were investigated in these patients. RESULTS: We have evaluated 146 seizures in 36 patients (17 lesional and 19 non-lesional according to MRI). There were 110 focal motor or nonmotor seizures, 18 bilateral tonic-clonic seizures, and 18 subclinical seizures. There were 16 patients with aura. The most common semiologic feature was hyperkinetic movements. Among the interictal EEGs, 30.5 % included focal anomalies. Among the ictal EEGs, 69.1 % were non-localizing or lateralizing. The most common ictal pattern was rhythmic theta activity (21.2 %). In four patients, who had non-localizing or lateralizing EEG, the postictal EEG was informative. Our study showed a low percentage of localized FDG-PET, which, however, involved visual analysis. CONCLUSION: Our results support the previously known difficulties in the determination of the epileptogenic zone of FLE. Semiologic and electrophysiologic correlation studies, longer postictal records, and quantitative analysis of FDG-PET may contribute to a better characterization of the disease.

[A case of progressive supranuclear palsy with late-onset supplementary motor area seizure].

We report a 75-year-old, right-handed man, presenting with supplementary motor area (SMA) seizure. The patient had suffered from frequent attacks of transient inability to speak and move without loss of awareness. On admission, he presented with vertical gaze paresis, axial rigidity, paratonia of extremities and gait disturbance. The attacks were preceded by discomfort on the head, followed by inability to move the whole body and arrest of vocalization with tonic posture and exaggerated breathing. Consciousness and cognitive function were preserved throughout the attacks. Electroencephalography recorded intermittently slow theta waves in the bifrontal regions. Brain MRI showed atrophy of the midbrain tegmentum with lacunar state suggesting progressive supranuclear palsy. SPECT with 123I-iomazenil revealed decreased uptake in the medial frontal areas including SMA, bilaterally. The seizures resolved completely following treatment with carbamazepine. Based on clinical features and neuroimagings, we speculated that the negative motor area within SMA was responsible for his seizure. Physicians should keep in mind that SMA seizure comprising negative motor phenomenon can occur in the elderly.

Interictal rhythmical midline theta differentiates frontal from temporal lobe epilepsies.

PURPOSE: We evaluated the role of interictal rhythmical midline theta (RMT) in the identification of frontal lobe epilepsy (FLE) and its differentiation from temporal lobe epilepsy (TLE) and nonepileptic controls. METHODS: We included 162 individuals in the study: 54 FLE patients, 54 TLE patients, and 54 nonepileptic controls. Continuous electroencephalographic (EEG)-video monitoring was performed in all individuals. Interictal RMT was included only if it occurred during definite awake states. RMT associated with drowsiness or mental activation and ictal RMT was excluded. RESULTS: We identified RMT significantly more frequently in FLE patients (48.1%, 26 of 54) than in TLE patients (3.7%, 2 of 54) (p < 0.01), and not in the control group. The average frequency was 6 Hz (range 5-7 Hz), and the average RMT bursts lasted 8 s (3-12 s). Interestingly, all mesial FLE patients (n = 4) (as established by invasive EEG recordings) showed RMT, whereas this was less frequently the case in the other FLE patients (44%, 22 of 50) (p = 0.03). Thirteen of our 54 patients with FLE (24%) did not have any interictal epileptiform discharges (IEDs), but RMT was observed in the majority of these patients (62%, 8 of 13). CONCLUSION: Interictal RMT is common and has a localizing value in patients with FLE, provided that conditions such as drowsiness and mental activation as confounding factors for RMT are excluded. RMT should be included in the evaluation of patients considered for resective epilepsy surgery.

[On the best strategies on the best results for surgery of frontal epilepsy]. / Quelles stratégies pour quels résultats dans la chirurgie des épilepsies partielles frontales?

Frontal lobe epilepsy surgery is the second most common surgery performed for drug-resistant partial epilepsy. We investigated the longitudinal outcome in a cohort of patients investigated since 1990 with SEEG and modern diagnostic techniques. We reviewed 105 patients who underwent surgery between 1990 and 2005 (mean follow-up, six years; range: one to 17 years) and analyzed the year-per-year follow-up according to Engel's classification. Favorable outcome (Class I) was observed for 70% and this result was stable at least five years after surgery. More than 90% of patients with lesion-related epilepsies (focal cortical dysplasia and dysembryoplastic neuroepithelial tumors) became seizure-free. Less than 50% of patients classified as having cryptogenic epilepsy (defined as normal imaging and neuropathology on surgical specimen) had a favorable outcome. Permanent neurological sequelae were subtle and rare, especially after surgery for dysplasia in eloquent cortex (primary motor cortex). Our data indicate that frontal surgery is a successful treatment in patients when electrophysiological and morphological investigations demonstrate a well-defined epileptogenic zone or lesion to be surgically resected. Progress in electrophysiological and brain-imaging techniques will further improve the selection of frontal lobe epilepsy surgery candidates.

Ictal SPECT reveals different epileptogenic zones in frontal lobe epilepsy.

We report a patient with frontal lobe epilepsy due to a right frontal astrocytoma (WHO Grade III) in whom two ictal SPECTs (single photon emission tomography) were performed during two seizures with different semiology and different EEG seizure patterns. Subtraction of ictal and interictal SPECT showed right lateral frontal hyperperfusion during a left face clonic seizure, and right mesial fronto-polar hyperperfusion during a subclinical seizure. This report demonstrates that ictal SPECT may reflect different seizure semiology from the frontal lobe of the same individual and that simultaneous EEG is indispensable for the correct interpretation of SPECT in epilepsy.

The role of the nicotinic acetylcholine receptors in sleep-related epilepsy.

The role of neuronal acetylcholine receptors (nAChRs) in epilepsy has been clearly established by the finding of mutations in a subset of genes coding for subunits of the nAChRs in a form of sleep-related epilepsy with familial occurrence in about 30% of probands and dominant inheritance, named autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Sporadic and familial forms have similar clinical and EEG features. Seizures begin in middle childhood as clusters of sleep-related attacks with prominent motor activity, and sustained dystonic posturing. In addition to nocturnal seizures, psychosis or schizophrenia, behavioral disorders, memory deficits and mental retardation were described in some individuals. Although over hundred families are on record, only a minority of them have been linked to mutations in the genes coding for the alpha4, alpha2 and beta2 (CHRNA4, CHRNA2, and CHRNB2) subunits of the nAChRs, indicating that ADNFLE is genetically heterogeneous despite a relatively homogeneous clinical picture. Functional characterization of some mutations suggests that gain of the receptor function might be the basis for epileptogenesis. In vitro and in vivo studies have shown high density of nAChRs in the thalamus, over activated brainstem ascending cholinergic pathway and enhanced GABAergic function, reinforcing the hypothesis that cortico-subcortical networks, regulating arousal from sleep, play a central role in seizure precipitation in ADNFLE.

Ictal SPECT analyzed by three-dimensional stereotactic surface projection in frontal lobe epilepsy patients.

We analyzed preoperative ictal SPECT results from 18 frontal lobe epilepsy patients who underwent epilepsy surgery (mean age 22.9 years). Seizure onset at implanted subdural electrodes was defined as the epileptic focus in 16 of 18 patients. In two additional patients, the resected area on postoperative magnetic resonance images was defined as the epileptic focus. The radioisotope 99mTc-ECD was injected in all patients within 5 s after seizure onset. SPECT images were analyzed by three-dimensional stereotactic surface projection (3-D SSP). Areas of hyperperfusion identified by ictal SPECT were concordant with the site of epileptic focus in 11 patients (61.1%, concordant group) and were non-concordant in 7 patients (38.9%, non-concordant group). The non-concordant group had a higher number of patients with a history of acquired brain damages, such as encephalitis or brain surgery (p < 0.05). Only 3 of 11 patients in the concordant group showed areas of localized hyperperfusion within epileptic foci, whereas 8 patients showed areas of hyperperfusion extending to other regions. Ictal SPECT analyzed by 3-D SSP is useful as a mode of presurgical evaluation in frontal lobe epilepsy patients without a history of encephalitis or surgical treatment. We caution that rapid seizure spread may result occasionally in areas of hyperperfusion extending to adjacent or remote regions.

Uncommon, exceptional and atypical: a case of frontal lobe epilepsy due to cortical dysplasia.

We report a case of frontal lobe epilepsy due to focal cortical dysplasia that included three independent unusual features. The patient, a 45-year-old, right-handed woman, had her first seizure at age 29, well into adulthood. Seizures had been easily controlled with medication for 15 years, then without provocation they became medically intractable during a single, identifiable day. Resection of the dysplastic tissue in the posterior dorsolateral right frontal cortex rendered the patient seizure-free, but produced a significant, non-fluent, Broca type, crossed aphasia. In addition, the seizure semiology was striking and remarkable, a common finding in frontal lobe epilepsy. [Published with video sequences].

Intractable cryptogenic frontal lobe epilepsy in a patient with MURCS association.

The MURCS association is a rare, nonrandom association of müllerian duct aplasia, renal aplasia and cervicothoracic somite dysplasia. The etiology is unknown. Although it is usually a sporadic disorder, familial cases with uterovaginal anomalies have been reported. Occasionally, it may be accompanied by abnormalities involving various other organs or systems. Malformations related to the central nervous system are very rare and the presence of seizures has not been reported previously. We present a 26-year-old female with MURCS association who had late onset, drug resistant partial seizures presumably originating in the frontal lobe.

[Analysis of risk factors for prognosis of frontal lobe epilepsy].

OBJECTIVE: To analyze the risk factors for the prognosis of frontal lobe epilepsy in order to predict the refractory frontal lobe epilepsy early, so as to provide theoretic basis for rational therapy early. METHODS: Forty-seven patients with medically refractory frontal lobe epilepsy and 92 patients with medically controllable epilepsy, totally 139 patients, underwent epidemiological savery, cranial CT or MRI, and video-electroencephalography (VEEG). Single factor analysis and Logistic stepwise regression analysis were done to analyze the relationship between the influential factors and the prognosis of disease. RESULT: Single factor analysis showed that the factors including earlier onset age, longer duration before taking reasonable medicine, more frequent seizure (> 1 time/day), asymmetric tonic seizures, seizures with hypermotor automatism, secondary generally tonic-clonic seizures, and a past history of taking medicine, exerted adverse effects on the prognosis of frontal lobe epilepsy (all P < 0.05). Logistic stepwise regression analysis screened out such factors including duration before taking reasonable medicine (OR = 1.384, 95% CI 1.133 - 1.689) and seizure frequency (OR = 6.512, 95% CI 1.637 - 25.911) as independent predictors for the prognosis of frontal lobe epilepsy. CONCLUSION: Long duration before taking reasonable medicine and frequent seizure onset are important risk factors for refractory frontal lobe epilepsy. It is possible to improve the prognosis of frontal lobe epilepsy by making a definite diagnosis and beginning rational therapy early.

[A case of coexistence with cavernous angioma and focal cortical dysplasia].

There have recently been a number of new pathological findings of specimens from epileptic foci that have become widespread of surgical treatment. We reported a case with seizures resulting from brain lesions which pathologically demonstrated a coexistence with a cavernous angioma and a focal cortical dysplasia. A 24-year-old man was admitted to our hospital because of generalized convulsion from 1 year ago. Brain MRI revealed an enhanced mass lesion, in diameter 1.5 cm, with hemosiderin rim in the left temporal tip. Ictal EEG showed the initiation of the spike from the lateral side of the left temporal lobe. Because the epileptogenic focus was thought to be the lateral side in the left temporal lobe, anterolateral temporal resection was performed and subsequently total removal of the tumor was performed. He had no seizure after surgery. A light microscopic examination was performed on specimens stained with hematoxilin and eosin. We verified to be pathologically coexistent with a cavernous angioma and a focal cortical dysplasia. We also found unusual neurons that were accompanied by perineuronal glial satellitosis in the subcortical white matter, those were occasionally observed in epileptic foci and were thought to be a form of neuronal migration disorders.

Epilepsy and variation in the frontal lobe artery.

A patient with a rare variation of fronto-orbital artery (FOA) that developed generalized tonic and clonic seizures is reported. The epilepsy focus was in her left frontal region, where blood was supplied by the contralateral fronto-orbital artery. The region was vulnerable to ischemic changes due to a decrease in blood CO2 gas caused by an increase in endogenous progesterone in the luteal period. The anomaly illustrates an important mechanism of ischemia in epilepsy.

June 2003: 33-year-old male with a frontal lobe mass.

The June 2003 COM. A 33-year-old male with a history of seizures was found to have an intra- and extra-axial frontal lobe mass. The histology of the resected tumor showed a meningioma with underlying meningioangiomatosis. Meningioangiomatosis (MA) is a benign intracortical plaque-like proliferation of meningothelial cells, microvasculature and fibroblast-like cells probably of hamartomatous origin. Very rarely, MA is associated with an overlying meningioma as in this case. When MA is accompanied by a meningioma, it is generally not associated with clinical evidence of neurofibromatosis. It is important to distinguish MA from an invasive meningioma, because of its favorable prognosis after resection.

Comparison of scalp electroencephalogram with subdural electrocorticogram recordings and functional mapping in frontal lobe epilepsy.

We compared the findings of scalp electroencephalogram with subdural electrode array (SEA) recordings in 19 patients with refractory frontal lobe epilepsy. Prolonged scalp interictal recordings localized the epileptogenic zone in 12 patients; seven had no interictal sharp waves. The SEAs showed multifocal interictal sharp waves in all patients. Seven patients with localized seizure onset on scalp recording showed extensive ictal onset on the SEA recording. Five patients with lateralized seizure onset to one hemisphere on scalp recording were found to have ictal onset on SEA restricted to a smaller area. Because of the large epileptogenic zone found on SEA recordings, a complete resection was possible in only five (33%) of the 15 patients who had resections. Eight (53%) of the 15 patients benefited from surgery (mean follow-up, 4.6 years). The SEAs also allowed functional localization in most patients. From these data, we suggest that a localizing scalp electroencephalogram in patients with frontal lobe epilepsy may be misleading because SEA recordings show larger epileptogenic zones than anticipated. Furthermore, we postulate that the larger extensive epileptogenic zone may account for the poorer surgical outcome in patients with frontal lobe epilepsy compared with patients with temporal lobe epilepsy.