PRESURGICAL EVALUATION OF INTRACTABLE EPILEPSY

DR. PIYUSH OJHADM RESIDENT

DEPARTMENT OF NEUROLOGYGOVT MEDICAL COLLEGE, KOTA

• Epilepsy - among the most serious primary disorders of the brain

• Accounts for 1% of the global burden of disease• Pharmacotherapy unsuccessful in controlling seizures in 20–

40% of patients (Berg, 2004)• 80% of the cost of epilepsy in the USA is accounted for by

patients with medically intractable seizures (Begley et al., 2000).

• Temporal lobe epilepsy (TLE) - Most common cause of pharmacoresistant seizures.

• Also TLE - Epilepsy most easily and effectively treated with surgery; 60–80% of these patients become free of disabling seizures.

• Drug resistance – reassessment of diagnosis of epilepsy adviced.

• Pharmacoresistant Epilepsy has severe consequences :– interference with school and work– loss of independence and social isolation and– increased risk of injury, depression and suicide

• Uncontrolled temporal lobe epilepsy - associated with slowly progressive cortical atrophy and cognitive deterioration.

• Patients with uncontrolled epilepsy also have a significantly increased long-term mortality rate (1.59% per year), with sudden unexpected death in epilepsy (SUDEP) being the most common cause.

• For selected patients, resection of epileptogenic brain has a far better chance of controlling drug-resistant seizures than further medication trials.

• Class I evidence for the efficacy of temporal lobectomy.

• Evidence that successful neurosurgical treatment reverses much of the disability and increased mortality associated with chronic epilepsy.

• Wiebe et al (2001) randomized patients (>16 years) who failed to respond to treatment with two or more anti-epileptic AEDs to medical or surgical arms.

• Randomization occurred only if they were considered as good surgical candidates.

• After 1 year of entry into the study, 58% in the surgical group had significant reduction as compared with 8% in the medical group (which had received the best possible medical therapy).

• Percentage of patients in the surgical group who experienced no seizures at all was 38%, vs 3% in the medical group.

• For those patients who are referred for surgery, there is an average duration of 22 years between onset of epilepsy and referral (Berg et al., 2003).

• American Academy of Neurology (AAN) Practice Parameter concluded that surgery is the treatment of choice for medically intractable TLE.

• Consensus definition of Drug-resistant epilepsy by the International League Against Epilepsy (Kwan et al., 2010).

• Drug resistance – defined as failure of adequate trials of two tolerated and appropriately chosen and used AEDs to achieve sustained seizure freedom for a sufficiently long period of time.

• A sufficiently long period of time is operationally defined for an individual patient as three times the longest inter-seizure interval for that patient, or 1 year, whichever is longer.

• Factors that may suggest sustained intractability, and thus support early surgery (Langfitt and Wiebe 2008) :-

– Lower efficacy towards first appropriate AED– Larger number of medications (even with high doses)

tried, with all causes of Pseusoresistance ruled out (Non-epileptic events, syndrome inappropriate medications)

– Longer duration of seizures– History of status epilepticus– Mental retardation and – Non-idiopathic epilepsy

• Surgically remediable epilepsy syndromes – identified pathophysiological and anatomic substrate with a known poor prognosis given failure of a few appropriate AEDs, but a demonstrated excellent prognosis with surgical therapy (Engel, 1996).

• Many cases these conditions are progressive, causing developmental delay in infants and small children, and behavioral disturbances in adolescents and adults.

• Early surgical intervention can avoid permanent disability. • Surgical treatment more cost-effective in these conditions

because, mostly, they can be evaluated noninvasively, and surgical outcome, by definition, is excellent.

• The prototype of a surgically remediable syndrome is Mesial temporal lobe epilepsy, which usually, but not always, is due to hippocampal sclerosis.

• Other examples of surgically remediable syndrome (Harvey et al., 2008) :– Discrete resectable structural lesions of neocortex– Diffuse lesions limited to one hemisphere such as

hemimegencephaly, Sturge–Weber syndrome, and large porencephalic cysts

– Rasmussen’s encephalitis– Gelastic seizures associated with hypothalamic

hamartomas.

• A focus group study assessing attitudes toward early epilepsy surgery found that some patients tend to have a preference for nonsurgical management of chronic problems, and to overestimate the risks and underestimate the benefits of epilepsy surgery (Swarztrauber et al., 2003).

• In addition, it has been demonstrated that physicians’ perceptions about patients and about therapies influence the type and amount of information they convey to patients, and contribute to the patients’ final decision to undergo a treatment (Katz, 2001).

• Earlier surgery is better from the clinical, psychosocial, and economic viewpoints (Engel, 2008).

• Patients who are typically not surgical candidates include:-– Clear evidence of bilateral onset of seizures – those with severe psychiatric or medical comorbidities

increasing surgical risk or compromising recovery– those with rapidly progressive CNS disease, and – those with primary generalized epilepsy.

• It is important to understand that an appropriate selection of a person having drug resistant epilepsy (DRE) is mandatory.

• Presurgical work-up is time and labor-intensive and has cost

implications.

• All patients with DRE may not be surgical candidates.

• In a study by Selwa et al. (2003), continued changes in AED regimen rendered about 20% of patients who were not candidates for epilepsy surgery seizure free at 4-year follow-up.

Many different surgical therapies available for epilepsy, depending on the type of epileptic seizures and the nature and location of the epileptogenic lesion.

PRESURGICAL EVALUATION• GOAL :- (1) Localize the epileptogenic zone. (2) Identify incongruent evidence that may indicate the need for

additional tests including invasive EEG, and (3) Determine whether planned surgical resection poses risk to

cerebral functions.

• The Epileptogenic zone :- zone whose resection is necessary and sufficient to eliminate seizures (Lüders, 2008; Rosenow and Lüders, 2001).

• This zone cannot be directly defined by any test but can be estimated by a number of other zones.

The Ictal onset zone (Seizure onset zone or Pacemaker zone):- • Area of cortex that is generating seizures (Carreño 2008). • This zone, if accurately defined, is contained within the

epileptogenic zone and smaller than the epileptogenic zone.• Thus it is possible that seizures start in a section of the

epileptogenic zone, but other parts of that zone are able to take on the function of seizure generation once the ictal onset zone is removed.

• Identifying and defining the ictal onset zone challenging, as the earliest detected ictal activity may have already undergone considerable spread.

• Even with Intracranial EEG recording, the ictal onset zone may be missed unless the electrodes placed directly over that zone.

The Irritative zone :- • Zone that generates interictal epileptiform discharges. • Usually localized within the epileptogenic zone. • However, in some cases there may be multiple irritative

zones, only one of corresponding to the epileptogenic zone.

The Ictal symptomatogenic zone :- • Region that produces the seizure manifestations. • This zone may be more valuable for lateralization than exact

localization, because most likely that seizures will spread within the hemisphere of origin before spreading to the contralateral hemisphere.

• However, this is not always the case.

The Epileptogenic lesion :- • Structural brain abnormality that is presumed to be the cause

of the epilepsy and usually identified on MRI. • The relationship of the epileptogenic lesion to the seizure

onset zone is variable. • Some lesions such as cortical dysplasia or hypothalamic

hamartoma are intrinsically epileptogenic, and seizures may arise from within the lesion.

• On the other hand, seizures usually arise from brain surrounding cavernous malformations and benign tumors.

• Certain lesions may be accidental findings and not necessarily related to the epilepsy. Eg. Arachnoid cysts and venous malformations.

The Functional deficit zone:- • Responsible for functional deficits.

• Can be measured in a variety of ways including neurological examination, neuropsychological testing, interictal EEG focal attenuation and slow activity, local glucose uptake by PET, or local cerebral blood flow by interictal PET with [15-O]H2O or interictal SPECT.

• While the functional deficit zone may include the epileptogenic zone, it is often considerably larger.

SURGICAL EVALUATION• Upon referral, the patient undergoes :

– Detailed neurologic history and examination– Neuroimaging– Video-EEG monitoring, and – Neuropsychological testing.

NEUROLOGIC HISTORY• Identifying specific risk factors in the history can help predict

the epileptogenic lesion.

• For example, a history of febrile status epilepticus in infancy has a strong correlation with the pathology of hippocampal sclerosis (Cendes et al., 1993).

• Meningitis and encephalitis occurring prior to age 5 also associated with temporal lobe epilepsy and hippocampal sclerosis, whereas the same risk factors occurring after age 5 appear to predict neocortical epileptogenic zones (Marks et al., 1992).

• Earlier head trauma may also predict hippocampal sclerosis.

• The description of the seizure aura and other early seizure semiology helps with the localization of Ictal symptomatogenic zone.

• The description of seizure semiology by witnesses is also helpful, particularly for lateralization.

• Analysis of video-EEG recorded seizure semiology supersedes the description provided by witnesses for the purpose of localization and lateralization.

• Neurological examination can identify focal neurological deficits – define the functional deficit zone, but often is noncontributory.

EEG & VIDEO-EEG MONITORING• Cornerstone of the presurgical evaluation. • The interictal focal attenuation and focal slow activity -

Functional deficit zone• Interictal epileptiform discharges – define the irritative zones• Electrographic localization of seizure onset helps define the

ictal onset zone. • Important to recognize that what appears to be the initial

localization of the ictal discharge may represent seizure activity propagated from a distant location not directly accessible to EEG electrodes.

• Additional closely spaced electrodes may help such as anterior temporal electrodes, sphenoidal electrodes, zygomatic electrodes, or cheek electrodes.

• The analysis of seizure semiology by video-EEG provides several localizing and lateralizing signs that help define the ictal symptomatogenic zone (Loddenkemper and Kotagal, 2005).

• Eg. Early head turning in temporal lobe epilepsy tends to be ipsilateral to the seizure focus, and late head turning preceding secondary generalization tends to be contralateral.

• Lip smacking and other oroalimentary automatisms characteristic of temporal lobe involvement.

• Extremity dystonic posturing is a strong contralateral lateralizing sign.

• Unilateral eye blinking tends to be ipsilateral to the seizure focus (Benbadis et al.,1996).

• Well-formed ictal speech – indicative of nondominant temporal lobe involvement

• Postictal aphasia suggests dominant temporal lobe involvement.

• Ictal vomiting, ictal spitting, ictal drinking, and postictal urinary urgency - associated with right temporal lobe origin, exceptions reported.

MRI• A high-resolution MRI crucial for definition of the

epileptogenic lesion.

• For optimal detection of MTS, MRI should include oblique coronal images perpendicular to the axis of the hippocampus, including T1-W, T2-W and FLAIR

• These images should ideally have a slice thickness of at most 1.5 mm.

• The importance of Neuroradiology expertise and optimal MRI is demonstrated by a study where (n =123) standard MRI interpreted by nonepilepsy-trained neuroradiologists revealed focal lesions in only 39% of the cases, whereas the images analyzed by epilepsy-trained neuroradiologists showed focal abnormalities in 91%.

• With respect to prediction of a neuropathologic diagnosis, only 22% of cases imaged via standard MR and analyzed by nonepilepsy-specialist radiologists were correct, as opposed to 89% imaged via epilepsy-protocol MR and interpreted by epilepsy-specialist neuroradiologists.

Von Oertzen J et al : Standard magnetic resonance imaging is inadequate for patients with refractory focal epilepsy. J Neurol Neurosurg Psychiatry 2002;73:643-7

Positron Emission Tomography (PET)• Uses positron-emitting isotopes to image metabolism,

perfusion, synthesis of neurotransmitters, and receptor density.

• Requires a cyclotron on site -> so PET availability has been relatively limited to major academic centers.

• Most commonly used ligand - 18 F-FDG – allows imaging of glucose uptake/metabolism in the brain.

• Almost always an interictal study; ictal PET difficult to plan. • FDG-PET defines the functional deficit zone. • 80% patients have a discrete region of hypometabolism -> has

a good correlation epileptic focus in Temporal lobe epilepsy. • PET hypometabolism has a greater correlation with the ictal

onset zone than scalp EEG-defined ictal onset.

• FDG-PET particularly useful in patients without MRI abnormalities.

• Identification of temporal hypometabolism corresponding to well-localized electrographic ictal onset and interictal epileptiform activity on EEG may permit sufficient confidence to proceed with epilepsy surgery without invasive monitoring (Carne et al., 2004).

• FDG-PET can be misleading in some patients with extratemporal epilepsy, showing temporal hypometabolic zones

• As with other diagnostic techniques, FDG-PET cannot be used in isolation.

• PET using Flumazenil images central benzodiazepine receptor density.

• Zones of decreased BZD receptor density are smaller than, and encompassed in, areas of hypometabolism by FDG-PET.

• Greater specificity for the ictal onset zone.

• In addition, flumazenil PET may identify heterotopic neurons not visible on MRI.

• PET scanning using 11 C-α-methyl-l-tryptophan(AMT) images serotonin synthesis and helpful in identifying the epileptogenic tuber in patients with tuberous sclerosis.

Single-Photon Emission Computed Tomography (SPECT)

• Widely available and less expensive than PET. • Interictally, regions of reduced metabolism also tend to have

reduced blood flow, but interictal SPECT is less sensitive than interictal FDG-PET and therefore is not widely used.

• Main benefit of SPECT is ictal imaging. • Ligand injected I/V at the very onset of seizures, greater

uptake is noted in the ictal onset zone. • If injection is late, the focal hyperperfusion may represent

seizure propagation.

Magnetic Resonance Spectroscopy (MRS)

• Most commonly measured substances are NAA – localized in neurons and decreased with neuronal injury, and creatine and choline, which are increased with gliosis and increased membrane turnover.

• The NAA to creatine ratio - highly sensitive in detecting mesial temporal structural and functional abnormalities.

• Ratio decreased in abnormal regions. • The ratio improves contralaterally with successful epilepsy

surgery (Kuzniecky et al., 2001).

Magnetoencephalography (MEG)• Electric currents on the scalp that serve as the basis for EEG

also produce magnetic fields that can be measured with magnetoencephalography (MEG).

• Advantage over EEG in that magnetic signals are not distorted by differences in conductivity between the brain, skull, and scalp.

• MEG does not detect pure hippocampal spikes but can detect propagated spikes, and the dipole orientation helpful to distinguish mesial from lateral sources.

• MEG appears slightly more sensitive for convexity neocortical sources than EEG, detecting sources involving 3 to 4 sq cm of cortex as opposed to 6 sq cm of cortex for the EEG.

• Neuropsychological testing establishes baseline measurements of any cognitive deficits, sometimes giving insight into the epileptic focus location.

• Also allows comparison with postoperative testing to measure cognitive outcomes.

• Predictors of higher risk of cognitive decline after temporal lobectomy :-– Dominant temporal lobe resection– Later age of epilepsy onset– Normal MRI results– Female gender and – Loss of memory function during injection of amobarbital

into the carotid artery on the side of planned surgery (Wada test)

INVASIVE VIDEO EEG MONITORING• Performed when noninvasive testing suggests a resectable

epileptic focus with some uncertainty. • Invasive video-EEG can also more precisely delineate the

extent of a neocortical epileptogenic zone and its relationship to areas of eloquent functional cortex.

• Arrays of disk electrodes embedded in sheets or strips of silastic are usually subdurally implanted.

• Depth electrodes can also be inserted into the brain, typically to record from deeper structures.

• Monitoring occurs in the patient’s room over several days to localize typical seizures.

• Following are examples of instances that may require Invasive intracranial monitoring:

1. Seizures are lateralized but not localized (e.g., a left-sided, widespread frontal–temporal onset). Seizures are localized but not lateralized (e.g., ictal EEG patterns that appear maximally over both temporal lobes).

2. Seizures are neither localized nor lateralized (e.g., stereotyped complex partial seizures with diffuse ictal changes or initial changes obscured by artifact).

3. Seizure localization is discordant with other data. [e.g., EEG ictal scalp data discordant with neuroimaging (MRI, PET, SPECT) or neuropsychological data].

4. Relationship of seizure onset to functional tissue must be determined (e.g., seizures with early involvement of language or motor function).

5. Relationship of seizure onset to lesion must be determined (e.g., dual pathology or multiple intracranial lesions).

6. If seizures are clinically suspected but video-EEG is inadequate for defining them [e.g., simple partial seizures with no detectable scalp EEG ictal discharge or suspected epileptic seizures with unusual semiology that suggests psychogenic seizures (pseudo seizures)]

FUNCTIONAL LOCALIZATION• Defining speech and language dominance for temporal and

some frontal resections is necessary.

• In addition, eloquent cortices essential for language, motor, or sensory functions must often be delineated so resection can be tailored to avoid causing deficits.

• The intracarotid amobarbital procedure - best validated method of determining the speech dominant hemisphere and can also assess risk of postoperative memory deterioration after temporal lobectomy.

• Amobarbital is injected into the internal carotid artery, temporarily disrupting function on that side, while language and memory tests are performed.

• In addition, functional MRI and magnetoencephalography are being developed as alternatives for lateralizing or localizing temporal language function.

• Although functional MRI can be used to locate functional neocortex and associated connections, the standard approach in epilepsy surgery is mapping by electrical cortical stimulation.

• This can be carried out intraoperatively (during brief period of wakefulness during the operation) or at bedside with the same subdural electrodes used for invasive EEG monitoring.

• Mapping of temporal language cortex then is done with the patient naming objects displayed on a computer screen while the physician systematically maps cortex by stimulating various brain regions.

COMMON SURGICALLYTREATABLE EPILEPSY SYNDROMES

Mesial Temporal Lobe Epilepsy• Most common surgically treated epilepsy, with efficacy of

lobectomy demonstrated in trials.• Seizures often begin with rising epigastric sensations, smells,

fear, deja vu or jamais vu, and progress to loss of responsiveness, often with behavioral arrest, orofacial automatisms, ipsilateral hand movements, and contralateral arm posturing.

• Most common associated pathology is MTS.• May be associated with a history of early-life febrile seizures

or neurologic insult• Pathologically characterized by hippocampal neuronal loss in

CA1 and CA3 as well as the dentate granule cell layer.

• Identical seizures can result from mesial temporal tumors, vascular malformations, and dysplasia.

• A few MTS patients have a second, ipsilateral cortical focus (ie, ‘‘dual pathology’’), with better surgical outcome if the second focus can also be resected.

• MC surgical procedure for MTLE is the anterior temporal lobectomy.

• Alternate techniques to amygdalohippocampectomy.• Radiosurgery and MRI-guided laser ablation of the

hippocampus are also being investigated as alternative approaches to treat hippocampal epilepsy while reducing injury to other nearby temporal structures.

NEOCORTICAL EPILEPSY :-• The clinical manifestations depend on the region involved.• Lateral temporal lobe seizures - more likely to have

experiential auras and less likely to have epigastric auras and contralateral dystonia.

• Frontal lobe seizures - tend to be shorter and more frequent than temporal lobe seizures, with manifestations varying from motionless staring to violent automatisms, and often may be confined to sleep.

• Parietal and occipital seizures - often have complex sensory symptoms such as visual hallucinations of objects or scenes.

• Convulsive seizures are more common with neocortical epilepsy.

• With neocortical foci, invasive monitoring is usually required for adequate localization and tailoring of the resection to spare eloquent cortex.

• Surgical procedures range from :-– Topectomy (ie, removal of cortex while sparing underlying

white matter)– Lesionectomy with removal of adjacent epileptogenic

cortex– Lobar and multilobar resections.

EPILEPSY DUE TO TUMORS• Benign or low-grade neoplasms such as meningiomas,

gangliogliomas, DNETs, astrocytomas, and oligodendrogliomas may cause chronic but surgically remediable epilepsy.

• Goal - completely remove the lesion and the surrounding epileptogenic brain, if possible.

• Sometimes invasive monitoring with mapping of the seizure-onset region and of brain function is needed.

THANK YOU

REFERENCES• Bradley’s Neurology in clinical practice 6th edition• Adams & Victor’s Principles of Neurology 10th edition• Epilepsy : who is a surgical candidate ? : Handbook of Clinical

Neurology, Vol. 108 (3rd series) :Epilepsy, Part II• Continuum Review Article : Surgical Treatment of Epilepsy :

2013• Epilepsy Surgery Recommendations for India : P. Sarat

Chandra : Ann Ind Acad Neurol 2010

CASE 1• 44-year-old, right-handed man • Cryptogenic epilepsy since age 18• Weekly seizures refractory to eight antiepileptic drug trials• Mainly Nocturnal seizures (made noises, thrashed, and

wandered around), and with infrequent convulsions.• Scalp EEG - independent left and right anterior temporal

epileptiform abnormalities in equal proportions, and three seizures with right anterior temporal ictal EEG changes.

• Repeat EEG - captured three left temporal seizures and a right temporal seizure with different semiology.

• MRI - Normal• SPECT(during a seizure) - Right temporal EEG changes showed

right temporal hyperperfusion.

• While this patient has focal onset epilepsy, there is no clear evidence all seizures are arising from a single focus (in fact,the data suggest otherwise).

• Normal MRI results do not provide any evidence to localize the seizures.

• EEG indicates that the seizures arise independently from the right and left temporal lobe.

• This patient is Not a surgical candidate since only unilateral resections can be safely performed.

• Bilateral mesial temporal lobe resection or injury may lead to devastating global amnesia.