The use of immunoglobulin in intractable epilepsy is one of its oldest applications in medicine, starting from the empirical observation of its beneficial effect on seizures.

The immune system and its associated inflammatory reactions have been implicated, by numerous experimental and clinical findings, in the pathogenesis of several forms of epil-epsy. The relationship between epilepsy, the immune system, and the inflammatory cascade is, however, exceedingly complex and possibly bidirectional.

The wide range of immune abnormalities observed in patients with epilepsy and the reported efficacy on seizure control of different immunomodulatory and/or anti-inflammatory treatments suggest the existence of different subtypes of epileptic syndromes associated with variable abnormalities of the immune system.

In this view, intravenous immunoglobulin (IVIg), with its broad immunomodulatory mechanism of action, could be effective in different forms of immune-dysregulated intractable epilepsies.

IVIg may also share nonimmunologic mechanisms of action: Its possible anticonvulsant properties and the ability of IVIg to interfere with the final common pathway of seizures at a cellular level, with a significant increase in seizure threshold, have been suggested by human epilepsy data and have been demonstrated in different experimental epilepsy models.

Although IVIg may represent a valuable resource in some drug-refractory epilepsies, and its effectiveness has important pathogenetic implications, controlled studies with the systematic monitoring of immunologic markers are needed to define more precise indications and to optimize the administration protocols.

The central nervous system (CNS) is considered an immuno-privileged site because of the presence of the blood–brain barrier (BBB), its ability to accept grafts, the absence of classical lymphatic drainage, and the reduced traffic of monocytes and lymphocytes; it is, however, also considered an immunologically specialized site, because immune and inflammatory reactions do occur in the CNS, originating in the CNS itself (innate immunity), or are imported by competent immune cells from the peripheral tissues (acquired immunity).^75,92 The transition between innate and acquired immunity is mediated by a large variety of inflammatory mediators (e.g., cytokines, Toll-like receptors) not detectable or barely detectable under physiologic conditions.³ Although such mediators are classically produced by cells of the immune system in response to infection or other pathologic stimuli, they are also produced by brain parenchymal cells such as microglia, astrocytes, and neurons, and by cells of the BBB and choroid plexus.^53,80

It is worthwhile to note that an immune response in the CNS may be also triggered by endogenous ligands. Signals from damaged cells or arising from molecules entering the brain through a damaged BBB may initiate an immunologic response followed by an inflammatory reaction. A large spectrum of injuries, such as ischemia, trauma, and seizures, may initiate such a pathological process.^4,49

The patterns of induction of inflammatory molecules and their time course of activation/persistence in brain tissue are related to the nature of the CNS injury and may be relevant in planning the treatment of epilepsy by immunomodulation.

Alterations of the immune system described in patients with different forms of epilepsy are numerous. Both humoral (predominantly IgA and IgG2 deficiencies)^29,33 or cellular^30,45,89 immunity may be impaired in these patients.

Conflicting reports have been published on serum immunoglobulin concentrations in patients with epilepsy. In a recent study serum IgA, IgG, and IgM concentrations were determined in a large cohort of epileptic patients and compared to a reference population.⁷⁶ The patients with epilepsy had lower serum IgA concentrations compared with controls. Low serum IgA levels were also found in patients taking phenytoin or who had previously been treated with that drug. No differences in serum IgG and IgM concentrations were observed between patients and control subjects.

Several recent reports have shown an increase in the markers of inflammation in serum, cerebrospinal fluid (CSF), and brain resident cells following seizures. Tonic–clonic seizures, for example, may induce a proinflammatory increase of cytokines such as interleukin (IL)-6, but may also reduce the IL-1RA/IL-1α ratio^46,68,71,72 in plasma and CSF. Experimental studies suggest that IL-1β prolongs seizure duration and, at the same time, promotes neuronal damage, whereas its effect is blocked by IL-1RA.⁹¹ Increased levels of IL-1β and other cytokines have been observed in the experimental model of glycerol-induced seizures,²⁶ as well as in patients with either partial or generalized epilepsy.⁶⁴ These observations and the association of polymorphisms in the IL-1 gene complex with temporal lobe epilepsy and hippocampal sclerosis⁵⁰ and other forms of drug-refractory, localization-related epilepsies,⁷⁰ together with an increase in the expression of proinflammatory molecules in neurons and glia in brain tissue obtained from patients surgically treated for drug-resistant epilepsies,^{9,23,58,77,83} are consistent with previous data suggesting a modulatory effect of cytokines and other proinflammatory molecules on neurotransmission and seizures.

Anti-brain antibodies^61,73 or autoantibodies^11,42 have also been related to different forms of epileptic syndromes and to more complex neurologic syndromes with prominent epilepsy, such as Rasmussen chronic encephalitis (RE).

Other evidence, although indirect, of the possible role played by the immune system in epilepsy includes the immunologic abnormalities induced by antiepileptic drugs (AEDs) such as phenytoin and carbamazepine,^34,65 and the anticonvulsant efficacy of immunosuppressive drugs such as adrenocorticotropic hormone (ACTH) and corticosteroids on the intractable seizures of West’s Syndrome (WS).

The inflammatory response is strictly regulated genetically: Different prevalences of human leukocyte antigen (HLA) class II haplotypes in epileptic patients, compared with the general population, have been described.⁴⁴ The analysis of IL-1β, IL-1α, and IL-1RA gene polymorphisms⁶⁹ in a cohort of drug-resistant epilepsy patients versus healthy controls suggested an association between cytokine gene haplotypes and development of intractable focal seizures, but this observation was not confirmed by other authors.^17,41

Clinical studies underscored the role of stress hormones in epilepsy. Increased ACTH and cortisol levels have been reported in human epilepsies and in status epilepticus (SE).^18,35,36 Activation of the ACTH/glucocorticoids axis in response to antecedent injury or stress has been suggested in the pathogenesis of WS.⁸

Dysfunction of the BBB has been demonstrated both in epilepsy experimental models¹⁰¹ and in human epilepsy.²² In most cases, however, routine examination does not provide evidence of BBB disruption with normal CSF.^87,99

Increased BBB permeability induced by seizures, inflammation, or both has several clinical implications, which include the entry of compounds with immunogenic or inflammatory potentials,⁶⁶ the upregulation in the expression of multidrug transport proteins limiting AED access to the brain,⁵² and facilitation of the entry of those compounds with therapeutic potential with limited or no access to the CNS, such as immunoglobulins.

From a clinical point of view, although the role of the immune system in the pathophysiology of human epilepsies is still only partially understood, the possibility of treating different forms of epilepsies by immunomodulatory agents is supported by extensive evidence.

IVIg, corticotropin, corticosteroids, plasma exchange, immuno-adsorption with protein A, and interferon (IFN)-α have been applied with some success in several epileptic syndromes: The antiepileptic effect of these agents may be at least partially mediated by their immunomodulatory and anti-inflammatory effects.

The concept that immunomodulatory and anti-inflamm-atory treatments may have a beneficial effect on epileptic seizures in human epilepsy has been first suggested after the empirical observation of Pechadre et al.⁶⁷ as early as 1977; the authors observed a decrease in the frequency and severity of seizures in children with epilepsy treated with intramuscular immunoglobulin for recurrent upper respiratory tract infections. Following this observation, the old allergic theory of epilepsy^24,97 was revised, and a new immunologic approach to epilepsy was proposed. Studies on the relationship between the immune and nervous systems flourished,⁷⁸ as did attempts to treat epileptic seizures with immunoglobulin. The anticonvulsant efficacy of immunomodulatory drugs with anti-inflammatory actions has been well documented. In particular, ACTH and steroids are very effective in severe childhood epileptic encephalopathies.^{27,37,39,79,84} The antiepileptic mechanisms of these drugs have not been completely elucidated: Seizure inhibition may involve, at least in part, the ability of steroids to modulate various neurotransmitters, including γ-aminobutyric acid (GABA).^51,74 Their immunosuppressant and anti-inflammatory activities may play a major role in epilepsies with an immune component, such as RE.

The use of IVIg in intractable epilepsy is one of its oldest applications in medicine.⁹³ This application followed its use for substitution in immunodeficiency states,¹⁶ but preceded the work of Imbach et al.⁴⁸ on idiopathic thrombocytopenic purpura in childhood and the subsequent use of this treatment in numerous non-neurologic and neurologic diseases.