MRI-negative epilepsy treatment

MRI-negative epilepsy treatment

Several methods for processing MRI postacquisition data have identified either previously undetectable or overlooked MRI abnormalities. The resection of these abnormalities is associated with excellent postsurgical seizure control. There have been major advances in functional imaging as well, one of which is the application of statistical parametric mapping analysis for comparing patient data against normative data. This approach has specifically improved the usefulness of both PET and single-photon emission computed tomography in MRI-negative epilepsy surgery evaluation. One other development of importance is that of PET-MRI coregistration, which has recently been shown to be superior to conventional PET. More recent publications on magnetoencephalography have added to the literature of its use in MRI-negative epilepsy surgery evaluation, which up to now remains somewhat limited. However, recent data now indicate that a single magnetoencephalography cluster is associated with better chance of concordance with intracranial EEG localization, and with excellent postsurgical seizure control if completely resected.

Summary: Advanced MRI and functional imaging and subsequent intracranial EEG confirmation of the seizure-onset zone are essential to make MRI-negative epilepsy surgery possible and worthwhile for the patient 1).


The optimal management of MRI-negative epilepsy may involve invasive monitoring followed by resection or responsive neurostimulation in most cases, as these treatments were associated with the best seizure outcomes in a cohort of the Yale New Haven Hospital. Unless multifocal epileptogenesis is clear from the non-invasive evaluation, epilepsy invasive monitoring is preferred before pursuing deep brain stimulation or vagus nerve stimulation directly 2).


Magnetoencephalography (MEG) is valuable for guiding in resective epilepsy surgery. MEG is a useful supplement for patients with MRI-negative epilepsy. MEG can be applied in minimally invasive treatment. MEG clusters can help identify better candidates and provide a valuable target for stereoelectroencephalography guided radiofrequency thermocoagulation, which leads to better outcomes. 3).


1)

So EL, Lee RW. Epilepsy surgery in MRI-negative epilepsies. Curr Opin Neurol. 2014 Apr;27(2):206-12. doi: 10.1097/WCO.0000000000000078. PMID: 24553461.
2)

McGrath H, Mandel M, Sandhu MRS, Lamsam L, Adenu-Mensah N, Farooque P, Spencer DD, Damisah EC. Optimizing the surgical management of MRI-negative epilepsy in the neuromodulation era. Epilepsia Open. 2022 Jan 17. doi: 10.1002/epi4.12578. Epub ahead of print. PMID: 35038792.
3)

Gao R, Yu T, Xu C, Zhang X, Yan X, Ni D, Zhang X, Ma K, Qiao L, Zhu J, Wang X, Ren Z, Zhang X, Zhang G, Li Y. The value of magnetoencephalography for stereo-EEG-guided radiofrequency thermocoagulation in MRI-negative epilepsy. Epilepsy Res. 2020 Mar 20;163:106322. doi: 10.1016/j.eplepsyres.2020.106322. [Epub ahead of print] PubMed PMID: 32278277.

Posttraumatic Epilepsy Epidemiology

Posttraumatic Epilepsy Epidemiology

In general, the incidence of Posttraumatic Epilepsy varies with the time period after injury and population age range under study, as well as the spectrum of severity of the inciting injuries, and has been reported to be anywhere from 4 to 53% 1).

Generally posttraumatic epilepsy accounts for less than 10% of epilepsy 2).


In a cohort study, the incidence of self-reported PTE after TBI was found to be 2.8% and was independently associated with unfavorable outcomes 3).


In a large cohort of post-concussion patients Wennberg et al. found no increased incidence of epilepsy. For at least the first 5-10 years post-injury, concussion/mTBI should not be considered a significant risk factor for epilepsy. In patients with epilepsy and a past history of concussion, the epilepsy should not be presumed to be post-traumatic 4).


The Vietnam Head Injury Study (VHIS) is a prospective, longitudinal follow-up of 1,221 Vietnam War veterans with mostly penetrating head injuries (PHIs). The high prevalence (45%-53%) of posttraumatic epilepsy (PTE) in this unique cohort makes it valuable for study.

A standardized multidisciplinary neurologic, cognitive, behavioral, and brain imaging evaluation was conducted on 199 VHIS veterans plus uninjured controls, some 30 to 35 years after injury, as part of phase 3 of this study.

The prevalence of seizures (87 patients, 43.7%) was similar to that found during phase 2 evaluations 20 years earlier, but 11 of 87 (12.6%) reported very late onset of PTE after phase 2 (more than 14 years after injury). Those patients were not different from patients with earlier-onset PTE in any of the measures studied. Within the phase 3 cohort, the most common seizure type last experienced was complex partial seizures (31.0%), with increasing frequency after injury. Of subjects with PTE, 88% were receiving anticonvulsants. Left parietal lobe lesions and retained ferric metal fragments were associated with PTE in a logistic regression model. Total brain volume loss predicted seizure frequency.

Patients with PHI carry a high risk of PTE decades after their injury, and so require long-term medical follow-up. Lesion location, lesion size, and lesion type were predictors of PTE 5).


A study was undertaken to determine the risk of developing posttraumatic epilepsy (PTE) within 3 years after discharge among a population-based sample of older adolescents and adults hospitalized with traumatic brain injury (TBI) in South Carolina. It also identifies characteristics related to development of PTE within this population.

A stratified random sample of persons aged 15 and older with TBI was selected from the South Carolina nonfederal hospital discharge dataset for four consecutive years. Medical records of recruits were reviewed, and they participated in up to three yearly follow-up telephone interviews.

The cumulative incidence of PTE in the first 3 years after discharge, after adjusting for loss to follow-up, was 4.4 per 100 persons over 3 years for hospitalized mild TBI, 7.6 for moderate, and 13.6 for severe. Those with severe TBI, posttraumatic seizures prior to discharge, and a history of depression were most at risk for PTE. This higher risk group also included persons with three or more chronic medical conditions at discharge.

These results raise the possibility that although some of the characteristics related to development of PTE are nonmodifiable, other factors, such as depression, might be altered with intervention 6).


Using Taiwan’s National Health Insurance Research Database of reimbursement claims, Yeh et al. conducted a retrospective cohort study of 19 336 TBI patients and 540 322 non-TBI participants aged ≥15 years as reference group. Data on newly developed epilepsy after TBI with 5-8 years’ follow-up during 2000 to 2008 were collected. HRs and 95% CIs for the risk of epilepsy associated with TBI were analysed with multivariate Cox proportional hazards regressions.

Results: Compared with the non-TBI cohort, the adjusted HRs of developing epilepsy among TBI patients with skull fracture, severe or mild brain injury were 10.6 (95% CI 7.14 to 15.8), 5.05 (95% CI 4.40 to 5.79) and 3.02 (95% CI 2.42 to 3.77), respectively. During follow-up, men exhibited higher risks of post-TBI epilepsy. Patients who had mixed types of cerebral haemorrhage were at the highest risk of epilepsy compared with the non-TBI cohort (HR 7.83, 95% CI 4.69 to 13.0). The risk of post-TBI epilepsy was highest within the first year after TBI (HR 38.2, 95% CI 21.7 to 67.0).

Conclusions: The risk of epilepsy after TBI varied by patient gender, age, latent interval and complexity of TBI. Integrated care for early identification and treatment of post-trauma epilepsy were crucial for TBI patients 7)


Christensen et al. aimed to assess the risk of epilepsy up to 10 years or longer after traumatic brain injury, taking into account sex, age, severity, and family history.

Methods: We identified 1 605 216 people born in Denmark (1977-2002) from the Civil Registration System. We obtained information on traumatic brain injury and epilepsy from the National Hospital Register and estimated relative risks (RR) with Poisson analyses.

Findings: Risk of epilepsy was increased after a mild brain injury (RR 2.22, 95% CI 2.07-2.38), severe brain injury (7.40, 6.16-8.89), and skull fracture (2.17, 1.73-2.71). The risk was increased more than 10 years after mild brain injury (1.51, 1.24-1.85), severe brain injury (4.29, 2.04-9.00), and skull fracture (2.06, 1.37-3.11). RR increased with age at mild and severe injury and was especially high among people older than 15 years of age with mild (3.51, 2.90-4.26) and severe (12.24, 8.52-17.57) injury. The risk was slightly higher in women (2.49, 2.25-2.76) than in men (2.01, 1.83-2.22). Patients with a family history of epilepsy had a notably high risk of epilepsy after mild (5.75, 4.56-7.27) and severe brain injury (10.09, 4.20-24.26) 8).


A total of 647 individuals (>/=16 y) with any of the following abnormal computed tomography (CT) scan findings: extent of midline shift and/or cisternal compression or presence of any focal pathology (eg, punctate, subarachnoid, or intraventricular hemorrhage; cortical or subcortical contusion; extra-axial lesions) during the first 7 days postinjury or best Glasgow Coma Scale (GCS) score of </=10 during the first 24 hours post-TBI. Subjects were enrolled from August 1993 through September 1997 and followed for up to 24 months, until death or their first late posttraumatic seizures.

Main outcome measures: Cumulative probability, relative risk, and survival analyses were used to stratify risks for development of late postttraumatic seizures on the basis of demographic factors, etiology of injury, initial GCS, early posttraumatic seizures, time post-TBI, types of intracerebral lesion by CT scan, and number and types of intracranial procedures.

Results: Sixty-six individuals had a late posttraumatic seizures; 337 had no late posttraumatic seizures during full 24-month follow-up; 167 had no late posttraumatic seizures during time followed (<24 mo); and 54 were placed on anticonvulsants without a late posttraumatic seizures, whereas 23 died before their first late posttraumatic seizures. The highest cumulative probability for late posttraumatic seizures included biparietal contusions (66%), dural penetration with bone and metal fragments (62.5%), multiple intracranial operations (36.5%), multiple subcortical contusions (33.4%), subdural hematoma with evacuation (27.8%), midline shift greater than 5mm (25.8%), or multiple or bilateral cortical contusions (25%). Initial GCS score was associated with the following cumulative probabilities for development of late posttraumatic seizures at 24 months: GCS score of 3 to 8, 16.8%; GCS score of 9 to 12, 24.3%; and GCS score of 13 to 15, 8.0%.

Conclusions: Stratification by CT scan findings and neurosurgical procedures performed were the most useful findings in defining individuals at highest risk for late posttraumatic seizures 9).


A cohort of 2747 patients with head injuries was followed for 28,176 person-years to determine the magnitude and duration of the risk of posttraumatic seizures. Injuries were classified as severe (brain contusion, intracerebral or intracranial hematoma, or 24 hours of eight unconsciousness of amnesia), moderate (skull fracture or 30 minutes to 24 hours of unconsciousness or amnesia), and mild (briefer unconsciousness or amnesia). The risk of posttraumatic seizures after severe injury was 7.1% within 1 year and 11.5% in 5 years, after moderate injury the risk was 0.7 and 1.6%, and after mild injury the risk was 0.1 and 0.6%. The incidence of seizures after mild head injuries was not significantly greater than in the general population 10)


The true incidence of PTE in children is still uncertain because most research has been based primarily on adults.

see Posttraumatic epilepsy in children.


1)

Frey LC. Epidemiology of posttraumatic epilepsy: a critical review. Epilepsia. 2003;44(s10):11-7. doi: 10.1046/j.1528-1157.44.s10.4.x. PMID: 14511389.
2)

Christensen J. The Epidemiology of Posttraumatic Epilepsy. Semin Neurol. 2015 Jun;35(3):218-22. doi: 10.1055/s-0035-1552923. Epub 2015 Jun 10. PMID: 26060901.
3)

Burke J, Gugger J, Ding K, Kim JA, Foreman B, Yue JK, Puccio AM, Yuh EL, Sun X, Rabinowitz M, Vassar MJ, Taylor SR, Winkler EA, Deng H, McCrea M, Stein MB, Robertson CS, Levin HS, Dikmen S, Temkin NR, Barber J, Giacino JT, Mukherjee P, Wang KKW, Okonkwo DO, Markowitz AJ, Jain S, Lowenstein D, Manley GT, Diaz-Arrastia R; TRACK-TBI Investigators, Badjatia N, Duhaime AC, Feeser VR, Gaudette E, Gopinath S, Keene CD, Korley FK, Madden C, Merchant R, Schnyer D, Zafonte R. Association of Posttraumatic Epilepsy With 1-Year Outcomes After Traumatic Brain Injury. JAMA Netw Open. 2021 Dec 1;4(12):e2140191. doi: 10.1001/jamanetworkopen.2021.40191. PMID: 34964854.
4)

Wennberg R, Hiploylee C, Tai P, Tator CH. Is Concussion a Risk Factor for Epilepsy? Can J Neurol Sci. 2018 May;45(3):275-282. doi: 10.1017/cjn.2017.300. Epub 2018 Mar 20. PMID: 29557322.
5)

Raymont V, Salazar AM, Lipsky R, Goldman D, Tasick G, Grafman J. Correlates of posttraumatic epilepsy 35 years following combat brain injury. Neurology. 2010 Jul 20;75(3):224-9. doi: 10.1212/WNL.0b013e3181e8e6d0. PMID: 20644150; PMCID: PMC2906177.
6)

Ferguson PL, Smith GM, Wannamaker BB, Thurman DJ, Pickelsimer EE, Selassie AW. A population-based study of risk of epilepsy after hospitalization for traumatic brain injury. Epilepsia. 2010 May;51(5):891-8. doi: 10.1111/j.1528-1167.2009.02384.x. Epub 2009 Oct 20. PMID: 19845734.
7)

Yeh CC, Chen TL, Hu CJ, Chiu WT, Liao CC. Risk of epilepsy after traumatic brain injury: a retrospective population-based cohort study. J Neurol Neurosurg Psychiatry. 2013 Apr;84(4):441-5. doi: 10.1136/jnnp-2012-302547. Epub 2012 Oct 31. PMID: 23117492.
8)

Christensen J, Pedersen MG, Pedersen CB, Sidenius P, Olsen J, Vestergaard M. Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study. Lancet. 2009 Mar 28;373(9669):1105-10. doi: 10.1016/S0140-6736(09)60214-2. Epub 2009 Feb 21. PMID: 19233461.
9)

Englander J, Bushnik T, Duong TT, Cifu DX, Zafonte R, Wright J, Hughes R, Bergman W. Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation. Arch Phys Med Rehabil. 2003 Mar;84(3):365-73. doi: 10.1053/apmr.2003.50022. PMID: 12638104.
10)

Annegers JF, Grabow JD, Groover RV, Laws ER Jr, Elveback LR, Kurland LT. Seizures after head trauma: a population study. Neurology. 1980 Jul;30(7 Pt 1):683-9. doi: 10.1212/wnl.30.7.683. PMID: 7190235.

Resective epilepsy surgery

Resective epilepsy surgery

Resective epilepsy surgery based on an invasive EEG-monitors performed with subdural grids (SDG) or depth electrodes (stereoelectroencephalographySEEG) is considered to be the best option towards achieving seizure-free state in drug resistant epilepsy.

Despite good outcomes from high-quality clinical trials, referrals of patients with seizures refractory to medical treatment remain infrequent 1).

Three RCTs (two adult RCTs and one pediatric RCT) consistently supported the efficacy of resective surgery as treatment for epilepsy with semiology localized to the mesial temporal lobe. In these studies, 58-100% of the patients who underwent resective surgery achieved seizure freedom, in comparison to 0-13% of medically treated patients. In another RCT, the likelihood of seizure freedom after resective surgery was independent of the surgical approach (transSylvian [64%] versus subtemporal [62%]). Two other RCTs demonstrated that hippocampal resection is essential to optimize seizure control. But, no significant gain in seizure control was achieved beyond removing 2.5 cm of the hippocampus. Across RCTs, minor complications (deficit lasting < 3 months) and major complications (deficit > 3 months) ranged 2-5% and 5-11% respectively. However, nonincapacitating superior subquadrantic visual-field defects (not typically considered a minor or major complication) were noted in up to 55% of the surgical cohort. The available RCTs provide compelling support for resective surgery as a treatment for mesial temporal lobe epilepsy and offer insights toward optimal surgical strategy 2)

Complete removal of the epileptogenic zone significantly increases the chances for postoperative seizure-freedom. In complex surgical candidates, delineation of the epileptogenic zone requires a long-term invasive video/EEG from intracranial electrodes. It is especially challenging to achieve a complete resection in deep brain structures such as opercular insular cortex 3).

Belohlavkova et al. retrospectively reviewed data of pediatric patients operated in Motol Epilepsy Center between October 2010 and June 2020 who underwent resections guided by intraoperative visual detection of depth electrodes following SEEG. The outcome in terms of seizure- and AED-freedom was assessed individually in each patient.

Nineteen patients (age at surgery 2.9-18.6 years, median 13 years) were included in the study. The epileptogenic zone involved opercular insular cortex in eighteen patients. The intraoperative detection of the electrodes was successful in seventeen patients and the surgery was regarded complete in sixteen. Thirteen patients were seizure-free at final follow-up including six drug-free cases. The successful intraoperative detection of the electrodes was associated with favorable outcome in terms of achieving complete resection and seizure-freedom in most cases. On the contrary, the patients in whom the procedure failed had poor postsurgical outcome.

The reported technique helps to achieve the complete resection in challenging patients with the epileptogenic zone in deep brain structures 4)


81 patients with tuberous sclerosis complex (TSC) who had undergone resective epilepsy surgery at Sanbo Brain Hospital, between April 2004 and June 2019. They estimated the cumulative probability of remaining seizure-free and plotted survival curves. Variables were compared using Mann-Whitney U, Pearson’s correlation, continuity correction, and Fisher’s exact chi-square tests. Prognostic predictors were analyzed using log-rank (Mantel-Cox) tests and Cox regression models.

At the last follow-up, 48 (59.3%) patients were classified as International League Against Epilepsy Class 1 (including 14 patients who had seizures <3 times postoperatively on the same or different day and were seizure-free at all other times). The estimated cumulative probability of remaining seizure-free postoperatively was 69.0% (95% confidence interval [CI] 58.8-79.2%), 61.9% (95% CI 51.1-72.7%), and 55.0% (95% CI 42.8-67.2%) at 2, 5, and 10 years, respectively. The mean time of remaining seizure-free was 7.24 ± 0.634 years (95% CI 6.00-8.49); en bloc resection was an essential positive predictor of postoperative seizure freedom, as was age at seizure onset, regional interictal video-electroencephalography pattern, and temporal lobe surgery. The longer the seizure-free time, the less likely a relapse. Patients who postoperatively experienced seizures remained likely to recover.

They demonstrated the efficacy of tuberous sclerosis complex treatment and intractable epilepsy with surgery. Detailed perioperative tests are a reliable predictor of postoperative seizure freedom 5)


1)

Jobst BC, Cascino GD. Resective epilepsy surgery for drug-resistant focal epilepsy: a review. JAMA. 2015 Jan 20;313(3):285-93. doi: 10.1001/jama.2014.17426. PMID: 25602999.
2)

Cramer SW, McGovern RA, Wang SG, Chen CC, Park MC. Resective epilepsy surgery: assessment of randomized controlled trials. Neurosurg Rev. 2021 Aug;44(4):2059-2067. doi: 10.1007/s10143-020-01432-x. Epub 2020 Nov 9. PMID: 33169227.
3) , 4)

Belohlavkova A, Jahodova A, Kudr M, Benova B, Ebel M, Liby P, Taborsky J, Jezdik P, Janca R, Kyncl M, Tichy M, Krsek P. May intraoperative detection of stereotactically inserted intracerebral electrodes increase precision of resective epilepsy surgery? Eur J Paediatr Neurol. 2021 Sep 25;35:49-55. doi: 10.1016/j.ejpn.2021.09.012. Epub ahead of print. PMID: 34610561.
5)

Huang Q, Zhou J, Wang X, Li T, Wang M, Wang J, Teng P, Qi X, Zhu M, Luan G, Zhai F. Predictors and Long-term Outcome of Resective Epilepsy Surgery in Patients with Tuberous Sclerosis Complex: A Single-centre Retrospective Cohort Study. Seizure. 2021 Mar 25;88:45-52. doi: 10.1016/j.seizure.2021.03.022. Epub ahead of print. PMID:
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