Posttraumatic epilepsy — Disease or comorbidity?

YEBEH-03734; No. of pages: 6; 4C: 4 Epilepsy & Behavior xxx (2014) xxx–xxx

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Review

Posttraumatic epilepsy — Disease or comorbidity? Asla Pitkänen a,b,⁎, Samuli Kemppainen c,d, Xavier Ekolle Ndode-Ekane a, Noora Huusko a, Joanna K. Huttunen e, Olli Gröhn e, Riikka Immonen e, Alejandra Sierra e, Tamuna Bolkvadze a a

Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland Department of Neurology, Kuopio University Hospital, PO Box 1777, FIN-70211 Kuopio, Finland Kainuu Central Hospital, Kainuu Social Welfare and Health Care Joint Authority, Kajaani, Finland d Northern Finland Laboratory Centre (NordLab), Sotkamontie 13, FIN-87300 Kajaani, Finland e Biomedical Imaging Unit, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland b c

a r t i c l e

i n f o

Article history: Revised 17 January 2014 Accepted 20 January 2014 Available online xxxx Keywords: Behavior Cognitive function Depression Epileptogenesis Functional magnetic resonance imaging Memory Recovery Traumatic brain injury

a b s t r a c t Traumatic brain injury (TBI) can cause a myriad of sequelae depending on its type, severity, and location of injured structures. These can include mood disorders, posttraumatic stress disorder and other anxiety disorders, personality disorders, aggressive disorders, cognitive changes, chronic pain, sleep problems, motor or sensory impairments, endocrine dysfunction, gastrointestinal disturbances, increased risk of infections, pulmonary disturbances, parkinsonism, posttraumatic epilepsy, or their combinations. The progression of individual pathologies leading to a given phenotype is variable, and some progress for months. Consequently, the different postTBI phenotypes appear within different time windows. In parallel with morbidogenesis, spontaneous recovery occurs both in experimental models and in human TBI. A great challenge remains; how can we dissect the specific mechanisms that lead to the different endophenotypes, such as posttraumatic epileptogenesis, in order to identify treatment approaches that would not compromise recovery? This article is part of a Special Issue entitled “NEWroscience 2013”.

1. Introduction Traumatic brain injury (TBI) refers to a brain injury caused by an external mechanical force such as an impact to the head, concussive forces, acceleration–deceleration forces, blast injury, and a projectile such as a bullet [1]. Traumatic brain injury is recognized as a critical public health problem worldwide, and it has been estimated that in the USA, a TBI occurs every 21 s [1,2]. As the problems experienced by those suffering from TBI may not be visible (e.g., impairments in memory or cognition), the disease is often referred to as a “silent epidemic” [3]. Depending on the location and type of brain injury, TBI can lead to a variety of comorbidities (Fig. 1). There is no one definition for the term “comorbidity”, and the definition can have different flavors depending on the purpose of its use [4]. A recent report from the ILAE/AES task

⁎ Corresponding author at: A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. Fax: +358 17 163025. E-mail address: asla.pitkanen@uef.fi (A. Pitkänen).

© 2014 Published by Elsevier Inc.

force defined comorbidity in the context of epilepsy as “a condition that occurs in association with another (i.e., epilepsy) at frequencies that are significantly greater than those observed in the appropriate control group. A co-morbidity may be a cause of epilepsy, a consequence of epilepsy, or a separate condition that is associated with epilepsy because there is a common cause for the epilepsy and the co-morbidity”. It was also noted that in the future, some of the comorbidities could be shown to result from a spurious association, in which case, they would not be true comorbidities [5]. The occurrence of seizures is not uncommon after experimental or human TBI. Depending on the time delay from TBI to the occurrence of the first seizure, they have been categorized into immediate (b24 h), early (1–7 days), or late (N 1 week after TBI) seizures [6]. According to definition, epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one unprovoked seizure [7]. Thus, TBI associated with one unprovoked late seizure qualifies for the diagnosis of posttraumatic epilepsy (PTE). It has been estimated that TBI accounts for 10–20% of symptomatic epilepsy in the general population and 5% of all epilepsies [8,9].

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Please cite this article as: Pitkänen A, et al, Posttraumatic epilepsy — Disease or comorbidity? Epilepsy Behav (2014), http://dx.doi.org/10.1016/ j.yebeh.2014.01.013

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Fig. 1. TBI results in variable structural endophenotypes in both humans and experimental models. A computed tomography (CT) image from a patient with (A) an acute subdural hematoma (car accident), (B) multiple traumatic intracerebral hemorrhages (fall), (C) a traumatic frontobasal subarachnoidal hemorrhage (fall in stairs), and (D) a frontotemporoparietal epidural hematoma on the right hemisphere (fall). (E) T2-weighted magnetic resonance images from two rats with lateral fluid percussion injury. Upper row: a rat (#10) with rapidly progressing injury imaged at 3 h, 3 days, 9 days, 23 days, 60 days, 90 days, and 180 days after lateral fluid percussion injury (FPI)-induced TBI. Lower row: another rat (#13) with lateral FPI. Even though the injury parameters were comparable, the severity of brain injury was milder and progressed less in rat #13 than in rat #10.

Depending on the neuronal network(s) damaged by the TBI, PTE can co-occur with one or more post-TBI morbidities such as mood disorders, posttraumatic stress disorder and other anxiety disorders, personality disorders, aggressive disorders, cognitive changes, chronic pain, sleep problems, motor or sensory impairments, endocrine dysfunction, gastrointestinal disturbances, increased risk of infections, pulmonary disturbances, and parkinsonism [10]. Thus, TBI can result in a spectrum of endophenotypes, some of which include epilepsy. Each endophenotype is composed of one or more affected neuronal networks in the same subject and, consequently, can be visualized as a “connectome” of affected networks/morbidities (Fig. 2A). Such phenotypic heterogeneity challenges the analysis of molecular and cellular mechanisms contributing specifically to each phenotypic aspect in a given individual such as PTE. There is another important question: how can we choose the best therapy to treat one impairment without compromising another that may be occurring in the same individual?

2. Progression of morbidogenesis after TBI in experimental models The term epileptogenesis refers to the development and extension of tissue capable of generating spontaneous seizures resulting in (a) the development of an epileptic condition and/or (b) the progression of the epilepsy after it is established [11]. In experimental models, spontaneous seizures have been shown to develop after TBI induced by fluid percussion injury (FPI) or controlled cortical impact (CCI) [12] (Table 1). In these models, the cumulative incidence of epilepsy progresses for several weeks to months, resulting in epilepsy in a subpopulation of animals (Table 1). In addition, both Feeney's and Marmarou's weight drop models of TBI have been shown to result in increased seizure susceptibility (Table 1). In the lateral FPI model, epileptogenesis occurs in parallel with the development and consequent spontaneous recovery of many post-TBI comorbidities. For example, the composite neuroscore test is a commonly

Please cite this article as: Pitkänen A, et al, Posttraumatic epilepsy — Disease or comorbidity? Epilepsy Behav (2014), http://dx.doi.org/10.1016/ j.yebeh.2014.01.013

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t1:1

Table 1

t1:1

Model

Seizure susceptibility in vivo

Epilepsy

Reference

t1:1 t1:1 t1:1 t1:1 t1:1 t1:1 t1:1 t1:1 t1:1 t1:1 t1:1 t1:1 t1:1 t1:1 t1:1 t1:1

Feeney's weight drop model Marmarou's weight drop model Central FPI Parasagittal FPI

Increased susceptibility to PTZ-induced seizures, 15 weeks post-TBI Increased seizure susceptibility to ECS-induced seizures, 7 days post-TBI No difference in PTZ kindling, started 24 h post-TBI n.d. Increased susceptibility to PTZ-induced seizures, 12 weeks post-TBI Increased susceptibility to PTZ-induced seizures, 2 weeks post-TBI Increased susceptibility to PTZ-induced seizures, 4 days post-TBI Increased susceptibility to PTZ-induced seizures, 5 weeks post-TBI Granule cell hyperexcitability, 1 week post-TBI Increased inhibition in the dentate gyrus, 15 days post-TBI No change in PTZ seizure threshold, 20 weeks post-TBI Increased susceptibility to PTZ-induced seizures, 12 months post-TBI Increased susceptibility to kainate-induced seizures, 6 weeks post-TBI No change in susceptibility to flurothyl-induced seizures, 3 and 6 weeks post-TBI Increased susceptibility to PTZ-induced seizures, 6 months post-TBI n.d.

n.d. n.d. n.d. 100% (follow-up: 7 months) n.d. no n.d. n.d. n.d. n.d. 0% (behavioral observation) 50% (follow-up: 12 months) n.d. n.d. 6% (follow-up: 9 months) 52% spontaneous seizures (30%) or epileptiform discharges (22%) n.d. Spontaneous seizures n.d.

[13] [14] [15] [16–18] [19] [20] [21] [22] [23] [24] [25] [26,27] [28] [29] [30] [31] [32] [33] [34]

1 of 8 (13%) (follow-up: 11 months) 20% (mild)–36% (severe injury) 40% 9% (follow-up: 9 months) 50% of vehicle-treated animalsa

[35] [36] [37] [30] [38]

t1:1 t1:1 t1:1

t1:1 t1:1 t1:1 t1:1 t1:1 t1:1 t1:1

Lateral FPI

CCI

Increased susceptibility to PTZ-induced seizures, 30 days post-TBI n.d. Unchanged threshold for tonic hindlimb extension or minimal clonic seizures in electroconvulsive seizure threshold test, testing on P34–40 Reduced threshold for minimal clonic seizures, testing on P60–63 n.d. n.d. n.d. Increased susceptibility to PTZ-induced seizures, 6 months post-TBI n.d.

Abbreviations: CCI, controlled cortical impact; ECS, electroconvulsive shock; FPI, fluid percussion injury; n.d., no data; P, postnatal day; PTZ, pentylenetetrazol; sz, seizure; TBI, traumatic brain injury. a Data from vehicle-treated mice that were included in the rapamycin treatment study.

used measure to assess somatomotor impairment after TBI in rodents [39]. Depending on the severity of TBI, performance in the neuroscore test typically recovers over a period of 2–3 weeks [40–42]. Similarly, somatosensory function recovers substantially over 2–3 weeks postTBI when assessed using the normalization of sensory stimulationinduced BOLD response in functional MRI [42]. Interestingly, recovery of spatial memory, when assessed using the Morris water maze, is incomplete even at 8 weeks post-TBI [39]. Recently, O'Brien and coworkers investigated the time course of psychiatric comorbidities after lateral FPI [31,43]. They found that the appearance of anxietylike behavior in open-field or elevated plus maze tasks at 1 month after lateral FPI-induced TBI was significantly alleviated when animals were retested at 3 or 6 months postinjury, suggesting spontaneous recovery of underlying network abnormalities. In the same animal group, enhanced anxiety-like behavior at 1 month was not associated with depression-like behavior as the rats did not show any impairment in the forced swim test or the sucrose preference test [43]. More recently, the authors assessed the same animals with lateral FPI using longterm video-EEG monitoring at 6 months post-TBI. They found that behavioral or memory impairments assessed at 1 month, 3 months, or 6 months post-TBI did not predict epileptogenesis at 6 months postinjury as there was no difference in anxiety-like behavior or spatial memory in animals with or without epilepsy [31]. Taken together, these studies suggest that different post-TBI comorbidities and the underlying network reorganizations can progress independently.

3. Progression of morbidogenesis after TBI in humans The epidemiological data on the time course of epileptogenesis in humans show that the latency from TBI to the occurrence of the 1st seizure varies greatly. A 30-year cumulative incidence of epilepsy is 2.1% for mild, 4.2% for moderate, and 16.7% for severe injuries [6,44]. After the first late seizure, 86% of patients were reported to develop a second seizure within 2 years, suggesting the establishment of an epileptogenic process [45]. Moreover, the risk of developing epilepsy remains higher for a longer period of time after severe TBI as compared with moderate TBI (10 vs. 30 years, see Fig. 2) [6].

Like in experimental models, recovery from functional impairments occurs in parallel with epileptogenesis after TBI in patients. Katz et al. [46] followed the recovery of arm function in 44 patients with moderate or severe TBI for up to 6 months. They found that, altogether, 86% recovered in 6 months and 72% of them within 2 months. Later recovery was found in patients with diffuse axonal injury rather than those with focal cortical contusion, hypoxic–ischemic injury, or herniation. Christensen et al. [47] followed the recovery of 15 cognitive domains in 75 patients with moderate or severe TBI for up to 1 year. They found that most of the recovery occurred during the first 5 months post-TBI. However, there were differences between the modalities employed. Particularly, the speed of cognitive processing and memory showed the most persistent deficits. Taken together, post-TBI epileptogenesis occurs in parallel with recovery from many co-occurring functional impairments in both experimental models and patients with TBI (Figs. 2B–C). However, the time course of epileptogenesis spans a much longer time period than, for example, motor or somatosensory recovery, or even recovery from anxiety-like or depression-like behaviors. This creates an interesting question of whether there would be a time window for molecular and cellular analyses that would specifically address the mechanisms of a given endophenotype.

4. Molecular and network reorganization Fig. 3 summarizes the different components of cellular reorganization in the brain revealed by studies in different experimental models of TBI [48,49]. Several laboratories have provided information on post-TBI molecular reorganization in gene transcription, epigenetics, or regulation of protein synthesis by noncoding RNAs [50,51]. Typically, however, the tissue has been collected for analysis within 3 days after TBI, and very few studies have analyzed samples at more chronic time points (at least ≈1 month post-TBI) [52]. Consequently, the studies have remained inconclusive whether the data obtained would imply mechanisms of any specific type of morbidogenesis. Even extracting information about the molecular basis of various types of circuitry reorganization known to occur during posttraumatic morbidogenesis is difficult.

Please cite this article as: Pitkänen A, et al, Posttraumatic epilepsy — Disease or comorbidity? Epilepsy Behav (2014), http://dx.doi.org/10.1016/ j.yebeh.2014.01.013

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Aggressive disorders

PTSD and other anxiety disorders Mood disorders

Parkinsonism

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Experimental TBI 60 50

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Motor, sensory, behavioral, and cognitive recovery

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GI-disturbances Chronic pain Substance abuse Sleep disorders

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%

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Moderate TBI

8 20

Severe TBI

6 4

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2 0

0 0

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10 12

Months after TBI

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Years after TBI

Fig. 2. Post-TBI morbidity connectome and timelines for morbidogenesis. (A) Post-TBI morbidity connectome summarizing different types of comorbidities, including epilepsy that can develop after TBI in humans. Hypothetically, one can think that each comorbidity has its own pathologic molecular/anatomic connectome, which forms a basis for a given brain abnormality/morbidity. Linking different morbidities links connectomes with other connectomes, resulting in a metaconnectome which associates with a given endophenotype. The blue lines link epilepsy to other morbidities described in animal models of PTE. (B) Epileptogenesis after lateral fluid percussion injury-induced TBI continues for up to 1 year. Motor, sensory, behavioral, and cognitive impairments are apparent within days after TBI. Importantly, spontaneous recovery is fastest during the first 1–3 months post-TBI. The y-axis shows the percentage of subjects with epilepsy over time (x-axis). (C) Like in experimental models, epileptogenesis has a substantially longer-lasting evolution time than the recovery of motor and cognitive functions in patients with TBI as well. See text for references.

Fig. 3. Posttraumatic epileptogenesis in experimental models. In vivo testing has demonstrated increased seizure susceptibility in Feeney's and Marmarou's weight drop models and in fluid percussion injury (FPI, both lateral and parasagittal) and controlled cortical impact (CCI) models of traumatic brain injury (TBI). Spontaneous seizures have been shown in FPI and CCI models. TBI triggers molecular changes at transcriptional, posttranslational, and epigenetic levels, some of which likely underlie the consequent circuitry reorganization. Recent data demonstrate also the development of several types of acquired channelopathies after TBI that can contribute to increased excitability [53]. Molecular and cellular plasticity can continue for weeks to months to years, and the pattern of changes is time-dependent, suggesting that the expression of treatment targets is also time-dependent. Functionally, morbidogenesis (including epileptogenesis) and spontaneous recovery progress in parallel, particularly at the early post-TBI phase. All the different aspects are under the influence of genetics. See text for references.

Please cite this article as: Pitkänen A, et al, Posttraumatic epilepsy — Disease or comorbidity? Epilepsy Behav (2014), http://dx.doi.org/10.1016/ j.yebeh.2014.01.013

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There is a clear need to explore the more chronic post-TBI time points to understand the molecular basis of chronic synaptic plasticity, which is a likely contributor to epileptogenesis. As the molecular alterations do not obey the man-made diagnostic borders, it is likely that some of the mechanisms modulating epileptogenesis could also represent mechanisms for persistence of other morbidities after TBI as well as for recovery. 5. Conclusions Traumatic brain injury initiates cascades of molecular and cellular changes which can result in several comorbidities, generating different kinds of endophenotypes, some of which include epileptogenesis and eventually posttraumatic epilepsy. It remains a major challenge to dissect the mechanisms that are specific for epileptogenesis and to target these mechanisms for antiepileptogenesis without compromising recovery processes or worsening other morbidities. Importantly, these studies can also reveal novel treatment approaches to alleviate comorbidogenesis. The data accumulating from patients with TBI with or without PTE, the increasing number of well-characterized animal models of PTE, and the better understanding of the molecular aftermath of TBI form a platform for the identification of treatments for post-TBI morbidities. Acknowledgments This study was supported by the Academy of Finland, the Sigrid Juselius Foundation, CURE, COST Action BM1001, and EUROEPINOMICS (EpiGENET) (A.P.). Conflict of interest The authors declare that there are no conflicts of interests. References [1] Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurol 2008;8:728–41. [2] Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC. The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation 2007;22(5): 341–53. [3] Langlois JA, Marr A, Mitchko J, Johnson RL. Tracking the silent epidemic and educating the public: CDC's traumatic brain injury-associated activities under the TBI Act of 1996 and the Children's Health Act of 2000. J Head Trauma Rehabil 2005;20(3):196–204. [4] Valderas JM, Starfield B, Sibbald B, Salisbury C, Roland M. Defining comorbidity: implications for understanding health and health services. Ann Fam Med 2009;7(4): 357–63. [5] Brooks-Kayal AR, Bath KG, Berg AT, Galanopoulou AS, Holmes GL, Jensen FE, et al. Issues related to symptomatic and disease-modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy. Epilepsia 2013;54(Suppl. 4):44–60. [6] Annegers JF, Hauser A, Coan SP, Rocca WA. A population-based study of seizures after traumatic brain injuries. N Engl J Med 1998;338:20–4. [7] Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46(4): 470–2. [8] Herman ST. Epilepsy after brain insult: targeting epileptogenesis. Neurology 2002;59:21–6. [9] Frey LC. Epidemiology of posttraumatic epilepsy: a critical review. Epilepsia 2003;44(Suppl. 10):11–7. [10] Textbook of traumatic brain injury. In: Silver JM, McAllister TW, Yudofsky SC, editors. American Psychiatric: Publishing Inc.; 2005 [11] Pitkänen A, Nehlig A, Brooks-Kayal AR, Dudek FE, Friedman D, Galanopoulou AS, et al. Issues related to development of antiepileptogenic therapies. Epilepsia 2013;54(Suppl. 4):35–43. [12] Pitkänen A, Bolkvadze T. Head trauma and epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper's basic mechanisms of the epilepsies. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US); 2012, pp. 331-42 [Available from http://www.ncbi.nlm.nih.gov/ books/NBK98197/]. [13] Golarai G, Greenwood AC, Feeney DM, Connor JA. Physiological and structural evidence for hippocampal involvement in persistent seizure susceptibility after traumatic brain injury. J Neurosci 2001;21(21):8523–37.

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Please cite this article as: Pitkänen A, et al, Posttraumatic epilepsy — Disease or comorbidity? Epilepsy Behav (2014), http://dx.doi.org/10.1016/ j.yebeh.2014.01.013