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Epilepsia, 52(Suppl. 3):45–51, 2011 doi: 10.1111/j.1528-1167.2011.03036.x

IMMUNITY AND INFLAMMATION IN EPILEPSY

Immuno- and antiinflammatory therapies in epileptic disorders

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*C¸ ig˘dem O zkara and y Federico Vigevano

*Department of Neurology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey; and y Division of Neurology, Bambino Gesu` Children’s Hospital IRCCS, Rome, Italy

SUMMARY

Several experimental and clinical studies demon- strated an immunologic basis for different forms of epilepsy. A wide range of immune abnormalities have been reported suggesting the existence of various subtypes of epileptic syndromes with different immunopathogenetic mechanisms. This

evidence gives rise to the development of immu- nologic and immunomodulatory treatments such as usage of steroids, plasmapheresis, and intrave- nous immunoglobulins, which will be discussed briefly in this article. KEY WORDS: Immunological therapies, Epilepsy, Steroids, IVIg, Plasmapheresis, ACTH.

Several experimental and clinical studies demonstrated an immunologic basis for different forms of epilepsy. A wide range of immune abnormalities have been reported suggesting the existence of various subtypes of epileptic syndromes with different immunopathogenetic mecha- nisms. This evidence gives rise to the development of immunologic and immunomodulatory treatments such as usage of steroids, plasmapheresis, and intravenous immu- noglobulins, which will be discussed briefly in this article.

Steroids for Treatment of Epilepsy (H. Cross, London, United Kingdom; O. Dulac, Paris, France)

The first report on the use of steroids in epilepsy dates back to 1942 and was based on an earlier observation that individuals with epilepsy had seizures provoked upon both increased water intake and administration of antidiuretic hormone (ADH). Working on the hypothesis that deoxy- cortisone had effects opposite to that of ADH and, there- fore, could have antiepileptic properties, it was used in one patient with benefit (McQuarrie et al., 1942). In 1950, another six patients were reported; they were treated with adrenocorticotropic hormone (ACTH) on the rationale

Address correspondence to ig˘ dem zkara, Department of Neurol- ogy, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey. E-mail: cigdemoz@istanbul.edu.tr

Wiley Periodicals, Inc. ª 2011 International League Against Epilepsy

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that they were looking for a treatment that produced meta- bolic effects similar to those of the ketogenic diet. Although it is now known that this was most likely not the true mechanism, a positive effect was seen in four of the six children (Klein & Livingston, 1950). Later on, several authors reported on the apparently serendipitous use of ACTH in infantile spasms (IS) with resolution of both spasms and the associated electroencephalography (EEG) abnormality) (O Regan & Brown, 1998). Steroid use for the treatment of epilepsy includes ACTH, prednisolone, and prednisone (a prodrug that on passage through the liver is converted to prednisolone) and hydrocortisone. ACTH is not a steroid, but a 39 amino-acid polypeptide secreted by the anterior pituitary; its release stimulates the adrenal gland to produce the glucosteroid cortisol. Steroids are well recognized to exert important antiinflammatory and immunosuppressive effects. However, their side effects cannot be ignored and may be considerably dependent on the dose and duration used. Short-term effects include irritability, weight gain, hypertension, glucose intolerance, gastric irritation, infec- tions, Cushing s syndrome, somnolence, and reversible brain atrophy. Although most of these effects are revers- ible after withdrawal of the steroids, many have the poten- tial to become life-threatening. A 15% decrease of cerebral blood flow in patients treated with hydrocortisone has been reported (Chiron et al., 1993). Furthermore, the long-term side effects of continued therapy need to be remembered: osteoporosis, growth impairment, and adre- nal suppression. Therefore, a sound risk–benefit estima- tion should precede their use.

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Steroids have been recognized to be possibly of benefit in a variety of childhood epilepsies, but the evidence to support this treatment is variably dependent on the syn- drome and limited at best in most situations. Efficacy has been demonstrated in IS by several randomized controlled trials (RCTs). A Cochrane review regarding the treatment of IS included 14 RCTs considering treatment with ACTH, oral prednisolone, and vigabatrin. Overall, ste- roids were viewed to result in faster resolution of spasms, with the possibility of an improved developmental outcome in a non–tuberous sclerosis population (Hancock et al., 2008). In particular, Lux et al. (2004) compared hormonal treatment against vigabatrin; they observed re- solution of spasms at days 13–14 to be more likely in the hormonal group. Overall outcome at 12 months was not different in both groups, but it was suggested that develop- mental outcome may be superior in the hormonal group (Lux et al., 2005). No difference in efficacy was demon- strated between ACTH and prednisolone. Vigabatrin was more effective than hydrocortisone in the control of spasms in patients with tuberous sclerosis complex (TSC) (Chiron et al., 1997). Steroids have also been reported in the treatment of nonconvulsive status epilepticus (NCSE). However, the problem in evaluating their benefit relies on defining the condition to be treated at the outset. By definition, an individual with NCSE should show a change in behavior and responsiveness compared to the baseline, with con- comitant EEG activity alterations showing continuous epileptic discharges. Treatment of NCSE with steroids can often result in dramatic beneficial effects on clinical state and EEG, but series of such patients are lacking. Steroids have been used in continuous spike-wave activ- ity in slow sleep (CSWS) with cognitive regression, also including Landau-Kleffner syndrome (LKS). In this situ- ation, it has to be tested whether objective measures of cognitive outcome correlate with EEG resolution. Out- come appears to be related to steroid response and dura- tion of CSWS/regression (Buzatu et al., 2009). However, the frequency of relapse after discontinuation of steroids is one of the major problems. Some authors suggest more prolonged courses to sustain the response (Buzatu et al.,

2009).

Steroid use in other epilepsies has been more anecdotal. There are several open-label series using steroids in drug- resistant epilepsies with variable benefit, but groups of patients were highly heterogeneous, their numbers small, and positive effects lasted only short term in the majority of cases. A Cochrane review of corticosteroids including ACTH for childhood epilepsy other than IS retrieved three RCTs only; two studies recruited patients with new-onset epilepsy and neurocysticercosis, respectively, and, there- fore, were excluded (Gayatri et al., 2009). The one remaining study compared an ACTH 4–9 analog in five children with intractable seizures against placebo using a

Epilepsia, 52(Suppl. 3):45–51, 2011 doi: 10.1111/j.1528-1167.2011.03036.x

double-blind crossover design. Three children only com- pleted the trial; four showed >50% reduction in seizures and one showed no change (Pentella et al., 1982). A recent study compared hydrocortisone versus deflazacort, an analog of prednisolone, in drug-resistant epilepsy of child- hood. Children were treated on an alternate basis with hydrocortisone for 6 months, or deflazacort continued for 12 months. No difference in response was seen between the two groups, although deflazacort was considerably better tolerated (Grosso et al., 2008). The mechanism of steroids in the treatment of epilep- sies has been widely debated. According to the common effects of steroids, the most likely hypothesis might be an immunosuppressant and antiinflammatory action; sup- pression of corticotropin-releasing hormone (CRH) levels in the CNS are thought to have an anticonvulsant action by decreasing neuronal excitability. However, there are also studies proposing that steroids may have an effect on c -aminobutyric acid (GABA) A receptors or on enhance- ment of action of neurosteroids. Some authors suggest that ACTH is more effective than other steroids, possibly related to its less direct effects through activation of cen- tral melanocortin receptors (Vigevano & Cilio, 2009). Ganaxolone, a compound related to the neurosteroid allopregnanolone and a positive allosteric modulator of GABA A receptors has been evaluated in epilepsy. The theory behind this assumes that it has similar effects on the nervous system as steroids, but not the peripheral side- effects. However, an initial RCT (Laxer et al., 2000) and an open-label study (Kerrigan et al., 2000) failed to demonstrate appreciable benefit. Steroids have been widely used in difficult-to-treat epi- lepsies (including the catastrophic epilepsies) in order not only to reduce seizures, but also to rescue developmental regression. There is limited evidence to suggest beneficial in selected populations, because except for IS studies are small, open-label, uncontrolled, and performed in het- erogeneous populations.

Future directions Further work is needed to resolve in which patient pop- ulations steroids should be used, using which regimen and for how long, and how to measure defined outcomes.

Steroids and Other Immunotherapies for Status Epilepticus (SE) in Immunologic Disorders (S. Shorvon, London, United Kingdom)

Status epilepticus (SE) is a common presenting symp- tom of a variety of immunologic conditions ( Tab le 1). Therapy in this area is entirely free of any high-level evi- dence, and based on case reports and small series. In

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Table 1. Conditions in which SE may occur

Table 1. Conditions in which SE may occur Hashimoto’s encephalopathy [or ‘‘steroid-responsive encephalopathy

Hashimoto’s encephalopathy [or ‘‘steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT)’’] Limbic encephalitis (LE)/autoimmune encephalopathies Paraneoplastic Nonparaneoplastic, associated with anti-GAD-, anti-NMDA-receptor-, anti-LGI1-antibodies, and so on. Vasculitis, for example SLE, Sjo¨ gren’s syndrome, primary angiitis

general, all these conditions share a number of common features: The longer the duration, the worse is the out- come. Treatment consists of conventional antiepileptic drugs (AEDs) and also immunotherapy. AEDs alone often are only partially successful and if possiblethe under- lying disorder should also be treated. The number of con- ditions identified is increasing, and immunologic therapy should probably be started in all cases of refractory SE of unknown cause.

Hashimoto s encephalopathy (HE) This disorder is the longest recognized autoimmune encephalopathy first explicitly described in 1966 (Brain et al., 1966). There have been three larger case series (Chong et al., 2003; Chaudhuri & Behan, 2003; Castillo et al., 2006). Most cases strikingly respond to steroids; therefore, it has been proposed to label the condition ‘‘ steroid-responsive encephalopathy associated with auto- immune thyroiditis ’’ (SREAT) (Sch uble et al., 2003). There are almost no trials or uniform guidelines. When treating SE in HE, AEDs alone are often unsuccessful and additional high-dose steroids and other kind of immuno- therapy are recommended. The usual regimen consists of induction of remission by intravenous methylprednisolone followed by oral pred- nisolone at a dose of 1 mg/kg. Steroids are then slowly tapered after 4–6 weeks. Relapses occur and are treated with reexposure to methylprednisolone and ‘‘ steroid sparing ’’ agents such as azathioprine, methotrexate, cyclo- phosphamide, and intravenous immunoglobulin (IVIG). Monitoring of therapy is on clinical not serologic grounds, since antibody titers may not closely reflect disease activ- ity. This condition has a tendency to recur: It was observed that in one case in which monthly IVIG (with rituximab) controlled all symptoms but when the IVIG was switched to a 6-weekly regimen, seizures recurred regularly at weeks 5 and 6 (Shorvon S, personal communi- cation).

Encephalopathy associated with NMDA-receptor antibodies This disorder is a common cause of SE, and may account for many cases previously categorized as ‘‘ crypto-

genic. ’’ If there is a tumor present, the neoplasm should be urgently removed (the longer the delay and duration of SE, the more the risk of cerebral damage). Beyond conventional AEDs, therapy of SE consists of high-dose steroids, plasma exchange, IVIGs, cyclophosphamide, or rituximab. The choice of drugs and their dosages vary in different centers, and will depend on severity and cause of the disorder, the clinical context, patient s age, and comorbid- ity. It is important and not only medically, but also scien- tifically justified, that treatment is protocol-driven and overseen by an immunologist. Immunotherapy schedules according to the protocols used in the UCL Institute of Neurology, London (United Kingdom) are summarized in Tab le 2.

Future directions The role of steroids in specific SE conditions, such as in some of the newly discovered autoantibody (Ab)–associ- ated limbic encephalitis (LE) (anti-NMDA-, anti-LGI1, anti-GABA B1 -, and anti-AMPA-Abs) has to be better defined, as well as dosage of steroids, their administration route, and duration of therapy. It might be important that

Table 2. Immunotherapy schedules (UCL Institute of Neurology, London (United Kingdom)

Disorders Nonvasculitic antibody-mediated immunologic disease a High-dose steroids Plasma exchange or IVIGs Cyclophosphamide or rituximab Vasculitic conditions High-dose steroids Cyclophosphamide

Regimens High-dose steroids Intravenous methylprednisolone 1,000 mg for 3 days, followed by 1 mg/kg for a period (usually 6 weeks, depending on cause/severity) and then taper

IVIG Two courses separated by 2 weeks, each course of 0.4 g/kg over 5 days Cyclophosphamide Following the ‘‘CYCLOPS’’ protocol 15 mg/kg IV over 1 h (capped at 1 g) Repeated every 2 weeks for three doses, then Every 3 weeks (in adults <60 years with normal renal function, with dose adjustments depending on WBC) Rituximab 500 mg repeated 2 weeks later (750 mg/m 2 ) and 375 mg every three months

a The response is better with surface antigens (e.g., VGKA, NMDA) than with intracellular (e.g., GAD).

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the still rare patients with these disorders are treated according to predetermined protocols within studies in order to obtain more clear and comparable data. In refractory SE of primarily noninflammatory origin, the role of steroid treatment has to be further investigated, with respect to the overall risk–benefit ratio and more specifically to the timing of administration, dosage, and duration.

Intravenous Immunoglobulins (G. Avanzini, Milan, Italy)

A beneficial effect of immunoglobulin (Ig) treatment of

epileptic seizures has been first suggested after the empiri- cal observation of Pechadre et al. (1977), who reported a decrease in frequency and severity of seizures in children with epilepsy treated with Ig for recurrent upper respira- tory tract infections. This report prompted further thera- peutic attempts with Ig in intractable epilepsies: In their review of the literature, van Engelen et al. (1994) found 24 papers published until 1993, 14 on mixed types of epi- lepsy, nine on IS and/or Lennox-Gastaut syndrome (LGS), and one on postencephalitic epilepsy. Overall, a 52% mean seizure reduction and 23% remis- sion were reported in the 368 patients who have been trea- ted with intramuscular or, in the large majority, intravenous (IVIG) Ig administration until 1993, with a very large variability across the different studies. Note- worthy, all the other studies were open-label, except one

placebo-controlled single-blind trial (Illum et al., 1990). Moreover, the duration was too short (only in seven stud- ies 6 months) in most studies and too small (only four studies were carried out in a population of >20 patients). Furthermore, the immunologic parameters were not sys- tematically investigated.

In a later double-blind study including 43 patients with

various types of epilepsies and 18 controls with different doses of IVIG, the responder/nonresponder ratio was clearly higher in the treated group, but the difference was statistically significant for the subgroup of patients with partial epilepsy only (van Rijckevorsel-Harmant et al., 1994). This study and the following three published more recently confirmed the previous ones (for references see Mikati et al., 2010). More consistent results were reported on selected popu- lations of patients with IS and/or LGS, LKS, and epilep- sies with CSWS, Rasmussen encephalitis (RE), and other types of paraneoplastic and nonparaneoplastic autoim- mune encephalitis currently defined as limbic encephalitis (see reviews in: Villani & Avanzini, 2002; Villani et al., 2008; Elovaara et al., 2008; Mikati et al., 2010; Vincent et al., 2010). Notably, the involvement of immune-medi- ated mechanisms is demonstrated for RE and limbic encephalitis and hypothesized for IS, LGS, and LKS. Intravenous Ig might have an immunorestorative effect by

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altering the kinetics of expression of disease-related auto- Abs (Dietrich et al., 1992). Alterations of immunologic and inflammation markers have been correlated with the clinical IVIG effect; however their interpretation is equiv- ocal and interferences of different factors (e.g., AEDs) cannot be ruled out. The use of IVIG in association with steroids is recom- mended as a first-line therapy in late-onset RE and as a third-line therapy in childhood-onset RE (Granata et al., 2003). The suggested dosing scheme is to start with three to five consecutive infusions of 0.4 g/kg/day and to pro- ceed with a monthly dose of 0.4–2.0 g/kg distributed over 1–5 consecutive days (Bien et al., 2005). Although in other types of epilepsies the pathogenetic role of immune-mediated mechanisms is less clear, all the studies with IVIG concur in demonstrating a beneficial effect in a substantial percentage of pharmacoresistant patients, supporting the experimental evidence of the role played by inflammatory and immunologic mechanisms in epilepsy (Vezzani & Granata, 2005; Vezzani et al., 2011). Indeed, the recently published guidelines of the European Federation of Neurological Societies (EFNS) include drug-resistant epilepsy of childhood among the 12 neuro- logic disorders where IVIGs are indicated (Elovaara et al., 2008). The recommended therapeutic scheme is similar to the one for RE (0.4 g/kg for 5 days at 4-week intervals fol- lowed by monthly maintenance). The treatment is usually well tolerated, the most fre- quent adverse effect being headache that occurred in 30% of the patients. In 4% of the cases, however, severe adverse events (thrombosis of the jugular vein, allergic reaction, and retrosternal pressure) were reported, lead- ing to discontinuation of the treatment. No clinically rel- evant changes in blood tests were observed; however, monitoring of laboratory findings is considered to be mandatory.

Future directions The same questions and goals as listed for the appli- cation of steroids might apply for the use of IVIGs as a treatment in epilepsy syndromes with a very likely, pos- sible, or probable autoimmune cause. Because treatment with IVIGs is resource and financially demanding, ques- tions about optimal duration of such treatment, dosage, and adminstration interval should be carefully evalu- ated.

Plasma Treatment (T. Granata, Milan, Italy)

Immune-mediated disorders are treated by corticoster- oids, immunosuppressants, and monoclonal antibodies (Abs). Moreover, the activity of auto-Abs can be modu- lated by treatment with IVIGs and by plasma treatment, which consists of the mechanical removal of Abs by

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plasmapheresis (plasma exchange, PE) or by semiselec- tive immunoadsorption (IA). The patient s plasma is sepa- rated from the cellular elements of blood by centrifugation during PE and substituted by replacement fluid; during IA, circulating Igs are selectively removed from the patient s plasma, which is adsorbed on-line and given back to the patient without any replacement fluid. Plasma treat- ment, either by PE or IA, is indicated in disorders associ- ated with pathogenic auto-Abs, specifically in autoimmune ion channel disorders such as myasthenia gravis, Lambert-Eaton myasthenic syndrome, or neuro- myotonia. In the recent years, a growing number of epileptic disor- ders associated with brain inflammation and potentially pathogenic Abs have been described; these patients do not respond, or only partially respond, to antiepileptic drugs but have been reported to benefit from immunomodula- tion, including plasma treatment. The first experience using PE to treat patients with ‘‘ inflammatory epilepsy ’’ dates back to 1994. Rogers and colleagues demonstrated that some rabbits immunized with recombinant glutamate receptor subunit 3 (GluR3) protein developed seizures and inflammatory reactions within the CNS resembling those observed in RE, and that some RE patients transiently benefited from PE (Rogers et al., 1994). Since then, plasma treatment has been used with the rationale of removing potentially pathogenic Abs. Unfortunately, only few patients were reported to be successfully treated by PE or IA (Andrews et al., 1996; Antozzi et al., 1998; Thilo et al., 2009), and in no cases was the plasma treatment proven to be effective as a long- term therapy (Granata et al., 2003; and Villani, personal communication on a series of five adult patients). These disappointing results may be probably explained in light of the recent advances in the knowledge of RE, which indicate a pivotal role for cell-mediated immunity in the pathogenesis of the disease. Nonetheless, given the dramatic, albeit transient, effect of plasma treatment (Andrews et al., 1996; Granata et al., 2003; Thilo et al., 2009), it may still be indicated in selected conditions, for example, in phases with acute neurologic deterioration, SE, and in relieving seizures before starting (or in associ- ation with) other immunomodulatory treatments. Plasma treatment was used in a few patients with steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) (also referred as Hashimoto s encephalitis) who did not benefit from corticosteroids (Nagpal & Pande, 2004; Hussain et al., 2005). More recently, experiences with plasma treatment have been increasingly reported in patients with seizure dis- orders with auto-Abs to specific neuronal proteins, such as voltage-gated potassium channels (VGKCs), N-methyl- D - aspartate (NMDA) receptors, and glutamic acid decarbox- ylase (GAD) (Vincent et al., 2004; Florance et al., 2009; Wong et al., 2010). In most case series, likely due to the

severity of these syndromes, plasma treatment was carried out in association with other immunotherapy (usually ste- roids or sequential IVIGs) and the proper effect of the dif- ferent treatments cannot be exactly specified. However, the contribution of plasma treatment may be derived from the analysis of the few case reports focusing on the effect of plasma treatment alone (Mat et al., 2008; Schimmel et al., 2009; Agrawal et al., 2010), where it was observed that clinical improvement paralleled the reduction of the specific circulating Abs (Irani et al., 2008, 2010; Mat et al., 2008) and from the reported trend toward a better outcome in patients in whom steroids were combined with other immunotherapy, including PE (Irani et al., 2010). Although there are no therapeutic guidelines, PE/IA can be considered in: (1) seizure disorders with auto- Abs to specific neuronal protein, conditions where anti- bodies are likely to play a major role in pathogenesis (e.g., limbic encephalitis). Given the increasing number of patients with these disorders, proper trials are war- ranted to reach a consensus on the immunomodulatory therapy, and specifically on the position of plasma treat- ment (as first-line or only in patients refractory to ste- roids or IVIGs, and so on); (2) conditions in which the role of humoral immunity is still undefined, but in which removal of Abs was proven to be at least tran- siently effective, for example, in RE; and (3) as a research tool in selected conditions where the observa- tion of a rapid response to Abs removal should prompt further pathogenetic immunologic studies.

Future directions Proper trials are warranted to reach a consensus on best modality of immunomodulatory therapy, and specifically on the position of plasma treatment (as first-line or only treatment in patients who are refractory to steroids or IVIGs, and so on). The role of humoral immunity in sev- eral clinical conditions should be further elucidated in order to better identify patients who will profit of plasma treatment therapy. Further pathogenetic immunologic studies in those patients with a rapid response to Abs removal may help to designate candidates who are most likely to improve on plasma treatment.

Clinical Trials with Antiinflammatory Agents (J. French, New York, NY, U.S.A.)

As more becomes known about the role of inflamma- tion in the development and perpetuation of epileptic sei- zures, there is a greater desire to introduce therapies that can address these mechanisms. At present, a number of existing therapies are used by clinicians, including ste- roids, IVIGs, and PE. These therapies are used in a number of pediatric syndromes such as LKS, CSWS, IS, and

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treatment-resistant focal epilepsy. Immune-modulating therapies are also given to patients with presumed auto- immune encephalopathies with or without auto-Abs, some cases of cryptogenic SE, and RE. In addition, the hypothe- sis that inflammation may underlie or perpetuate epilepsy more broadly, even without an autoimmune etiology, prompted the development of novel therapeutics for adjunctive use in treatment-resistant focal epilepsies (http://clinicaltrials.gov/ct2/show/NCT01048255). There is an urgent need to perform clinical trials and studies con- firming the effectiveness of these therapies in specific patient populations. Trials in these disorders present substantial difficulties. First, the underlying disorders are heterogeneous, and a variable degree of success would be expected. Second, because use of antiinflammatory and/or immune-modulat- ing therapies is entrenched for some conditions and cir- cumstances, a placebo-control study would be difficult to perform. This issue is complicated by the sense that delay in initiation of treatment may be detrimental. Third, the therapies themselves are by their nature often difficult to blind. Fourth, all these issues are compounded by the fact that the conditions for which these treatments are used are relatively rare, and trials would require a large number of centers. There are very few randomized, placebo-con- trolled trials of antiinflammatory or immune-modulatory therapies for patients with epilepsy. Most publications outline case series, often retrospective. A few are prospec- tive, but they often lack properly allocated controls. Base- line seizure rates are rarely captured. A recent survey of http://clinicaltrials.gov, the website on which all spon- sored trials must be listed, did not uncover any ongoing tri- als when the words ‘‘ epilepsy and steroids, ’’ ‘‘ epilepsy and inflammation, ’’ and ‘‘ seizures and corticosteroids ’’ were searched. A recent Cochrane review of the use of ACTH in childhood epilepsy found only one RCT, which had recruited only five patients (Gayatri et al., 2007).

Future directions There is a need for more rigorous assessment of both current and novel therapies. There is no doubt that antiin- flammatory and immune-modulatory therapies, both existing and future, can provide a substantial benefit to patients who otherwise have few available effective treatments. It is hoped that well-designed clinical research can elucidate their benefits and potential harms, if any, thereby allowing a better perspective on risk– benefit ratio.

Additional Contributors

Giuliano Avanzini, Milan, Italy; Helen Cross, London, United King- dom; Olivier Dulac, Paris, France; Jacqueline French, New York, NY, U.S.A.; Tiziana Granata, Milan, Italy; Simon Shorvon, London, United Kingdom.

Epilepsia, 52(Suppl. 3):45–51, 2011 doi: 10.1111/j.1528-1167.2011.03036.x

Disclosures

None of the authors has any conflict of interest to disclose. We con- firm that we have read the Journals position on issues involved in eth- ical publication and affirm that this report is consistent with those guidelines.

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Epilepsia , 52(Suppl. 3):45–51, 2011 doi: 10.1111/j.1528-1167.2011.03036.x