Melanie Siv, Doctor of Pharmacy Candidate, Wingate University School of Pharmacy
Intractable Childhood Epilepsy Alliance Drug Information Rotation
Harriet Davies, PharmD
The aim of this article is to review evidence discovered regarding the link between epilepsy and inflammation including the use of IVIg for treatment in epilepsy. Trauma and infection in the brain will initiate and recruit the immune system to the site of damage. Inflammation has been observed in both animal and humans. Pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α have been detected to be present in seizure induced rodents and humans with epilepsy. Intravenous immunoglobulin (IVIg) has been implicated for use in epilepsy since 1977. Improvement was seen in children with severe epilepsy being treated for respiratory infections with IVIg. Other anti-inflammatory agents, corticosteroids, nonsteroidal anti-inflammatory drugs, and adrenocorticotropic hormone have also been employed as viable treatment options as they have shown to have an anti-epileptic effect. Variable dose have been used in trials and there are no consistent protocols as what dose to use. Nevertheless, IVIg has demonstrated itself to be a promising treatment option. It has shown positive results in intractable epilepsies such as West syndrome. Also, no major adverse effects have been reported; at least none that has rendered the need to discontinue from the studies. Despite positive evidence, current guidelines do not include IVIg for treatment of epilepsy. Further studies are needed to fully establish use.
Immunology response overview
Epilepsy is characterized by recurrent, unprovoked, spontaneous seizure activities and affects 0.5-1.5% of the world’s population. 1 Over the years, it has been suggested that inflammation plays a role in epilepsy. Inflammation is evoked by pro-inflammatory modulators meant to protect from and heal injuries to the body. This paper will describe the normal process of inflammation, how the inflammatory cascade is initiated, and how inflammation relates to epilepsy.
In the past, the central nervous system (CNS) was considered to be immunoprivileged. This means it is less likely to reject graft tissue because there are low levels of monocytes and leukocyte present, and due to the blood brain barrier (BBB).2 Now it is evident that an immune response and inflammatory reaction occurs in the CNS. We now know that the immune system is active in the CNS and inflammatory reactions occur beyond the BBB. The reaction can occur systemically from a damaged BBB or it can be intrinsic. 2,3 In a normal condition, the BBB serves as a protective feature to the CNS. It prevents the entry of undesirable substances, such as plasma born substances and immune cells. 2,3
Pro-inflammatory and anti-inflammatory cytokines, chemokines, and prostaglandins are responsible for the production of an early immune response. These immune-mediators are released due to trauma, infection and ischemia by microglia and astrocytes.1, 4,5 It has been suggested by Rodgers et al (2009) and Bernardio et al (2005) that microglia plays a greater role compared to astrocytes.1, 4 Microglia is part of a major class of glial cells and are a part of the brain’s immune system. Glial cells monitor for signals from brain damage, such as that caused by seizures.4 According to Choi and Koh (2008) and Vezzani and Granta (2005), astrocytes are a major player in inflammation of the CNS as well and are thought to create a balance between endothelial stability and the permeability of the blood brain barrier (BBB).2-3 Once damage has been detected by glial cells they will proceed to the area to repair.4
Rodgers et al. (2009) proposes that early inflammation largely increases in neuronal excitability.4 After injury to the brain, an inflammation response is produced, as demonstrated by glial cells’ rapid release of pro-inflammatory cytokines. It is suggested that rapid triggering of immune response is in the brain can be a precursor to seizures.4 The most well-known cytokines include interleukin -6 (IL-6), Tumor Necrosis Factor – alpha (TNF-α) and Interleukin-1 beta (IL-1). IL-1 is involved in the synthesis of IL-6 and TNF-α.6 Increase in these cytokines is usually followed by a cascade of inflammatory events that could possibly recruit other cells of the adaptive immune system for a response; the responses are remembered and each time a stronger response is produced.7
In order to assess the connection between inflammation and epilepsy and the use of immunomodulators such as IVIg, for the treatment of epilepsy, a search for publications was performed. Articles were searched using PubMed with limits set to find publications in English. They could be clinical trials, case reports, guidelines, controlled trials, reviews or editorials. Trials were not limited to human studies. No limits were set based on gender or age. All material found were assessed for information regarding history of use, mechanism of action, and efficacy of efficacy of IVIg. Also, an explanation of the link between inflammation and epilepsy was included in the search and evaluation.
Inflammation and Epilepsy
Inflammation is known to cause several neurological disorders such as Parkinson’s disease, meningitis, and encephalitis. Inflammation associated with epilepsy has only recently been acknowledge and is the subject of discussion, abstracts and publications at professional epilepsy meetings worldwide. The discoveries of involvement in microglia and astrocytes have been noted to be found associated with seizures in both human and animal models
Genes are manipulated in mice and it can help to identify causes of epilepsy.2 Mouse models display evidence of inflammatory mediators.8 An increase in cytokines has been found in the brains of rodents which have had either chemically or electrically induced seizures.2
In another animal model, it was found that IL-1, IL-6 and TNF-α are released by seizures and were found to be upregulated within 24 hours of seizure induction.9, 10 In models where microglia and astrocytes were activated, IL-1β was greatly increased and found in the forebrain of rats during an acute seizure. IL-1β levels did not drop to the initial level even after the seizure had subsided. IL-6 and TNF-α in glial cells were also increased, but only briefly. Due to the presence of IL-1β after the seizure cessation, it is thought that this cytokine has a mechanistic role in production of spontaneous seizure.8
There have been eminent findings in transgenic mice with over expression of IL-6 or TNF-α; they are in a state of chronic inflammation. Chronic IL-6 results in more astrocytes, microglia, pro-inflammatory cytokines, and impaired BBB. The mice also developed neurological deficits and spontaneous seizures due to the increase in IL-6. They are therefore more inclined to seizures and neuronal cell loss. In addition, seizures were more likely to occur due to increase in glutamate produced by TNF-α and inhibitor or reuptake from IL-1β.2 In comparison, mice with no IL-6 have an impaired inflammatory response.
IL-1β in is present in astrocytes during chronic inflammation. During a seizure, there are more astrocytes containing IL-1β than microglia containing IL-1β. In astrocytes, IL-1β is present independent of seizure activity; however, in microglia, IL-1β is present only during high frequency seizures.7 IL-1 acts as a pro-convulsant and when present in ictal stage, exacerbates seizure activity. The pro-convulsant activity is hypothesized to be due to increased glutamatergic neurotransmission. In mouse models, a chronic pro-inflammatory state can risk for seizure and other neurogenic disorders.1 IL-1Ra in astrocytes inhibits IL-1β. It has been observed that in mice given more IR-1Ra, which is a naturally occurring antagonist to IL-1β, have fewer seizures. This is an indication of astrocytes role in epilepsy since IL-1β is in astrocytes.5 IL-1B alters BBB permeability and increases neuronal hyperexcitability. Compromised BBB and responding leakage correlates with seizure frequency in rats.7
In rodents, lipopolysaccharide (LPS) has been injected to trigger the brain to produce an inflammatory response which is similar to one that would occur with a systemic infection. An increase in cytokinins such as, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6 is seen after injury or damage to the CNS.5
During epileptic activity in rodents there is an increase in pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. Experimental models have shown that after induction of an event in the brain which exposes it to the inflammatory process, chronic inflammation is observed.7 Based on this observation, an immune related mechanism may produce seizures in humans.5
It has been seen in other neurological disorders, such as Alzheimer’s and Parkinson’s disease that the inflammation is present and contributes to the cause of disease. While still hypothetical, a link between inflammation induced epilepsy as a theory is highly supported. The most significant proof that inflammation and the immune system plays a role is based on studies on Rassmussen encephalitis, an epileptic syndrome characterized by inflammation.2,5 Inflammation is not only seen in Rasmussen’s encephalitis, but is noted in other epilepsies which do not involve inflammatory reactions, for example, temporal lobe epilepsy and tuberous sclerosis.2,7 Also, there are suspicions of inflammatory response involvement stemming from the presence of pleocytosis, an increase in cells, in cases of no infection present in the CSF in those with general convulsions .2
Similar to the chronic brain inflammation seen in rodents, in human with total lobe epilepsy (TLE) and hypcampal sclerosis (HS) have chronic brain inflammation based on brain tissue staining, of 12 specimen, revealing IL-1β activation by glial cells.7 In particular, IL-1 production is increased in those with TLE.11 Vezzani (2005) indicates findings which demonstrated presence of immunoreactive cell, IL-1, which was three times greater in an epileptic sample compared to control tissue.5 It was also noted that the cells had activated microglia.5 IL-1β and NF-κB are present in neurons and glia in TLE, indicating involvement of the immune system and inflammatory activity.2 This was observed by Choi and Koh (2008) in children who had epilepsy surgery.2 IL-6 has been noted to be significantly elevated in epilepsy patients, both in plasma and CSF in patients with tonic–clonic seizures.2 In patients with West syndrome and tuberous sclerosis, an increased level in pro-inflammatory cytokines and markers of inflammation have been found in the CSF and is suspected to originate from the brain.5,8 Brain inflammation is a chronic process that develops after the primary insult and can continue despite absence of ongoing seizures.7
In addition, there has been an abundance finding of inflammatory markers in the CSF, serum, and brain in patients with epilepsy. The proof is presence of pro-inflammatory markers’ in the brain tissue from patients undergoing surgery due to drug resistance epilepsy.3 One major discovery is the antiepileptic effect noted with the use of anti-inflammatory agents, steroid, ibuprofen, and indomethacin.3,5
IVIg and other anti-inflammatory agents used for treatment
Thirty percent of patients with epilepsy do not experience adequate seizure control spite current available treatment options. Many alternatives are sought in hopes of controlling seizures and reducing morbidity and mortality. Corticosteroids and adrenocorticotropic hormone (ACTH) are used to treat certain types of epilepsy, including Lennox-Gastaut syndrome (LGS), myoclonic seizures, and West syndrome. Both steroids and ACTH act as anti-inflammatory mediators and suppresses immune responses.2 In retrospective studies, these agents have produced large improvements in seizure control prior to the acknowledgement of immune system involvement.10 The exact mechanism is unknown, but it is suspected that steroids act on neurotransmitters, GABA and glutamate, and thus causing an inhibition of seizures. IVIg provides a broad immunomodulating effects.12 There are potential toxicities caused by interactions of antibodies in IVIg, increase in IgG levels, or even due to manufacturing impurities. 14
ACTH was first used for treatment in drug resistant epilepsy in the 1950s, and later was found to have astounding results in the treatment of infantile spasms, or West Syndrome. 12, 13 Use of ACTH or steroids for treatment of seizures in West syndrome and LGS has lead to a decrease in frequency of seizure in some patients, and sometimes up to 6-8 weeks elapsed before seizure freedom was attained.13
Intravenous immunoglobulin (IVIg) is a human polyclonal IgG product pooled from 2,000-10, 000 donors.12,14 It is typically used for the treatment of immunodeficiency, severe infections, autoimmune and inflammatory disorders.9,14 It is sometimes used in intractable epilepsies such as West syndrome and Lennox Gastaut Syndrome (LGS).15 In 1977, Pechadre et al. used IVIg for treatment of upper respiratory tract infection in children with severe epilepsy noted a decrease in seizure frequency and severity. Another link between immune deficits was noted in the 1980’s treatment with IVIg provided successful results in childhood epilepsies. Decreased levels of IgA in10 – 20% of childhood epileptics and decreased levels of IgG have been associated with chronic infections. However, much of the available studies have reported conflicting results, possibly due to a variety of factors in the patient population.9 It has also been suggested by Ishizaka et al that the low levels of IgA and IgG are possibly if treated with phenytoin and carbamazapine (Duse et al 1996) as it is known to cause such deficiency.16 However, Duse et al. (1996) cited the findings of Gilhus and Lea, that the large number of IgA deficit cannot all be attributed to phenytoin.16
Mechanism of Action
Based upon van Engelen, Renier, Weemaes (1994), IgG concentrations were increased in the CSF, in patients with West Syndrome or LGS, therefore IgG crosses the blood-CSF barrier.17 Therefore, it is plausible that IVIg is capable of reaching the brain and acting centrally.
IVIg may work on the brain if the BBB is damaged or abnormal in which case IgG can pass through the BBB. When the brain is injured, lymphocytes are recruited to the site; IVIg’s immunomodulator effects act as a mediator. IVIg may work differently depending on the epileptic syndrome due to the variations in the course of the different epilepsies. 10, 18 In addition, it is now known it is necessary to have intact IgG, to display immunoglobulin treatment.19 The Fc fragment must be present in order for the immunoglobulin to have a therapeutic effect. This was evidence by an experiment using intact IgG with Fc fragment compared with pepsin-treated IgG, which is composed of F(ab)2. The results indicated pepsin treated IgG to be ineffective.14
The mechanism of action by which IVIg decreases seizure frequency and severity is not fully elucidated. One theory is that IVIg works by compensating for IgG deficiency which is prevalent in about 25% of patients. This is based on the study by Duse et al (1996) where the children, whom had IgG deficiencies, were treated with IVIg responded and after IVIg was discontinued, they had a relapse.16 This theory was abandoned since only two of the five children had IgG levels return to baseline, or pretreatment levels, after discontinuation.14
IVIg reduces IL-1 in macrophages and IL-6 produced by monocytes. TNF-α reduction had conflicting data. IVIg is also able to increase IL-1 receptor antagonist IL-1Ra.20 Mikati et al (2010) proposes possible seizure related mechanism of IVIg is an increase of natural killer cell activity and a decrease of cytokine levels in the brain based upon the theory of cytokine involvement in epilepsy and its role in inflammation.21
IVIg may work via non-immunological mechanisms as well. It is suspected IVIg interferes with the seizure pathway with a neuromodulating effect creating an anticonvulsant effect. The anticonvulsant effect has been evident in cats with epilepsy given IVIg treatment.14 An immediate response suggest of possible neuromodulating effect.12
There have not been many large or double-blinded, placebo controlled studies regarding the efficacy of IVIg for the use of epilepsy. It has been reported that IVIg responds differently in different forms of epilepsies. For example, there is good response rate in patients with West Syndrome and Lennox-Gastaut syndrome (LGS).9, 14
In a review article written by van Engelen et al (1994), 23% of patients achieved complete seizure remission.14 He reviewed twenty-four studies with 368 patients; all patients had intractable epilepsy. In nine cases, it was reported that the patients had West syndrome, Lennox-Gastaut (LGS) or both. Dosing varied from 0.3g/kg to 6.8g/kg for duration as short as 0.15 months up to 12 months. Later, studies performed by Ariizumi et al reported that treatment with doses of IVIg, 100 mg/kg, in 16 children with epilepsy had an improvement in 50%.10 They also noted that better results were seen in those with low IgA levels and in patient that have had seizures for less than 2 years.10 Resulted with the same finding that about 50% of cases had an improvement and were also deficient in IgA or IgG (van Rijckevorsel 1999) had been seen as well.10
Children with Rasmussen encephalitis and Landau-Kleffner syndromes have had beneficial results and improvements with IVIg treatment. Billiau et al (2005) conducted a study and found none of the participants became seizure free.9 However, he noted that 31% of the studied population demonstrated a beneficial improvement with ≥ 50% reduction of seizure frequency and 23% had a 20-50% seizure reduction.
Landau-Kleffner syndrome (LKS) is a rare, epileptic aphasia (language disturbance), neurological disorder.2,22 In LKS, the preferred treatment option currently is corticosteroids. The setback with use is the long duration of action of high dose steroids which may potentiate significant and serious adverse effects.18 Furthermore, no controlled studies have been completed. IVIg has been tested in patients with LKS. It was given for five days at a dose of 400 mg/kg, followed by 400 mg/kg every three weeks up until week 25. After treatment, there was a one year follow-up. Positive results were noticed, but it is still not a confirmed treatment option because a lack of controlled, randomized studies.18 From the study, only six children were included, all of which had normal IgA and IgG levels. During administration of IVIg, none of the participants had a seizure. The trial concluded with three of the six children having withdrawn and only one of the three who completed the study had a favorable response. The history of seizure frequency in participants was not reported. Based upon such findings, Arts et al (2009) concluded that no conclusion could not be made on the use if IVIg for LKS, and corticosteroids still remain the drug therapy of choice.18
Uran et al (2000) used IVIg for treatment of intractable epilepsy. The study included ten patients with intractable epilepsy between the ages of four and eight. 400 mg/kg of IVIg was given during the first week for five doses. Then one dose was give during the second and fourth week. IVIg administration continued for six months and patients received a dose every four week. The result was response in sixty percent. One patient had complete remission while the other five patients had 50-75% reduction of seizures.15
Other benefits from use of IVIg observed includes EEG improvements.15 Billiau (2005) writes that there is improvement in language and EEG after treatment with corticosteroids and IVIg or with IVIg alone in patients with LKS.9
Despite positive responses in studies, according to the European Federation of Neurological Science Society, use of IVIg for childhood with refractory epilepsy resulted in improvement in only half of the patients and relapse was common.21
Currently no standard protocol for IVIg treatment in epilepsy exists. Different studies have used a variety of dosing strategies; it has varied between 0.3 to 6.8 g/kg.14,15 No studies mentioned the need to discontinue or stop IVIg treatment due to adverse events.15,17 Some adverse effects include fever, malaise, myalgia. More severe but rarer effects include alopecia, septic meningitis, and possibly nephrotoxicitiy.14
Current treatment guidelines do not include the use of IVIG for treatment of epilepsies. The guidelines by the EFNS also do not recommend use of IVIG in patients with intractable childhood epilepsy. Lack of controlled studies using IVIg for treatment of epilepsy is the greatest prevention for not using this treatment as an alternative.12
Insults to the brain, such as trauma and infections, can cause inflammation.3 It has become clear there is some relationship between the immune system causing inflammation which can induce seizures. If left untreated, inflammation can become chronic and predispose patients to seizures. ACTH and steroid use for treatment of certain epileptic syndromes provides a foundation to support use of IVIg. Furthermore, there has been successful use of IVIg, especially in patients with West syndrome and LGS. However, further studies in the use of IVIg as treatment for epilepsy are still warranted. With more recent evidence of links between inflammation and epilepsy, it is apparent more long term studies are needed, especially in epileptic syndromes that leave children permanently neurologically impaired and have high mortality rates.
Systemic progesterone as anti-inflammatory treatment is a new option studied for the treatment of epilepsy. Progesterone is a neurosteroid that could potentially have immunosuppression effects and contributions to neuronal excitability changes; firing to neurotransmitters are suppressed.2,23,24 Current findings have suggested benefits mostly in females with decreases in spike frequency. This is largely based upon noted protection in female rats and none in male rats23. Anti-inflammatory agent research for the treatment of epilepsy is a well warranted and exciting possibility for the future of epilepsy treatment.
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