Remote infarct of the temporal lobe with coexistent hippocampal sclerosis in mesial temporal lobe epilepsy

Remote infarct of the temporal lobe with coexistent hippocampal sclerosis in mesial temporal lobe epilepsy

Human Pathology (2016) 48, 111–116 www.elsevier.com/locate/humpath Original contribution Remote infarct of the temporal lobe with coexistent hippoc...

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Human Pathology (2016) 48, 111–116

www.elsevier.com/locate/humpath

Original contribution

Remote infarct of the temporal lobe with coexistent hippocampal sclerosis in mesial temporal lobe epilepsy☆,☆☆ Jordan M. Gales BS, Richard A. Prayson MD, MEd ⁎ Cleveland Clinic Department of Anatomic Pathology and Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195 Received 16 July 2015; revised 2 September 2015; accepted 16 September 2015

Keywords: Hippocampal sclerosis; Remote infarct; Epilepsy; Focal cortical dysplasia; Dual pathology

Summary In patients undergoing surgery for temporal lobe epilepsy, hippocampal sclerosis remains the most commonly observed pathology. In addition to hippocampal sclerosis, 5% to 30% of these resections on magnetic resonance imaging contain a second independently epileptogenic lesion, commonly referred to as dual pathology. A second etiology of seizure activity, as seen in dual pathology, may serve as an important cause of treatment failure in striving for post-operative seizure control. Dual pathology, consisting of hippocampal sclerosis and a remote infarct of the adjacent cortex, has been rarely reported. Cases of pathologically confirmed hippocampal sclerosis diagnosed between January 2000 and December 2012 (n = 349) were reviewed, and 7 cases of coexistent infarct (2%) formed the study group. Seven individuals (mean age, 29 years; range, 5-47 years) with a mean epilepsy duration of 12.5 years (3.3-25 years) and a mean pre-surgery frequency of 15 seizures per week (range, 0.5-56 seizures/week) were followed up postoperatively for a mean duration of 64 months (range, 3-137 months). Pathologically, the most common form of hippocampal sclerosis observed was International League against Epilepsy type Ib or severe variant (n = 4). Four of the six individuals with post-surgery follow-up were seizure free at last encounter. The reported incidence of dual pathology, including hippocampal sclerosis and remote infarct, is low (2% in the present study) but may indicate a slightly increased risk of developing hippocampal sclerosis in the setting of a remote infarct. Surgical intervention for such cases anecdotally appears effective in achieving seizure control. © 2015 Elsevier Inc. All rights reserved.

☆ Competing interests: The authors whose names are listed above certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript. ☆☆ Funding/Support: No relevant financial relationships exist. ⁎ Corresponding author at: Department of Anatomic Pathology, L25, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. E-mail address: [email protected] (R. A. Prayson).

http://dx.doi.org/10.1016/j.humpath.2015.09.024 0046-8177/© 2015 Elsevier Inc. All rights reserved.

1. Introduction Hippocampal sclerosis is the most common pathology seen in patients undergoing surgical resection for chronic temporal lobe epilepsy. While surgical resection of the epileptogenic tissue can provide marked improvement in seizure frequency for most patients, it fails to provide adequate seizure control in up to 20% to 30% of mesial temporal lobe epilepsy patients [1]. Current opinion is that this failure may be the result of residual epileptogenic tissue

112 (eg, inadequate resection or dual pathology), the unmasking of new epileptogenic foci, or more diffuse cortical dysfunction [2,3]. A second focus of independent seizure activity, as seen in dual pathology, may serve as an important cause of treatment failure in obtaining seizure control in up to 10% of patients [3]. On pathology, 5% to 30% of surgical specimens are found to have dual pathology, eg, hippocampal sclerosis in combination with focal cortical dysplasia, tumors, or vascular lesions [1,4]. The most commonly reported pattern of dual pathology comprises hippocampal sclerosis and adjacent focal cortical dysplasia [5]. The coexistence of hippocampal sclerosis and remote infarct is less commonly observed. One large series observed a frequency of hippocampal sclerosis and ipsilateral remote infarct of the temporal lobe in 2.7% of patients [4]. Although rare, this combination may be a potential source of treatment resistance in individuals with surgical failure. This study reports 7 cases of dual pathology comprised of remote infarct with hippocampal sclerosis in patients with a history of intractable epilepsy of the mesial temporal lobe and who underwent surgical resection of the epileptogenic focus.

2. Materials and methods Institutional review board approval of the authors’ home institution was obtained prior to identification of eligible study cases. The Cleveland Clinic Department of Anatomic Pathology surgical specimen files were retrospectively reviewed to identify cases of hippocampal sclerosis in patients undergoing resection for intractable mesial temporal lobe epilepsy. Hippocampal sclerosis was defined and diagnosed according to criteria set forth by International League against Epilepsy (ILAE) guidelines [6]. Three hundred forty-nine cases were identified during the study period of January 1, 2000, to December 31, 2012. To meet inclusion criteria, screened cases must have included full hippocampal and ipsilateral temporal lobe resections. Patients with a prior history of brain surgery were excluded to prevent false positive reporting of iatrogenic injury. Seven screened cases had coexistent remote infarct of the excised ipsilateral temporal lobe. The study group comprised 7 eligible cases including 4 males and 3 females, ranging in age from 5 to 47 years (mean age, 29 years). Observed patterns of cortical disorganization adjacent to the remote infarct were classified using both the Palmini et al and ILAE consensus classifications of focal cortical dysplasia [7,8]. Relevant clinical data were abstracted from the patients' medical record with most recent data retrieval being June 2015.

3. Results All patients had medically intractable medial temporal lobe epilepsy refractory to pharmacologic intervention. Table 1 summarizes the preoperative clinical features of

J. M. Gales, R. A. Prayson the study group. Seizure duration prior to surgery ranged from 3.3 to 25 years (mean duration, 12.5 years). The mean age at seizure onset was 16.7 years (age range, 21 months to 40 years). The most common pre-surgical seizure subtype was complex partial seizures (n = 5). Pre-surgical seizure frequency ranged widely from 1 to 56 weekly seizures (median frequency 15). Prior to surgery, the cohort was on a mean of 3 daily anti-epileptic drugs (range, 2-4 medications). Mean duration of postoperative follow-up was 64 months (range, 3.5-138 months). One subject was an international patient who was lost to follow-up after surgical resection. At last follow-up, 4 (67%) of the 6 remaining patients were seizure free. Of the patients with seizure recurrence, one experienced a generalized tonic-clonic seizure during anti-epileptic drug withdrawal but, at last follow-up, was anti-epileptic drug free with no recurrent symptoms. The second patient experienced recurrent absence seizures occurring at an average of 35 per week; at last follow-up, this patient remained on 3 anti-epileptic medications. Of the 4 patients with no post-surgical seizure recurrence, one remained on anti-epileptic medication at last follow-up. Six of the cases (86%) had a history of prior head trauma, with motor vehicle accident being the most common etiology. None of these patients underwent surgical evacuation or placement of clips for intracranial hemorrhage. The remaining case had a known history of a perinatal ischemic event. All 7 patients underwent temporal lobe resection and displayed ipsilateral hippocampal sclerosis. Each hippocampus was completely submitted for sectioning. Table 2 summarizes the pathologic findings in the study group. The most commonly observed pattern of hippocampal sclerosis was of the ILAE type Ia or classic subtype (n = 4, 57%). These cases were marked by severe neuronal loss and astrogliosis of the CA1 region with variable amounts of neuronal loss in the remaining hippocampal subsectors CA2-4 (Fig. 1). Two patients (28.6%) presented with the severe pattern of hippocampal sclerosis, consistent with the ILAE Ib subtype; these hippocampi displayed greater than 50% neuronal loss in all hippocampal sectors. One case of hippocampal sclerosis showed a predominantly CA1 distribution of neuronal loss with relative sparing of the remaining hippocampal sectors consistent with the ILAE type II (Fig. 2A and B). Of the 7 temporal lobes with evidence of remote infarct, three were completely submitted for sectioning. Commonly observed post-infarct changes included evidence of cavitary change, reactive astrogliosis, and atrophy of the adjacent cortex (Figs. 3-5). Five resections showed focal disruption of the cortical architecture (focal cortical dysplasia) adjacent to the remote infarction (Fig. 6). These lesions would be analogous to type IA focal cortical dysplasia using the Palmini et al schema [7]. The lesions phenotypically resemble ILAE focal cortical dysplasia type Ib, but technically do not fit into the current consensus classification system. Of the five focal cortical

Remote infarct with coexistent hippocampal sclerosis Table 1

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Summary of preoperative clinical features of the study group

Case Seizure risk factor

Age onset (y) Age at surgery (y) Generalized tonic- Primary seizure description clonic

1 2 3 4 5 6 7

16 23 14 19 40 1.8 3

MVA MVA MVA Fall from height Fall from height MVA Perinatal stroke

28 47 27 44 45 5 8

Yes Yes No Yes No Yes Yes

Seizure frequency (/wk)

CPS, automotor seizures with aura 4 CPS, automotor seizures with aura 3.5 CPS, automotor seizures with aura 2.5 CPS, automotor seizures with aura 1.5 CPS, automotor seizures with aura 0.5 Generalized tonic-clonic seizure 35 Myoclonic and atonic seizures 56

Abbreviations: MVA, motor vehicle accident; CPS, complex partial seizures.

dysplasia cases, three had coexistent hippocampal sclerosis of the classic subtype. Of the 2 patients who had no cortical architectural disorganization adjacent to the remote infarct, one had coexistent hippocampal sclerosis of the severe subtype and the other the classic subtype. Other coexistent temporal lobe pathology noted in the study group included subpial or Chaslin’s gliosis (n = 2, 29%), perivascular white matter atrophy (n = 3, 43%) and vascular sclerosis (n = 2, 29%). Temporal lobe specimens from the two individuals who underwent pre-operative invasive electroencephalography showed evidence of acute hemorrhage and mild focal perivascular chronic inflammation.

4. Discussion Despite optimal medical management, one third of patients with mesial temporal lobe epilepsy will have continued seizure activity [9]. Surgery can provide lasting benefit to most patients, but up to 20% to 30% of patients’ seizures will fail to be controlled [1]. Commonly identified causes for epilepsy surgery failure in mesial temporal lobe epilepsy include insufficient resection of the mesial structures, recurrence of epileptogenesis from the contralateral hemisphere, and dual pathology. Improved imaging and histopathological techniques have highlighted the role dual

Table 2

pathology plays in refractory mesial temporal lobe epilepsy; 15% of surgical patients will have evidence of dual pathology on magnetic resonance imaging, and up to 30% will show evidence on pathology [9]. Remote infarct has not been as well described in the literature compared to other dual pathology entities (focal cortical dysplasia/hippocampal sclerosis and low-grade glioneuronal tumors/focal cortical dysplasia). Remote infarct of the temporal lobe adjacent to hippocampal sclerosis may be an underreported cause of mesial temporal lobe epilepsy surgery failure. Inadequate resection of subtle cortical infarcts may leave behind an active epileptogenic focus and drive recurrent seizure activity. This hypothesis is analogous to the concern that many other temporal lobe epilepsy surgery patients with treatment failure have residual foci of subtle cortical dysplasia, poorly visualized by current imaging techniques [9]. This idea is supported by the observation that the only study subject to experience recurrent seizures had a history of perinatal ischemic injury; this history implies a potentially more global process of brain injury, which may theoretically be associated with an increased risk of seizure recurrence. In general, surgical strategy is dependent upon the location of the temporal lobe lesion and its relative role in seizure generation. Further awareness of the role a remote infarct can play in dual pathology may improve lesion identification and surgical outcomes. Previously reported surgical outcomes and

Summary of pathology and postoperative outcomes of the study group

Case Duration of Anti-epileptic use Seizure free at Seizure type and frequency follow-up (mo) at last follow-up study end 1 2 3 4 5 6 7

34 56 3.5 48 138 129 40

Yes No Not available No No No Yes

Yes No Not available Yes Yes Yes No

ILAE HS FCD FCD type subtypes present (Palmini et al [7])

Ia Generalized-tonic clonic seizure, rare Ia Ib II Ib Ib Absence of seizure recurrence at Ib 4 months; 42 per week

Abbreviations: FCD, focal cortical dysplasia; HS, hippocampal sclerosis; ILAE, International League against Epilepsy.

Yes No Yes Yes No Yes Yes

IA IA IA IA IA

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Fig. 1 Patient 1. The CA4 region of the hippocampus shows a marked loss of neurons in a patient with classical hippocampal sclerosis (ILAE type Ia) (hematoxylin and eosin, original magnification ×100).

the descriptive data presented in this study suggest that simultaneous resection of the mesial temporal lobe structures along with the temporal lobe cortical infarction is effective in producing seizure control. In comparison to the overall rate of cure for patients with temporal lobe epilepsy undergoing temporal lobe resection at the authors' home institution (eg, 68%), the results of this cohort were favorable [10]. The pathogenesis of dual pathology remains unclear. It is uncertain if hippocampal sclerosis and the extra hippocampal pathologies seen in dual pathology are causally linked, related by an underlying common etiology, or coexistent by

happenstance. The observation in the current study of five patients with peri-infarct focal cortical dysplasia is of particular interest. Focal cortical dysplasia is the most commonly observed extrahippocampal lesion in dual pathology with estimates of incidence ranging from 20% to 70% in the literature [11]. It has been well established that the focal cortical dysplasia adjacent to a remote infarct mimics de novo focal cortical dysplasia in appearance [12,13]. It is possible that any distinction between the two phenomena is arbitrary, as focal cortical dysplasia may be secondary to vascular insult during early development in

Fig. 2 A, Patient 4. Hippocampal sclerosis marked by a severe loss of neurons in the CA1 or Sommer section region of the hippocampus (hematoxylin and eosin, original magnification ×50). B, Patient 4. A section showing a normal dentate nucleus at the bottom and the CA4 or endplate region of the hippocampus with minimal loss of neurons. This patient had an ILAE type II hippocampal sclerosis or CA1 sclerosis (hematoxylin and eosin, original magnification ×100).

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Fig. 3 Patient 3: Cavitated remote infarct involving cortical layers 2 and 3 (hematoxylin and eosin, original magnification ×100).

Fig. 5 Patient 6. Microcalcifications in an area of remote infarct (hematoxylin and eosin, original magnification ×200).

some cases [8]. Although a direct causal relationship between temporal lobe infarction and ipsilateral hippocampal sclerosis cannot be made, one might hypothesize that the hippocampal sclerosis may be secondary to seizure activity produced by the peri-infarct areas of focal cortical dysplasia. The current ILAE classification of focal cortical dysplasia does not accommodate cases with multiple coexistent pathologies, in this case infarct and hippocampal sclerosis [8]. In the schema, focal cortical dysplasia in the setting of hippocampal sclerosis represents a type IIIa lesion, and infarct with cortical dysplasia a type IIId lesion. Although the number of cases in the current study is small, there appears to be no obvious correlation of infarct with the hippocampal sclerosis subtype or post-operative freedom from seizure. In addition, the duration of epilepsy did not appear to correlate with the severity of hippocampal neuron loss and gliosis. The small sample size and retrospective nature of this report

prevent the authors from inferring any significant association between observed phenomena. A limitation of the retrospective study design was the lack of documentation of the date of initial insult within the patient record. Therefore, the duration between initial insult and onset of seizure was not known. The observation that 6 cases within the cohort had a history of head trauma supports a role for a post-traumatic focus of seizure activity. The fact that not all individuals with evidence of post-traumatic infarct develop symptomatic epilepsy highlights the role lesion location and underlying individual seizure threshold played in these particular cases. Approximately 20% of symptomatic epilepsy is attributed to some kind of trauma [14]. The association is greater in epilepsy of the temporal and frontal lobes, where cortical contusions are most common. Late posttraumatic seizures

Fig. 4 Patient 4. Cortical atrophy with loss of neurons and gliosis due to remote ischemic damage (hematoxylin and eosin, original magnification ×100).

Fig. 6 Patient 4. Cortical architectural disorganization showing a loss of cortical layer two and a haphazard arrangement of large cortical neurons, consistent with a focal cortical dysplasia (hematoxylin and eosin, original magnification ×200).

116 are thought to result from cortical damage caused by free radicals generated by iron deposition from extravasated blood; along with increased excitotoxicity via glutamate accumulation [15]. The predominant late post-traumatic seizure type observed is complex partial seizures [16]. Complex partial seizures were observed in five study group members. The incidence of late post-traumatic seizure ranges from 2% to 10% in the literature, and given improvements in neurological trauma care this prevalence will likely increase as patients survive longer after injury [16].

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[6]

[7] [8]

[9] [10]

References [11] [1] Li LM, Cendes F, Andermann F, et al. Surgical outcome in patients with epilepsy and dual pathology. Brain 1999;122(Pt 5): 799-805. [2] Hemb M, Palmini A, Paglioli E, et al. An 18-year follow-up of seizure outcome after surgery for temporal lobe epilepsy and hippocampal sclerosis. J Neurol Neurosurg Psychiatry 2013;84:800-5. [3] Ramos E, Benbadis S, Vale FL. Failure of temporal lobe resection for epilepsy in patients with mesial temporal sclerosis: results and treatment options. J Neurosurg 2009;110:1127-34. [4] Salanova V, Markand O, Worth R. Temporal lobe epilepsy: analysis of patients with dual pathology. Acta Neurol Scand 2004;109:126-31. [5] Miyata H, Hori T, Vinters HV. Surgical pathology of epilepsyassociated non-neoplastic cerebral lesions: A brief introduction with

[12] [13] [14]

[15] [16]

special reference to hippocampal sclerosis and focal cortical dysplasia. Neuropathology 2013;33:442-58. Blumcke I, Thom M, Aronica E, et al. 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. Palmini A, Najm I, Avanzini G, et al. Terminology and classification of the cortical dysplasias. Neurology 2004;62:S2-8. Blumcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc task force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52:158-74. Harroud A, Bouthillier A, Weil AG, Nguyen DK. Temporal lobe epilepsy surgery failures: a review. Epilepsy Res Treat 2012;2012:10. Jeha LE, Najm IM, Bingaman WE, et al. Predictors of outcome after temporal lobectomy for the treatment of intractable epilepsy. Neurology 2006;66:1938-40. Kim DW, Lee SK, Nam H, et al. Epilepsy with dual pathology: surgical treatment of cortical dysplasia accompanied by hippocampal sclerosis. Epilepsia 2010;51:1429-35. Perry A. Practical surgical neuropathology: a diagnostic approach. New York: Churchill Livingstone; 2010. Prayson RA. Diagnostic challenges in the evaluation of chronic epilepsyrelated surgical neuropathology. Am J Surg Pathol 2010;34:e1-13. Englander J, Bushnik T, Duong TT, et al. Analyzing risk factors for late posttraumatic seizures: A prospective, multicenter investigation. Arch Phys Med Rehabil; 2003;84:365-73. D'Ambrosio R, Perucca E. Epilepsy after head injury. Curr Opin Neurol 2004;17:731. Garga N, Lowenstein DH. Posttraumatic epilepsy: a major problem in desperate need of major advances. Epilepsy Curr 2006;6:1-5.