18F-FDG PET and high-resolution MRI co-registration for pre-surgical evaluation of patients with conventional MRI-negative refractory extra-temporal lobe epilepsy.

PURPOSE: Epilepsy that originates outside of the temporal lobe can present some of the most challenging problems for surgical therapy, especially for patients with conventional magnetic resonance imaging (MRI)-negative refractory extra-temporal lobe epilepsy (ETLE). This study aimed to evaluate the clinical value of pre-surgical 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) and high-resolution MRI (HR-MRI) co-registration in patients with conventional MRI-negative refractory ETLE, and compare their surgical outcomes. METHODS: Sixty-seven patients with conventional MRI-negative refractory ETLE were prospectively included for pre-surgical 18F-FDG PET and HR-MRI examinations. Under the guidance of 18F-FDG PET and HR-MRI co-registration, HR-MRI images were re-read. Based on the image result changes from first reading to re-reading, patients were divided into three groups: Change-1 (lesions of subtle abnormality could be identified in re-read), Change-2 (non-specific abnormalities reported in the first reading were considered as lesions on HR-MRI re-read) and No-change. Post-surgical follow-ups were conducted for up to 59 months. RESULTS: Visual analysis of 18F-FDG PET showed focal or regional abnormality in 46 patients (68.6%), while the abnormal rate increased to 94.0% (P < 0.05) by co-registration. Of the 67 patients, 46.3% of them were identified as Change-1, and 11.9% as Change-2 after co-registration and HR-MRI re-read. Patients with Change-1 and -2 were more likely to be recommended to receive surgical resection (P < 0.001). In the 17 post-surgical patients, 88% had good outcomes, whereas 11.7% had poor outcomes during our study period. CONCLUSION: Pre-surgical evaluation by co-registration of 18F-FDG PET and HR-MRI could improve the identification of the epileptogenic onset zone (EOZ), and may further guide the surgical decision-making and improve the outcome of the refractory ETLE with normal conventional MRI; therefore, it should be recommended as a standard procedure for pre-surgical evaluation of these patients.

Voxel-based morphometric magnetic resonance imaging (MRI) postprocessing in MRI-negative epilepsies.

OBJECTIVE: In the presurgical workup of magnetic resonance imaging (MRI)-negative (MRI(-) or "nonlesional") pharmacoresistant focal epilepsy (PFE) patients, discovering a previously undetected lesion can drastically change the evaluation and likely improve surgical outcome. Our study utilizes a voxel-based MRI postprocessing technique, implemented in a morphometric analysis program (MAP), to facilitate detection of subtle abnormalities in a consecutive cohort of MRI(-) surgical candidates. METHODS: Included in this retrospective study was a consecutive cohort of 150 MRI(-) surgical patients. MAP was performed on T1-weighted MRI, with comparison to a scanner-specific normal database. Review and analysis of MAP were performed blinded to patients' clinical information. The pertinence of MAP(+) areas was confirmed by surgical outcome and pathology. RESULTS: MAP showed a 43% positive rate, sensitivity of 0.9, and specificity of 0.67. Overall, patients with the MAP(+) region completely resected had the best seizure outcomes, followed by the MAP(-) patients, and patients who had no/partial resection of the MAP(+) region had the worst outcome (p < 0.001). Subgroup analysis revealed that visually identified subtle findings are more likely correct if also MAP(+) . False-positive rate in 52 normal controls was 2%. Surgical pathology of the resected MAP(+) areas contained mainly non-balloon-cell focal cortical dysplasia (FCD). Multiple MAP(+) regions were present in 7% of patients. INTERPRETATION: MAP can be a practical and valuable tool to: (1) guide the search for subtle MRI abnormalities and (2) confirm visually identified questionable abnormalities in patients with PFE due to suspected FCD. A MAP(+) region, when concordant with the patient's electroclinical presentation, should provide a legitimate target for surgical exploration.

Reduced complications from intracranial grid insertion by using a small grid size and a precise protocol during monitoring.

BACKGROUND: A study of the risk factors associated with complications during intracranial EEG monitoring led to a change in protocol for monitoring and implantation at our centres. We conducted a study to identify any reduction in complications following the changed protocols involving the use of smaller subdural electrode arrays, continuous ICP monitoring, use of a central line, and intake of prophylactic antibiotics and dexamethasone. METHODS: We prospectively collected data on patient outcomes between 2005 and 2012 (group B) compared with patients between 1988 and 2004 (group A) before the protocol changes. RESULTS: Seventy-one patients in group A and 58 patients in group B underwent intracranial electrode implantation. Complications directly related to grids occurred in 25 % of group A vs. 8.6 % in group B (p < 0.05) and those indirectly related to grids were 11.2 % in group A vs. none in group B. The rate of transient complications requiring no treatment was 12.5 % in group A versus 1.7 % in group B. The rate of transient complications requiring treatment was 10 % in group A and 6.9 % in group B. There were two deaths in group A. The infection rate was higher in group B than group A (5.2 % vs. 2.8 %; p = 0.90). Since 2008 there have been no infective complications. Complications directly related to intracranial EEG monitoring were significantly reduced using the revised protocol (p < 0.05). Regression analysis identifying only the size of the grids (≤4 × 8 grid arrays) implanted was an independent predictor of more complications in group A (P < 0.05). CONCLUSIONS: Complication rates following intracranial implantation decreased following the use of a small grid size and adherence to a stringent protocol.

The relationship between neuropsychological functioning and FDG-PET hypometabolism in intractable mesial temporal lobe epilepsy.

We examined the relationship between baseline neuropsychological functioning and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in intractable mesial temporal lobe epilepsy (MTLE). We hypothesized relationships between dominant temporal lobe hypometabolism and verbal memory and between nondominant temporal lobe hypometabolism and nonverbal memory in line with the lateralized material-specific model of memory deficits in MTLE. We also hypothesized an association between performance on frontal lobe neuropsychological tests and prefrontal hypometabolism. Thirty-two patients who had undergone temporal lobectomy for treatment of MTLE and who completed both presurgical FDG-PET and comprehensive neuropsychological investigations with widely used standardized measures were included. Age-adjusted composite measures were calculated for verbal memory, nonverbal memory, relative material-specific memory, IQ, executive function, attention/working memory, and psychomotor speed. Fluorodeoxyglucose positron emission tomography was analyzed with statistical parametric mapping (SPM) to identify hypometabolism relative to healthy controls. Pearson's correlation was used to determine the relationship between regions of hypometabolism and neuropsychological functioning. Dominant temporal lobe hypometabolism was associated with relatively inferior verbal memory, while nondominant temporal lobe hypometabolism was associated with inferior nonverbal memory. No relationship was found between performance on any frontal lobe measures and prefrontal hypometabolism. Statistical parametric mapping-quantified lateralized temporal lobe hypometabolism correlates with material-specific episodic memory impairment in MTLE. In contrast, prefrontal hypometabolism is not associated with performance on frontal lobe measures. We suggest that this is because frontal lobe neuropsychology tests may not be good measures of isolated frontal lobe functioning.

The cognitive profile of occipital lobe epilepsy and the selective association of left temporal lobe hypometabolism with verbal memory impairment.

We investigated the cognitive profile of structural occipital lobe epilepsy (OLE) and whether verbal memory impairment is selectively associated with left temporal lobe hypometabolism on [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET). Nine patients with OLE, ages 8-29 years, completed presurgical neuropsychological assessment. Composite measures were calculated for intelligence quotient (IQ), speed, attention, verbal memory, nonverbal memory, and executive functioning. In addition, the Wisconsin Card Sorting Test (WCST) was used as a specific measure of frontal lobe functioning. Presurgical FDG-PET was analyzed with statistical parametric mapping in 8 patients relative to 16 healthy volunteers. Mild impairments were evident for IQ, speed, attention, and executive functioning. Four patients demonstrated moderate or severe verbal memory impairment. Temporal lobe hypometabolism was found in seven of eight patients. Poorer verbal memory was associated with left temporal lobe hypometabolism (p = 0.002), which was stronger (p = 0.03 and p = 0.005, respectively) than the association of left temporal lobe hypometabolism with executive functioning or with performance on the WCST. OLE is associated with widespread cognitive comorbidity, suggesting cortical dysfunction beyond the occipital lobe. Verbal memory impairment is selectively associated with left temporal lobe hypometabolism in OLE, supporting a link between neuropsychological dysfunction and remote hypometabolism in focal epilepsy.

Myoclonic status epilepticus as a presentation of caspr2 antibody-associated autoimmune encephalitis.

We present a case of autoimmune encephalitis associated with antibodies targeting contact in-associated protein-like 2. This case is notable because of the presentation with myoclonic status epilepticus and the prolonged clinical course of refractory seizures, which are demonstrated in the accompanying videos, and not previously associated with this condition. Treatment with prednisone, intravenous immunoglobulin, plasma exchange, rituximab, cyclophosphamide, and mycophenolate mofetil resulted in significant functional improvement. Historically, myoclonic status epilepticus is associated with a grave prognosis and minimal chance of meaningful recovery. This case demonstrates that autoimmune encephalitis remains an important differential diagnosis in patients with such a presentation, and that early recognition and the appropriate institution of immunotherapy can result in seizure control and functional recovery. [Published with video sequences].

Neuroimaging characteristics of MRI-negative orbitofrontal epilepsy with focus on voxel-based morphometric MRI postprocessing.

PURPOSE: The orbitofrontal (OF) region is one of the least explored regions of the cerebral cortex. There are few studies on patients with electrophysiologically and surgically confirmed OF epilepsy and a negative magnetic resonance imaging (MRI) study. We aimed to examine the neuroimaging characteristics of MRI-negative OF epilepsy with the focus on a voxel-based morphometric MRI postprocessing technique. METHODS: We included six patients with OF epilepsy, who met the following criteria: surgical resection of the OF lobe with/without adjacent cortex, seizure-free for ≥12 months, invasive video-electroencephalography (EEG) monitoring showing ictal onset from the OF area, and preoperative MRI regarded as negative. Patients were investigated in terms of their image postprocessing and functional neuroimaging characteristics, electroclinical characteristics obtained from noninvasive and invasive evaluations, and surgical pathology. MRI postprocessing on T1 -weighted high-resolution scans was implemented with a morphometric analysis program (MAP) in MATLAB. KEY FINDINGS: Single MAP+ abnormalities were found in four patients; three were in the OF region and one in the ipsilateral mesial frontal area. These abnormalities were included in the resection. One patient had bilateral MAP+ abnormalities in the OF region, with the ipsilateral one completely removed. The MAP+ foci were concordant with invasive electrophysiologic data in the majority of MAP+ patients (four of five). The localization value of 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) and ictal single-photon emission computed tomography (SPECT) is low in this cohort. Surgical pathology included focal cortical dysplasia, remote infarct, Rosenthal fiber formation and gliosis. SIGNIFICANCE: Our study highlights the importance of MRI postprocessing in the process of presurgical evaluation of patients with suspected orbitofrontal epilepsy and "normal" MRI. Using MAP, we were able to positively identify subtle focal abnormalities in the majority of the patients. MAP results need to be interpreted in the context of their electroclinical findings and can provide valuable targets in the process of planning invasive evaluation.

Relationship between preoperative hypometabolism and surgical outcome in neocortical epilepsy surgery.

PURPOSE: Fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) hypometabolism has been used to localize the epileptogenic zone. However, glucose hypometabolism remote to the ictal focus is common and its relationship to surgical outcome has not been considered in many studies. We investigated the relationship between surgical outcome and FDG-PET hypometabolism topography in a large cohort of patients with neocortical epilepsy. METHODS: We identified all patients (n = 68) who had interictal FDG-PET between 1994 and 2004 and who underwent resective epilepsy surgery with follow up for more than 2 years. The volumes of significant FDG-PET hypometabolism involving the resected epileptic focus and its surrounding regions (perifocal hypometabolism) and those distant to and not contiguous with the perifocal hypometabolism (remote hypometabolism) were determined statistically using Statistical Parametric Mapping (voxel threshold p = 0.01, extent threshold ≥ 250 voxels, uncorrected cluster-level significance p < 0.05) and were compared with magnetic resonance imaging (MRI) and clinical and demographic variables using a multiple logistic regression model to identify independent predictors of seizure outcome. KEY FINDINGS: Remote hypometabolism was present in 39 patients. Seizure freedom was 49% (19 of 39 patients) in patients with glucose hypometabolism remote from the epileptogenic zone compared to 90% (26 of 29 patients) in patients without remote hypometabolism. In 43 patients with an MRI-identified lesion, seizure freedom was 79% (34 of 43 patients). In patients with normal MRI, cortical dysplasia was the predominant pathologic substrate. Multiple logistic regression analysis identified a larger volume of significant remote hypometabolism (p < 0.005) and absence of a MRI-localized lesion (p = 0.006) as independent predictors of continued seizures after surgery. SIGNIFICANCE: In patients with widespread glucose hypometabolism that is statistically significant when compared to controls, epilepsy surgery may not result in complete seizure freedom despite complete removal of the MRI-identified lesion. The volume of significant glucose hypometabolism remote to the ictal-onset zone may be an independent predictor of the success of epilepsy surgery.

Investigating the Precise Localization of the Grasping Action in the Mid-Cingulate Cortex and Future Directions.

Objective: To prospectively study the cingulate cortex for the localization and role of the grasping action in humans during electrical stimulation of depth electrodes. Methods: All the patients (n = 23) with intractable focal epilepsy and a depth electrode stereotactically placed in the cingulate cortex, as part of their pre-surgical epilepsy evaluation from 2015 to 2017, were included. Cortical stimulation was performed and examined for grasping actions. Post-implantation volumetric T1 MRIs were co-registered to determine the exact electrode position. Results: Five patients (male: female 4:1; median age 31) exhibited contralateral grasping actions during electrical stimulation. All patients had electrodes implanted in the ventral bank of the right cingulate sulcus adjacent to the vertical anterior commissure (VAC) line. Stimulation of other electrodes in adjacent regions did not elicit grasping. Conclusion: Grasping action elicited from a localized region in the mid-cingulate cortex (MCC) directly supports the concept of the cingulate cortex being crucially involved in the grasping network. This opens an opportunity to explore this region with deep brain stimulation as a motor neuromodulation target for treatment in specific movement disorders or neurorehabilitation.

Brain activation patterns of versive, hypermotor, and bilateral asymmetric tonic seizures.

PURPOSE: Patients who have seizure onset from different brain regions can produce seizures that appear clinically indistinguishable from one another. These clinically stereotypic manifestations reflect epileptic activation of specific networks. Several studies have shown that ictal perfusion single photon emission computed tomography (SPECT) can reveal propagated ictal activity. We hypothesize that the pattern of hyperperfusion may reflect neuronal networks that generated specific ictal symptomatology. METHODS: All patients were identified who were injected with (99m)Tc-hexamethyl-propylene-amine-oxime (HMPAO) during versive seizures (n = 5), bilateral asymmetric tonic seizures (BATS; n = 5), and hypermotor seizures (n = 7) in the presurgical epilepsy evaluation between 2001 and 2005. The SPECT ictal­interictal difference image pairs of each subgroup were compared with image pairs of 14 controls using statistical parametric mapping (SPM 2) to identify regions of significant hyperperfusion. Hyperperfused regions with corrected cluster-level significance p < 0.05 were considered significant. RESULTS: We have identified a distinct ictal perfusion pattern in each subgroup. In versive seizure subgroup, prominent hyperperfusion was present in the frontal eye field opposite to the direction of head version. In addition, there was associated caudate and crossed cerebellar hyperperfusion. The BATS subgroup showed pronounced hyperperfusion supplementary sensorimotor area ipsilateral to the epileptogenic region, bilateral basal ganglia, and contralateral cerebellar hemisphere. The hypermotor seizure subgroup demonstrated two clusters of significant hyperperfusion: one involving bilateral frontomesial regions, cingulate gyri, and caudate nuclei, and another involving ipsilateral anteromesial temporal structures, frontoorbital region, insula, and basal ganglia. DISCUSSION: We have identified distinct hyperperfusion patterns for specific ictal symptomatology. Our findings provide further insight into understanding the anatomic basis of seizure semiology.

The topography and significance of extratemporal hypometabolism in refractory mesial temporal lobe epilepsy examined by FDG-PET.

PURPOSE: This study aims to map the temporal and extratemporal 18-fluorodeoxyglucose positron emission tomography (FDG-PET)-defined hypometabolism in mesial temporal lobe epilepsy (MTLE). We hypothesize that quantitative analysis will reveal extensive extratemporal glucose hypometabolism (EH), that the EH is related to seizure propagation beyond the temporal lobe, hypometabolism restricted to one temporal lobe predicts a good outcome following surgery, and EH predicts a poor outcome. METHODS: Sixty-four patients were studied who had undergone temporal lobectomy for intractable MTLE and had at least 2 years of postoperative follow-up. Spatial preprocessing and statistical analysis on preoperative interictal FDG-PET using statistical parametric mapping (SPM 2) identified significant regions of hypometabolism compared to normal controls. The predictors of outcome were determined by univariable and multiple logistic regression analyses. RESULTS: EH was common and widespread, occurring most frequently in the ipsilateral insula and frontal lobe. The extent of EH was not significantly associated with age of onset or the duration of epilepsy. Presence of secondarily generalized tonic--clonic seizures (SGTCS) was associated with a larger extent of remote hypometabolism (RH, p < 0.005). Multiple logistic regression analysis identified the extent of RH and the age at surgery as independent predictors of seizure outcome. DISCUSSION: Our results indicate that RH in MTLE is associated with a poorer surgical outcome, especially if seen in the contralateral hemisphere. The extent of RH relates to SGTCS but not to duration of epilepsy.

Successful epilepsy surgery for tuberous sclerosis complex evaluated by stereoelectroencephalography.

Evaluating the candidacy for epilepsy surgery in patients with tuberous sclerosis can be challenging, particularly when non-invasive investigations do not show a clear epileptogenic zone. Stereoencephalography may be useful in such cases. We present a case in which the primary epileptogenic tuber was successfully identified by stereoencephalography, which resulted in seizure freedom following epilepsy surgery. [Published with video sequences].

Risk factors for complications during intracranial electrode recording in presurgical evaluation of drug resistant partial epilepsy.

BACKGROUND: Intracranial electrode monitoring is still required in epilepsy surgery; however, it is associated with significant morbidity. OBJECTIVE: To identify risk factors associated with complications during invasive intracranial EEG monitoring. MATERIALS AND METHODS: Retrospective study of all patients undergoing invasive monitoring at Westmead between 1988-2004. From detailed chart reviews, the following variables were recorded: duration of intracranial monitoring, the site of grid implantation, number of grids and electrodes, seizure frequency, postoperative complications and seizure outcome. RESULTS: Seventy-one patients (median age: 24 years) underwent subdural electrode implantation; 62% had extratemporal lobe epilepsy and 46% were non-lesional. Of the 58 monitored patients who had cortical resections, 45 had good seizure outcomes. Complications related to subdural electrode implantation included transient complications requiring no treatment (12.7%), transient complications requiring treatment (9.9%) and two deaths (2.8%). Specific complications included subdural haemorrhage, transient neurological deficit, infarction and osteomyelitis. The two deaths occurred within 48 h of implantation were related to raised intracranial pressure (one venous infarction, one unexplained). Complications were associated with maximal size of grid (p < 0.001), greater number of electrodes (p < 0.001), electrode density per cortical surface implanted (p < 0.001), right central surface implantation (p = 0.003) and left central surface implantation (p = 0.013). Multiple logistic regression identified larger size grids and right central surface implantation as independent predictors of complications. CONCLUSION: There are significant complications during intracranial EEG evaluations but the majority of these are transient. We found a relationship between the size of the electrode arrays and the incidence of complications. The results of this study have been used to modify our implantation and monitoring protocols.

The varied semiology of seizures in the context of small anterior temporal encephaloceles.

Small encephaloceles of the anterior temporal pole have been increasingly recognised as an underlying epileptogenic substrate in patients with medically refractory epilepsy. The current report aims to expand on the current knowledge by emphasising that seizure semiology in such patients can vary significantly. Patients were selected from an epilepsy surgery database between 2012 and 2017. Of the 143 patients who underwent epilepsy surgery, six patients had a temporal encephalocele. Four of these patients had stereo-EEG implantation. Of the four patients studied, each had a seizure semiology discordant with an ictal focus in the temporal lobe. Intracranial EEG assessment demonstrated, irrespective of this semiology, seizures originated from the anterior temporal pole. Seizures were observed to rapidly propagate to the orbitofrontal cortex, insula, temporo-occipital junction, and posterior language regions. Engagement of the mesial temporal structures could occur early or late, however, a good surgical outcome was achieved following a focused lesionectomy in either situation. The major finding was that seizures arising from anterior temporal encephaloceles can have an extra-temporal semiology. The varied clinical semiology and the rapid propagation to seemingly distant cortical regions could be explained by the connectivity of the anterior temporal lobe.

Metabolic changes in occipital lobe epilepsy with automatisms.

PURPOSE: Some studies suggest that the pattern of glucose hypometabolism relates not only to the ictal-onset zone but also reflects seizure propagation. We investigated metabolic changes in patients with occipital lobe epilepsy (OLE) that may reflect propagation of ictal discharge during seizures with automatisms. METHODS: Fifteen patients who had undergone epilepsy surgery for intractable OLE and had undergone interictal Fluorine-18-fluorodeoxyglucose positron-emission tomography ((18)F-FDG-PET) between 1994 and 2004 were divided into two groups (with and without automatisms during seizure). Significant regions of hypometabolism were identified by comparing (18)F-FDG-PET results from each group with 16 healthy controls by using statistical parametric mapping. KEY FINDINGS: Significant hypometabolism was confined largely to the epileptogenic occipital lobe in the patient group without automatisms. In patients with automatisms, glucose hypometabolism extended from the epileptogenic occipital lobe into the ipsilateral temporal lobe. SIGNIFICANCE: We identified a distinctive hypometabolic pattern that was specific for OLE patients with automatisms during a seizure. This finding supports the postulate that seizure propagation is a cause of glucose hypometabolism beyond the region of seizure onset.

Long duration between presentation of probable anti-N-methyl-D-aspartate receptor encephalitis and either clinical relapse or positive serum autoantibodies.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune encephalitis first described in 2007. This condition has a well-characterised clinical phenotype with a multistage presentation beginning with prodromal symptoms, psychosis, cognitive deficits, and seizures, which can progress to involve movement disorders, catatonia, autonomic instability, and central hypoventilation requiring ventilatory support. Our first patient demonstrates, to our knowledge, the longest duration between the presentation of anti-NMDAR encephalitis and clinical relapse that has thus far been described. Our second patient highlights a clinical scenario where positive serum autoantibodies are demonstrated six years following complete clinical recovery, in the absence of clinical features of a relapse or a malignancy on screening. These patients highlight the importance of long-term follow up and tumour surveillance, and the role of electroconvulsive therapy in the management of catatonia. These cases also support the need for future studies evaluating the role of maintenance immunosuppression in patients at high risk for relapses.

Dysexecutive behaviour following deep brain lesions--a different type of disconnection syndrome?

The suppression of automatic prepotent behaviour in favour of more successful, more 'appropriate' behaviour is the primary function of the frontal lobe. Five frontal-subcortical circuits connect the frontal lobe to the basal ganglia and the thalamus. We report 17 patients with small lesions in the downstream structures of the frontal-subcortical circuits displaying severe dysexecutive behaviour. Positron emission tomography (PET) demonstrated hypometabolism of the frontal lobe in some of these patients. The literature on frontal lobe dysfunction after lesions in the basal ganglia and thalamus is discussed and the semiology of frontal lobe dysfunction in relation to the frontal-subcortical circuits is highlighted. Derived from our findings we suggest a disconnection syndrome of the frontal lobe caused by lesions in the downstream structures of the frontal-subcortical circuits.