A pathogenic role of immunity in epilepsies has long been suggested based on observations of the efficacy of immune-modulating treatments and, more recently, by the finding of inflammation markers including autoantibodies in individuals with a number of epileptic disorders. Clinical and experimental data suggest that both innate and adaptive immunity may be involved in epilepsy. Innate immunity represents an immediate, nonspecific host response against pathogens via activation of resident brain immune cells and inflammatory mediators. These are hypothesized to contribute to seizures and epileptogenesis. Adaptive immunity employs activation of antigen-specific B and T lymphocytes or antibodies in the context of viral infections and autoimmune disorders.
Rasmussen’s encephalitis (RE) is a rare, acquired chronic inflammatory devastating disease, which progressively affects one hemisphere and is characterized by a hemispheric brain inflammation resulting in unilateral brain atrophy, drug-resistant focal seizures, worsening unilateral motor deficits, and cognitive decline.
Both humoral and cell mediated immunity have been implicated in the pathogenesis of Rasmussen’s encephalitis.
Humoral immunity: AntiGluR3 and other antibodies (Abs) directed against antigens of brain resident cells (namely, the presynaptic protein Munc18-1, N-methyl-D-aspartate glutamate receptor (NMDA-type GluR) ɛ2 subunit [NMDA-GluRɛ2], and anti-alpha7 nicotinic acetylcholine receptors [α7nAChR]) have been demonstrated in patients with the condition. However it is possible that presence of circulating Abs could be secondary to the cerebral damage and that humoral immunity is not the primary trigger.
Cell mediated immunity: The pathology of Rasmussen’s’ encephalitis is characterised by brain inflammation dominated by T cells, microglial activation, and microglial nodules, followed by neuronal loss and astrogliosis restricted to the affected hemisphere. The Infiltrating T cells are CD8+ cells containing granules positive for granzyme B+. Granzyme B is a protease released by activated cytotoxic T cells into target cells that undergo apoptosis. Astrocytic apoptosis and loss are seen within the cortex and the white matter.
Since this is not seen in other forms of epilepsy Ammon’s horn sclerosis or focal cortical dysplasia, it has been suggested that T-cell–mediated death of astrocytes is a specific feature of RE.
Granzyme B+ lymphocytes were found in close contact with astrocytes with granules polarized toward the astrocytic membranes, suggesting that astrocytes might be a target for T cells leading to astrocytic degeneration.
It is possible that astrocyte degeneration might enhance neuronal loss and contribute to seizure induction and maintenance
The analysis of clonal composition and T-cell receptor repertoire of CD4+ and CD8+ T cells by means of CDR3 spectratyping and immunohistochemistry of peripheral blood and brain specimens from patients with RE have also pointed towards antigen-driven MHC class I–restricted T-cell attack against neurons and astrocytes in RE
Viral infection: Viral infections can initiate cytotoxic T-cell response and It is possible that a viral antigen may be the trigger for the complex pathogenetic mechanisms resulting in damage. The peculiar hemispheric distribution with centrifugal expansion observed in RE also favours this hypothesis
Patients with RE have been shown to have the Heat Shock Protein Hsp 70 in the infected cells. Viruses use endogenous Heat shock protein (Hsp70) for their protein synthesis. Hsp70 translocates in infected cells from the cytoplasm to the nucleus and colocalizes with viral inclusions and Heat shock protein 70 (Hsp70) is thus a general marker for the virus-infected cells
Hence it is possible that RE might be a form of viral encephalitis and that cytotoxic T cells are directed against a specific viral protein present in both neurons as well as astrocytes. However currently it is not known whether RE is due to an unknown virus, or due to an abnormal immune mediated response to a common virus. In addition a direct pathogenic action of the virus itself should also be considered. The role of antiviral, anti-inflammatory drug treatments should be investigated before large resective surgery is decided.
West Syndrome (Infantile Spasms)
West syndrome (WS), or infantile spasms is an age-related epileptic encephalopathy with onset in the first year of life characterised by clustered spasms and hypsarrhythmia on EEG. It occurs more frequently in infants with congenital or acquired neurologic problems and diseases and may occur in previously healthy children
The beneficial effect of anti-inflammatory drugs like adrenocorticotropic (ACTH) and/or steroid treatment irrespective have been found beneficial in WS regardless of the etiology suggests a potential inflammatory or immune-mediated pathogenesis for WS. However there is minimal direct evidence for a role of inflammation in WS. In WS for e.g. the CSF levels of IL-1ra (an anti-inflammatory cytokine that has been shown to act as an anticonvulsant in experimental settings) have been shown to be reduced.
The mechanisms by which ACTH and steroids suppress WS include direct effects on neuronal excitability, suppression of the levels of endogenous proconvulsant molecules including corticotropin-releasing hormone (CRH) and antiinflammatory effects.
Melanocortin receptors (MCRs). The efficacy of ACTH and its superiority over steroids may be explained by its direct activation of the melanocortin receptors (MCRs). Melanocortin receptors MCRs suppress the endogenous convulsant CRH, a stress hormone expressed in numerous brain regions and seen in increased levels in WS. The MCRs also suppress endogenous convulsant CRH and inhibit nuclear factor-kB (NF-kB), a nuclear factor that induces the transcription of CRH and most of the molecules involved in inflammation.
The role of MCRs in ictogenesis and epileptogenesis in West syndrome is not completely understood. Direct MCR agonists and drugs that inhibit NF-kB and suppress CRH are potential therapeutic agents against West Syndrome.
Landau-Kleffner Syndrome and Continuous SpikeWaves during Sleep
Originally described as electric status epilepticus during sleep (ESES) Landau-Kleffner syndrome (LKS) and continuous spike-waves during sleep (CSWS) are both characterized by continuous EEG epileptic activity during sleep associated with neuropsychological disturbances and are considered to belong to the same LKS-CSWS spectrum.
The clinical syndrome in LKS is thought to result from the “functional ablation” of cortical areas concerned with linguistic or other cognitive functions due to persistent convulsive discharge.
Autoimmune pathogenesis has been suggested following the observation of positive autoimmune reaction to central and peripheral myelin during the attacks of clinical worsening in LKS. Both Corticosteroid and IVIGS have shown consistent benefit in LKS by significantly improving the speech function. The raised CSF immunoglobulin G (IgG)/protein ratio seen in the condition is lowered after treatment.
Higher incidence of serum auto-Abs to brain-derived neurotrophic factor (BDNF) and to endothelial cells are present in children with LKS compared to healthy controls. Auto-Abs have also been demonstrated in CSWS and also limited efficacy demonstrated for steroids and immunoglobulins in CSWS. These findings have suggested an autoimmune etiology for the LKS-CSWS spectrum of conditions.
Limbic Encephalitis & Ammon’s Horn Sclerosis
Limbic encephalitis (LE) is a syndrome defined by at least one of the following: disturbance of episodic memory, epileptic seizures of temporal semiology, or affective disturbances plus at least one of the following features: diagnosis of a neoplasm; demonstration of a characteristic auto-Ab in the patient’s serum or CSF (see below); a chronic lymphocytic–microglial encephalitis shown on histopathologic examination of a mediotemporal brain specimen; or, a mediotemporal fluid attenuated inversion recovery (FLAIR)–T2-signal increase shown in an magnetic resonance imaging (MRI) scan that is not otherwise explainable.
Evolution of the initial hippocampal swelling to atrophy may occur over time. MRI of the affected hippocampi show features of Ammon’s horn sclerosis (AHS), and reveal segmental pyramidal cell loss and astrogliosis with accompanying signs of chronic encephalitis on histopathologic examination.
The most frequently accounted Abs in LE are directed to the voltage-gated potassium channel complex (VGKC) on the surface of neurons. The Auto-Abs in affected patients are important in making a definite diagnosis of LE and predicting prognosis. The Abs to surface antigens predict a better prognosis under immunosuppressive treatment than Abs to intracellular antigens.
The second most frequently found Ab in patients with LE is directed to the intracellular enzyme glutamic acid decarboxylase (GAD). Onconeural Abs, which are directed to intracellular antigens (Hu, Ma, amphiphysin, CV2, Sox1), are the third most frequent Abs in LE if considered as one group. Further Abs associated with LE are directed against the N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or γ-aminobutyric acid (GABA) B receptors.
Patients with anti-VGKC-Abs under monthly intravenous methylprednisolone pulses rapidly became seizure free and improved in terms of memory performance along with a fall of VGKC antibody titers. On the other hand patients with anti-GAD-Abs are reported to take a chronic course with little clinical improvement and persistently elevated antibody concentrations.
Ammon’s horn sclerosis (AHS) - In children with prolonged febrile seizures, increased hippocampal T2 signal intensity may be seen in the “acute” period within a few days after the episode with some children developing evidence for AHS. The exact pathology of AHS is uncertain regarding whether it is due to inflammation or excitotoxic injury, edema, and blood–brain barrier (BBB) breakdown. Several MRI techniques, such as magnetization transfer, gadolinium enhancement, diffusion-weighted imaging, and magnetic resonance spectroscopy (MRS) may be able to show aspects of active inflammatory processes.
However In epilepsy, MRI has shown potential evidence for inflammation only in a few instances. The role of infections with common childhood viruses like HHV-6 and their reactivation during adulthood or upon immune dysfunction as triggers for AHS is being investigated.
Latent infection with a ubiquitous childhood virus, human herpesvirus-6 (HHV-6), associated with the common, self-limited childhood illness roseola infantum and febrile seizures, are thought to play a role in mTLE. In patients with immune compromise, reactivation may lead to severe limbic encephalitis. An ongoing multicenter study is investigating possible links between HHV-6 infection, febrile status epilepticus, and development of mesial temporal sclerosis (MTS).
Temporal lobectomy specimens has shown evidence of active HHV-6B, but not HHV-6A replication, in hippocampal astrocytes in a majority of patients with mesial temporal sclerosis (MTS), but not other causes of epilepsy. It would be important to identify the individuals who are at an increased risk for the development of AHS as a consequence of a viral infection.
Hemiconvulsion–hemiplegia syndrome (HHS) is a condition characterized by the occurrence of prolonged unilateral convulsions in the context of a febrile illness, in children younger than 4 years of age followed by the development of an ipsilateral hemiplegia, persisting for at least one week. Later a focal epilepsy is often observed and hence the acronym hemiconvulsion–hemiplegia–epilepsy (HHE).
Hemiconvulsion–hemiplegia syndrome is included among the epilepsy syndromes and epilepsies in the most recent update of the ILAE classification.
The hippocampal sclerosis following prolonged seizures has been suggested to be a variant of the syndrome but hasn’t been proved yet. Neuroradiologic studies have shown unilateral edematous swelling of the affected hemisphere at the time of initial status, followed by hemiatrophy independent of any vascular territory. The presence of an underlying brain malformation and/or cortical dysplasia as possible trigger for the events or neuronal injury induced by venous thrombosis and/or cytotoxicity have been suggested as possible etiologic and pathophysiologic mechanisms.
Acute scanning in the periseizural state has shown abnormalities on diffusion-weighted imaging, suggesting cytotoxic edema of the seizing hemisphere. Neuropathologic studies have also suggested that edema is responsible for neuronal damage. Cell death however has not been demonstrated.
Acute infection or an antibody-mediated inflammatory process has not been implicated in this condition
even though it might be possible.
The juvenile onset form of Batten disease (JNCL) is the result of mutations in the CLN3 gene. Cln3-deficient mice display both pathologic and neurologic signs of the disorder including visual failure and motor coordination deficits.
Cln3-knockout mice have been shown to have an autoimmune response to GAD65, and the autoantibody to GAD65 binds to the brain protein resulting in inhibition of glutamic acid decarboxylase activity in the brain. The GAD65 autoantibody has been demonstrated to be associated with astrocytic hypertrophy and a metabolic shift within the brain for the neurotransmitter glutamate.
A size-selective breach in the BBB integrity in these mice has suggests that systemically produced autoantibodies can access the CNS during disease progression and contribute to a progressive inflammatory response.
The Cln3−/− mice when crossed with the B-cell deficient μMT mouse to generate mice that were immune deficient through the inability to produce B cells as well as lacking a functional CLN3 protein, they were unable to produce endogenous IgGs. Cln3−/− mice lacking B cells showed an amelioration in the characteristic deterioration of motor skills, which was attributed to an observed decrease in the inflammatory response as well as immune-mediated pathologies.
Sera from inviduals with Batten disease have a circulating autoantibody to GAD65.
Presence of additional autoreactive antibodies in Batten disease that clearly bind to neuronal antigens have also been shown indicating that it is likely that a general breakdown in autoimmunity to neuronal proteins exists. Evidence of IgG deposition and lymphocytic infiltration has been shown in human and murine Batten disease
Mycophenolate mofetil (MMF) has been used to treat Cln3−/− mice as a pharmacologic means to attenuate the immune response. MMF inhibits inosine monophosphate dehydrogenase, an enzyme involved in the de novo pathway of purine synthesis in proliferating B and T lymphocytes, thereby attenuating any immune response. MMF, similar to the genetic ablation of B cells, resulted in suppression of both inflammatory response as well as immune-mediated pathologies and also improved the motor function ofCln3−/− mice.
The role of MMF in the treatment of children with Batten disease needs investigation taking into account the risks and benefits of chronic immunosuppression. The role of other immunomodulating drugs currently available and also of human stem cell transplantation to reset the immune system could be potential experimental therapeutic option.