epilepsy

Temporal lobe epilepsy

Temporal lobe epilepsy

Mesial temporal sclerosis (MTS) is the most common cause of intractable temporal lobe epilepsy.

Clinical features

Temporal lobe epilepsy (TLE) is a chronic neurological condition characterized by recurrent seizures (epilepsy) which originate in the temporal lobe with progressive neurological disabilities, including cognitive deficit, anxiety and depression.

The seizures involve sensory changes, for example smelling an unusual odour that is not there, and disturbance of memory.

Treatment

Based on the promising results of randomized controlled trials, deep brain stimulation (DBS) and responsive neurostimulation (RNS) are increasingly used in the treatment of patients with drug-resistant epilepsy. Drug-resistant temporal lobe epilepsy (TLE) is an indication of either DBS of the anterior nucleus of the thalamus (ANT) or temporal lobe (TL) RNS, but there are no studies that directly compare seizure benefits and adverse effects associated with these therapies in this patient population.

Mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy.

Neocortical temporal lobe epilepsy

Neocortical temporal lobe epilepsy

Unilateral temporal lobe epilepsy

Unilateral temporal lobe epilepsy

Case series

Sixty patients with drug-resistant temporal lobe epilepsy who underwent anterior temporal lobectomy were enrolled. Anterior hippocampal samples were collected after surgery and analyzed by immunofluorescence (n = 7/group). They also evaluated the expression of HMGB1 in TLE patients with hippocampal sclerosis and measured the level of plasma HMGB1 by enzyme-linked immunosorbent assay. The results showed that 28.3% of the patients (17/60) had comorbid depression. HMGB1 was ubiquitously expressed in all subregions of the anterior hippocampus. The ratio of HMGB1-immunoreactive neurons and astrocytes was significantly increased in both TLE patients with hippocampal sclerosis and TLE patients with comorbid depression compared to patients with TLE only. The ratio of cytoplasmic to nuclear HMGB1-positive neurons in the hippocampus was higher in depressed patients with TLE than in non-depressed patients, which suggested that more HMGB1 translocated from the nucleus to the cytoplasm in the depressed group. There was no significant difference in the plasma level of HMGB1 among patients with TLE alone, TLE with hippocampal sclerosis, and TLE with comorbid depression. The results of the study revealed that the translocation of HMGB1 from the nucleus to the cytoplasm in hippocampal neurons may play a previously unrecognized role in the initiation and amplification of epilepsy and comorbid depression. The direct targeting of neural HMGB1 is a promising approach for anti-inflammatory therapy 1)

Yang et al., therefore, examined all patients who underwent ANT-DBS or TL-RNS for drug-resistant TLE.

They performed a retrospective review of patients who were treated with either ANT-DBS or TL-RNS for drug-resistant TLE with at least 12 months of follow-up. Along with the clinical characteristics of each patient’s epilepsy, seizure frequency was recorded throughout each patient’s postoperative clinical course.

26 patients underwent ANT-DBS implantation, and 32 patients underwent TL-RNS for drug-resistant TLE. Epilepsy characteristics of both groups were similar. Patients who underwent ANT-DBS demonstrated a median seizure reduction of 58% at 12-15 months, compared to a median seizure reduction of 70% at 12-15 months in patients treated with TL-RNS (p > 0.05). The responder rate (percentage of patients with a 50% decrease or more in seizure frequency) was 54% for ANT-DBS and 56% for TL-RNS (p > 0.05). Incidence of complications and stimulation-related side effects did not significantly differ between therapies.

They demonstrated in a single-center experience that patients with drug-resistant TLE benefit similarly from either ANT-DBS or TL-RNS. Selection of either ANT-DBS or TL-RNS may therefore depend more heavily on patient and provider preference, as each has unique capabilities and configurations. Future studies will consider subgroup analyses to determine if specific patients have greater seizure frequency reduction from one form of neuromodulation strategy over another 2).

1)

Li XL, Wang S, Tang CY, Ma HW, Cheng ZZ, Zhao M, Sun WJ, Wang XF, Wang MY, Li TF, Qi XL, Zhou J, Luan GM, Guan YG. Translocation of High Mobility Group Box 1 From the Nucleus to the Cytoplasm in Depressed Patients With Epilepsy. ASN Neuro. 2022 Jan-Dec;14:17590914221136662. doi: 10.1177/17590914221136662. PMID: 36383501.
2)

Yang JC, Bullinger KL, Dickey AS, Karakis I, Alwaki A, Cabaniss BT, Winkel D, Rodriguez-Ruiz A, Willie JT, Gross RE. Anterior Nucleus of the Thalamus Deep Brain Stimulation Versus Temporal Lobe Responsive Neurostimulation for Temporal Lobe Epilepsy. Epilepsia. 2022 Jun 15. doi: 10.1111/epi.17331. Epub ahead of print. PMID: 35704344.

Epilepsy diagnosis

Epilepsy diagnosis

The accurate diagnosis of seizures is essential as some patients will be misdiagnosed with epilepsy, whereas others will receive an incorrect diagnosis. Indeed, errors in diagnosis are common, and many patients fail to receive the correct treatment, which often has severe consequences

Imaging

Imaging is pivotal in the evaluation and management of patients with seizure disorders.

Positron emission tomography (PET) is the most commonly performed interictal functional neuroimaging technique that may reveal a focal hypometabolic region concordant with seizure onset. Single photon emission computed tomography (SPECT) studies may assist the performance of ictal neuroimaging in patients with pharmacoresistant focal epilepsy being considered for neurosurgical treatment 1).

Magnetic resonance imaging

Elegant structural neuroimaging with magnetic resonance imaging (MRI) may assist in determining the etiology of focal epilepsy and demonstrating the anatomical changes associated with seizure activity. The high diagnostic yield of MRI to identify the common pathological findings in individuals with focal seizures including mesial temporal sclerosis, vascular anomalies, Low-grade glioma and malformations of cortical development has been demonstrated.

Positron emission tomography in epilepsy

Positron emission tomography (PET) imaging in epilepsy is an in vivo technique that allows the localization of a possible seizure onset zone (SOZ) during the interictal period. Stereo-electro-encephalography (SEEG) is the gold standard to define the SOZ. The objective of aresearch was to evaluate the accuracy of PET imaging in localizing the site of SOZ compared with SEEG.

Seven patients with refractory temporal lobe epilepsy (Ep) and 2 healthy controls (HC) underwent 2 PET scans, one with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and another with 2′-[18F]fluoroflumazenil (FFMZ), acquired 1 day apart. FDG was acquired for 10 min (static scan) 1 h after administration. An FFMZ scan was acquired for 60 min from radiopharmaceutical administration in a dynamic mode. Each brain PET image was segmented using a standard template implemented in PMOD 3.8. The pons was used as the reference region for modeling of the nondisplaceable binding potential (BPND)for FFMZ, and to obtain uptake ratios for FDG. SEEG studies of patients were performed as a part of their surgical evaluation to define the SOZ.

Well-defined differences between HC and Ep were found with both radiopharmaceuticals, showing the utility to identify abnormal brain regions using quantitative PET imaging. Lateralization of the SOZ findings by PET (lower uptake/binding in a specific brain hemisphere) matched in 86% for FFMZ and 71% for FDG with SEEG data.

Quantitative PET imaging is an excellent complementary tool that matches reasonably well with SEEG to define SOZ in presurgical evaluation 2).

Cerebrospinal fluid analysis

Cerebrospinal fluid analysis for epilepsy

Automatic seizure detection

Automatic seizure detection.

Genetic testing

Results of a cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes 3).

1)

Cendes F, Theodore WH, Brinkmann BH, Sulc V, Cascino GD. Neuroimaging of epilepsy. Handb Clin Neurol. 2016;136:985-1014. doi: 10.1016/B978-0-444-53486-6.00051-X. PubMed PMID: 27430454.
2)

Avendaño-Estrada A, Velasco F, Velasco AL, Cuellar-Herrera M, Saucedo-Alvarado PE, Marquez-Franco R, Rivera-Bravo B, Ávila-Rodríguez MA. Quantitative Analysis of [18F]FFMZ and [18F]FDG PET Studies in the Localization of Seizure Onset Zone in Drug-Resistant Temporal Lobe Epilepsy. Stereotact Funct Neurosurg. 2019 Nov 13:1-9. doi: 10.1159/000503692. [Epub ahead of print] PubMed PMID: 31722358.
3)

McKnight D, Morales A, Hatchell KE, Bristow SL, Bonkowsky JL, Perry MS, Berg AT, Borlot F, Esplin ED, Moretz C, Angione K, Ríos-Pohl L, Nussbaum RL, Aradhya S; ELEVIATE Consortium, Haldeman-Englert CR, Levy RJ, Parachuri VG, Lay-Son G, de Montellano DJD, Ramirez-Garcia MA, Benítez Alonso EO, Ziobro J, Chirita-Emandi A, Felix TM, Kulasa-Luke D, Megarbane A, Karkare S, Chagnon SL, Humberson JB, Assaf MJ, Silva S, Zarroli K, Boyarchuk O, Nelson GR, Palmquist R, Hammond KC, Hwang ST, Boutlier SB, Nolan M, Batley KY, Chavda D, Reyes-Silva CA, Miroshnikov O, Zuccarelli B, Amlie-Wolf L, Wheless JW, Seinfeld S, Kanhangad M, Freeman JL, Monroy-Santoyo S, Rodriguez-Vazquez N, Ryan MM, Machie M, Guerra P, Hassan MJ, Candee MS, Bupp CP, Park KL, Muller E 2nd, Lupo P, Pedersen RC, Arain AM, Murphy A, Schatz K, Mu W, Kalika PM, Plaza L, Kellogg MA, Lora EG, Carson RP, Svystilnyk V, Venegas V, Luke RR, Jiang H, Stetsenko T, Dueñas-Roque MM, Trasmonte J, Burke RJ, Hurst ACE, Smith DM, Massingham LJ, Pisani L, Costin CE, Ostrander B, Filloux FM, Ananth AL, Mohamed IS, Nechai A, Dao JM, Fahey MC, Aliu E, Falchek S, Press CA, Treat L, Eschbach K, Starks A, Kammeyer R, Bear JJ, Jacobson M, Chernuha V, Meibos B, Wong K, Sweney MT, Espinoza AC, Van Orman CB, Weinstock A, Kumar A, Soler-Alfonso C, Nolan DA, Raza M, Rojas Carrion MD, Chari G, Marsh ED, Shiloh-Malawsky Y, Parikh S, Gonzalez-Giraldo E, Fulton S, Sogawa Y, Burns K, Malets M, Montiel Blanco JD, Habela CW, Wilson CA, Guzmán GG, Pavliuk M. Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice. JAMA Neurol. 2022 Oct 31. doi: 10.1001/jamaneurol.2022.3651. Epub ahead of print. PMID: 36315135.

Epilepsy surgery indications

Epilepsy surgery indications

Epilepsy surgery is an established safe and effective treatment for selected candidates with drug-resistant epilepsy. In a opinion piece, Hale et al. from the Children’s of Alabama, Great Ormond Street Hospital, Nemours Children’s Hospital outlined the clinical and experimental evidence for selectively considering epilepsy surgery prior to drug resistance. The rationale for expedited surgery is based on the observations that, 1) a high proportion of patients with lesional epilepsies (e.g. focal cortical dysplasia, epilepsy associated tumours) will progress to drug-resistance, 2) surgical treatment of these lesions, especially in non-eloquent areas of brain, is safe, and 3) earlier surgery may be associated with better seizure outcomes. Potential benefits beyond seizure reduction or elimination include less exposure to anticonvulsants (ASM), which may lead to improved developmental trajectories in children and optimize long-term neurocognitive outcomes and quality of life. Further, there exists emerging experimental evidence that brain network dysfunction exists at the onset of epilepsy, where continuing dysfunctional activity could exacerbate network perturbations. This in turn could lead to expanded seizure foci and contribution to the comorbidities associated with epilepsy. Taken together, they rationalize that epilepsy surgery, in carefully selected cases, may be considered prior to drug resistance. Lastly, they outlined the path forward, including the challenges associated with developing the evidence base and implementing this paradigm into clinical care 1).

20% of patients continue to have seizures despite aggressive medical management with antiepileptic drugs AEDs. Many of these patients may be candidates for surgical procedures to control their seizures 2).

Seizure disorder must be severe, medically refractory with satisfactory trials of tolerable medication for at least 1 year, and disabling to the patient. Medically refractory epilepsy is usually considered two attempts of high-dose monotherapy with two distinct AEDs, and one attempt at polytherapy.

The three general categories of patients suitable for seizure surgery have 3):

  1. partial seizures

a) temporal origin: the largest group of surgical candidates (especially mesial temporal lobe epilepsy (MTLE) which is often medically refractory)

b) extratemporal origin

  1. symptomatic generalized seizures: e.g. Lennox-Gastaut syndrome.

  2. unilateral, multifocal epilepsy associated with infantile hemiplegia syndrome.

The goal is to eliminate seizures or significantly reduce seizure burden.

In most state-of-the-art epilepsy units, resective epilepsy surgery is currently the standard treatment for intractable epilepsy. Generally, the success rate, defined as a seizure-free status or Engel class I, is between 62% and 71%, as compared to 14% in non-operated cases 4) 5).

Generally, surgery is considered in patients whose seizures cannot be controlled by adequate trials of two different medications. Epilepsy surgery has been performed for more than a century, but its use dramatically increased in the 1980s and ’90s, reflecting its efficacy in selected patients.

Patients with comorbid psychosis and temporal lobe drug-resistant epilepsy may benefit from epilepsy surgery under close psychiatric supervision 6).

Epilepsy surgery is an effective and safe therapeutic modality in childhood. In children with extratemporal epilepsy, more careful interpretation of clinical and investigative data is needed to achieve favorable seizure outcome 7).

Tuberous sclerosis complex surgery

see Tuberous sclerosis complex surgery.

1)

Hale AT, Chari A, Scott RC, Cross JH, Rozzelle CJ, Blount JP, Tisdall MM. Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing? Brain. 2022 Jul 27:awac275. doi: 10.1093/brain/awac275. Epub ahead of print. PMID: 35883201.
2)

Engel JJ. Surgery for Seizures. N Engl J Med. 1996; 334:647–652
3)

National Institutes of Health Consensus Development Conference. Surgery for Epilepsy. JAMA. 1990; 264:729–733
4)

Edelvik A, Rydenhag B, Olsson I, et al. Long-term outcomes of epilepsy surgery in Sweden: a national prospective and longitudinal study. Neurology 2013;81:1244–51.
5)

Sarkis RA, Jehi L, Najm IM, et al. Seizure outcomes following multilobar epilepsy surgery. Epilepsia 2012;53:44–50.
6)

D’Alessio L, Scévola L, Fernandez Lima M, Oddo S, Solís P, Seoane E, Kochen S. Psychiatric outcome of epilepsy surgery in patients with psychosis and temporal lobe drug-resistant epilepsy: A prospective case series. Epilepsy Behav. 2014 Jul 15;37C:165-170. doi: 10.1016/j.yebeh.2014.06.002. [Epub ahead of print] PubMed PMID: 25036902.
7)

Kim SK, Wang KC, Hwang YS, Kim KJ, Chae JH, Kim IO, Cho BK. Epilepsy surgery in children: outcomes and complications. J Neurosurg Pediatr. 2008 Apr;1(4):277-83. doi: 10.3171/PED/2008/1/4/277. PubMed PMID: 18377302.

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.

Temporal plus epilepsy

Temporal plus epilepsy

Temporal plus epilepsy (TPE) represents a rare type of epilepsy characterized by a complex epileptogenic zone including the temporal lobe and the close neighboring structures 1)

A previous history of brain trauma, a history of tonic clonic seizures, and previous central nervous system infection are risk factors. They likely allowed the generation of complex hippocampal and extrahypocampic neural networks. Clinical manifestations will depend on the location of the epileptogenic zone as well as the rapid propagation into temporal mesial structures. Video-electroencephalography usually shows involvement of the temporal lobe, with rapid propagation into the perisilvian, orbitofrontal or temporo-parieto-occipital regions. The magnetoelectroencephaography has lesser muscle contamination and could be considered as a biomarker of early states in the diagnosis process. Brain MRI is usually negative or shows non-specific mesial temporal abnormalities. Stereoelectroencephalography is the invasive method of choice. 2).

Temporal plus epilepsy is considered to be the most common cause of temporal lobe epilepsy surgery failure and represents up to 30% 3).

The reasons why surgery fails remain speculative. Possible explanations include the following:

The temporal lobe was not the true seizure onset zone, and seizures originate somewhere else not included in the resection;

There is more than one seizure onset zone or dual pathology, and only one focus was resected;

Temporal lobe epilepsy (TLE) is actually bilateral and was not identified as such;

Our concept of focal epilepsy is an inappropriate model for epilepsy. TLE is a network disease, and not enough network nodes were resected;

The resection margin becomes a new focus;

Not enough of the epileptogenic tissue that extended out of the temporal lobe into other areas of the brain was resected 4).

Case series

Barba et al. investigated whether the complete resection of temporal plus epileptogenic zone as defined through stereoelectroencephalography (SEEG) might improve seizure outcome in 38 patients with TPE.

Inclusion criteria were as follows: epilepsy surgery performed between January 1990 and December 2001, SEEG defining a temporal plus epileptogenic zone, unilobar temporal operations (“temporal lobe epilepsy [TLE] surgery”) or multilobar interventions including the temporal lobe (“TPE surgery”), magnetic resonance imaging either normal or showing signs of hippocampal sclerosis, and postoperative follow-up of at least 12 months. For each assessment of postoperative seizure outcome, at 1, 2, 5, and 10 years, we carried out descriptive analysis and classical tests of hypothesis, namely, Pearson χ2 test or Fisher exact test of independence on tables of frequency for each categorical variable of interest and Student t-test for each continuous variable of interest, when appropriate.

Twenty-one patients underwent TPE surgery and 17 underwent TLE surgery with a follow-up of 12.4 ± 8.16 years. In the multivariate models, there was a significant effect of the time from surgery on Engel Class IA versus IB-IV outcome, with a steadily worsening trend from 5-year follow-up onward. TPE surgery was associated with better results than TLE surgery.

This study suggests that surgical outcome in patients with TPE can be improved by a tailored, multilobar resection and confirms that SEEG is mandatory when a TPE is suspected 5).

A small case series of temporal plus cases successfully identified by SEEG who were seizure-free after resective surgery.

Bottan et al. conducted a retrospective analysis of 156 patients who underwent SEEG in 5 years. Six cases had TPE and underwent anterior temporal lobectomy (ATL) with additional extra-temporal resections.

Five cases had a focus on the right hemisphere and one on the left. Three cases were non-lesional and three were lesional. Mean follow-up time since surgery was 2.9 years (SD ± 1.8). Three patients had subdural electrodes investigation prior or in addition to SEEG. All patients underwent standard ATL and additional extra-temporal resections during the same procedure or at a later date. All patients were seizure-free at their last follow-up appointment (Engel Ia = 3; Engel Ib = 2; Engel Ic = 1). Pathology was nonspecific/gliosis for all six cases.

TPE might explain some of the failures in temporal lobe epilepsy surgery. Bottan et al. presented a small case series of six patients in whom SEEG successfully identified this phenomenon and surgery proved effective 6).

All patients from two epilepsy surgery programmes who fulfilled the following criteria were included: (i) operated from an anterior temporal lobectomy or disconnection between January 1990 and December 2001; (ii) magnetic resonance imaging normal or showing signs of hippocampal sclerosis; and (iii) postoperative follow-up ≥ 24 months for seizure-free patients. Patients were classified as suffering from unilateral temporal lobe epilepsy, bitemporal epilepsy or temporal plus epilepsy based on available presurgical data. Kaplan-Meier survival analysis was used to calculate the probability of seizure freedom over time. Predictors of seizure recurrence were investigated using Cox proportional hazards model. Of 168 patients included, 108 (63.7%) underwent stereoelectroencephalography, 131 (78%) had hippocampal sclerosis, 149 suffered from unilateral temporal lobe epilepsy (88.7%), one from bitemporal epilepsy (0.6%) and 18 (10.7%) from temporal plus epilepsy. The probability of Engel class I outcome at 10 years of follow-up was 67.3% (95% CI: 63.4-71.2) for the entire cohort, 74.5% (95% CI: 70.6-78.4) for unilateral temporal lobe epilepsy, and 14.8% (95% CI: 5.9-23.7) for temporal plus epilepsy. Multivariate analyses demonstrated four predictors of seizure relapse: temporal plus epilepsy (P < 0.001), postoperative hippocampal remnant (P = 0.001), past history of traumatic or infectious brain insult (P = 0.022), and secondary generalized tonic-clonic seizures (P = 0.023). Risk of temporal lobe surgery failure was 5.06 (95% CI: 2.36-10.382) greater in patients with temporal plus epilepsy than in those with unilateral temporal lobe epilepsy. Temporal plus epilepsy represents a hitherto unrecognized prominent cause of temporal lobe surgery failures. In patients with temporal plus epilepsy, anterior temporal lobectomy appears very unlikely to control seizures and should not be advised. Whether larger resection of temporal plus epileptogenic zones offers greater chance of seizure freedom remains to be investigated 7).

1)

Kahane P, Barba C, Rheims S, Job-Chapron AS, Minotti L, Ryvlin P. The concept of temporal ‘plus’ epilepsy. Rev Neurol (Paris). 2015 Mar;171(3):267-72. doi: 10.1016/j.neurol.2015.01.562. Epub 2015 Mar 5. PMID: 25748333.
2)

Toro-Pérez J, Suller-Martí A, Herrera M, Bottan J, Burneo JG. Epilepsia del lóbulo temporal plus: revisión [Temporal plus epilepsy: a review]. Rev Neurol. 2020 Sep 16;71(6):225-233. Spanish. doi: 10.33588/rn.7106.2020339. PMID: 32895906.
3)

Giulioni M, Martinoni M, Marucci G. Temporal plus epilepsy is a major determinant of temporal lobe surgery failures. Brain. 2016 Jul;139(Pt 7):e35. doi: 10.1093/brain/aww040. Epub 2016 Mar 10. PMID: 26966137.
4)

Jobst BC. Temporal Plus Epilepsy: Epileptic Territory Beyond the Temporal Lobes. Epilepsy Curr. 2016 Sep-Oct;16(5):305-307. doi: 10.5698/1535-7511-16.5.305. PMID: 27799855; PMCID: PMC5083048.
5)

Barba C, Rheims S, Minotti L, Grisotto L, Chabardès S, Guenot M, Isnard J, Pellacani S, Hermier M, Ryvlin P, Kahane P. Surgical outcome of temporal plus epilepsy is improved by multilobar resection. Epilepsia. 2022 Feb 15. doi: 10.1111/epi.17185. Epub ahead of print. PMID: 35165888.
6)

Bottan JS, Suller Marti A, Parrent AG, MacDougall KW, McLachlan RS, Burneo JG, Steven DA. Seizure Freedom in Temporal Plus Epilepsy Surgery Following Stereo-Electroencephalography. Can J Neurol Sci. 2020 May;47(3):374-381. doi: 10.1017/cjn.2020.26. PMID: 32036799.
7)

Barba C, Rheims S, Minotti L, Guénot M, Hoffmann D, Chabardès S, Isnard J, Kahane P, Ryvlin P. Temporal plus epilepsy is a major determinant of temporal lobe surgery failures. Brain. 2016 Feb;139(Pt 2):444-51. doi: 10.1093/brain/awv372. Epub 2015 Dec 22. PMID: 26700686.

Mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is a chronic neurological condition characterized by recurrent seizures (epilepsy) which originate in the temporal lobe of the brain with progressive neurological disabilities, including cognitive deficit, anxiety and depression.

The seizures involve sensory changes, for example smelling an unusual odour that is not there, and disturbance of memory.

Epidemiology

Mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) is the most common type of focal epilepsy.

Etiology

see Temporal lobe epilepsy etiology.

Pathophysiology

In order to understand the pathophysiology of temporal lobe epilepsy (TLE), and thus to develop new pharmacological treatments, in vivo animal models that present features similar to those seen in TLE patients have been developed during the last four decades. Some of these models are based on the systemic administration of chemoconvulsants to induce an initial precipitating injury (status epilepticus) that is followed by the appearance of recurrent seizures originating from limbic structures.

Kainic acid and pilocarpine models, have been widely employed in basic epilepsy research. Their behavioral, electroencephalographic and neuropathologic features and response of these models to antiepileptic drugs and the impact they might have in developing new treatments are explained in the work of Lévesque et al. 1).

The transition to the ictal stage is accompanied by increasing global synchronization and a more ordered spectral content of the signals, indicated by lower spectral entropy. The interictal connectivity imbalance (lower ipsilateral connectivity) is sustained during the seizure, irrespective of any appreciable imbalance in the spectral entropy of the mesial recordings 2).

Clinical features

Recurrent seizures (epilepsy) which originate in the temporal lobe of the brain with progressive neurological disabilities, including cognitive deficit, anxiety and depression.

The seizures involve sensory changes, for example smelling an unusual odour that is not there, and disturbance of memory.

Olfactory function was significantly impaired in patients with MTLE compared with healthy controls in all domains, namely threshold, discrimination, and identification. In addition, the olfactory bulb volume was smaller in patients with olfactory dysfunction 3).

Earlier tachycardia for seizures originating from the right versus left hemisphere in a patient with bilateral mesial temporal lobe epilepsy 4).

A strong association of this ailment has been established with psychiatric comorbidities, primarily mood and anxiety disorders. The side of epileptogenic may contribute to depressive and anxiety symptoms; thus, in a study, Radaelli et al. performed a systematic review to evaluate the prevalence of depression in TLE in surgical patients. The literature search was performed using PubMed/Medline, Web of Science, and PsycNet to gather data from inception until January 2019. The search strategy was related to TLE, depressive disorder, and anxiety. After reading full texts, 14 articles meeting the inclusion criteria were screened. The main method utilized for psychiatric diagnosis was Diagnostic and Statistical Manual of Structured Clinical Interview for DSM Disorders. However, most studies failed to perform the neuropsychological evaluation. For those with lateralization of epilepsy, focus mostly occurred in the left hemisphere. For individual depressive diagnosis, 9 studies were evaluated, and 5 for anxiety. Therefore, from the data analyzed in both situations, no diagnosis was representative in preoperative and postoperative cases. In order to estimate the efficacy of surgery in the psychiatry episodes and its relation to seizure control, the risk of depression and anxiety symptoms in epileptic patients need to be determined before surgical procedures. Rigorous preoperative and postoperative evaluation is essential for psychiatry conditions in patients with refractory epilepsy candidates for surgery 5).

Diagnosis

A pilot study demonstrates that seizures in mesial temporal and temporal-plus epilepsies (i.e., temporoperisylvian) can be detected reliably in the anterior thalamic nucleus (ATN). Further studies are needed to validate these findings 6).

Fractional anisotropy asymmetry (FAA) values can be potentially used to identify the seizures of origin of TLE and to help understand the relationship between fiber tracts with the side of seizure origin of TLE 7).

The area of predominant perifocal 18F positron emission tomography hypometabolism and reduced [11C]flumazenil (11C-FMZ) -binding on PET scans is currently considered to contain the epileptogenic zone and corresponds anatomically to the area localizing epileptogenicity in patients with temporal lobe epilepsy (TLE).

Differential diagnosis

Mesial temporal lobe epilepsy differential diagnosis.

Complications

Drug resistant epilepsy is a major clinical challenge affecting about 30% of temporal lobe epilepsy (TLE) patients.

The reasons for failure of surgical treatment for mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) remain unclear.

Treatment

Mesial temporal lobe epilepsy treatment.

Outcome

Temporal lobe epilepsy (TLE) is considered to be the most common form of epilepsy, and it has been seen that most patients are refractory to antiepileptic drugs.

After surgery for intractable mesiotemporal lobe epilepsy (mTLE) seizures recur in 30-40%. One predictor for seizure recurrence is the distribution of seizure onset and interictal epileptiform discharges (IED).

Preoperative bilateral ictal foci are a negative predictor for seizure outcome. Contrarily, IED exceeding the affected temporal lobe in the ipsilateral hemisphere or even bilateral IED had favorable seizure outcome if seizure onset is strictly limited to the affected temporal lobe. Reoperation for seizure persistence constitutes a promising therapeutic option 8).

The extent of pre-surgical perifocal PET abnormalities, the extent of their resection, and the extent of non-resected abnormalities were not useful predictors of individual freedom from seizures in patients with TLE 9).

Case series

see Mesial temporal lobe epilepsy case series.

References

1)

Lévesque M, Avoli M, Bernard C. Animal Models of temporal Lobe Epilepsy Following Systemic Chemoconvulsant Administration. J Neurosci Methods. 2015 Mar 10. pii: S0165-0270(15)00091-6. doi: 10.1016/j.jneumeth.2015.03.009. [Epub ahead of print] PubMed PMID: 25769270.
2)

Vega-Zelaya L, Pastor J, de Sola RG, Ortega GJ. Disrupted Ipsilateral Network Connectivity in Temporal Lobe Epilepsy. PLoS One. 2015 Oct 21;10(10):e0140859. doi: 10.1371/journal.pone.0140859. eCollection 2015. PubMed PMID: 26489091.
3)

Türk BG, Metin B, Tekeli H, Sayman ÖA, Kızılkılıç O, Uzan M, Özkara Ç. Evaluation of olfactory and gustatory changes in patients with mesial temporal lobe epilepsy. Seizure. 2020 Jan 7;75:110-114. doi: 10.1016/j.seizure.2020.01.001. [Epub ahead of print] PubMed PMID: 31945715.
4)

Yanai K, Shimada S, Kunii N, Takasago M, Takabatake K, Saito N. Earlier tachycardia for seizures originating from the right versus left hemisphere in a patient with bilateral mesial temporal lobe epilepsy [published online ahead of print, 2020 Jun 25]. Clin Neurophysiol. 2020;131(9):2168-2170. doi:10.1016/j.clinph.2020.06.011
5)

Radaelli G, Majolo F, Leal-Conceição E, de Souza Santos F, Escobar V, Zanirati GG, Portuguez MW, Scorza FA, da Costa JC. Left Hemisphere Lateralization of Epileptic Focus Can Be More Frequent in Temporal Lobe Epilepsy Surgical Patients with No Consensus Associated with Depression Lateralization. Dev Neurosci. 2021 Mar 31:1-8. doi: 10.1159/000513537. Epub ahead of print. PMID: 33789300.
6)

Pizarro D, Ilyas A, Toth E, Romeo A, Riley KO, Esteller R, Vlachos I, Pati S. Automated detection of mesial temporal and temporoperisylvian seizures in the anterior thalamic nucleus. Epilepsy Res. 2018 Jul 23;146:17-20. doi: 10.1016/j.eplepsyres.2018.07.014. [Epub ahead of print] PubMed PMID: 30055392.
7)

Li H, Xue Z, Dulay MF Jr, Verma A, Karmonik C, Grossman RG, Wong ST. Fractional anisotropy asymmetry and the side of seizure origin for partial onset-temporal lobe epilepsy. Comput Med Imaging Graph. 2014 Jul 2. pii: S0895-6111(14)00102-5. doi: 10.1016/j.compmedimag.2014.06.009. [Epub ahead of print] PubMed PMID: 25037096.
8)

Schmeiser B, Zentner J, Steinhoff BJ, Brandt A, Schulze-Bonhage A, Kogias E, Hammen T. The role of presurgical EEG parameters and of reoperation for seizure outcome in temporal lobe epilepsy. Seizure. 2017 Sep 6;51:174-179. doi: 10.1016/j.seizure.2017.08.015. [Epub ahead of print] PubMed PMID: 28888215.
9)

Stanišić M, Coello C, Ivanović J, Egge A, Danfors T, Hald J, Heminghyt E, Mikkelsen MM, Krossnes BK, Pripp AH, Larsson PG. Seizure outcomes in relation to the extent of resection of the perifocal fluorodeoxyglucose and flumazenil PET abnormalities in anteromedial temporal lobectomy. Acta Neurochir (Wien). 2015 Sep 8. [Epub ahead of print] PubMed PMID: 26350516.

Vagus nerve stimulation for drug-resistant epilepsy

Vagus nerve stimulation for drug-resistant epilepsy

see also Responsive neurostimulation.

Vagus nerve stimulation for drug-resistant epilepsy was first approved in Europe in 1994 and in the United States (US) in 1997. Subsequent modifications improved the safety and the efficacy of the system. The most recent application of vagal neurostimulation is represented by transcutaneous devices that are claimed to have strong therapeutic potential. In a review, Toffa et al. sought to analyze the most meaningful available data describing the indications, safety and efficacy of the different approaches of VNS in clinical practice. Therefore, they identified studies reporting VNS efficacy and/or safety in epilepsy and its comorbidities from January 1990 to February 2020 from various databases including PubMed, Scopus, Cochrane, US government databases and VNS manufacturer published resources. In general, VNS efficacy becomes optimal around the sixth month of treatment and a 50-100 % seizure frequency reduction is achieved in approximately 45-65 % of the patients. However, some clinically relevant differences have been reported with specific factors such as epilepsy etiology or epilepsy classification, patient age as well as the delay of VNS therapy onset. VNS efficacy on seizure frequency has been demonstrated in both children and adults, in lesional and non-lesional cases, in focal and generalized epilepsies, on both seizures and epilepsy comorbidities. Regarding the latter, VNS can lead to an improvement of about 25-35 % in depression scores, 35 % in anxiety scores and 25 % in mood assessment scores. If non-invasive devices are undeniably safer, their efficacy is limited due to the scarcity of large cohort studies and the disparity of methodological approaches (study design and stimulation parameters). Overall, they believe that there is a progress margin for improving the safety of implantable devices and, above all, the effectiveness of the various VNS approaches 1).

Indications

see also Vagus nerve stimulation for drug-resistant epilepsy in children

VNS is indicated for symptomatic localization-related epilepsy with multiple and bilateral independent foci, symptomatic generalized epilepsy with diffuse epileptogenic abnormalities, refractory idiopathic generalized epilepsy, failed intracranial epilepsy surgery, and other several reasons of contraindications to epilepsy surgery. Programing of the parameters is a principal part in VNS. Output current and duty cycle should be adjusted to higher settings particularly when a patient does not respond to the initial setting, since the pivotal randomized trials performed in the United States demonstrated high stimulation made better responses in seizure frequency. These trials revealed that a ≥ 50% seizure reduction occurred in 36.8% of patients at 1 year, in 43.2% at 2 years, and in 42.7% at 3 years in 440 patients. Safety of VNS was also confirmed because side effects including hoarseness, throat discomfort, cough, paresthesia, and headache improved progressively during the period of 3 years. The largest retrospective study with 436 patients demonstrated the mean seizure reduction of 55.8% in nearly 5 years, and also found 75.5% at 10 years in 65 consecutive patients. The intermediate analysis report of the Japan VNS Registry showed that 60% of 164 cases got a ≥ 50% seizure reduction in 12 months. In addition to seizure reduction, VNS has positive effects in mood and improves energy level, memory difficulties, social aspects, and fear of seizures. VNS is an effective and safe option for patients who are not suitable candidates for intracranial epilepsy surgery 2).

Vagus nerve stimulation (VNS) is becoming an increasingly popular therapy for patients with drug resistant epilepsy 3) 4) 5) 6) 7) 8) 9) 10).

Mechanism of action

The use of functional neuroimaging such as SPECT, PET and fMRI in patients undergoing peripheral nerve stimulation can help us to understand these mechanisms.

Bari et al., reviewed the literature for functional neuroimaging performed in patients implanted with peripheral nerve stimulators. These studies suggest that brain activity in response to peripheral nerve stimulation is a complex interaction between the stimulation parameters, disease type and severity, chronicity of stimulation, as well as nonspecific effects. From this information we may be able to understand which brain structures are involved in the mechanism of peripheral nerve stimulation as well as define the neural substrates underlying these disorders 11).

Effectiveness, safety, and cost

Connor et al., performed a review of available literature published between 1980 and 2010. Inclusion criteria for articles included more than 10 patients evaluated, average follow-up of 1 or more years, inclusion of medically refractory epilepsy, and consistent preoperative surgical evaluation. Articles were divided into 4 classes of evidence according to criteria established by the American Academy of Neurology.

A total of 70 publications were reviewed, of which 20 were selected for review based on inclusion and exclusion criteria. There were 2 articles that provided Class I evidence, 7 that met criteria for Class II evidence, and 11 that provided Class III evidence. The majority of evidence supports VNS usage in partial epilepsy with a seizure reduction of 50% or more in the majority of cases and freedom from seizure in 6%-27% of patients who responded to stimulation. High stimulation with a gradual increase in VNS stimulation over the first 6 weeks to 3 months postoperatively is well supported by Class I and II data. Predictors of positive response included absence of bilateral interictal epileptiform activity and cortical malformations.

Vagal nerve stimulation is a safe and effective alternative for adult and pediatric populations with epilepsy refractory to medical and other surgical management 12).

A study looked at the research available on the effectiveness, safety, and cost of two types of electrical stimulation devices currently licensed for treatment of epilepsy for adults and children in Canada: vagus nerve stimulation (VNS) and deep brain stimulation (DBS). Both approaches appear to be effective at reducing the frequency of seizures in adults. However, the evidence on DBS is limited to a single study with adults; Chambers and Bowen found no studies of DBS with children. Studies on VNS showed that both adults and children had fewer hospitalizations and emergency department visits after the procedure. Both procedures carry serious risks, but several longer-term studies have found that adverse events appear to be limited. The cost of VNS, including the process of assessing whether or not patients are good candidates for the procedure, is estimated to be about $40,000 per person (and higher for DBS because the device is more expensive and the operating time is longer). Of the 70,000 people in Ontario with epilepsy, about 1,400 (300 children and 1,110 adults) may be candidates for VNS to reduce their seizures 13).

Complications

Complications and failure of the device can result from lead fracture, device malfunction, disconnection, or battery displacement and can result in a variety of symptoms.

D’Agostino et al., present an interesting case of stimulator malfunction with increased impedance change seen only with a change in head position.

The patient is a 25-year-old male with a vagal nerve stimulator (VNs) placed for medically refractory epilepsy who presented with neck pain and an electrical pulling sensation in his neck whenever he turned his head to the right. Initial interrogation of the VNs showed normal impedance. Subsequent interrogation with the patient’s head turned found increased impedance only when the head was turned to the right. The patient had successful removal and replacement of the device with resolution of his preoperative complaints. Partial lead fracture was seen at explant.

Vagus nerve stimulator malfunction can present in atypical ways. Positional maneuvers may help with its timely diagnosis 14).

Outcome

It is still difficult to predict which patients will respond to VNS treatment and to what extent.

Liu et al., aimed to explore the relationship between preoperative heart rate variability (HRV) and VNS outcome. 50 healthy control subjects and 63 DRE patients who had received VNS implants and had at least one year of follow up were included. The preoperative HRV were analyzed by traditional linear methods and heart rhythm complexity analyses with multiscale entropy (MSE). DRE patients had significantly lower complexity indices (CI) as well as traditional linear HRV measurements than healthy controls. We also found that non-responders0 had significantly lower preoperative CI including Area 1-5, Area 6-15 and Area 6-20 than those in the responders0 while those of the non-responders50 had significantly lower RMSSD, pNN50, VLF, LF, HF, TP and LF/HF than the responders50. In receiver operating characteristic (ROC) curve analysis, Area 6-20 and RMSSD had the greatest discriminatory power for the responders0 and non-responders0, responders50 and non-responders50, respectively. Our results suggest that preoperative assessment of HRV by linear and MSE analysis can help in predicting VNS outcomes in patients with DRE 15).

Data suggest that sudden unexpected death in epilepsy patients (SUDEP) risk significantly decreases during long-term follow-up of patients with refractory epilepsy receiving VNS Therapy. This finding might reflect several factors, including the natural long-term dynamic of SUDEP rate, attrition, and the impact of VNS Therapy. The role of each of these factors cannot be confirmed due to the limitations of the study 16).

Systematic reviews

Boon et al., conducted a systematic review on the currently available neurostimulation modalities primarily with regard to effectiveness and safety.

For vagus nerve stimulation (VNS), there is moderate-quality evidence for its effectiveness in adults with drug-resistant partial epilepsies. Moderate-to-low-quality evidence supports the efficacy and safety of deep brain stimulation (DBS) and responsive neurostimulation (RNS) in patients with DRE. There is moderate-to-very low-quality evidence that transcranial direct current stimulation (tDCS) is effective or well tolerated. For transcutaneous vagus nerve stimulation (tVNS), transcranial magnetic stimulation (TMS) and trigeminal nerve stimulation (TNS), there are insufficient data to support the efficacy of any of these modalities for DRE. These treatment modalities, nevertheless, appear well tolerated, with no severe adverse events reported.

Head-to-head comparison of treatment modalities such as VNS, DBS and RNS across different epileptic syndromes are required to decide which treatment modality is the most effective for a given patient scenario. Such studies are challenging and it is unlikely that data will be available in the near future. Additional data collection on potentially promising noninvasive neurostimulation modalities like tVNS, TMS, TNS and tDCS is warranted to get a more precise estimate of their therapeutic benefit and long-term safety 17).

Case series

see Vagus nerve stimulation for drug resistant epilepsy case series.

Case reports

Arhan et al., describe the first child with drug-resistant epilepsy in whom vagus nerve stimulation aggravated seizures and emerged status epilepticus after the increase in vagal nerve stimulation current output.

A 13-year-old girl presented with refractory secondary generalized focal epilepsy. Vagal nerve stimulator was implanted because of drug-resistant epilepsy. After the increase of vagal nerve stimulator current output to a relatively high level, the patient experienced seizure aggravation and status epilepticus.

They conclude that vagus nerve stimulation may induce paradoxical seizures and may lead to status epilepticus, similarly to some antiepileptic drugs 18).

References

1)

Toffa DH, Touma L, El Meskine T, Bouthillier A, Nguyen DK. Learnings from 30 years of reported efficacy and safety of vagus nerve stimulation (VNS) for epilepsy treatment: A critical review. Seizure. 2020 Oct 10;83:104-123. doi: 10.1016/j.seizure.2020.09.027. Epub ahead of print. PMID: 33120323.
2)

Yamamoto T. Vagus nerve stimulation therapy: indications, programing, and outcomes. Neurol Med Chir (Tokyo). 2015;55(5):407-15. doi: 10.2176/nmc.ra.2014-0405. Epub 2015 Apr 28. Review. PubMed PMID: 25925759; PubMed Central PMCID: PMC4628168.
3)

Alexopoulos AV, Kotagal P, Loddenkemper T, Hammel J, Bingaman WE (2006) Long-term results with vagus nerve stimulation in children with pharmacoresistant epilepsy. Seizure 15: 491–503. pmid:16859931 doi: 10.1016/j.seizure.2006.06.002
4)

Chambers A, Bowen JM (2013) Electrical stimulation for drug-resistant epilepsy: an evidence-based analysis. Ont Health Technol Assess Ser 13: 1–37. pmid:24379898
5)

Coady MA, Adler F, Davila JJ, Gahtan V (2000) Nonrecurrent laryngeal nerve during carotid artery surgery: case report and literature review. J Vasc Surg 32: 192–196. pmid:10876223 doi: 10.1067/mva.2000.105680
6)

Elliott RE, Rodgers SD, Bassani L, Morsi A, Geller EB, et al. (2011) Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases. J Neurosurg Pediatr 7: 491–500. doi: 10.3171/2011.2.PEDS10505. pmid:21529189
7)

Englot DJ, Chang EF, Auguste KI (2011) Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response. Journal of neurosurgery 115: 1248–1255. doi: 10.3171/2011.7.JNS11977. pmid:21838505
8)

Milby AH, Halpern CH, Baltuch GH (2009) Vagus nerve stimulation in the treatment of refractory epilepsy. Neurotherapeutics 6: 228–237. doi: 10.1016/j.nurt.2009.01.010. pmid:19332314
9)

Rutecki P (1990) Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve stimulation. Epilepsia 31 Suppl 2: S1–6. pmid:2226361 doi: 10.1111/j.1528-1157.1990.tb05843.x
10)

Tanganelli P, Ferrero S, Colotto P, Regesta G (2002) Vagus nerve stimulation for treatment of medically intractable seizures. Evaluation of long-term outcome. Clin Neurol Neurosurg 105: 9–13. pmid:12445916 doi: 10.1016/s0303-8467(02)00018-5
11)

Bari AA, Pouratian N. Brain imaging correlates of peripheral nerve stimulation. Surg Neurol Int. 2012;3(Suppl 4):S260-8. doi: 10.4103/2152-7806.103016. Epub 2012 Oct 31. PubMed PMID: 23230531; PubMed Central PMCID: PMC3514912.
12)

Connor DE Jr, Nixon M, Nanda A, Guthikonda B. Vagal nerve stimulation for the treatment of medically refractory epilepsy: a review of the current literature. Neurosurg Focus. 2012 Mar;32(3):E12. doi: 10.3171/2011.12.FOCUS11328. Review. PubMed PMID: 22380853.
13)

Chambers A, Bowen JM. Electrical stimulation for drug-resistant epilepsy: an evidence-based analysis. Ont Health Technol Assess Ser. 2013 Oct 1;13(18):1-37. eCollection 2013. Review. PubMed PMID: 24228081; PubMed Central PMCID: PMC3817921.
14)

D’Agostino E, Makler V, Bauer DF. Vagal Nerve Stimulator Malfunction with Change in Neck Position: Case Report and Literature Review. World Neurosurg. 2018 Mar 16. pii: S1878-8750(18)30551-5. doi: 10.1016/j.wneu.2018.03.073. [Epub ahead of print] PubMed PMID: 29555606.
15)

Liu HY, Yang Z, Meng FG, Guan YG, Ma YS, Liang SL, Lin JL, Pan LS, Zhao MM, Qu W, Hao HW, Luan GM, Zhang JG, Li LM. Preoperative Heart Rate Variability as Predictors of Vagus Nerve Stimulation Outcome in Patients with Drug-resistant Epilepsy. Sci Rep. 2018 Mar 1;8(1):3856. doi: 10.1038/s41598-018-21669-3. PubMed PMID: 29497072; PubMed Central PMCID: PMC5832772.
16)

Ryvlin P, So EL, Gordon CM, Hesdorffer DC, Sperling MR, Devinsky O, Bunker MT, Olin B, Friedman D. Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy. Epilepsia. 2018 Mar;59(3):562-572. doi: 10.1111/epi.14002. Epub 2018 Jan 16. PubMed PMID: 29336017.
17)

Boon P, De Cock E, Mertens A, Trinka E. Neurostimulation for drug-resistant epilepsy: a systematic review of clinical evidence for efficacy, safety, contraindications and predictors for response. Curr Opin Neurol. 2018 Apr;31(2):198-210. doi: 10.1097/WCO.0000000000000534. PubMed PMID: 29493559.
18)

Arhan E, Serdaroğlu A, Hirfanoğlu T, Kurt G. Aggravation of seizures and status epilepticus after vagal nerve stimulation therapy: the first pediatric case and review of the literature. Childs Nerv Syst. 2018 Apr 22. doi: 10.1007/s00381-018-3806-x. [Epub ahead of print] PubMed PMID: 29680919.

Mesial temporal lobe epilepsy treatment

Mesial temporal lobe epilepsy treatment

Radiofrequency thermocoagulation

Stereoelectroencephalography guided radiofrequency thermocoagulation.

Radiosurgery

see Mesial temporal lobe epilepsy radiosurgery.

Surgery

see Temporal lobe epilepsy surgery.

Surgical resection is the gold standard treatment for drug-resistant focal epilepsy, including mesial temporal lobe epilepsy (MTLE) and other focal cortical lesions with correlated electrophysiological features.

Surgical approaches for medically refractory mesial temporal lobe epilepsy (MTLE) that previously have been reported include anterior temporal lobectomy (ATL), transcortical selective amygdalohippocampectomy, transsylvian amygdalohippocampectomy, and subtemporal amygdalohippocampectomy.

Each approach has its advantages and potential pitfalls.

Anterior temporal lobectomy

see Anterior temporal lobectomy.

Subiculum stimulation

Evidence has been provided that the subiculum may play an important role in the generation of seizures.Electrical stimulation at this target has been reported to have anticonvulsant effects in kindling and pilocarpine rat models, while in a clinical study of hippocampal deep brain stimulation (DBS), contacts closest to the subiculum were associated with a better anticonvulsive effect.

Vázquez-Barrón et al. evaluated the effect of electrical stimulation of the subiculum in patients with refractory mesial temporal lobe epilepsy (MTLE) who have hippocampal sclerosis (HS).

Six patients with refractory MTLE and HS, who had focal impaired-awareness seizures (FIAS) and focal to bilateral tonic-clonic seizures (FBTCS), had DBS electrodes implanted in the subiculum. During the first month after implantation, all patients were OFF stimulation, then they all completed an open-label follow-up of 24 months ON stimulation. DBS parameters were set at 3 V, 450 µs, 130 Hz, cycling stimulation 1 min ON, 4 min OFF.

There was a mean reduction of 49.16% (±SD 41.65) in total seizure number (FIAS + FBTCS) and a mean reduction of 67.93% (±SD 33.33) in FBTCS at 24 months. FBTCS decreased significantly with respect to baseline, starting from month 2 ON stimulation.

Subiculum stimulation is effective for FBTCS reduction in patients with MTLE and HS, suggesting that the subiculum mediates the generalization rather than the genesis of mesial temporal lobe seizures. Better results are observed at longer follow-up times 1).

1)

Vázquez-Barrón D, Cuéllar-Herrera M, Velasco F, Velasco AL. Electrical Stimulation of Subiculum for the Treatment of Refractory Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis: A 2-Year Follow-Up Study. Stereotact Funct Neurosurg. 2020 Oct 28:1-8. doi: 10.1159/000510295. Epub ahead of print. PMID: 33113540.

Epilepsy surgery

Epilepsy surgery

see also Pediatric Epilepsy Surgery.

Technology

Dorfer et al. emphasized the role of the technological progress in changing the landscape of epilepsy surgery and provides a critical appraisal of robotic applications, laser interstitial thermal therapy, intraoperative imaging, wireless recording, new neuromodulation techniques, and high-intensity focused ultrasound. Specifically, (a) it relativizes the current hype in using robots for stereoelectroencephalography (SEEG) to increase the accuracy of depth electrode placement and save operating time; (b) discusses the drawback of laser interstitial thermal therapy (LITT) when it comes to the need for adequate histopathologic specimen and the fact that the concept of stereotactic disconnection is not new; © addresses the ratio between the benefits and expenditure of using intraoperative magnetic resonance imaging (MRI), that is, the high technical and personnel expertise needed that might restrict its use to centers with a high caseload, including those unrelated to epilepsy; (d) soberly reviews the advantages, disadvantages, and future potentials of neuromodulation techniques with special emphasis on the differences between closed and open-loop systems; and (e) provides a critical outlook on the clinical implications of focused ultrasound, wireless recording, and multipurpose electrodes that are already on the horizon. This outlook shows that although current ultrasonic systems do have some limitations in delivering acoustic energy, the further advance of this technique may lead to novel treatment paradigms. Furthermore, it highlights that new data streams from multipurpose electrodes and wireless transmission of intracranial recordings will become available soon once some critical developments will be achieved such as electrode fidelity, data processing, and storage, heat conduction as well as rechargeable technology. A better understanding of modern epilepsy surgery will help to demystify epilepsy surgery for the patients and the treating physicians and thereby reduce the surgical treatment gap 1).

Indications

Epilepsy surgery indications.

Pre-surgical evaluation

Epilepsy surgery pre-surgical evaluation.

Techniques

Resective epilepsy surgery.

Hemispherectomy.

Magnetic resonance guided laser induced thermal therapy for epilepsy.

Temporal lobe epilepsy surgery

Vagus nerve stimulation for drug resistant epilepsy.

Neuromodulation

Several palliative neuromodulation treatment modalities are currently available for adjunctive use in the treatment of medically intractable epilepsy. Over the past decades, a variety of different central and peripheral nervous system sites have been identified, clinically and experimentally, as potential targets for chronic, nonresponsive therapeutic neurostimulation. Currently, the main modalities in clinical use, from most invasive to least invasive, are anterior thalamus deep brain stimulation, vagus nerve stimulation, and trigeminal nerve stimulation. Significant reductions in seizure frequency have been demonstrated in clinical trials using each of these neuromodulation therapies 2).

see Vagus nerve stimulation for drug resistant epilepsy.

see Epilepsy surgery in India.

The current practice under which patients with refractory epilepsy are surgically treated is based mainly on the identification of specific cortical areas, mainly the epileptogenic zone, which is believed to be responsible for generation of seizures. A better understanding of the whole epileptic network and its components and properties is required before more effective and less invasive therapies can be developed.

Epilepsy surgery is constantly researching for new options for patients with refractory epilepsy.

see Magnetic resonance guided laser induced thermal therapy for epilepsy

Despite significant underutilization of surgical treatment for drug-resistant epilepsy, no studies have quantified patient desire for surgery within a representative population.

An online survey was administered to all clients connected with a core epilepsy community access center. It obtained information about demographics, clinical characteristics, knowledge of epilepsy surgery, and interest in receiving surgery before and after receiving risk/benefit information about it.

Of 118 potential respondents, 48 (41%) completed the questionnaire, of which 67% had failed more than two AEDs and 78% experienced seizures in the past year. Eleven ( 26%) were uninterested in receiving surgery at baseline, and this decreased significantly to 7 (16%) following knowledge translation regarding the benefits (p = 0.001). Significance was lost with subsequent complication rate information despite fewer respondents still being uninterested compared to baseline (20% vs. 26%). Having experienced seizures within the past month was correlated with being interested in or undecided regarding surgery at baseline and following all steps of knowledge translation. Subjects had conservative views regarding the benefits of surgery and largely overestimated the risks.

A significant portion of those with active epilepsy in the community do not desire surgical treatment. Passive knowledge translation regarding the risks and benefits enhanced optimistic attitudes and mobilized interest within a subset of participants. Preexisting views regarding the risks of surgery were exaggerated, and analysis suggests that these views can be modified with information about the benefits of surgery. However, exaggerated risk perceptions return following crude descriptions of the risks, underlying the importance of sensitive counseling from primary care physicians 3).

In Epilepsy surgery where resective surgery is not indicated, deep brain stimulation (DBS) may be an effective alternative. The majority of available literature targets the thalamic nuclei (anterior; centromedian), subthalamic nucleus, hippocampus, and cerebellum.

Data show DBS may be a safe and effective treatment option for refractory epilepsy 4).

Surgery is a safe and effective option for some patients, however the opportunity exists to develop less invasive and more effective surgical options. To this end, multiple minimally invasive, image-guided techniques have been applied to the treatment of epilepsy. These techniques can be divided into thermoablative and disconnective techniques. Each has been described in the treatment of epilepsy only in small case series. Larger series and longer follow up periods will determine each option’s place in the surgical armamentarium for the treatment of refractory epilepsy but early results are promising 5).

Outcome

see Epilepsy Surgery outcome.

Books

Engel J Jr, Van Ness PC, Rasmussen T, Ojemann LM: Outcome with respect to epileptic seizures, in Engle J Jr (ed): Surgical Treatment of the Epilepsies, ed 2. New York: Raven Press, 1993, pp 609–621

Case series

Epilepsy surgery case series.

References

1)

Dorfer C, Rydenhag B, Baltuch G, Buch V, Blount J, Bollo R, Gerrard J, Nilsson D, Roessler K, Rutka J, Sharan A, Spencer D, Cukiert A. How technology is driving the landscape of epilepsy surgery. Epilepsia. 2020 Mar 29. doi: 10.1111/epi.16489. [Epub ahead of print] PubMed PMID: 32227349.
2)

Krishna V, Sammartino F, King NK, So RQ, Wennberg R. Neuromodulation for Epilepsy. Neurosurg Clin N Am. 2016 Jan;27(1):123-131. doi: 10.1016/j.nec.2015.08.010. Epub 2015 Oct 24. Review. PubMed PMID: 26615114.
3)

Zuccato JA, Milburn C, Valiante TA. Balancing health literacy about epilepsy surgery in the community. Epilepsia. 2014 Sep 23. doi: 10.1111/epi.12791. [Epub ahead of print] PubMed PMID: 25251908.
4)

Klinger NV, Mittal S. Clinical efficacy of deep brain stimulation for the treatment of medically refractory epilepsy. Clin Neurol Neurosurg. 2015 Nov 14;140:11-25. doi: 10.1016/j.clineuro.2015.11.009. [Epub ahead of print] Review. PubMed PMID: 26615464.
5)

Bandt SK, Leuthardt EC. Minimally Invasive Neurosurgery for Epilepsy Using Stereotactic MRI Guidance. Neurosurg Clin N Am. 2016 Jan;27(1):51-8. doi: 10.1016/j.nec.2015.08.005. Epub 2015 Oct 24. Review. PubMed PMID: 26615107.