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Glossary AMPA receptor: Ligand-gated non-selective cation channel that allows the flow of Na + , K + and in some cases Ca2 + in response to binding of glutamate; ligands, such as glutamate, that gate (open) the channel are referred to as agonists. Channel block: Functional inhibition of an ion channel by a blocking drug that binds inside the ion conduction pore preventing flow of ions through the channel. Heteromeric receptor/homomeric receptor: Heteromeric applies when at least one subunit is non-identical to the others; homomeric applies when all subunits are identical. Ketone body: Three molecules (acetone, b-hydroxybutyrate and acetoacetate) produced in the liver during the metabolism of fats that serve as an alternative source of energy to glucose. MCT diet: A dietary treatment for epilepsy more commonly used in Europe than in the United States that is high in fats containing predominantly medium chain triglycerides; causes ketosis, a state where there are elevated concentrations of ketone bodies in the blood. Non-competitive antagonist: In the case of ionotropic glutamate receptors, an inhibitor whose blocking action is not reduced progressively as the agonist (glutamate) concentration is increased as occurs for competitive antagonists. Non-competitive antagonists allosterically inhibit the channel by binding to a site other than the ligand binding domain. Triglyceride: The storage form of fatty acids in the body; specifically, an ester derived from glycerol and three fatty acids, such as decanoic acid (capric acid) triglyceride, which is composed of glycerol and three decanoic acid molecules covalently linked.

Michael A. Rogawski Department of Neurology, School of Medicine, University of California, Davis Sacramento, California, USA

E-mail: [email protected] doi:10.1093/brain/awv369

References Adkison KD, Shen DD. Uptake of valproic acid into rat brain is mediated by a medium-chain fatty acid transporter. J Pharmacol Exp Ther 1996; 276: 1189–200. Chang P, Augustin K, Boddum K, Williams S, Sun M, Terschak JA, et al. Seizure control by decanoic acid through direct

AMPA receptor inhibition. Brain 2016; 139: 431–43. Chang P, Terbach N, Plant N, Chen PE, Walker MC, Williams RS. Seizure control by ketogenic diet-associated medium chain fatty acids. Neuropharmacology 2013; 69: 105–14. Hartman AL, Gasior M, Vining EP, Rogawski MA. The neuropharmacology of the ketogenic diet. Pediatr Neurol 2007; 36: 281–92. Huttenlocher PR, Wilbourn AJ, Signore JM. Medium-chain triglycerides as a therapy for intractable childhood epilepsy. Neurology 1971; 21: 1097–103. Liu M-J, Pollack GM. Pharmacokinetics and pharmacodynamics of valproate analogues in rats. IV. Anticonvulsant action and neurotoxicity of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid. Epilepsia 1994; 35: 234–43. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, et al. A randomized trial of classical and medium-

chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 2009; 50: 1109–17. Sills MA, Forsythe WI, Haidukewych D. Role of octanoic and decanoic acids in the control of seizures. Arch Dis Child 1986a; 61: 1173–7. Sills MA, Forsythe WI, Haidukewych D, MacDonald A, Robinson M. The medium chain triglyceride diet and intractable epilepsy. Arch Dis Child 1986b; 61: 1168–72. Wlaz´ P, Socala K, Nieoczym D, Luszczki JJ, Zarnowska I, Zarnowski T, et al. Anticonvulsant profile of caprylic acid, a main constituent of the medium-chain triglyceride (MCT) ketogenic diet, in mice. Neuropharmacology 2012; 62: 1882–9. _ arnowski Wlaz´ P, Socala K, Nieoczym D, Z _ T, Zarnowska I, Czuczwar SJ, et al. Acute anticonvulsant effects of capric acid in seizure tests in mice. Prog Neuropsychopharmacol Biol Psychiatry 2015; 57: 110–16.

When is temporal lobe epilepsy not temporal lobe epilepsy? This scientific commentary refers to ‘Temporal plus epilepsy is a major determinant of temporal lobe surgery failures’, by Barba et al. (doi:10.1093/ brain/awv372). Stereotactic electroencephalography (SEEG) originated in France in the 1950s. Bancaud and Talairach, at St.

Anne’s Hospital in Paris, introduced this approach to define the 3D extent of dysfunctional brain tissue surrounding intraparenchymal brain tumours, and more specifically, to define epileptogenic brain tissue in patients with pharmacoresistant epileptic seizures (Bancaud et al., 1975). The approach required a hypothesis that would

enable the placement of multiple, mostly unilateral, depth electrodes to sample a reasonably limited number of regions of interest. The results then guided a tailored surgical resection. This technique was adapted by Crandall et al. (1963) at UCLA for patients with suspected mesial temporal lobe epilepsy. Crandall,

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the only mechanism of the MCT diet requires further investigation.

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| BRAIN 2016: 139; 304–316 At the 1991 Palm Desert Conference, Claudio Munari, the principal disciple of Bancaud and Talairach, explained that in mesial temporal lobe epilepsy, he not only resected the structures where EEGrecorded ictal discharges began, but also those to which they propagated within 5 s, even if this included extratemporal areas (Lu¨ders et al., 1993). This was perhaps the first description, at least in the English literature, of TPE. It is somewhat surprising, therefore, that the epilepsy surgery programmes at Grenoble and Lyon, direct descendants of the St. Anne school, carried out classical SEEG in patients with suspected mesial temporal lobe epilepsy, identified TPE in some, but then (at least up until 2001) performed the same standardized anteromesial temporal resection routinely used in North America. This is fortuitous, however, because the results presented by Barba et al. clearly demonstrate that patients with TPE usually do not benefit from removal of mesial temporal limbic structures only. It appears that tailored resections were carried out in patients with TPE after 2001, so we can look forward to more recent data revealing whether more extensive additional extratemporal removals lead to better outcomes. The pressing question addressed by Barba et al., and countless other surgical series, as well as two randomized controlled trials (Wiebe et al., 2001; Engel et al., 2012), is: why does standard anteromesial temporal resection fail to control seizures in a significant number of patients who appear to have unilateral mesial temporal lobe epilepsy? A simple-minded answer to this question is that focal epilepsy is usually not focal, but rather, large areas of brain, often including subcortical and contralateral brain structures, are epileptogenically abnormal, and necessary to support the generation of consistently localized spontaneous ictal events. Surgical treatment therefore does not usually remove the entire area of abnormality, but rather a critical mass necessary and sufficient for spontaneous seizure

generation, commonly referred to as the epileptogenic region or zone (Lu¨ders et al., 1993). There is no diagnostic test that accurately delineates the extent of the epileptogenic region, so its boundaries can only be approximated by a variety of studies, including neuroimaging, scalp EEG, invasive EEG when necessary, and neuropsychological testing. For mesial temporal lobe epilepsy, there is usually a common pathological substrate, hippocampal sclerosis, but this does not indicate a singular disease—there are, in fact, multiple types of hippocampal sclerosis, ranging from the classical form with a characteristic histological pattern of CA2 sparing, often associated with a history of prolonged febrile seizures, to more diffuse patterns that include atrophy of CA2, as well as the contralateral hippocampus (Mathern et al., 1997; Ogren et al., 2009; Blu¨mcke et al., 2013) (Fig. 1). There also can be various degrees of extrahippocampal atrophy, including parahippocampal structures, ipsilateral and bilateral neocortex, and thalamus (Lin et al., 2007). The presence of hippocampal sclerosis, diagnosed by hippocampal cell counts and Timm’s stain, can be missed by MRI and even routine histopathology (Mathern et al., 1997). Disregarding the situation where the standardized anteromesial temporal lobe resection was inadequate, leaving a large hippocampal remnant, three other common explanations for failure of this procedure to eliminate all seizures can be offered: (i) The epileptogenic region is extratemporal in an area of ‘silent cortex’ that preferentially projects to mesial temporal structures, or there is more than one epileptogenic region, one of which is extratemporal (e.g. dual pathology), or there is an epileptogenic region in the contralateral temporal lobe. These are rarely the cause of surgical failures today, owing to high-resolution MRI, PET, and SEEG in patients where the clinical history and ictal semiology raise suspicion of extratemporal or bilateral epileptogenic regions.

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however, used a standardized, bilaterally symmetrical, depth electrode approach, designed to sample those structures known to be primarily involved in generating limbic seizures. Because French law did not allow Bancaud and Talairach to leave their electrodes in place for more than a few hours, their analyses were based on interictal activity, as well as electrically and chemically induced seizures. Crandall, therefore, was the first to perform chronic depth electrode recording, over days and weeks, in order to capture spontaneous ictal events. Because investigators at UCLA had recently developed an EEG telemetry device for NASA to record from chimpanzees orbiting in space, Crandall was also able to use this new technology to establish EEG telemetry for long-term monitoring of epileptic seizures. Data were used to determine that the epileptogenic region was contained within the area of a standardized anterior temporal resection (Falconer, 1953), which was then performed routinely. Two schools of invasive presurgical evaluation for epilepsy surgery then evolved: the French school, which performed classical SEEG, using multiple electrodes placed predominantly around a suspected unilateral lesion to guide a tailored surgical resection; and a North American school, which used more or less standardized bilateral depth electrode placements to inform performance of a standardized anterior temporal resection. Over the years, advanced neuroimaging made invasive EEG unnecessary in many patients with mesial temporal lobe epilepsy, and the limits of the resections were refined to include only those structures subsequently identified as most important for generation of mesial temporal seizures (Spencer et al., 1984). The paper by Barba et al. (2016) in this issue of Brain is the latest report from the French School to examine why surgery for refractory mesial temporal lobe epilepsy does not always eliminate all seizures. At least one reason appears to be the existence of ‘temporal plus’ epilepsy (TPE).

Scientific Commentaries

Scientific Commentaries

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(ii) The epileptogenic region involves more extensive temporal lobe tissue than is usually included in the standardized anteromesial temporal resection. This could result from the progressive nature of mesial temporal lobe epilepsy (Cendes et al., 2005), and could explain why the seizure-free outcome was 85% for patients with complete data in the Early Randomized Surgical Epilepsy Trial (ERSET), who were operated on within 2 years of pharmacoresistance (Engel et al., 2012), whereas only 60–70% of patients were seizure-free in most surgical series, including the Western Ontario randomized controlled trial (Wiebe et al., 2001), where patients typically had had epilepsy for an

average of 420 years (Berg et al., 2003). (iii) The epileptogenic region includes extratemporal structures, the condition of TPE. In some patients this could be an extension of the progressive nature of classical mesial temporal lobe epilepsy, while in others it likely represents different epileptogenic processes, involving more than the temporal lobe from the start.

The presence of different types of hippocampal sclerosis strongly suggests that there are multiple disease processes that can present as mesial temporal lobe epilepsy. Improved surgical outcomes will result from further elucidation of the various epileptogenic mechanisms and their aetiologies,

which ultimately manifest clinically as mesial temporal lobe epilepsy. Jerome Engel, Jr. Departments of Neurology, Neurobiology and Psychiatry and Biobehavioral Sciences and the Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, USA

E-mail: [email protected] doi:10.1093/brain/awv374

Funding Original research reported by the author was supported in part by Grants NS02808, NS15654, NS33310, and NS80818.

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Figure 1 Mapping 3D hippocampal atrophy. Surface contour maps depicting areas of local atrophy show regions of significant differences between patients with hypersynchronous (HYP) and low-voltage fast (LVF) ictal depth EEG onsets, relative to controls. White and red indicate areas of significant atrophy (P 5 0.05), whereas blue indicates areas without significant atrophy (P 4 0.10). (A) Superior and inferior aspects of the hippocampus demonstrating relationship of surface maps to hippocampal subfields. (B) Superior and inferior aspects of the ipsilateral hippocampus demonstrating sparing of CA2 in patients with HYP onset, and atrophy of CA2 in patients with LVF onset. (C) Superior, lateral, and inferior aspects of the contralateral hippocampus demonstrating substantially more atrophy with LVF ictal onset than with HYP ictal onset. Adapted from Ogren et al. (2009), with permission.

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Glossary

References Bancaud J, Talairach J, Lamarche M, Bonis A, Trottier S. Hypothe´ses neurophysiopathologiques sur l’e´pilepsie-sursaut chez l’homme. Rev Neurol 1975; 131: 559–71. Barba C, Rheims S, Minotti L, Guenot M, Hoffman D, Chabardes S, et al. Temporal plus epilepsy is a major determinant of temporal lobe surgery failures. Brain 2016; 139: 444–51. Berg AT, Langfitt J, Shinnar S, Vickrey BG, Sperling MR, Walczak T, et al. How long does it take for partial epilepsy to become intractable? Neurology 2003; 60: 186–90. Blu¨mcke I, Thom M, Aronica E, Armstrong DD, Bartolomei F, Bernasconi A. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a task force report from the ILAE commission on diagnostic methods. Epilepsia 2013; 54: 1315–29.

Cendes F. Progressive hippocampal and extrahippocampal atrophy in drug resistant epilepsy. Curr Opin Neurol 2005; 18: 173–7. Crandall PH, Walter RD, Rand RW. Clinical applications of studies on stereotactically implanted electrodes in temporal lobe epilepsy. J Neurosurg 1963; 20: 827–40. Engel J Jr, McDermott MP, Wiebe S, Langfitt JT, Stern JM, Dewar S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA 2012; 307: 922–30. Falconer MA. Discussion on the surgery of temporal lobe epilepsy: surgical and pathological aspects. Proc R Soc Med 1953; 46: 971–4. Lin JJ, Salamon N, Lee AD, Dutton RA, Geaga JA, Hayashi KM, Luders E, et al. Reduced neocortical thickness and complexity mapped in mesial temporal lobe epilepsy with hippocampal sclerosis. Cereb Cortex 2007; 17: 2007–18.

Lu¨ders HO, Engel J Jr, Munari C. General principles. In: Engel J, Jr, editor. Surgical treatment of the epilepsies, 2nd edn. New York: Raven Press; 1993, p. 137–53. Mathern GW, Babb TL, Armstrong DL. Hippocampal sclerosis. In: Engel J Jr, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: LippincottRaven; 1997, p. 133–55. Ogren JA, Bragin A, Wilson CL, Hoftman GD, Lin JJ, Dutton RA, et al. Three-dimensional hippocampal atrophy maps distinguish two common temporal lobe seizure-onset patterns. Epilepsia 2009; 50: 1361–70. Spencer DD, Spencer SS, Mattson RH, Williamson PD, Novelly RA. Access to the posterior medial temporal lobe structure in surgical treatment of temporal lobe epilepsy. Neurosurgery 1984; 15: 667–71. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal lobe epilepsy. N Engl J Med 2001; 345: 311–18.

Habitual and goal-directed behaviours and Tourette syndrome This scientific commentary refers to ‘Enhanced habit formation in Gilles de la Tourette syndrome’, by Delorme et al. (doi:10.1093/brain/awv307). Tourette syndrome is characterized by the presence of tics, which have a fluctuating, waxing and waning

course, and are typically exacerbated by stress, anxiety, excitement, anger or fatigue. Tics are known to diminish when an individual is absorbed in an activity, concentrating, focused or pleased. Studies have also shown that tics can occur during sleep, although understandably patients fail to report

their presence. Further, many individuals with tics, especially older children and adults, describe a sensory phenomenon (premonitory urge), such as a tension, impulse, tingle, or feeling located in the relevant body part, prior to the tic. Although it has been suggested that tics should

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Epileptogenic region or zone: The area of brain tissue necessary and sufficient to generate spontaneous seizures. This determines the minimal resection necessary to achieve seizure freedom. Hippocampal sclerosis: The most common pathological substrate of mesial temporal lobe epilepsy, consisting of different patterns of hippocampal cell loss. Standardized depth electrode recording: A standardized approach to intracerebral depth electrode recording for temporal lobe epilepsy, where electrodes are placed bilaterally in areas known to generate the typical limbic seizures. This approach is designed to localize the epileptogenic region and determine that it is within the boundaries of a standardized anteromesial temporal resection. Standardized temporal resections: Surgical resections of the temporal lobe designed to remove the typical epileptogenic region of mesial temporal lobe epilepsy, most commonly anteromesial temporal resection, which includes the temporal pole and extensive removal of mesial temporal structures, but also selective amygdalohippocampectomy, which spares the temporal pole. Stereoencephalography (SEEG): An individualized approach to intracerebral depth electrode recording whereby multiple electrodes are placed to obtain 3D information from specific regions of interest. This approach is designed to localize the epileptogenic region, and determine its boundaries. Tailored temporal lobe resection: Individualized resections of the temporal lobe, and occasionally extratemporal tissue, where the boundaries of the resection are guided by results of presurgical evaluation, particularly neuroimaging, SEEG and/or intraoperative electrocorticography, designed to determine the actual extent of the epileptogenic region. Temporal plus epilepsy (TPE): A form of temporal lobe epilepsy characterized by focal seizures generated by an epileptogenic region involving both mesial temporal and extratemporal structures.

When is temporal lobe epilepsy not temporal lobe epilepsy?

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