Dravet Syndrome

Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is a type of epilepsy with seizures that are often triggered by hot temperatures or fever.

Dravet and Bureau in 1981 described “benign myoclonic epilepsy in infancy” in 7 normal children with onset of myoclonic seizures in the first 3 years of life 1). The syndrome was defined as including myoclonic seizures only, except rare simple febrile seizures, with good prognosis regarding response to therapy and cognitive functions.

Dravet Syndrome (DS) is a severe epileptic encephalopathy of childhood involving intractable seizures, recurrent status epilepticus and cognitive decline. Because DS is a rare disease, available data is limited and evidence-based treatment guidelines are lacking.

Both VNS and corpus callosotomy (CC) can be effective at reducing seizure frequency. Patients with DS may benefit from earlier and more aggressive surgical intervention. Studies using larger patient cohorts will help clarify the role that surgery may play in the multidisciplinary approach to controlling seizures in DS. Further studies will help determine the appropriate timing of and type of surgical intervention 2).

Loss of function in the Scn1a gene leads to Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures.

Ritter-Makinson et al., showed enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. The study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. They propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment 3).


Vagus nerve stimulation (VNS) is an established neurostimulation treatment for intractable epilepsy, however little evidence is published on its efficacy in patients with DS.

Dibué-Adjei et al., performed a meta-analysis of all peer-reviewed English language studies reporting seizure outcomes of patients with DS treated with adjunctive vagus nerve stimulation. The primary and secondary outcome measures were ≥50% reduction of seizures or of the most-debilitating seizure type and seizure reduction per patient.

13 studies comprising 68 patients met the inclusion criteria of which 11 were single-center retrospective case series, one was a multi-center retrospective analysis and one was a case report. 52.9% of patients experienced a ≥50% reduction of seizures and the average seizure reduction, which could only be assessed in n=28 patients was 50.8%. 7 out of 13 studies reported additional benefits of VNS, however this could not be assessed systematically.

Vagus nerve stimulation appears to reduce seizure frequency in patients with DS. Based on this preliminary analysis, controlled trials of VNS in this rare condition using patient-centric outcome measures are indicated 4).

1)

Dravet C, Bureau M. [The benign myoclonic epilepsy of infancy (author’s transl)]. Rev Electroencephalogr Neurophysiol Clin. 1981 Dec;11(3-4):438-44. French. PubMed PMID: 6808601.
2)

Dlouhy BJ, Miller B, Jeong A, Bertrand ME, Limbrick DD Jr, Smyth MD. Palliative epilepsy surgery in Dravet syndrome-case series and review of the literature. Childs Nerv Syst. 2016 Sep;32(9):1703-8. doi: 10.1007/s00381-016-3201-4. Epub 2016 Jul 27. Review. PubMed PMID: 27465677.
3)

Ritter-Makinson S, Clemente-Perez A, Higashikubo B, Cho FS, Holden SS, Bennett E, Chkaidze A, Eelkman Rooda OHJ, Cornet MC, Hoebeek FE, Yamakawa K, Cilio MR, Delord B, Paz JT. Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome. Cell Rep. 2019 Jan 2;26(1):54-64.e6. doi: 10.1016/j.celrep.2018.12.018. PubMed PMID: 30605686.
4)

Dibué-Adjei M, Fischer I, Steiger HJ, Kamp MA. Efficacy of adjunctive vagus nerve stimulation in patients with Dravet syndrome: A meta-analysis of 68 patients. Seizure. 2017 Aug;50:147-152. doi: 10.1016/j.seizure.2017.06.007. Epub 2017 Jun 17. Review. PubMed PMID: 28666193.

MATLAB

MATLAB is a multi-paradigm numerical computing environment and proprietary programming language developed by MathWorks.


Miller et al., from the Department of Neurosurgery of Stanford and Kaiser Permanente Redwood City Medical Center, proposed and presented a novel stereotactic coordinate system based on mesial temporal anatomical landmarks to facilitate the planning and delineation of outcomes based on extent of ablation or region of stimulation within mesial temporal structures.

The body of the hippocampus contains a natural axis, approximated by the interface of cornu ammonis (CA4) and the dentate gyrus. The uncal recess of the lateral ventricle acts as a landmark to characterize the anterior-posterior extent of this axis. Several volumetric rotations are quantified for alignment with the mesial temporal coordinate system. First, the brain volume is rotated to align with standard anterior commissureposterior commissure (AC-PC) space. Then, it is rotated through the axial and sagittal angles that the hippocampal axis makes with the AC-PC line.

Using this coordinate system, customized MATLAB software was developed to allow for intuitive standardization of targeting and interpretation. The angle between the AC-PC line and the hippocampal axis was found to be approximately 20°-30° when viewed sagittally and approximately 5°-10° when viewed axially. Implanted electrodes can then be identified from CT in this space, and laser tip position and burn geometry can be calculated based on the intraoperative and postoperative MRI.

With the advent of stereotactic surgery for mesial temporal targets, a mesial temporal stereotactic system is introduced that may facilitate operative planning, improve surgical outcomes, and standardize outcome assessment 1).


Using an administrative database and chart review, Ramayya et al., identified 101 first-time external ventricular drain placements performed at the bedside. They collected data regarding demographics, medical comorbidities, complications, and catheter tip location. They performed univariate and multivariate statistical analysis using MATLAB. They corrected for multiple comparisons using the false discovery rate (FDR) procedure.

Multivariate regression analyses revealed that revision procedures were more likely to occur after drain blockage (odds ratio [OR] 17.9) and hemorrhage (OR 10.3, FDR-corrected P values < 0.01, 0.05, respectively). Drain blockage was less frequent after placement in an “optimal location” (ipsilateral ventricle or near foramen of Monroe; OR 0.09, P = 0.009, FDR-corrected P < 0.03) but was more likely to occur after placement in third ventricle (post-hoc P values < 0.015). Primary diagnoses included subarachnoid hemorrhage (n = 30, 29.7%), intraparenchymal hemorrhage with intraventricular extravasation (n = 24, 23.7%), tumor (n = 20, 19.8%), and trauma (n = 17, 16.8%). Most common complications included drain blockage (n = 12, 11.8%) and hemorrhage (n = 8, 7.9%). In total, 16 patients underwent at least 1 revision procedure (15.8%).

Bedside external ventricular drain placement is associated with a 15% rate of revision, that typically occurred after drain blockage and postprocedure hemorrhage. Optimal placement within the ipsilateral frontal horn or foramen of Monroe was associated with a reduced rate of drain blockage 2).

References

1)

Miller KJ, Halpern CH, Sedrak MF, Duncan JA, Grant GA. A novel mesial temporal stereotactic coordinate system. J Neurosurg. 2018 Jan 1:1-9. doi: 10.3171/2017.7.JNS162267. [Epub ahead of print] PubMed PMID: 29372873.
2)

Ramayya AG, Glauser G, Mcshane B, Branche M, Sinha S, Kvint S, Buch V, Abdullah KG, Kung D, Chen HI, Malhotra NR, Ozturk A. Factors Predicting Ventriculostomy Revision at a Large Academic Medical Center. World Neurosurg. 2018 Nov 29. pii: S1878-8750(18)32755-4. doi: 10.1016/j.wneu.2018.11.196. [Epub ahead of print] PubMed PMID: 30503293.

Anterior temporal lobectomy (ATL)

Anterior temporal lobectomy for mesial temporal sclerosis is a very effective measure to control seizures, and the probability of being seizure-free is approximately 70-90%. However, 30% of patients still experience seizures after surgery.

In neurosurgery there are several situations that require transgression of the temporal cortex. For example, a subset of patients with temporal lobe epilepsy require surgical resection (most typically, en-bloc anterior temporal lobectomy). This procedure is the gold standard to alleviate seizures but is associated with chronic cognitive deficits. In recent years there have been multiple attempts to find the optimum balance between minimising the size of resection in order to preserve cognitive function, while still ensuring seizure freedom. Some attempts involve reducing the distance that the resection stretches back from the temporal pole, whilst others try to preserve one or more of the temporal gyri. More recent advanced surgical techniques (selective amygdalohippocampectomy) try to remove the least amount of tissue by going under (sub-temporal), over (trans-Sylvian) or through the temporal lobe (middle-temporal), which have been related to better cognitive outcomes. Previous comparisons of these surgical techniques focus on comparing seizure freedom or behaviour post-surgery, however there have been no systematic studies showing the effect of surgery on white matter connectivity. The main aim of this study, therefore, was to perform systematic ‘pseudo-neurosurgery’ based on existing resection methods on healthy neuroimaging data and measuring the effect on long-range connectivity. We use anatomical connectivity maps (ACM) to determine long-range disconnection, which is complementary to existing measures of local integrity such as fractional anisotropy or mean diffusivity. ACMs were generated for each diffusion scan in order to compare whole-brain connectivity with an ‘ideal resection’, nine anterior temporal lobectomy and three selective approaches. For en-bloc resections, as distance from the temporal pole increased, reduction in connectivity was evident within the arcuate fasciculusinferior longitudinal fasciculusinferior frontooccipital fascicle, and the uncinate fasciculus. Increasing the height of resections dorsally reduced connectivity within the uncinate fasciculus. Sub-temporal amygdalohippocampectomy resections were associated with connectivity patterns most similar to the ‘ideal’ baseline resection, compared to trans-Sylvian and middle-temporal approaches. In conclusion, we showed the utility of ACM in assessing long-range disconnections/disruptions during temporal lobe resections, where we identified the subtemporal resection as the least disruptive to long-range connectivity which may explain its better cognitive outcome. These results have a direct impact on understanding the amount and/or type of cognitive deficit post-surgery, which may not be obtainable using local measures of white matter integrity 1).

Anterior temporal lobectomy (ATL) with amygdalohippocampectomy (ATLAH) has been shown to be more efficacious than continued medical therapy in a randomized, controlled trial 2).

Minimally invasive approaches to treating MTLE might achieve seizure freedom while minimizing adverse effects.

Anterior temporal lobectomy as described by Penfield and Baldwin 3). is the most established neurosurgical procedure for temporal lobe epilepsy, for those in whom anticonvulsant medications do not control epileptic seizures.

It consists in the complete removal of the anterior portion of the temporal lobe of the brain.

Knowledge of the temporomesial region, including neurovascular structures around the brainstem, is essential to keep this procedure safe and effective 4).

The techniques for removing temporal lobe tissue vary from resection of large amounts of tissue, including lateral temporal cortex along with medial structures, to more restricted anterior temporal lobectomy (ATL) to more restricted removal of only the medial structures (selective amygdalohippocampectomy, SAH).

Limits of resection

The measurements are made along the middle temporal gyrus.

Dominant temporal lobe: Up to 4-5 cm may be removed

Non Dominant: 6- 7 cm.


Nearly all reports of seizure outcome following these procedures indicate that the best outcome group includes patients with MRI evidence of mesial temporal sclerosis (hippocampal atrophy with increased T-2 signal.) The range of seizure-free outcomes for these patients is reported to be between 80 and 90%, which is typically reported as a sub-set of data within a larger surgical series.

Open surgical procedures such as ATL have inherent risks including damage to the brain (either directly or indirectly by injury to important blood vessels), bleeding (which can require re-operation), blood loss (which can require transfusion), and infection. Furthermore, open procedures require several days of care in the hospital including at least one night in an intensive care unit. Although such treatment can be costly, multiple studies have demonstrated that ATL in patients who have failed at least two anticonvulsant drug trials (thereby meeting the criteria for medically intractable temporal lobe epilepsy) has lower mortality, lower morbidity and lower long-term cost in comparison with continued medical therapy without surgical intervention.

The strongest evidence supporting ATL over continued medical therapy for medically refractory temporal lobe epilepsy is a prospective, randomized trial of ATL compared to best medical therapy (anticonvulsants), which convincingly demonstrated that the seizure-free rate after surgery was ~ 60% as compared to only 8% for the medicine only group.

Furthermore, there was no mortality in the surgery group, while there was seizure-related mortality in the medical therapy group. Therefore, ATL is considered the standard of care for patients with medically intractable mesial temporal lobe epilepsy.

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. Anterior temporal lobectomy with amygdalohippocampectomy (ATLAH) has been shown to be more efficacious than continued medical therapy in a randomized, controlled trial 5).

The most common surgical procedure for the mesial temporal lobe is the standard anterior temporal resection or what is commonly called the anterior temporal lobectomy. There are, however, a number of other more selective procedures for removal of the mesial temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus) that spare much of the lateral temporal neocortex. Included in these procedures collectively referred to as selective amygdalohippocampectomy are the transsylvian, subtemporal, and transcortical (trans-middle temporal gyrus) selective amygdalohippocampectomy 6).

The ATL group scored significantly worse for recognition of fear compared with selective amygdalohippocampectomy (SAH) patients. Inversely, after SAH scores for disgust were significantly lower than after ATL, independently of the side of resection. Unilateral temporal damage impairs facial emotion recognition (FER). Different neurosurgical procedures may affect FER differently 7).

Outcome

Functional MRIResting state fMRIdiffusion tensor imaging modalities can be used effectively, in an additive fashion, to predict functional reorganization and cognitive outcome following anterior temporal lobectomy 8).

Complications

Case series

Of 1214 patients evaluated for surgery in the epilepsy Center of Faculdade de Medicina de São Jose do Rio Preto (FAMERP), a tertiary Brazilian epilepsy center, 400 underwent ATL for MTS. Number and type of auras was analyzed and compared with Engel Epilepsy Surgery Outcome Scalefor outcome.

Analyzing the patients by the type of aura, those who had extratemporal auras had worst result in post-surgical in Engel classifcation. While mesial auras apparently is a good prognostic factor. Patients without aura also had worse prognosis. Simple and multiple aura had no difference. In order to identify the most appropriate candidates for ATL, is very important to consider the prognostic factors associated with favorable for counseling patients in daily practice 9).


Boucher et al. compared preoperative vs. postoperative memory performance in 13 patients with selective amygdalohippocampectomy (SAH) with 26 patients who underwent ATL matched on side of surgery, IQ, age at seizure onset, and age at surgery. Memory function was assessed using the Logical Memory subtest from the Wechsler Memory Scales – 3rd edition (LM-WMS), the Rey Auditory Verbal Learning Test (RAVLT), the Digit Span subtest from the Wechsler Adult Intelligence Scale, and the Rey-Osterrieth Complex Figure Test. Repeated measures analyses of variance revealed opposite effects of SAH and ATL on the two verbal learning memory tests. On the immediate recall trial of the LM-WMS, performance deteriorated after ATL in comparison with that after SAH. By contrast, on the delayed recognition trial of the RAVLT, performance deteriorated after SAH compared with that after ATL. However, additional analyses revealed that the latter finding was only observed when surgery was conducted in the right hemisphere. No interaction effects were found on other memory outcomes. The results are congruent with the view that tasks involving rich semantic content and syntactical structure are more sensitive to the effects of lateral temporal cortex resection as compared with mesiotemporal resection. The findings highlight the importance of task selection in the assessment of memory in patients undergoing TLE surgery10).

References

1)

Busby N, Halai AD, Parker GJM, Coope DJ, Lambon Ralph MA. Mapping whole brain connectivity changes: The potential impact of different surgical resection approaches for temporal lobe epilepsy. Cortex. 2018 Nov 17;113:1-14. doi: 10.1016/j.cortex.2018.11.003. [Epub ahead of print] PubMed PMID: 30557759.
2) , 5)

Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5):311–318.
3)

PENFIELD W, BALDWIN M. Temporal lobe seizures and the technic of subtotal temporal lobectomy. Ann Surg. 1952 Oct;136(4):625-34. PubMed PMID: 12986645; PubMed Central PMCID: PMC1803045.
4)

Schaller K, Cabrilo I. Anterior temporal lobectomy. Acta Neurochir (Wien). 2016 Jan;158(1):161-6. doi: 10.1007/s00701-015-2640-0. Epub 2015 Nov 23. PubMed PMID: 26596998.
6)

Wheatley BM. Selective amygdalohippocampectomy: the trans-middle temporal gyrus approach. Neurosurg Focus. 2008 Sep;25(3):E4. doi: 10.3171/FOC/2008/25/9/E4. Review. PubMed PMID: 18759628.
7)

Wendling AS, Steinhoff BJ, Bodin F, Staack AM, Zentner J, Scholly J, Valenti MP, Schulze-Bonhage A, Hirsch E. Selective amygdalohippocampectomy versus standard temporal lobectomy in patients with mesiotemporal lobe epilepsy and unilateral hippocampal sclerosis: post-operative facial emotion recognition abilities. Epilepsy Res. 2015 Mar;111:26-32. doi: 10.1016/j.eplepsyres.2015.01.002. Epub 2015 Jan 16. PubMed PMID: 25769370.
8)

Osipowicz K, Sperling MR, Sharan AD, Tracy JI. Functional MRI, resting state fMRI, and DTI for predicting verbal fluency outcome following resective surgery for temporal lobe epilepsy. J Neurosurg. 2016 Apr;124(4):929-37. doi: 10.3171/2014.9.JNS131422. Epub 2015 Sep 25. PubMed PMID: 26406797.
9)

da Cruz Adry RAR, Meguins LC, Pereira CU, da Silva Júnior SC, de Araújo Filho GM, Marques LHN. Auras as a prognostic factor in anterior temporal lobe resections for mesial temporal sclerosis. Eur J Neurol. 2018 Jun 28. doi: 10.1111/ene.13740. [Epub ahead of print] PubMed PMID: 29953714.
10)

Boucher O, Dagenais E, Bouthillier A, Nguyen DK, Rouleau I. Different effects of anterior temporal lobectomy and selective amygdalohippocampectomy on verbal memory performance of patients with epilepsy. Epilepsy Behav. 2015 Oct 12;52(Pt A):230-235. doi: 10.1016/j.yebeh.2015.09.012. [Epub ahead of print] PubMed PMID: 26469799.
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