Temporal lobe epilepsy

Temporal lobe epilepsy

1. Temporal lobe epilepsy Siva Pesala MD  Department of Neurology

2. Epilepsy “A condition characterized by two or more recurrent epileptic seizures over a period longer than 24 hours, unprovoked by any immediate identified cause”.  Ref-Jacobs et al., 2001

3. ILAE 2017 TLE

4. Temporal lobe epilepsy -Introduction The temporal lobe is the most epileptogenic region of the human brain. Hippocampal sclerosis (HS) is the commonest cause of TLE. It is estimated that it represents about 40% of all epilepsies in adult people. Tatum 2012- J Clinical neurophysiology, Cendes , 2005 & Blair, 2012

5. Epidemiology   Per available epidemiological data on TLE, the Incidence rate was 10.4 per 100,000 and the prevalence was 1.7 per 1000 people . They represent approximately two third of the intractable seizure population requiring surgical management. Hauser & Kurland, 1975, (Spencer & Spencer, 1985; Semah et al., 1998).

6. Types of TLE The ILAE (Commission on classification and terminology of the ILAE, 1989) recognizes two syndromes. Mesial temporal lobe epilepsy( most frequent) Lateral or neocortical temporal epilepsy (NTE )

7. Mesial temporal lobe epilepsy M ost common form of partial epilepsy in adolescents and adults. These patients usually have known risk factors such as perinatal injury, CNS infection , FS, head trauma, and fam h/o of epilepsy . Up to 60% of patients with MTS may have a previous history of FS before developing seizures . Cendes 2004-2005 ; French et al.,1993 & Tatum 2012

8. Mesial temporal lobe epilepsy- Seizure pattern The typical aura is an indescribable rising epigastric sensation, often described as butterflies and followed by staring, behavioral arrest and oroalimentary or hand automatisms, accompanied by autonomic phenomena as pupillary dilatation, hyperventilation, piloerection, and tachycardia . Contralateral dystonic posturing with ipsilateral automatisms during the seizure are reliable lateralizing signs . Acharya et al., 1998, Thompson et al., 2000 ; Tatum, 2012 .

9. Mesial temporal lobe epilepsy Typically, by the end of the first or second decade, patients present with their first complex partial seizure, although it may be a simple partial or a generalized seizure. Afterwards, some patients remain seizure-free for variable periods that range from one to two decades, or even longer (honeymoon-period) . Seizures restart as adults .

10. TLE can be associated with a magnetic resonance imaging (MRI) lesion or be non- lesional .

11. Lesional TLE Hippocampal sclerosis Benign tumors – Gangliglioma , DNET. Vascular malformations Cortical development malformations Post traumatic/Post infectious gliosis Woermann & Vollmar , 2009 & Cendes 2005

12. Etiology  -Pathophysiology HS is the most common cause of TLE, representing greater than 80% of cases. It is a combination of atrophy and astrogliosis of the hippocampus , amygdala, uncus , parahipocampal gyrus, and the entorhinal cortex.   S elective neuronal loss that affects various sectors to a different degree. Tatum 2012- J Clinical neurophysiology

13. HS -Macroscopic Source: Wiki

14. Etiology -Pathophysiology The most vulnerable to damage : CA1 (Sommer’s sector) and CA3-CA4 ( endfolium )- CA2 pyramidal and dentate gyrus granule cells are most seizure resistant . The majority of hippocampal specimens also reveal alterations within the dentate gyrus, i.e., granule cell dispersion.  Cendes , 2004 & 2005

15. Hippocampal microanatomy Cresyl -violet and Luxol -Fast-Blue staining of a postmortem human hippocampus SUB, subiculum CA1 –CA4, sectors of the Cornu ammonis DG , dentate gyrus HF , remnant of hippocampal fissure ALV , alveus FIM , fimbria. Blumcke 2013

16. ILAE - HS Blumcke 2013 = no obvious neuronal loss or moderate astrogliosis only. 1 =moderate neuronal loss and gliosis 2=severe neuronal loss and gliosis

17. HS-ILAE Type 1 Blumcke et al.,  2013 ILAE hippocampal sclerosis type 1 shows pronounced preferential pyramidal cell loss in both CA4 and CA1 sectors. This is the most common type of HS. The CA1 segment is most severely affected (with >80% cell loss;). Other segments also show significant neuronal cell loss , affecting 30–50% of pyramidal neurons in CA2, 30–90% of neurons in CA3, and 40–90% of neurons in CA4. The dentate gyrus (DG) is usually affected by 50–60% granule cell loss. Note variable cell loss also in the dentate gyrus . NeuN immunohistochemistry with hematoxylin counterstaining using 4-μm–thin paraffin embedded sections

18. HS-ILAE Type 2 Blumcke 2013 CA1 predominant neuronal cell loss and gliosis.

19. HS –ILAE Type 3 Blumcke 2013 CA4 predominant neuronal cell loss and gliosis

20. HS-ILAE Type 4 Blumcke 2013 No hippocampal sclerosis .

21. Etiology -Pathophysiology Granule cell dispersion may be associated with early seizure onset or status epilepticus at an initial stage of the disease. MTS can occur in combination with a second temporal lobe epileptogenic pathology such as - cortical dyslamination (i.e., Focal Cortical Dysplasia type I ) ectopic white matter neurons low-grade glioneuronal tumors. Blümcke , 2008

22. Etiology -Pathophysiology The most common types of extra-hippocampal lesions found in dual pathology are cortical dysgenesis gliotic lesions Volume loss is present in ipsilateral thalamus, caudate, and amygdala in mesial TLE, and thalamic cell loss is present in epilepsy patients . Cendes et al., 1995 & Spencer, 2002b

23. Importance of HS classification   HS ILAE type 1 is more often associated with a history of initial precipitating injuries before age 5 years , with early seizure onset, and favorable postsurgical seizure control . CA1 predominant HS ILAE type 2 and CA4 predominant HS ILAE type 3 have been studied less systematically so far, but some reports point to less favorable outcome. Blümcke I, et al. Epilepsia . 2013.

24. Neocortical Temporal Epilepsy NTE has a different clinical profile than mesial epilepsy. A history of FS, CNS infection, perinatal complications or head injury is less common than in patients with MTS. Seizures in patients with NTE appear five or ten years later than in MTS. Gil -Nagel & Risinger , 1997, O'Brien et al., 1996; Maillard et al., 2004; Kennedy & Schuele , 2012

25. Neocortical Temporal Epilepsy Around 60% of seizures are preceded by an aura, such as auditory phenomena, psychic experiences or déjà vu and jamais vu, visual distortions, and vertiginous symptoms. Motionless staring and unresponsiveness are the first objective clinical signs, often followed by early contralateral clonic movements and secondary generalization .

26. Familial Autosomal Dominant Lateral Temporal Lobe Epilepsy ( Autosomal Dominant Focal Epilepsy with Auditory Features)   Age at onset: Teenage or early adult hood Genetics: Autosomal dominant with high(80%) penetrance Mutations : LG1( leucine -rich, glioma-inacivated ) / Epitempin gene on Chromosome 10 Q Clinical sx : Simple focal seizures that are most common consist of simple auditory hallucinations ( ringing, humming, clicking) Infrequently progress into CP seizures and GTC .

27. Mesial vs Neocortical Loddenkemper & Kotagal , 2005; So, 2006; Jan & Girvin , 2008; Noachtar & Peters, 2009; Foldvary -Schaefer & Unnwongse , 2011

28. Mesial vs Neocortical Loddenkemper & Kotagal , 2005; So, 2006; Jan & Girvin , 2008; Noachtar & Peters, 2009; Foldvary -Schaefer & Unnwongse , 2011

29. Aura Auras are usually subjective symptoms with no objective signs. This lasts for seconds up to minutes, although they can be seen in isolation as well. Aura itself is a simple partial/focal aware seizure. Noachtar & Peters, 2009

30. Abdominal aura Most common type of autonomic aura. An indescribable unpleasant feeling in the peri -umbilical area that can be static, or ascend to the chest and throat , and can also descend into the lower abdominal region . Often accompanied by nausea . Thompson et al. , 2000; Foldvary -Schaefer & Unnwongse , 2011, Noachtar & Peters, 2009

31. Psychic aura Psychic auras consist of fear , anxiety , distortions of familiarity ( déja ̀ vu, jamais vu ) and multisensory hallucinations. Fear is a limbic aura, considered to be amygdaloid in origin. (Primary fear) Noachtar & Peters, 2009, Ebner , 1994, Jan & Girvin , 2008, Elliott et al. , 2009b .

32. Olfactory aura Noachtar & Peters, 2009; Foldvary -Schaefer & Unnwongse , 2011, Chen et al 2003, Jan&Girvin 2008 C lassically described, as “ uncinate fits ” are typically unpleasant smells, often associated with gustatory phenomena. Although historically these are typical auras, they are rare phenomena occurring in only 5% of TLE patients . Gustatory auras are even less common than olfactory auras , and are highly suggestive of a temporal onse t .

33. Auditory aura Auditory auras usually manifest as auditory hallucination such as sounds, which are generated by activation of the Heschl’s gyrus . Complex auditory hallucinations , such as hearing voices or tunes, can also occur. Noachtar & Peters, 2009; Foldvary -Schaefer & Unnwongse , 2011, Chen et al 2003, Jan&Girvin 2008

34. Other aura Noachtar & Peters, 2009; Foldvary -Schaefer & Unnwongse , 2011, Chen et al 2003, Jan&Girvin 2008

35. Automatisms Automatisms are repetitive, involuntary, purposeless movements that are usually inappropriate , but occasionally may simulate relatively normal events. Oro-alimentary automatisms, consisting of lip smacking, sucking, swallowing or chewing movements , along with gestural automatisms such as picking or fumbling movements are suggestive of TLE . Jan & Girvin , 2008

36. Automatisms Non lateralizing automatisms Oral automatisms- Temporal/Hippocampal Dacrystic seizures- Temporal/Hippocampal/Hypothalamic Speech changes Ictal speech arrest-Temporal Post ictal dysphasia and aphasia- Temporal-Dominant Vocalization- Frontal Jan & Girvin , 2008

37. Lateralizing signs- Ipsilateral Ipsilateral signs Unilateral hand automatism- Temporal Early nonforced head turn - Temporal Postictal nose wiping- Temporal Unilateral eye blinking- Temporal Jan & Girvin , 2008

38. Lateralizing signs- Contralateral Contralateral signs - Unilateral emotional face alteration- Temporal mesial, frontal , Insular Unilateral dystonic/ tonic posturing- Temporal/frontal Unilateral clonic movements- Frontal Figure of 4 sign (70 % temporal and 30 % extratemporal ) Ictal hemiparesis & postictal hemiparesis- Frontal Late contraversive force head turn- Frontal ( Broadmann 6 area) or temporal

39. Work up Initial work up : EEG & MRI Work up for refractory seizures / Presurgical work up: Phase I –Video EEG Imaging- PET, SPECT Neuropsych testing Wada testing Phase 2 Invasive monitoring- Subdural grids/Depth electrodes

40. Surface EEG and Video EEG S urface EEG recordings are less sensitive than invasive studies. First EEG is abnormal in only 30-50% of seizure patients Serial EEG (by the 3 rd ) raise the sensitivity to 80-90% Sensitivity can be increased by: Sleep deprivation- IED (inter ictal epileptiform discharges) IED are activated after seizure Anterior temporal electrodes, sphenoidal electrodes or closely placed electrodes Longer duration of scalp EEG Noachtar & Rémi , 2009

41. Video EEG Video -EEG allows increasing the likelihood of detecting interictal epileptiform activity, as well as allowing visual analysis of seizure.

42. Interictal findinings Lateralized arrhythmic (irregular) delta activity may be found in up to 66% of patients with TLE and is highly concordant with temporal spiking . Temporal intermittent rhythmic delta activity (TIRDA) is a more specific and accurate interictal indicator of TLE . TIRDA consists of trains of rhythmic delta activity lasting 4- 20 seconds . It is related with epilepsy in 80% of cases . Koutroumanidis et al. , 2004, Geyer et al. , 1999; Jan et al. , 2010, Geyer et al. , 1999, Javidan , 2012

43. Interictal -TIRDA Javidan 2012 - Hindwai   Repetitive , rhythmic, saw-toothed or sinusoidal Predominantly over the anterior temporal region Short bursts or trains of 3 seconds or more Temporal Intermittent Rhythmic Delta Activity (TIRDA) recorded in a patient with left temporal lobe epilepsy

44. Interictal -Sharp wave Javidan 2012 – Hindwai , erles et al. , 1998; Noachtar & Rémi , 2009).   29 -year-old woman with history of complex partial seizures. Scalp EEG demonstrates sharp waves over F7- T3. The classic interictal EEG abnormality of mesial TLE is a spike or sharp wave , which usually are electronegative waves over the anterior temporal region (F7/F8 ). Mid temporal (T3/T4) and posterior temporal (T5/T6 ) spikes or sharp waves are more likely to originate from the temporal neo- cortex . Interictal spikes predict the epileptogenic focus with a probability greater than 95% . Patients with TLE frequently have interictal epilepti form discharges independently in both temporal lobes .

45. Ictal EEG pattern The Type I is characterized by rhythmic 5-9 Hz theta activity that slowly evolves and remains localized to the temporal or sub-temporal regions. It is the most specific pattern for seizures originating from the hippocampal areas . The type II is characterized by rhythmic slow activity (2-5 Hz) with widespread temporal distribution. It is frequently associated with neocortical seizures . The type III is characterized by diffuse ictal EEG changes or attenuation without clear lateralization. This pattern can be seen in hippocampal and temporal neocortical seizures Ebersole & Pacia , 1996

46. Scalp EEG On the left: A coronal T2-weighted 3T MRI section shows reduced hippocampal volume and increased signal, consistent with left mesial temporal sclerosis. On the right: scalp EEG recording shows interictal epileptiform activity on the left anterior temporal region (maximum at F7 electrode). Abundant spikes over the left temporal region, maximum at F7-T3 with spread to T5 electrode.

47. Scalp EEG Scalp EEG recording showing lateralized ictal rhythmic 7 Hz activity, maximally at F7 Ref:Lady D. Ladino, Farzad Moien-Afshari and José F. Téllez-Zenteno

48. Intracranial recording The main purpose of intracranial recording is to delineate the area of onset and early propagation of a seizure. M ain reasons for invasive recordings : S eizures lateralized, but not localized D iscrepancy between electrographic seizure location and the rest of the data (e.g. location of lesion on imaging) seizures localized in eloquent cortical areas Lady D. Ladino, Farzad Moien-Afshari and José F. Téllez- Zenteno 2014

49. Advantages of intracranial recording Better spatial resolution I ncreased sensitivity N o attenuation from scalp and skull R educed ictal electromyographic artifacts Providing the option of cortical stimulation Lady D. Ladino, Farzad Moien-Afshari and José F. Téllez- Zenteno 2014

50. Intracranial recording Ultimately, the localization is achieved by combining the data from invasive monitoring with a detailed analysis of the clinical semiology, and the information obtained from the video-EEG monitoring and other tests such as MRI, SPECT or PET. Ref:Lady D. Ladino, Farzad Moien-Afshari and José F. Téllez-Zenteno

51. Intracranial recording Currently, subdural electrodes are the most common invasive method used in the United States. http:// www.annalsofian.org /

52. Intracranial recording Despite the high spatial resolution provided by the subdural methodology, relatively deep epileptogenic foci cannot be sampled.

53. Subdural vs d epth electrodes http:// www.annalsofian.org /

54. Depth electrode

55. Depth electrode Depth electrodes or stereo-electroencephalography is a safe and accurate procedure for invasive assessment of the epileptogenic zone. A llows direct electrical recording from deep -seated brain structures, providing essential information in the most complex cases of DRE . Allows sampling from deep zones such as, amygdala, hippocampus, entorhinal cortex, and insular cortex . Cardinale et al. , 2012

56. Depth electrodes On the left: at the top coronal Fluid-attenuated inversion recovery (FLAIR) 3T MR, at the bottom axial FLAIR 3T MRI. Both sequences showing bilateral implanted depth electrodes . On the right: at the top intracranial EEG recording showing ictal lateralized fast activity (12Hz), maximally at RPH3-4 (Right Posterior Hippocampus) , at the bottom there is ictal lateralized fast activity (16Hz), maximally at LPH3 (Left Posterior Hippocampus).

57. Depth electrode Intracranial EEG recording with depth electrodes showed a clear onset over the mesial electrodes in the right temporal region RHH1 -2 (Right hippocampus head) and RHB1-2 (right hippocampus body).

58. MRI The coronal T2WI and FLAIR images show right-sided mesial temporal sclerosis. Notice the volume loss, which indicates atrophy and causes secondary enlargement of the temporal horn of the lateral ventricl e. The high signal in the hippocamous reflects gliosis. Classical findings: Reduced hippocampal volume :Hippocampal atrophy(95%) Increased T2 signal( 85%) Abnormal morphology : loss of internal architecture ( interdigitations of hippocampus )(60-95%) Lady D. Ladino, Farzad Moien-Afshari and José F. Téllez-Zenteno

59. PET scan - FDG The glucose analog FDG is the tracer most widely used. It is an indirect marker of neuronal activity. The epileptogenic focus in the interictal phase usually appears as a hypometabolic area on FDG- PET. H ypometabolism is likely due to factors such as neuronal loss and reduction in synaptic density . The area of decreased glucose utilization in TLE is typically more extensive than the epileptogenic zone and may extend into the adjacent inferior frontal or parietal lobe cortex, as well as the ipsilateral thalamus. La fougère et al. , 2009, Van Paesschen et al. , 2007; Wehner & Lüders , 2008; Carne et al. , 2007

60. PET Thus FDG-PET has lateralizing value rather than localizing significance in TLE , mainly by confirming hypometabolism in the area considered for surgical resection . As a rule, PET and SPECT scans must be used only as an adjunct test in surgical planning of patients with epilepsy. Van Paesschen et al. , 2007; Richardson, 2010, Carne et al. , 2007

61. PET- Hypometabolism in left temporal lobe  13-year-old boy with partial complex epileptic seizures. (a) Coronal PET image, (b) MRI image. MRI does not show any clear abnormality, while on the PET image, there is marked hypometabolism in the left temporal pole. Radiologykey.com

62. SPECT A pplication is based on the assumption that the increased ictal neuronal activity during epileptic seizures is associated with increased metabolism and regional cerebral blood flow ( rCBF ). Ictal SPECT has a high sensitivity to localize the epileptic focus. It utilizes 99m Tc-hexamethyl - propyleneamine oxime ( 99m Tc -HMPAO ) or 99m Tc-ethylcysteinate dimer ( 99m Tc -ECD ) to study cerebral perfusion in the ictal state . Lee et al. , 2011, Van Paesschen et al. , 2007, Wehner & Lüders , 2008

63. SPECT rCBF changes during seizures may begin with hyperperfusion in the epileptic zone followed by rapid extension to other regions due to seizure spread and generalization . Thus, a SPECT hyperperfusion pattern often contains both the ictal onset zone and the propagation pathways. It has been estimated that the seizure should last at least ten seconds after the injection in order to obtain localizing information. La fougère et al. , 2009, Richardson, 2010, Wehner & Lüders , 2008, Newton et al. , 1992 .

64. SPECT I nterictal technetium-99m ECD brain SPECT scan (top) as compared with an ictal technetium-99m ECD brain SPECT scan . Substraction images show increased hyperremia in left temporal lobe

65. SISCOM http:// www.synapticom.net / nucmedlab /

66. Language and memory tests Wada Neuropsych evaluation fMRI

67. WADA test The intracarotid amobarbital procedure (IAP) was first reported by Wada in 1949 and was used for language lateralization. Since the early 60s the Wada test also has been used to predict postoperative amnesia , memory decline and language disability in the presurgical evaluation of TLE. This test uses the functional inactivation of a single hemisphere by injection of sodium amobarbital into the ipsilateral internal carotid artery . During this temporary deficit , the language and memory abilities of the active contralateral hemisphere can be assessed in isolation . Both hemispheres are tested consecutively with about 30 minutes between injections.

68. fMRI P resurgical evaluation, to determine the hemispheric dominance for language . Numerous studies have demonstrated a very good correlation between fMRI and the Wada test . Advantages over Wada test , which include being a non-invasive risk-free technique, lower cost, repeatability, and generating continuous measure of language lateralization. The main limitations of the fMRI are the presence of artifacts mainly generated by movement and patient’s high cooperation demand in order to perform the tasks Sabbah et al. , 2003, Rabin et al. , 2004

69. Neuropsychological (NP) testing Mandatory part of presurgical evaluation TLE – memory and language Dominant TLE – verbal memory deficits Non dominant TLE – visuospatial memory deficits Memory decline – most common deficit after TLE surgery Patients with average or above average memory and language function are at higher risk for developing postoperative deficits

70. Treatment Antiepileptic drugs Surgical resection

71. Antiepileptic drugs About 60% of patients with TLE respond to AEDs , and 40% have DRE epilepsy. The drug of choice for the first-line monotherapy in TLE is carbamazepine or oxcarbazepine . Other monotherapy options are lamotrigine, levetiracetam , valproate , Lacosamide and topiramate . Kwan & Sander, 2004

72. Antiepileptic drugs ILAE defines DRE as failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. Kwan et al. , 2010

73. Surgical treatment 40 percent of patients with partial epilepsy will eventually become refractory to medical treatment and could be potential candidates for epilepsy surgery. Kwan & Sander, 2004 ,

74. DRE-epilepsy surgery DRE is associated with significant risks for death, physical injury, cognitive impairment, and psychosocial problems. Early referral for epilepsy surgery is advisable in selected cases.

75. Surgical treatment The safety and efficacy of surgery for TLE was well established in a randomized clinical trial by Wiebe . In this study, 80 patients with TLE were randomized to receive medical treatment versus surgical treatment . Wiebe et al. , 2001

76. Surgical treatment At the end of the first year of follow-up 58% of patients in the surgical group were seizure-free compared with only 8% of those receiving medical treatment (P < 0.0001) Wiebe S et al. N Engl J Med 2001;345:311-318

77. Surgical treatment The most common epilepsy surgery procedure is temporal lobe resection. The procedures more frequently practiced are standard anterior temporal resection and amygdalo - hippocampectomy . Several studies report similar success rate with both techniques achieving seizure freedom between 60 and 70 % . Lutz et al. , 2004

78. Surgical treatment After left temporal lobectomy: 44 % of patients exhibit verbal memory decline 34 % show naming difficulties. The most common neurologic complication after resective epilepsy surgery is a minor visual field deficit (one quadrant or less ) seen in 12.9% of patients, and the majority of cases are asymptomatic. Sherman et al. , 2011 & Macrodimitris et al. , 2011a, Hader et al. , 2013.

79. Surgical treatment Téllez-Zenteno et al performed a systematic review evaluating long-term outcomes in epilepsy surgery. On average- Patients with temporal lobe surgery 14 % achieved long-term AED discontinuation 50 % achieved monotherapy 33 % remained on polytherapy . Téllez-Zenteno et al. , 2007

80. Surgical treatment Seizure freedom after surgery was associated with lower mortality . Additionally , successful epilepsy surgery can halt or improve the cognitive decline seen in chronic epilepsy, and that left temporal resections have a higher risk of additional post- operative verbal memory impairment . Téllez-Zenteno et al. , 2007

81. VNS The vagus nerve stimulator has been approved as adjunctive therapy for the treatment of adults and adolescents with refractory epilepsy. “VNS is not more effective than AEDs and has a very low chance of achieving seizure freedom in drug- resistant epilepsy , so it should NOT be considered before resective surgery, and should be reserved for patients who are poor candidates or who refuse surgery.” Milby et al., 2009; Burakgazi et al. , 2011, Miller, Hakimian . Surgical Treatment of Epilepsy. Continuum. 2013 June;19:730-42

82. Radiosurgical Treatment A prospective multicenter European study evaluating Gamma Knife(R) surgery for MTS showed comparable efficacy rates (65%) for seizure reduction by conventional surgery or radiosurgery, after two years of follow up . Benefial effects of radiosurgery are not displayed immediately . Most patients achieve seizure reduction at 9–12 months and complete cessation of seizures between 18–24 months after radiosurgical treatment. This procedure is an attractive option for TLE treatment because of its low morbidity and mortality, however prospective trials with larger numbers of patients will be required to establish radiosurgery as a standard therapy for mesial TLE. Régis et al. , 2004, Yang & Barbaro , 2008

83. Neuropace Responsive n eurostimulation

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