Immunological perspectives of temporal lobe seizures

Immunological perspectives of temporal lobe seizures

JNI-475767; No of Pages 7 Journal of Neuroimmunology xxx (2013) xxx–xxx Contents lists available at ScienceDirect Journal of Neuroimmunology journal...

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JNI-475767; No of Pages 7 Journal of Neuroimmunology xxx (2013) xxx–xxx

Contents lists available at ScienceDirect

Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim

Review article

Immunological perspectives of temporal lobe seizures Suvi Liimatainen a,b,⁎, Lehtimäki Kai c, Palmio Johanna a, Alapirtti Tiina a, Peltola Jukka a a b c

Department of Neurology and Rehabilitation, Tampere University Hospital, P.O. Box 2000, 33521, Tampere, Finland Emergency Department Acuta, Tampere University Hospital, P.O. Box 2000, 33521, Tampere, Finland Department of Neurosurgery, Tampere University Hospital, P.O. Box 2000, 33521, Tampere, Finland

a r t i c l e

i n f o

Article history: Received 12 November 2012 Received in revised form 21 July 2013 Accepted 5 August 2013 Available online xxxx Keywords: Innate immunity Adaptive immunity Cytokine Antibody Neurodegeneration Neuromodulation

a b s t r a c t The temporal lobes are affected in many different neurological disorders, such as neurodegenerative diseases, viral and immunological encephalitides, and epilepsy. Both experimental and clinical evidence suggests a different inflammatory response to seizures in patients with temporal lobe epilepsy (TLE) in comparison to those with extraTLE (XTLE). Proinflammatory cytokines and several autoantibodies have been shown to be associated with TLE compared to other epilepsy types suggesting the specific role and structure of the temporal lobe. Abundant experience suggests that activation of both innate and adaptive immunity is associated with epilepsy, particularly refractory focal epilepsy. Limbic encephalitis often triggers temporal lobe seizures, and a proportion of these disorders are immune-mediated. Histological evidence shows activation of specific inflammatory pathways in resected temporal lobes of epileptic patients, and certain epileptic disorders have shown increased incidence in patients with autoimmune diseases. Rapid activation of proinflammatory cytokines is observed after single seizures, but there is also evidence of chronic overproduction of cytokines and other inflammatory mediators in patients with TLE, suggesting a neuromodulatory role of inflammation in epilepsy. In this review we summarize current data on the presence and the role of immunological factors in temporal lobe seizures, and their possible involvement in epileptogenesis. © 2013 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . Neurodegeneration in temporal lobe seizures . . . . . . . . The role of innate and adaptive immunity in seizure disorders 3.1. Innate immunity in temporal lobe seizures . . . . . . 3.1.1. The role of cytokines . . . . . . . . . . . 3.2. Adaptive immunity in temporal lobe seizures . . . . 3.2.1. Antibodies to NMDA receptor . . . . . . . 3.2.2. Antibodies to VGKC complex . . . . . . . . 3.2.3. Antibodies to GAD . . . . . . . . . . . . 3.2.4. Antibodies to GM1 . . . . . . . . . . . . 4. Other immunological entities associated with temporal lobe seizures . . . . . . . . . . . . . . . . . . . . . . . 4.1. Viral etiology . . . . . . . . . . . . . . . . . . . 4.2. Immunoglobulins . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction ⁎ Corresponding author at: Department of Neurology and Rehabilitation, Tampere University Hospital, P.O. Box 2000, 33521, Tampere, Finland. Tel.: +358 3 311 66339; fax: +358 3 311 65346. E-mail address: [email protected]fimnet.fi (S. Liimatainen).

There is abundant evidence suggesting that both acute and chronic activation of inflammatory pathways are associated with the occurrence of seizures (Aronica and Crino, 2011; Friedman and Dingledine, 2011; Vezzani et al., 2011; Bauer et al., 2012). Proinflammatory cytokines are

0165-5728/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jneuroim.2013.08.001

Please cite this article as: Liimatainen, S., et al., Immunological perspectives of temporal lobe seizures, J. Neuroimmunol. (2013), http://dx.doi.org/ 10.1016/j.jneuroim.2013.08.001

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induced after experimental seizures and seizures in patients (Vezzani et al., 1999; Peltola et al., 2000a; Lehtimäki et al., 2003, 2007; Vezzani et al., 2011). There is also evidence for the chronic overproduction of proinflammatory cytokines in epilepsies of differing etiologies (Crespel et al., 2002; Ravizza et al., 2008; Alapirtti et al., 2009; Liimatainen et al., 2009a; reviewed by Vezzani et al., 2011). The activation of immunity mechanisms in seizures is further suggested by the fact that many different autoantibodies are associated with certain epileptic syndromes (Rogers et al., 1994; Bartolomei et al., 1996; Palace and Lang, 2000; Peltola et al., 2000b, 2000c; Eriksson et al., 2001; Ranua et al., 2004; Liimatainen et al., 2009a, 2009b; Bien and Scheffer, 2011; Irani et al., 2011a, 2011b; Quek et al., 2012). Clinical data indicate inflammatory changes in the brain tissue of posttraumatic epilepsy patients and an increased incidence of epilepsy in autoimmune diseases (MackworthYoung and Hughes, 1985; Bartfai et al., 2007). Moreover, immunomodulatory drugs may control seizures in the catastrophic epileptic encephalopathies that occur during childhood, such as ACTH treatment for infantile spasms and intravenous immunoglobulin (IVIG) for other refractory epilepsies (Mackworth-Young and Hughes, 1985; Aarli, 2000; Palace and Lang, 2000; Villani et al., 2007; Granata et al., 2011; Özkara and Vigevano, 2011). In addition to epilepsy, the temporal lobe is the primary affected brain area in both infectious and immunological encephalitides. Both anatomical factors and immunopathological etiologies, such as the relatively simple structure, the proximity of hypophysis–pituitary axis, and the tendency of neurotropic viruses and disorders causing limbic encephalitis to affect this brain region might explain the vulnerability of the temporal lobe. There is also evidence of a different inflammatory response to seizures in blood of patients with temporal lobe epilepsy (TLE) in comparison to those who have extra-TLE (XTLE) (Alapirtti et al., 2009; Liimatainen et al., 2009a). 2. Neurodegeneration in temporal lobe seizures TLE is the most common refractory epilepsy type in adults. The relationship between seizure activity and neuronal damage has been assessed in both experimental and clinical studies. Hippocampal circuit alterations, neuronal loss and mossy fiber sprouting induced by repeated seizures, can result in atrophy and long-term consequences, i.e. cognitive decline and intractability in TLE (Cavazos et al., 1991, 1994; Kälviäinen and Salmenperä, 2002; Kotloski et al., 2002). An association between the severity of hippocampal damage and the estimated total seizure number, seizure frequency, and duration of epilepsy has been shown also in humans by brain magnetic resonance imaging (MRI) studies or by histopathological studies in patients with refractory epilepsy (Van Paesschen et al., 1997; Salmenperä et al., 2001; Mathern et al., 2002). Elevated levels of neuron specific enolase (NSE), a marker of brain damage, have been found in a subset of patients acutely after single, brief seizures (Pitkänen and Sutula, 2002). Serial serum levels of NSE and S-100b protein, another marker of brain damage, were measured before and after epileptic seizures in patients with refractory epilepsy and elevated levels were found in TLE but not in XTLE patients (Palmio et al., 2008). 3. The role of innate and adaptive immunity in seizure disorders Inflammation is not a rare phenomenon in the epileptic brain. Brain inflammation constitutes from innate and adaptive arms. The innate immunity refers to an acute reaction of neuronal tissue to a particular stimulus, such as injury or seizures. This reaction includes a release of interleukins (ILs), interferons, complement proteins, prostaglandins (PG), chemokines and adhesion molecules, and activation of intracellular signaling pathways, such as nuclear factor kappa B (NFκB). The cell types involved in the innate immunity are mainly microglial cells, astrocytes, neurons (under specific circumstances) and potentially infiltrating granulocytes and macrophages. The adaptive immunity instead

refers to more selective reaction against specific antigens by infiltrating T- and B-leucocytes or microglial cells. Both innate and adaptive immunity have been detected in animal models of seizures but the role of innate immunity in the triggering of seizures is crucial (Bauer et al., 2012). Importantly, studies of the brains in animal models and of epilepsy patients suggest that both innate and adaptive immunity are activated during epileptogenesis (Ravizza et al., 2008; Vezzani et al., 2011) (Fig. 1). Especially TLE has shown inflammatory reactions in experimental studies of seizures (de Simoni et al., 2000; Vezzani et al., 2008a, 2008b). 3.1. Innate immunity in temporal lobe seizures 3.1.1. The role of cytokines Several experimental studies have revealed that cytokines modulate the susceptibility to limbic seizures (Vezzani et al., 1999, 2000). Pro- and anti-inflammatory mediators have been measured in brain tissue in experimental models of limbic status epilepticus or limbic seizures (structures of temporal lobe), including the rapid and robust activation of interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), IL-1 receptor antagonist (IL-1RA) and inducible nitric oxide synthase (iNOS) (de Simoni et al., 2000; Vezzani et al., 2008a, 2008b). IL-1β has proconvulsant properties in limbic seizure models (Vezzani et al., 1999, 2000); however, IL-1β is also induced in astrocytes in a rat genetic model of absence epilepsy, where it contributes to spike-wave discharges (Akin et al., 2011). Inhibition of IL-1β activity by IL-1RA or IL-1 converting enzyme (ICE) inhibitors has anti-convulsant effects (Vezzani et al., 2000; Ravizza et al., 2006). Furthermore, IL-6 has been reported to have both pro-convulsant (Kalueff et al., 2004) and anticonvulsant (Penkowa et al., 2001) properties. The effect of tumor necrosis factor-alpha (TNF-α) on seizures appears to be dependent on the type of exposure. Low concentrations of TNF-α may have anticonvulsant effect either when administered exogenously or expressed chronically in astrocytes (Balosso et al., 2005). Chronic over-expression of TNF-α may cause severe neurological dysfunction including seizures (Probert et al., 1997). Prostaglandin E2 (PGE2) is an inflammatory mediator produced by COX-2, an enzyme that is induced after seizures (Marcheselli and Bazan, 1996). PGE2 is thought to enhance excitatory neurotransmission in the hippocampus, and thereby act potentially as a proconvulsant molecule (Chen and Bazan, 2005). Studies in immature rats have shown that neuronal injury related to limbic seizures is closely dependent on age-specific production of cytokines (Rizzi et al., 2003; Ravizza et al., 2005). At early postnatal age (P9) rats were resistant to seizure induced neuronal damage and showed no glial activation or induction of pro-inflammatory cytokines. At P15, rats showed both up-regulation of pro-inflammatory cytokines and neuronal injury. Age at seizure occurrence has crucial role in epileptogenesis. Limbic seizures at P15 induced a decrease in seizure threshold at adult age compared to rats without postnatal seizures (Somera-Molina et al., 2007). Rats with previous postnatal seizures showed pronounced glial activation after seizures in the adulthood. Preventing pro-inflammatory up-regulation of cytokine after seizures in P15 rats using minozac, a small molecule cytokine inhibitor, this decrease in seizure threshold in adult rats was not observed. Also glial activation and release of proinflammatory cytokines was less prominent (Somera-Molina et al., 2009). These results indicate that limbic seizures and especially activation of cytokines in early life “prime” the brain and increase the susceptibility to seizures. Table 1 presents clinical studies on the role of cytokines in temporal lobe seizures. A robust increase of proinflammatory cytokine IL-6 was observed in recurrent generalized tonic–clonic seizures, whereas the increase was milder in single generalized and partial seizures (Peltola et al., 1998; Lehtimäki et al., 2004). The findings were similar in patients with new-onset seizures (Peltola et al., 1998). In patients with refractory focal epilepsy, video-EEG study demonstrated a rapid postictal increase

Please cite this article as: Liimatainen, S., et al., Immunological perspectives of temporal lobe seizures, J. Neuroimmunol. (2013), http://dx.doi.org/ 10.1016/j.jneuroim.2013.08.001

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The putative role of immunological activation in different stages of seizure disorders modified from Pitkänen and Sutula, Lancet Neurology 2002.

Immunological lesion (i.e. limbic encephalitis)

Initial insult Epileptogenic lesion

Traumatic brain injury Cerebrovascular disease Structural abnormality Infection

Latency period (epileptogenesis)

Inflammation Gliosis Neuronal loss Plasticity Molecular reorganisation

NMDA VGKC complex GAD Neurotropic viruses

IL-1β IL-6 TNF-α IL-1RA iNOS

Epilepsy (spontaneous seizures)

Refractory temporal lobe epilepsy

Controlled epilepsy

Cognitive and mood disorders

Disease modification

Innate immunity: βAPP, IL-1 β, IL-1RA, NFκB, IDO Adaptive immunity: GAD, GM1, glutein ab, IgA

Fig. 1. The putative role of immunological activation in different stages of seizure disorders modified from Pitkänen and Sutula, Lancet Neurology 2002. Immune-mediated lesion can act as a triggering event in the process leading eventually to development of epilepsy. Autoantibodies may be the cause of epilepsy in the context of limbic encephalitis (LE) affecting the temporal lobes. During the period of epileptogenesis activation of cytokines activation as a part of the complex system of innate immunity is significant leading to the development of refractory temporal lobe epilepsy (TLE). Recurrent seizures can activate both innate and adaptive immunity leading to further neuronal damage, which also involves cognitive decline and mood disorders. NMDA = N-Methyl-D-aspartic acid receptor antibody; VGKC complex = voltage gated potassium channel complex antibodies; GAD = glutamic acid decarboxylase antibody; IL-1α = interleukin-1α; IL-6 = interleukin-6; TNF-α = tumor necrosis factor-α; IL-1RA = interleukin-1 receptor antagonist; iNOS = inducible nitric oxide synthase; βAPP = β amyloid precursor protein; NFκB = nuclear factor kappa B; IDO = indoleamine 2,3-dioxygenase; GM1 = monosialoganglioside 1 antibody; IgA = immunoglobulin A.

in plasma IL-6 levels in those with TLE but not in patients with XTLE (Alapirtti et al., 2009). A similar difference was chronically observed in patients with TLE compared to patients with XTLE (Liimatainen et al., 2009a). The close relationship between the structures of mesial temporal and hypophysis–pituitary brain regions might explain the activation of inflammation in TLE compared to XTLE. On the other hand, therapeutic responses seem to be associated with cytokine production. Studies of the effects of vagus nerve stimulation (VNS) in patients with intractable epilepsy revealed a shift from a proinflammatory to an anti-inflammatory profile in blood. Higher IL-6 levels were detected in responders who showed a decrease in IL-6 levels following the administration of VNS; however, in non-responders, the level of IL-6 increased. Additionally, cortisol levels normalized after VNS administration, with a concomitant increase in neuroprotective tryptophan metabolite activity (Majoie et al., 2011). These findings suggest the significance of seizure type (TLE vs. XTLE) in generating proinflammatory reactions Table 1 The presence of cytokine activation in clinical studies of epilepsy patients with TLE. Cytokines Patient population

Findings

IL-1

Activation of IL-β

IL-6

Epilepsy surgery, 12 TLE + HS patients (Ravizza et al., 2008) (Sheng et al., 1994) 25 TLE patients, video-EEG study (Bauer et al., 2009) 20 patients, video-EEG study (Alapirtti et al., 2009) 86 patients with refractory and 5 patients with controlled focal epilepsy (Liimatainen et al., 2009a)

Activation of IL-1α Postictal IL-6 increase in TLE-HS Postictal IL-6 increase in TLE but not in extra-TLE Chronic increase of IL-6 in TLE but not in extra-TLE

IL = immunoglobulin; TLE = temporal lobe epilepsy; TLE + HS = temporal lobe epilepsy associated with hippocampal sclerosis; EEG = electroencephalogram.

in blood, probably reflecting the proinflammatory activity in the brain via hypophysis–pituitary–adrenal axis. Additional evidence for activation of cytokine network in TLE comes from histological studies. Levels of immunoreactive beta-amyloid precursor protein and IL-1 immunoreactive glial cells have been found to be increased in the resected temporal lobes of patients with TLE who have undergone epilepsy surgery, thus correlating with several experimental studies showing IL-1beta and IL-1ra immunoreactivity mainly in microglial cells (Sheng et al., 1994; Eriksson et al., 1999; Vezzani et al., 1999). Study of patients with TLE associated with hippocampal sclerosis (TLE + HS), patients with TLE without hippocampal sclerosis (TLE-HS) and non-epileptic control patients has revealed an overexpression of NFκB with severe neuronal loss in the hippocampi of the patients with TLE + HS in comparison to the other two study groups (Crespel et al., 2002). IL-1β and IL-1R activation has been observed in the brains of both epileptic rats and human TLE + HS patients. Studies of both experimental specimens and patient tissues derived from epilepsy surgery reinforce the idea that there exists an inflammatory reaction in TLE, although the bias associated with patient selection has to be taken into account. Interestingly, a correlation between IL-1beta positive neurons and number of seizures was found in specimen of cortical malformation or glioneuronal tumors, showing that cytokine network may modulate seizure susceptibility also in extratemporal epilepsies (Ravizza et al., 2006). 3.2. Adaptive immunity in temporal lobe seizures Different autoantibodies and autoimmune diseases have been associated with epilepsy. Some of these epileptic syndromes respond well to immunotherapy. NMDA receptor, voltage-gated potassium channel (VGKC) complex, glutamic acid decarboxylase (GAD), GM1 and glutein-

Please cite this article as: Liimatainen, S., et al., Immunological perspectives of temporal lobe seizures, J. Neuroimmunol. (2013), http://dx.doi.org/ 10.1016/j.jneuroim.2013.08.001

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specific antibodies, among others, have been associated with TLE or nonparaneoplastic limbic encephalitis with seizures (Bartolomei et al., 1996; Palace and Lang, 2000; Peltola et al., 2000b; Vincent et al., 2004; Dalmau et al., 2008; Irani et al., 2008; Peltola et al., 2009; Liimatainen et al., 2010; Malter et al., 2010; Irani et al., 2011a, 2011b; Quek et al., 2012) (Table 2). Despite the causative agent, limbic encephalitis is characterized by severe illness with memory problems, cognitive symptoms and seizures that usually originate in the temporal lobe. A paraneoplastic etiology was initially considered, but nowadays non-paraneoplastic form of limbic encephalitis is considered more common that paraneoplastic one. Antibodies against both neural surface antigens and intracellular antigens have been observed to be associated with autoimmune limbic encephalitis. NMDA receptor and VGKC complex antibodies are regarded as surface antibodies with a direct pathogenetic mechanism in neurological autoimmune diseases. Neurological symptoms in these disorders usually are immunotherapy responsive with a significant decrease of antibodies, whereas those limbic encephalitides with intracellular antibodies such as GAD antibody are considered poorly responsive to immunotherapeutic interventions and the overall prognosis are considered worse. The recent study demonstrated the differences between antibodies against neural surface antigens and intracellular antigens, T cell mediated cytotoxicity being an important mechanism of neurodegeneration in cases with intracellular antigens (Bien et al., 2012). 3.2.1. Antibodies to NMDA receptor New particularly interesting evidence has demonstrated that immunotherapy-responsive encephalitis can be associated with NMDA receptor antibodies (Dalmau et al., 2008). Immunoreactivity is directed to NR1/NR2 subunit of NMDA receptor. The disorder is characterized by psychiatric symptoms, memory problems, seizures, dyskinesias and autonomic instability (Dalmau et al., 2008). Although the cortex is more or less diffusely affected in this disorder, there are reports of patients with signal changes only in the temporal lobe (Graus et al., 2008; Zandi et al., 2009). The pathophysiological role of NMDA receptor antibodies is suggested by in vitro and in vivo findings where these antibodies are capable of reducing NMDA receptors on hippocampal neurons selectively and reversibly (Dalmau et al., 2008; Hughes et al., 2010). Majority of the patients are women in whom the disorder is associated with ovarian teratoma (Dalmau et al., 2008). However, in 40% of the patients no evidence of tumor was found. 76% has seizures in acute stage. Intrathecal synthesis of NMDAR was observed frequently and the serum antibody titer was associated with the outcome. Irani

and co-workers emphasized the non-paraneoplastic form of NMDAR encephalitis to be more common than was previously expected; they also described the temporal evolution of the symptoms from cortical to subcortical structures (Irani et al., 2010b). In some patients the most striking phenotype is epilepsy. There is a small series of women with new-onset epilepsy of unknown etiology; five out of 19 patients had NMDAR antibodies. However, four of them had other symptoms of limbic encephalitis such as psychiatric lability (Niehusmann et al., 2009). 3.2.2. Antibodies to VGKC complex Antibody associated with limbic encephalitis that strongly affects the temporal lobe is the VGKC complex antibody (Vincent et al., 2004; Irani et al., 2008). The VGKC complex is associated with three different proteins, CASPR2, LGI1 and Contactin-2, two former being the principal targets of VGKC antibodies (Irani et al., 2010a). This encephalopathy seems to be reversible especially when treated with immunotherapy (Vincent et al., 2004). The most common symptoms are memory loss, confusion and seizures (in 90% of patients). Majority of patients with VGKC complex/LGI1 limbic encephalitis have specific seizure type called faciobrachial dystonic seizures as a prodromal feature of this disorder (Irani et al., 2011b). Measurements of brain activity via MRI have shown a signal increase (or atrophy in later stages) in the temporal lobes with variable changes in the cerebrospinal fluid (CSF) of patients with encephalitis and VGKC complex antibodies (Vincent et al., 2004). Immunotherapy such as IVIG and plasma exchange has proved effective by diminishing the symptoms and decreasing the titer of VGKC complex antibodies. Epileptogenic properties of LGI1 antibodies have been observed in an experimental study with incubation of serum of a patient with limbic encephalitis containing these antibodies in hippocampal cells (Lalic et al., 2011). 3.2.3. Antibodies to GAD The phenotype of GAD antibodies in patients with seizures can be divided into two different groups, one with an acute or subacute form of GAD antibody associated with limbic encephalitis that affects the temporal lobes and another with chronic epilepsy where a proportion of patients have high GAD antibody titer and intrathecal synthesis of GAD antibody. A high titer of GAD antibody was observed in some patients with limbic encephalitis (Malter et al., 2010). Their seizures proved refractory to the use of antiepileptic drugs (AEDs) and immunotherapy. We measured the concentration of GAD antibodies in 252 well-

Table 2 Autoantibodies in patients with temporal lobe seizures. Antibody

Patient population

Epilepsy type in antibody positive patients

AMPA GABA GAD

Encephalitis (Lai et al., 2009) Encephalitis (Lancaster et al., 2010) Drug resistant epilepsy (Peltola et al., 2000b) Drug resistant epilepsy (McKnight et al., 2005) Mixed epilepsy syndromes (Errichiello et al., 2009) Controlled and refractory epilepsy (Liimatainen et al., 2010) Encephalitis (Malter et al., 2010) Therapy-resistant, localisation-related epilepsy (Peltola et al., 2009) Mixed epilepsy syndromes (Bartolomei et al., 1996) Encephalitis (Dalmau et al., 2008) Cryptogenic new-onset epilepsy in young women (Niehusmann et al., 2009) Encephalitis (Irani et al., 2010b) Encephalitis (Vincent et al., 2004) Encephalitis (Thieben et al., 2004) Neurological patients (Tan et al., 2008) Encephalitis and epilepsy (Irani et al., 2008, 2010a) Encephalitis (Lai et al., 2010) Encephalitis (Malter et al., 2010) (Irani et al., 2011b)

Focal or generalized seizures Complex partial and generalized seizures TLE Long standing epilepsy TLE TLE and IGE TLE TLE + HS Cryptogenic complex partial seizures Complex partial and other types of seizures Diffuse seizure origins (extra-TLE) Seizures Partial or generalized seizures Temporal lobe origin complex partial Seizures Temporal lobe seizures Temporal lobe seizures TLE Faciobrachial dystonic and temporal lobe seizures

Gluten GM1 NMDA receptor

VGKC complex

AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA = γ-aminobutyric acid; GAD = glutamic acid decarboxylase; IGE = idiopathic generalized epilepsy; GM1 = monoganglioside 1; NMDA receptor = N-methyl-D-aspartate receptor; VGKC complex = voltage gated potassium channel complex; TLE = temporal lobe epilepsy; TLE + HS = temporal lobe epilepsy associated with hippocampal sclerosis.

Please cite this article as: Liimatainen, S., et al., Immunological perspectives of temporal lobe seizures, J. Neuroimmunol. (2013), http://dx.doi.org/ 10.1016/j.jneuroim.2013.08.001

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examined patients with epilepsy and observed a high titer of GAD antibody in a distinct group of patients with refractory epilepsy (Liimatainen et al., 2010). Six of the seven patients with a high titer had TLE, and two had intrathecal synthesis of GAD antibody. All of the patients had several autoantibodies, and 71% of them had autoimmune diseases that supported an immunological etiology for their epilepsy. One of the TLE patients with a very high concentration of GAD antibody was included in our previous study of 51 patients with refractory focal epilepsy (Peltola et al., 2000b), during which the patient showed signs of the intrathecal synthesis of GAD antibody. Between these two studies, the patient underwent amygdalohippocampal resection, which resulted in the elimination of seizures and an absence of intrathecal synthesis. In a previous study, two patients had very high concentrations of GAD antibody, both of whom had long-standing TLE and intrathecal synthesis (Peltola et al., 2000b). Although the pathogenic significance of GAD antibody in neurological diseases is not fully known, there is evidence that GAD antibody in patients with stiff person syndrome (SPS), late onset cerebellar ataxia (LOCA), or epilepsy, reduces GAD enzyme activity and GABA synthesis or transmission (Dinkel et al., 1998; Ishida et al., 1999; Mitoma et al., 2000; Takenoshita et al., 2001; Vianello et al., 2005). However, the serum from GAD antibody-negative patients did not affect GABA production in rat cerebellar samples, suggesting disease-specific epitope recognition in GAD antibody-mediated disorders (Dinkel et al., 1998). Despite the intracellular nature of GAD (in addition to onconuclear antigens in paraneoplastic disorders) it can be used as a diagnostic biomarker for the autoimmune origin of epilepsy. This is supported by TLE with high titer GAD antibody and intrathecal synthesis of GAD antibody in these patients (Peltola et al., 2000b; Liimatainen et al., 2010). 3.2.4. Antibodies to GM1 The presence of antibodies to GM1 gangliosides was measured in 64 patients with epilepsy. In that study, researchers observed four patients with increased titers of GM1 antibodies, all of whom suffered from complex partial seizures and had normal brain MRIs (Bartolomei et al., 1996). The reactivity of sera of these patients was different from sera of patients with peripheral neuropathies and GM-antibodies suggesting different antibody properties in patients with diseases affecting CNS and peripheral nervous system (Bartolomei et al., 1996). GM1-antibodies of epilepsy patients did not react against Gal(β1–3)GalNAc epitope which is the main target of autoantibodies in peripheral neuronal diseases (Bartolomei et al., 1996). However, there is no clear evidence of propensity of GM1 antibodies to affect specifically temporal lobe. 4. Other immunological entities associated with temporal lobe seizures 4.1. Viral etiology The tendency of neurotropic viruses and other virus types that are capable of triggering seizures to invade the mesial temporal lobe serves as an example of the vulnerability of this brain region. Patients with viral encephalitis most commonly develop seizures during the acute period, and a proportion will develop remote symptomatic epilepsy. The data suggest that the activation of the immune cascade is an important event in triggering seizures (Leung and Robson, 2007; Getts et al., 2008). The studies of brain tissue samples obtained from epileptic patients have shown the presence of herpes virus DNA in TLE. Polymerase chain reaction (PCR) and immunofluorescence tests were used to study the presence of human herpes virus-6 (HHV-6) in patients with epilepsy. HHV-6B DNA was detected in 69% of patients with mesial TLE (MTLE) in contrast to no evidence in patients with other epilepsy syndromes (Fotheringham et al., 2007). In HHV-6 infected astrocyte cultures a significant decrease of glutamate transporter EAAT-2 expression was observed. A fascinating hypothesis of immune system activation in

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temporal lobe seizures was presented in the retrospective study of patients with TLE + HS (Bien et al., 2007). In that study, 9 out of 38 patients had a diagnosis of definite limbic encephalitis based on history, and another 11 patients exhibited a possible diagnosis of limbic encephalitis with typical MRI findings. Considering the high incidence of HS in TLE and the strong data regarding the immunological factors in TLE, a subclinical infectious etiology or autoimmune encephalitis could contribute to epilepsy in some circumstances. 4.2. Immunoglobulins Immunoglobulin (Ig) subclass abnormalities have traditionally been linked to the side effects of conventional AEDs, such as phenytoin and carbamazepine. Conversely, more specific data suggest that the tendency for patients with epilepsy to acquire changes in Igs is associated with epilepsy itself (Callenbach et al., 2003). In a study of 282 children with new-onset epilepsy, increased concentrations of IgA and IgG were found before the administration of AED treatment (Callenbach et al., 2003). The associated findings have been highly inconsistent with decrease or increase of IgA, IgG and IgM without association with certain clinical features with epilepsy. However, in our comprehensive, wellexamined patient group of 272 consecutive epilepsy patients, most of them with refractory epilepsy (all had AED treatment), we discovered that an abnormally high level of IgA was associated with TLE compared with other epilepsy types. In the group of patients with high levels of IgA all had TLE (Liimatainen et al., 2013). These findings support and confirm the idea that immunological activity is involved in the mechanism of refractory TLE in contrast to XTLE and PGE. 5. Conclusions In this review we have evaluated the most important mechanisms of inflammatory reactions in TLE. There is evidence that several inflammatory mediators have a specific role in temporal lobe seizures; however, in some circumstances other brain regions are affected as well. From the clinical point of view, in epilepsy patients the significance of the activation of the immune system and the induction of inflammatory mediators is still unclear. The cause–effect relations are difficult to evaluate in cross-sectional studies including patients with different kinds of epilepsy. Thus far, it is not known whether inflammation is the cause, effect or both, of temporal lobe seizures. There are, however, several hypotheses based on experimental evidence on how specific inflammatory pathways might be activated in the epileptic brain, and may contribute to epilepsy. It is far too simplistic to consider etiology as the only explanatory factor for induction of immunity-related mechanisms in epilepsy. This is supported by the fact that an epileptogenic lesion does not always explain the observed alterations. An autoimmune mechanism may be one pathogenic factor in some symptomatic epilepsies. Patients with a polyautoimmune pattern and refractory TLE should be identified, and immunomodulatory or immunosuppressive treatment should be attempted. Immunological markers could be used as a diagnostic tool in the differentiation of TLE from XTLE and as putative biomarkers for refractoriness in patients with an unclear clinical condition. Further research is needed to more precisely determine the significance of immune and inflammatory markers in seizures, epileptogenesis and refractory TLE. Conflicts of interest None of the authors has any conflict of interest to disclose. References Aarli, J.A., 2000. Epilepsy and the immune system. Arch. Neurol. 57, 1689–1692. Akin, D., Ravizza, T., Maroso, M., Carcak, N., Eryigit, T., Vanzulli, I., Aker, R.G., Vezzani, A., Onat, F.Y., 2011. IL-1β is induced in reactive astrocytes in the somatosensory cortex

Please cite this article as: Liimatainen, S., et al., Immunological perspectives of temporal lobe seizures, J. Neuroimmunol. (2013), http://dx.doi.org/ 10.1016/j.jneuroim.2013.08.001

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Please cite this article as: Liimatainen, S., et al., Immunological perspectives of temporal lobe seizures, J. Neuroimmunol. (2013), http://dx.doi.org/ 10.1016/j.jneuroim.2013.08.001