Drug interactions are generally slight. However, topiramate levels can be lowered by co-med ication with carbamazepine, phe- nobarbital and phenytoin. Topiramate co-medication can inc rease phenytoin levels. oxford textbook of epilepsy and epileptic seizures 288 available AED. It also has other signi \201 cant side effects, including depression and ps ychosis. It has a strong effect in infantile spasms, and is often effective in cases resist ant to ACTH, and because of this has become a drug of \201 rst choice in this small indic ation. It is particularly effective in cases in which the infantile spasms are due to tuber ous sclerosis. concern and is a further reason for avoiding valproate in female patients where pregnancy i s an issue. Its use in young children, especially those under 2 years of age, carries a sma ll but de \201 nite risk of hepatic failure and where other drugs are available, these ten d now to be used. It is contraindicated in the presence of hepatic or pancreatic disease. V alproate pharmacokinetics are complex and there are many and varied interactions. It slight ly inhibits the metabolism of other AEDs, usually without consequence, but does cause major rises in lamotrigine levels when given as co-medica- tion. Imipenem antibiotics profoundly lower valproate levels and should not be used in co-medication. Valproate concentra- tions are lowered by co-medication with commonly used antineo- plastic drugs and elevated by co- medication with commonly used antidepressant and psychotropic drugs. Other drugs, such as i soni- azid, can increase valproic acid levels. Valproic acid inhibits the metabolism of a n umber of drugs, most notably phenobarbital, lamotrigine, and ru \201 namide. Valproic acid displaces phenytoin from plasma protein binding sites and can also inhibit phenytoin metab olism. Apart from the visual \201 eld restrictions and the psychiatric effects, other common and important side effects of vigabatrin include nausea, abdominal pain, drowsiness, dizziness , encephalopathy, stupor, confusion, visual \201 eld restriction, weight gain, headache, tremor, and paraesthesia. Vigabatrin has no important or common drug interactions. The usual indication for use is as adjunctive therapy in partial epilepsy, but only in exceptional circumstances and where su per- vised by a specialist, and infantile spasm. The available prepara- tions are tablets 5 00 mg size, and powder 500 mg/sachet. The usual adult dosage is initially 500 mg, increasin g by 500 mg increments to 2 \200\2233 g/day. The usual dosage in children is: 10 \200\22315 kg: 0.5 \200\2231 g/ day; for children 15 \200\22330 kg: 1 \200\2231.5 g/day; and for chil dren 30 \200\22350 kg: 1.5 \200\2233 g/day. Common and important side effects include nausea, vomiting, hyperammonaemia and other metab olic effects, endocrine effects, weight gain, severe hepatic toxicity, gastrointestinal dis tur- bance, pancreatitis, drowsiness, cognitive disturbance, aggressive- ness, tremor, atax ia, weakness, encephalopathy, extrapyramidal symptoms, oedema, thrombocytopenia, neutropeni a, platelet and coagulation dysfunction, aplastic anemia, hair thinning and hair loss, poly cystic ovarian syndrome, Fanconi syndrome, and hyponatraemia. Dosing interval is 2 times/day. Serum level monitoring is not useful. Zonisamide Zonisamide is a chemically distinctive sulfonamide drug, with striking effective ness in a wide spectrum of partial and generalized seizures. It has been licensed in Japan for some years, although has become available in Europe only since 2002. It has multiple po ten- tial mechanisms of action, and inhibits the voltage-gated sodium channel and T-type ca lcium channel currents, acts to enhance the benzodiazepine GABA A receptor, is a carbonic a nhydrase and also has actions on excitatory glutaminergic transmission. It is prone to caus e various side effects and tolerability can be improved by slow introduction. The risk of r enal stones has been a concern particu- larly in Europe and the US, but less so in Japan, a nd patients should be advised to remain well hydrated when taking this drug. It has about 5 0 % protein binding, and a very long half life (50 \200\22370 hours) but this is signi \201 cantly reduced (25 \200\22340 hours) by co-medication with enzyme-inducing AEDs and do se changes when co- medicating are appropriate. Vaproate is indicated in all forms of epilepsy at all age groups. The usual preparations ar e enteric-coated tablets: 200, 500 mg; crushable tablets: 100 mg; capsules: 150, 300, 500 m g; solution or syrup: 200 mg/5 mL, 250 mg/5 mL; sustained-release tablets: 200, 300 500 mg; sustained-release microspheres, sachets: 100, 250, 500, 750, 1000 mg; divalproex tablets: 125, 300, 500 mg (as valproic acid equivalents); divalproex tablets delayed release: 125, 2 50, 500 mg (as valproic acid equivalents); divalproex sprinkles, 125 mg (as val- proic acid equivalents); divalproex tablets extended release: 250, 500 mg (as valproic acid equivalen ts); solution for intravenous injection: 100 mg/mL The usual adult dosage initially is 200 \200\223500 mg/day increasing by 200 \200\223500mg increments every 2 weeks to maintenance doses of 600 \200\2232000 mg/day. The usual dosage in children initially is 15 mg/ kg/day (children <20 kg); and 40 mg/kg/day (children > 20 k g). Maintenance doses in children < 20kg: 20 \200\22340 mg/kg/day, and in children > 20 kg: 20 \200\22330 mg/kg/day. Dosing intervals is 2 times/day. Blood levels show marked diurnal variation, but serum level monitoring can be useful in occasional cases. The target range is 50 \200\223100 mg/L. It should be noted that the drug can be very effective at low serum levels, and as with other agents clinical parameters should be used to guide therapy where ver possible. Serum zonisamide levels are markedly lowered by carbamazepine, phenytoin, and barbiturates. Zonisamide co-medication does not usually signi \201 cantly in \202 uence levels of othe r drugs. Common and important adverse events are somnolence, ataxia, dizziness, insomnia, headache, attention and concentration dif \201 culties, memory impairment, irritability, confusion, depres- sion, impaired concentration, mental slowing, speech distur- bance, fatigue, nausea , vomiting, weight loss, anorexia, itching, abdominal pain, hyperthermia, nephrolithiasis, acidosis, pyrexia, renal impairment, oligohidrosis and risk of heat stroke. Rash and other manifestations of a hypersensitivity are rare but can be serious. Vigabatrin Vigabatrin is a GABA agonist, which was introduced in 1989 for the treatment of partial seizures. It was then discovered in 1997 to cause visual \201 eld constriction, a side effect which is now known to occur in over 40 % of treated patients ( 22 ). Because o f this, its use has become severely limited to a very small number of patients with partial epilepsy whose seizures are controlled with no other Usual indications include adjunctive therapy in partial and generalized epilepsy, Lennox \200\223Gastaut syndrome, West syndrome, and progressive myoclonic epilepsy. It is licensed in Europe, Japan and Asia in children and adults. It is licensed in the US only for refrac tory partial epilepsy in patients 16 or more years of age The usual preparations are capsules 25, 50, 100 mg size, tablets 25 and 100 mg size, and po wder: 20 % . Initial dose in adults is CHAPTER 26 the pharmacokinetics and clinical therapeutics of the antiepileptic drugs 289 50 mg/day, increased by 50 mg increments each 2 weeks, to a main- tenance dose of 200 \200 \223500 mg/day. In children the initial dose is 2 \200\2234 mg/kg/day, and maintenance 4 \200\2238 mg/kg/day. 9. Ng YT , Conry JA , Drummond R , Stolle J , Weinberg MA , OV-1012 Study Investigators . Randomized, phase III study results of clobazam in Lennox-Gastaut syn drome . Neurology 2011 ; 77 ( 15 ): 1473 \200\223 81 . 10. Glauser TA , Cnaan A , Shinnar S , Hirtz DG , Dlugos D , Masur D , et al . Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy . N Engl J Med 2010 ; 362 ( 9 ): 790 \200\223 99 . Dosing intervals are 1 \200\2232 times/day. Serum level monitoring may be useful in some ca ses. The target range is 10 \200\22340 mg/L (30 \200\223120 mol/L). 11. Simms KM , Kortepeter C , Avigan M . Lamotrigine and aseptic meningitis . Neurology 2012 ; 78 ( 12 ): 921 \200\223 7 . Acknowledgement Some of the text is based on: Shorvon S. Epilepsy (Oxford Neurology Library Series). Oxford: Oxford University Press, 2009. 12. Genton P . When antiepileptic drugs aggravate epilepsy . Brain Dev 2000 ; 22 ( 2 ): 75 \200\223 80 . 13. Pennell PB , Newport DJ , Stowe ZN , Helmers SL , Montgomery JQ , Henry TR . The impact of pregnancy and childbirth on the metabolism of lamotrigine . Neurol ogy 2004 ; 62 ( 2 ): 292 \200\223 95 . References 14. Nowack A , Malarkey EB , Yao J , Bleckert A , Hill J , Bajjalieh SM . Levetiracetam reverses synaptic de \201 cits produced by overexpression of SV2A . PLoS ONE 2011 ; 6 ( 12 ): e29560 . 1. Prunetti P , Perucca E . New and upcoming anti-epileptic drugs . Curr Opin Neurol 2011 ; 24 ( 2 ): 159 \200\223 64 . 15. Delanty N , Jones J , Tonner F . Adjunctive levetiracetam in children, 2. Stephen LJ , Forsyth M , Kelly K , Brodie MJ . Antiepileptic drug adolescents, and adults with primary generalized seizures: open-label, noncomparative, mult icenter, long-term follow-up study . Epilepsia 2012 ; 53 ( 1 ): 111 \200\223 19 . combinations-Have newer agents altered clinical outcomes? Epilepsy Res 2012 ; 98 ( 2 \200 \2233 ): 194 \200\223 8 . 3. Bialer M . Chemical properties of antiepileptic drugs (AEDs) . Adv Drug 16. Kanner AM . Can antiepileptic drugs unmask a susceptibility to Deliv Rev 2011; Nov 21 . [Epub ahead of print] psychiatric disorders? Nature clinical practice Neurology 2009 ; 5 ( 3 ): 132 \200\223 3 . 4. Beghi E , Beghi M , Cornaggia CM . The use of recently approved antiepileptic drugs: use with caution, use in refractory patients or use as \201 rst-line indications? Expert Rev Neurother 2011 ; 11 ( 12 ): 1759 \200\223 67 . 17. Hu F-Y , Wu X-T , An D-M , Yan B , Stefan H , Zhou D . Pilot association study of oxcar bazepine-induced mild cutaneous adverse reactions with HLA-B * 1502 allele in Chinese Han p opulation . Seizure 2011 ; 20 ( 2 ): 160 \200\223 2 . 5. Lason W , Dudra-Jastrze bska M , Rejdak K , Czuczwar SJ . Basic mechanisms of antiepi leptic drugs and their pharmacokinetic/ pharmacodynamic interactions: an update . Pharmacol Rep 2011 ; 63 ( 2 ): 271 \200\223 92 . 18. Gunthorpe MJ , Large CH , Sankar R . The mechanism of action of retigabine (ezogabine), a \201 rst-in-class K( + ) channel opener for the treatment of ep ilepsy . Epilepsia 2012 ; 53 ( 3 ): 412 \200\223 24 . 6. Johannessen Landmark C , Patsalos PN . Drug interactions involving the 19. Fisher JL . The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator . Neuropharmacology 2009 ; 56 ( 1 ): 190 \200\223 7 . new second- and third-generation antiepileptic drugs . Expert Rev Neurother 2010 ; 10 ( 1 ) : 119 \200\223 40 . 7. Chung W-H , Hung S-I , Hong H-S , Hsih M-S , Yang L-C , Ho H-C , et al . Medical genetic s: a marker for Stevens-Johnson syndrome . Nature 2004 ; 428 ( 6982 ): 486 . 20. Chiron C , Dulac O . The pharmacologic treatment of Dravet syndrome . Epilepsia 2011 ; 52 (Suppl 2) : 72 \200\223 5 . 21. Bauer J , Cooper-Mahkorn D . Tiagabine: ef \201 cacy and safety in partial seizures \200\224 current status . Neuropsychiatr Dis Treat 2008 ; 4 ( 4 ): 731 \200\223 6 . 22. Ch iron C , Dulac O . Epilepsy: Vigabatrin treatment and visual \201 eld loss . 8. McCormack M , Al \201 revic A , Bourgeois S , Farrell JJ , Kasperavic \207iu te \231 D , Carrington M , et al . HLA-A * 3101 and carbamazepine-induced hypersensitivity reactions in Europeans . N Engl J Med 2011 ; 364 ( 12 ): 1134 \200\223 43 . Nat Rev Neurol 2011 ; 7 : 189 \200\223 90 . This page intentionally left blank CHAPTER 27 Principles of Epilepsy Surgery Samden D. Lhatoo 1. Firstly to conclusively identify the focus of the individual \200\231s med- Epilepsy surgery is generally understood to mean resective sur- gery where the primary surg ical imperative is the control of sei- zures rather than the underlying pathology causing s eizures (e.g. brain tumor), although on occasion both epilepsy as well as its cause merit e qual surgical attention. It is primarily used for refractory focal epilepsy syndromes and h as no role in the primary generalized epilepsy syndromes (with the exception of vagal nerve or potentially, deep brain stimulation). Since up to a third of patients with epilepsy do not respond to medication, surgery becomes a viable treatment alternative in up to half of the patient population with refractory focal epilepsy, carrying with it the promise of seiz ure freedom, a reduction in seizure or medication-related morbidity, and a reduction in the risk of sudden unexpected death. Non-resective surgery, where brain tissue is not removed but where seizure control is the main indication, is now also a distinct category of epilep sy surgery (Table 27. 1 ). ically refractory epilepsy. 2. Second, to remove this focus in order to render the individual seizure free. 3. Third, to avoid harm to the patient in doing so (e.g. permanent postoperative de \201 cits). 4. Fourth, if principles 1 \200\2233 are not possible, to reduce the individ- ual \200\231s seizure burden (palliate) as much as possible. The manner in which these are achieved and the principles that guide the processes involved are described next and in subsequent chapters. Table 27.1 Types of epilepsy surgery Resective surgeries The era of modern epilepsy surgery can be said to have begun with Victor Horsley (Fig. 27.1 ) in 1886 when, as a young neurosur- geon newly appointed to the National Hospital for the Paralyzed and the Epileptic at Queen Square, London, he operated on a 22-year-old man with focal motor seizures and a depressed skull fracture ( 1 ). This was followed a month later by surgery on a 20-year-old man with left-hand clonic seizures and postictal palsy caused by what turned out to be a tuberculoma in the predicted frontoparietal juncture. This predi ction was made on the basis of the patient \200\231s seizure semiology, at that time the on ly available tool for the localization of the epileptogenic zone \200\224 the brain area c riti- cal to seizure generation and the resection of which renders a patient seizure free. \227\206 Lobar/sublobar resections a \226 Frontal \226 Temporal: Standard resection (anterior temporal lobe + mesial structures) \227\217 Selective amygdal ohippocampectomy \227\217 Tailored resections (variations of the above 2) \226 Parietal \226 Occipital \226 Other \200\224 insula, cingulate \227\206 Multilobar resections \227\206 Hemispherectomies: \226 Functional hemispherectomy/hemispherotomy \226 Anatomical hemispherectomy \227\206 Corpus callosotomy b Since then, a number of sophisticated technologies, described in this and following chapter s, have been developed to supplement semiological information in the direct or indirect ide nti \201 cation of the epileptogenic zone as well as the identi \201 cation of eloquent b rain tissue. The latter is an important consideration as the surgi- cal decision-making pro cess has to account for the risk and proba- bility of postsurgical de \201 cits rendered b y resections involving these areas. Modern epilepsy surgery is now therefore a highly compl ex, multimodal, and multidisciplinary process. Its fundamental principles however, are simp le: Non-resective surgeries \227\206 Multiple subpial transection b \227\206 Hippocampal tran section \227\206 Gamma knife surgery \227\206 Deep brain stimulation b \227\206 Vagal ne rve stimulation b a Many \200\230lobectomies \200\231 are tailored to individual patients according to the p resurgical inves- tigation \201 ndings and range from small corticectomies to large subto tal or rarely, total lobectomies. b These are generally considered to be primarily palliative procedures. oxford textbook of epilepsy and epileptic seizures 292 lesion. This area is usually in close relation to the epileptogenic zone and sometimes with in the epileptogenic zone itself as in the case of hippocampal sclerosis (Fig. 27. 2 ). On the other hand, in cases of tumoural epilepsy, for example, the epileptogenic zone often li es along the borders of the lesion zone. 3. The irritative zone . This is the area represented by epileptiform activity as evidenced by electroencephalography (EEG) or mag- netoencephalography (MEG) in the form of spikes or sharp waves. In the case of hippocampal sclerosis, there is an extremely close relationshi p with the lesion zone and the epileptogenic zone is usually contained within it. However, with some close to midline, extratemporal epilepsies such as a mesial parietal epi- lepsy, for example, the sharp waves can appear elsewhere and thus provide \200\230discordant \200 \231 information. 4. The ictal-onset zone . This area is identi \201 ed by the initial seizure pattern and t he EEG electrodes on surface or intracranial EEG where it is recorded. More recently, ictal single-positron emis- sion computed tomography (SPECT) and, to a lesser extent, MEG are al so used. It is usually in intimate relation to the epi- leptogenic zone and its identi \201 cation is crucial to successful epi- lepsy surgery. The concept of the ictal onset zon e can be expanded to include the actual seizure onset zone as recorded by the earlier menti oned investigations, and the potential seizure onset zone. If both are not included in the surgical resection, the patient may not become seizure free or will develop seizure recurre nce at some time after surgery, perhaps even years later (Fig. 27. 3 ). Fig. 27.1 Victor Horsley (14 April 1857 \200\22316 July 1916). Image courtesy of the Queen Square Library, Archive and Museum. Copyright National Hospital for Neurology & Neurosurger y. The epileptogenic zone The main purpose of epilepsy surgery is the removal of the seat of a n individual \200\231s focal epilepsy \200\224 the epileptogenic zone. The epilep- togenic zone has been de \201 ned as that \200\230area of cortex that is indis- pensable for the generation of epileptic seizures \200\231 ( 2 ). However, only after complete and lasting seizure freedom from surgical resection of a particular cortical area can that area be said to de \201 - nitely represent the epileptogenic zone. The challenge of the pre- surgical work-up therefore lies in the identi \201 cation of a number of other \200\230zones \200 \231 that if consistently indicative of the same brain area as abnormal (i.e. \200\230conc ordant \200\231), provide the best indication of where the true epileptogenic zone might li e (Fig. 27. 2 ). \200\230Discordance \200\231 on the other hand, where there is poor congr uity between zones, pre- dicts poor seizure freedom outcomes with surgery. These zones are identi \201 ed by different clinical and investigative tools. 5. The functional de \201 cit zone . This is an area of dysfunctional brain identi \201 e d in the interictal period, consequent to structural or functional abnormalities arising fr om a focal epilepsy. It is iden- ti \201 ed by a variety of means including physical exami nation (e.g. hemiparesis implies a functional de \201 cit zone in the contralateral Epileptogenic zone Ictal onset zone Irritative zones Functional deficit zone Symptomatogeni c zone 1. The symptomatogenic zone . This is the part of the brain that gives rise to the clinical symptoms and signs (semiology) of the epi- lepsy. It may or may not be in close relation t o the epileptogenic zone. For example, seizures arising from an epileptogenic zone in the l eft hippocampus may not be symptomatic until the sei- zure discharge reaches the left insul ar area (Fig. 27. 2 ) where it may cause the patient to experience a rising epigastric sens ation. This area is then the symptomatogenic zone, relatively distant from the epileptogeni c zone. In such cases, information from other zones becomes mandatory in strengthening the case for surgery. In general, close attention to history of the patient \200\231s aura and video recordings of seizures provide excellent clues to the location of the symptomatogenic zone. Amygdala Hippocampus Fig. 27.2 (Also see Color plate 13.) The epileptogenic zone and its relationship with relat ed zones in a patient with left hippocampal sclerosis. These are: (1) Epileptogenic zone = left hippocampus and amygdala. (2) Epileptic lesion zone and ictal onset zone = left hippoc ampus. (3) Irritative zones = left and right hippocampus + adjacent temporal neocortex. (4) Functional de \201 cit zone = left temporal lobe (reduced left temporal neuropsychologica l measures \200\224 e.g. verbal memory). (5) Symptomatogenic zone = left insula and lower motor strip (e.g. causing epigastric sensation followed by a right face clonic seizure). Co pyright Samden D. Lhatoo. 2. The epileptic lesion zone . Neuroimaging, namely high-resolution magnetic resonance imag ing (MRI), best identi \201 es the epileptic CHAPTER 27 principles of epilepsy surgery 293 Table 27.2 Some auras and their usual symptomatogenic zones frontal lobe), positron emission tomography (PET) imaging (regional hypometabolism), functi onal MRI, neuropsychologi- cal testing (verbal memory de \201 cits in a right-handed indiv idual may indicate a left mesial temporal functional de \201 cit zone), the intracarotid a mobarbital or Wada test (poor memory function in one hemisphere) evoked potentials (reduced amplitude or delay in appropriate cortex), and others. The functional de \201 cit zone is often, but not always, large and in proximity to the epi- leptogenic zone. Aura manifestation Symptomatogenic zone Unilateral sensory aura Contralateral primary sensory area Bilateral sensory aura Secondary sensory area Supplementary sensorimotor area Simple auditory aura Primary auditory cortex Complex auditory aura Auditory association area Simple hemi \201 eld visual hallucination Contralateral primary visual cortex Often, one or more zones may not be evident. For example, in a patient who has normal high- resolution brain MRI scans, the epi- leptic lesion zone is by de \201 nition unidenti \201 able. When several zones are poorly or not at all identi \201 able, the case for succ essful surgery is weakened and any such undertaking becomes extremely challenging. Equally, the presence of more than one ictal onset zone, several irritative zones and/or more than one epileptic lesion zone (dual or multiple pathology) render surgery a far from straightfo rward option. Complex visual hallucination Visual association area Fear Amygdala Olfactory aura Amygdala Gustatory aura Parietal opercular area Abdominal aura Insula D j vu aura Basal temporal area Seizure semiology in epilepsy surgery Stringent analysis of the seizure symptoms and signs is a crucial part of the presurgical work-up of the patient. This identi \201 es the sympt omatogenic zones which in turn can (1) lateralize the seizure to one hemisphere and (2) loc alize the seizure to a speci \201 c brain region in that hemisphere. This allows the clini cian to focus atten- tion on a speci \201 c area of interest. symptomatogenic zone (Table 27. 2 ), information that can then be used to analyze the prese nce or absence of discordance with other investigations. Much of what we know of aura local ization is derived from brain stimulation studies where electrical stimulation of speci \201 c brain areas using intracranial electrodes in epilepsy patients consistently reproduc ed a speci \201 c symptom relating to that patient \200\231s epileptic aura ( 3 , 4 ). Since the aura of the partial seizure constitutes its beginning, the cortical area producin g the aura is likely to be closer to the seizure focus than the areas responsible for the l ater manifestations of the seizure. For example, in a seizure that begins with a simple aud i- tory aura, progresses to a complex visual hallucination and then a secondary generalized tonic \200\223clonic seizure, the epileptogenic zone is likely to lie closer to the primar y auditory cortex in the superior temporal area (Heschl \200\231s gyrus) than to the visual associa- tion areas or motor areas which produce the later symptoms and signs. Hence the a ura provides important information about the Semiological analysis of the seizure does not end with the aura, however, and indeed, many patients either do not have or cannot remember their auras. Speci \201 c features of the s eizures can point to the symptomatogenic zone. The twitching thumb (a thumb clonic Table 27.3 Some seizure features used in localization and lateralization in epilepsy surger y a ( 5 ) Seizure manifestation Localization/lateralization of seizure Hypermotor movements Frontal lobe Unsuccessful surgical resection Successful surgical resection Potential seizure onset zone Actual seizure onset zone Bilateral asymmetric tonic posturing Supplementary sensorimotor area Dystonic hand posturing in a seizure with early automatisms Contralateral temporal lobe \200\230Sign of four \200\231 posturing at onset of a secondary generalized seizure (one a rm extends, one arm \202 exes over chest) Hemisphere contralateral to extended arm Forced head version at onset of a secondary generalized seizure Hemisphere contralateral to side of version Ictal speech Non-dominant temporal lobe Preserved consciousness and memory during a seizure with automatisms Non-dominant temporal lobe Ictal piloerection Ipsilateral hemisphere Amygdala Unilateral eye blinking Ipsilateral hemisphere Hippocampus Postictal aphasia Dominant hemisphere Postictal limb weakness Contralateral hemisphere Postictal nose wiping Ipsilateral hemisphere Fig. 27.3 (Also see Color plate 14.) Surgical resection and the epileptogenic zone. Copyrig ht Samden D. Lhatoo. a Sensitivities and speci \201 cities of individual manifestations vary. oxford textbook of epilepsy and epileptic seizures 294 Table 27.4 Neuroimaging investigations in epilepsy surgery Table 27.5 MRI in epilepsy surgery Technique Zone identi \201 ed MRI techniques Use MRI Epileptic lesion zone Standard epilepsy protocol MRI Identi \201 cation of structural abnormalities fMRI Eloquent cortex Voxel-based analysis Identi \201 cation of structural abnormalities EEG-fMRI Irritative zone Manual and automated hippocampal volumetry Identi \201 cation of hippocampal atrophy PET Functional de \201 cit zone DTI Identi \201 cation of structural abnormalities SPECT/SISCOM a Ictal onset zone Tractography Identi \201 cation of white matter tracts a SISCOM, subtraction Ictal SPECT co-registered to MRI fMRI Identi \201 cation of eloquent cortex EEG-fMRI Identi \201 cation of the irritative zone seizure) will be produced by epileptic activity in the contralateral thumb area of the moto r strip. A sudden bilateral asymmetric tonic posturing of the upper limbs indicates seizure symptoms arising from one of the supplementary sensorimotor areas, located in the mesial a spect of the frontal lobe just anterior to the motor strip. A complex partial seizure with prominent, early oral and distal upper limb automatisms usually suggests a temporal lobe se izure. A hyper motor seizure suggests a frontal lobe seizure, usually arising from the mesi al or orbitofrontal areas. The postictal period can also pro- vide clues to seizure localiz ation. Ictal and postictal localizing and lateralizing signs are detailed in Table 27. 3 . Pre and postsurgical image co-registration Identi \201 es positions of subdural and depth electrodes in patients undergoing epilepsy surgery radiation, primary motor, primary sensory, and language tracts may make the difference betw een the presence or absence of major postoperative de \201 cits. Functional MRI (fMRI) is based on the principle of cerebral blood oxygen level-dependent (B OLD) signal changes in response to activation of speci \201 c brain areas. Language testin g paradigms can provide a reliable, non-invasive means of lateralizing and local- izing exp ressive language (Broca \200\231s area); identi \201 cation of receptive language areas ma y not be as reliable. Motor activation fMRI and sensory activation fMRI can reliably identi fy motor and sensory cortices. EEG-fMRI is an investigation that combines the ability of EE G to provide information on electrophysiological changes very quickly (temporal resolution) , in the millisecond range, and the ability of MRI to provide very detailed spatial informa tion (in mil- limetres). When epileptiform spikes are analyzed using this tech- nique, info rmation on the source of these spikes can be obtained. This has not yet achieved widespread clinical utility but holds promise. Neuroimaging in epilepsy surgery A variety of neuroimaging techniques are used in epilepsy surgery. These help de \201 ne one or more zones and are extremely important to the presur gical work-up (Table 27. 4 ). MRI in epilepsy surgery Focal structural brain abnormalities are the usual cause of focal e pilepsies. Modern MRI techniques, vastly superior to CT scan- ning, have revolutionized epi lepsy surgery where identi \201 cation of a lesion renders the hunt for the epileptogenic zone much easier ( 6 ). There are several additional uses that further emphasize the impor- tance of this tool (Table 27. 5 ). 3 Tesla MRI scans have a distinct yield advantage over older 1 and 1.5 Tesla MRI scans; 7 Tesla machines which are now undergoing clinical evaluat ion may increase yield in previously \200\230lesion negative \200\231 cases. The use of su r- face coils, targeting brain regions identi \201 ed as abnormal by other investigations, e.g. EEG, can also contribute in identifying abnor- mal brain areas previously thought nor mal on standard MRI or better de \201 ning characteristics and extent of known abnormaliti es. It is important that MRI scans are carried out according to speci \201 c epilepsy prot ocols. These usually involve \201 ne cut (1 \200\2232 mm) images using volumetric T1-weig hted sequences, proton density T2-weighted sequences, fluid attenuated inversion recovery ( FLAIR) sequences, and gradient echo sequences in the oblique coronal and axial planes. An important function of MRI in epilepsy surgery is the co-reg- istration of pre- and posto perative brain images in order to de \201 ne the positions of electrodes in relation to br ain structures. This is done through specialized commercially available software pro- grams . Knowledge of the location of electrodes is important in identifying cortex from which sei zures arise and in identifying cortex where speci \201 c brain functions are located. PET in epilepsy surgery The main utility of PET is in the identi \201 cation of the functi onal de \201 cit zone in patients in whom there is no demonstrable struc- tural lesion. Th e standard PET ligand used is 18 F- \202 uorodeoxyglucose and imaging is carried out in th e interictal state to identify areas of hypometabolism. The sensitivity and speci \201 cit y of PET varies according to the brain region producing epilepsy. In temporal lobe epilepsy (see Chapter 28) in particular, there can be a close correla- tion between the areas of PE T abnormality, the epileptogenic zone, and surgical outcome. In extratemporal epilepsies, i t provides con- tributory information less often. In clinical practice, co-registering PET information with the patient \200\231s MRI scan can identify areas of abnormality previousl y missed when either investigation is used alone. Subtle gyral abnormalities due to malform ations of cortical development can become more evident. Voxel-based analysis of MRI scans can be helpful where visual analysis does not show abnorm alities. Diffusion tensor imaging (DTI) can show abnormal diffusivity in areas known to be epilep- togenic and so is a potential additional tool although it is not rou- tinely used i n clinical practice. Tractography is a technique used for imaging white matter tracts which standard MRI cannot. The direction of diffusion of water in each voxel determines the orie n- tation of the white matter tracts. It potentially has substantial clini- cal utility in surgical planning where information on the optic CHAPTER 27 principles of epilepsy surgery 295 EEG in epilepsy surgery Information from EEG is critical to the presurgical process without which epilepsy surgery is usually inadvisable and the outcome much less predictable. EEG p erforms two crucial functions \200\224 iden- tifying the irritative and ictal onset zones (Fig. 27. 2 ). Some patients have two or more potentially epileptogenic lesions (dual or mu lti- focal pathology). Identi \201 cation of the true focus or both foci as epileptogenic can usually only be achieved through EEG. As described in Chapter 9, EEG information is der ived from pro- longed video-EEG monitoring where a patient is admitted for sev- eral days o f continuous EEG recording under video surveillance in an epilepsy monitoring unit manned b y trained nurses and EEG personnel. The assessment is carried out using the standard scalp or surface electrode array (10 \200\22320 electrode system) although a denser array with mo re electrodes (the 10 \200\22310 system) is required in many cases. In many centers, specia l electrodes such as deep sphe- noidal electrodes are used. These sample EEG activity from the mesial and basal temporal lobes and are inserted under local anaes- thesia through the lateral face into the proximity of the foramen ovale in the skull base. Table 27.6 Some common indications for intracranial electrode studies High-resolution MRI does not show a lesion although other evidence suggests a single focus MRI shows two or more potentially epileptogenic lesions MRI shows large lesion and precise estimation of the ictal onset zone cannot be reliably ma de Discordance between investigations, e.g. MRI shows left hippocampal sclerosis, EEG shows ri ght temporal ictal onset zone Identi \201 cation of relationship between eloquent cortex and candidate epileptogenic zon e SPECT in epilepsy surgery In contrast to PET, this investigation is carried out in the icta l stage and so provides information on the ictal onset zone although in common with PET, it s greatest utility is in lesion-negative patients with focal epilepsy. Technetium 99-m is t he radiolabelled tracer used to identify areas of increased cerebral blood \202 ow or hyp erper- fusion. Testing has to be carried out under ideal conditions. A pre- ictal SPECT sca n establishes baseline. The tracer is injected within seconds of seizure onset. Injection a nd focal tracer uptake within 10 seconds of the start of the seizure is much more likely to indicate the area of seizure onset than an injection 60 seconds later when spread of the s eizure discharge makes the information much less meaningful. The seizure also has to be of suf \201 cient duration and a very brief partial seizure of less than 10 seconds is unlike ly to provide substantial information. Co-registration of the subtracted SPECT images to th e patient \200\231s MRI (SISCOM) can provide further anatomical information on the location of the seizure focus. Neither PET nor SPECT information independently make the case for su rgery in a particular brain area in lesion-negative epilepsy and it is usually advisable th at information from these investigations is used together with clinical and EEG information . EEG and the irritative zone Sharp waves seen in the interictal record indicate the irritati ve zone (Fig. 27. 4 ). There can be more than one irritative zone in unilateral hippocampal sclerosis (illustrative case in Fig. 27. 3 ) where two irri- tative zones produce both lef t and right sharp waves although all the other information available is concordant with a l eft mesial temporal epileptogenic zone and surgical resection of this area renders the pati ent seizure free. Simultanous recordings from depth electrodes inserted into both hippocamp i con \201 rm that both of these areas generate sharp waves independently and are not indi cative of spread from one to the other. Surface recorded sharp waves from more than one bra in region can indicate a multifocal, or tendency to multifocal, epilepsy. Sometimes, multip le irritative zones in the same hemisphere can indicate a unifocal epilepsy with Fig. 27.4 Surface EEG of a patient with left hippocampal sclerosis showing interictal left mesial temporal sharp waves (two boxes on left), maximum in the left sphenoidal recording e lectrode (Sp1) and a seizure starting in the same region (two boxes on right), suggesting b oth irritative and ictal onset zones in the left mesial temporal lobe. Copyright Samden D. Lhatoo. oxford textbook of epilepsy and epileptic seizures 296 to the number of electrodes implanted. Studies of the entire brain or even one whole hemisp here \200\224 so-called \200\230 \201 shing expeditions \200\231 are therefore inadvisab le and unlikely to succeed. either propagation of sharp wave discharges from a single deeper focus in different directi ons at different times or a change in the orientation of the focus (dipole) that generates the sharp wave dis- charge which is then seen in different brain regions at different times . In general, a single irritative zone is a good indicator that the epileptogenic zone is w ithin it. There are two main approaches to intracranial EEG studies: (1) the use of depth electrodes which are stereotactically implanted into the brain (stereo-EEG) and (2) the use of subdura l EEG elec- trodes which are placed on the brain surface, both targeting speci \201 c brai n areas. Each has its advantages and disadvantages and so centers that have expertise in bo th can use either technique according to the clinical situation. The ictal onset zone Seizures captured during video-EEG monitoring provide impor- tant semi ological clues as described earlier but also allow close examination of the EEG seizure rec ord. Analysis of the EEG onset often indicates the brain region that comprises the ictal on set zone which in turn is intimately related to the epileptogenic zone. The EEG onset can b e focal (Fig. 27. 4 ), more widespread but restricted to one hemisphere (lateralized), or g eneralized (non-lateralizable). In general, the more localized the EEG onset, the more prec ise the depiction of the ictal onset zone .