Autoimmune Epilepsy: The Evolving Science of Neural Autoimmunity and Its Impact on Epilepsy Management

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1 90 Autoimmune Epilepsy: The Evolving Science of Neural Autoimmunity and Its Impact on Epilepsy Management Amy M.L. Quek, MBBS, MRCP 1, Orna O Toole, MD 3 1 Division of Neurology, Department of Medicine, National University Hospital, Singapore Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 3 Department of Neurology, Mercy University Hospital, Grenville Place, Cork, Ireland Address for correspondence Amy M.L. Quek, MBBS, MRCP, Division of Neurology, Department of Medicine, National University Hospital, Level 10, NUHS Tower Block, 1E Kent Ridge Road, Singapore 1198 ( amy_quek@nuhs.edu.sg). Semin Neurol 018;38: Abstract Keywords autoimmune epilepsy encephalitis seizures antibodies Epilepsy is a chronic neurologic disease that affects both the young and old. Although epilepsy can arise from different structural, metabolic, and infective etiologies, the cause of epilepsy remains unclear in a substantial proportion of patients. 1 Current treatment strategies, which center around symptomatic epilepsy management, are suboptimal, as close to a third of patients do not achieve seizure freedom. Autoimmune epilepsy describes recurrent seizures that have a putative immune-mediated origin. Autoimmune epilepsy was first recognized in patients with refractory epilepsy with serum neural autoantibodies, prompting neurologists to commence immune-suppressing treatments, which, in turn, reduced the frequency and severity of seizures. 3,4 The definition of autoimmune epilepsy is evolving, depending on the presence and type of associated neural autoantibody detected and its associated clinical phenotype, and whether epilepsy is the sole presentation or part of a Autoimmune epilepsy is increasingly recognized as a distinct clinical entity, driven in large part by the recent discovery of neural autoantibodies in patients with isolated or predominant epilepsy presentations. Detection of neural autoantibodies in high-risk epilepsy patients supports an immune-mediated cause of seizures and, if applicable, directs the search for an underlying cancer when the paraneoplastic association of the associated antibody is compelling. Early diagnosis of autoimmune epilepsy is crucial, as prompt initiation of immunosuppressive treatment increases the likelihood of achieving either seizure freedom or a substantial reduction in seizure frequency. A practical clinical approach that incorporates risk scores to guide patient selection on the basis of clinical features, neural autoantibodies, and a treatment trial of immunotherapy is suggested. Elucidating an immunological basis of epilepsy provides neurologists with wider treatment options (incorporating immune-suppressive treatment), in addition to standard antiepileptic drugs, which often improves patient outcomes. broader spectrum of associated features of limbic encephalitis (e.g., encephalopathy, behavioral, cognitive changes, and movement disorders). Isolated seizures as a forme fruste of autoimmune limbic encephalitis and their association with neural autoantibodies are increasingly recognized. Accurate diagnosis and appropriate treatment of autoimmune epilepsy can significantly improve clinical outcomes, as affected patients often have medically refractory seizures that respond favorably to immunotherapy. Although the trigger for autoimmunity is often unknown, an underlying cancer driving a paraneoplastic immune response may be identified in some patients. This new concept of immune-mediated epileptogenesis offers further avenues of treatment that target the root cause of seizure generation. 3,5 The International League Against Epilepsy (ILAE) has now recognized autoimmune epilepsy as a distinct entity in their epilepsy classification. 1 Issue Theme Autoimmune Neurology; Guest Editor, Stacey L. Clardy, MD, PhD. Copyright 018 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(1) DOI /s ISSN

2 Autoimmune Epilepsy Quek, O Toole 91 Significant progress has been made in refining the definition, pathological basis, diagnosis, and treatment of autoimmune epilepsy. This review aims to summarize the accumulating scientific and clinical progress in neural autoimmunity, with a focus on adult autoimmune epilepsy. We describe the proposed mechanisms underlying neural autoimmunity and seizure generation, and how the detection of neural autoantibodies guides the recognition and treatment of patients with autoimmune epilepsy. Neural Autoantibodies Associated with Encephalitis and Epilepsy Neural Autoantibodies Discovery of neural autoantibodies is central to the recognition of an immune-mediated epilepsy. A majority of these neural-specific antibodies target antigens in the central nervous system that have been implicated in seizure generation. The involvement of these target antigens is deciphered through genetic and pharmacological studies in which modification of these targets is associated with reduced epileptogenesis. Furthermore, T-cell mediated neuroinflammation and antibody-mediated disruption of synaptic neurotransmitter receptors and ion channels are associated with seizures that are often focal or multifocal in onset and more responsive to immunotherapy than to standard epilepsy therapies. Neural autoantibodies target intracellular antigens or cell membrane surface antigens. 6 Intracellular nuclear and cytoplasmic antibodies are terms that were initially used by neuro-oncologists to describe the paraneoplastic or onconeural antibodies linking neurologic syndromes arising from an underlying cancer. These antibodies (e.g., antineuronal nuclear type 1 [ANNA-1], ANNA-, amphiphysin, collapsin response mediator protein 5 [CRMP-5], and Ma/Ta antibodies) are markers of an immune process involving both B and T cells. The underlying immunopathogenic process involves a cytotoxic T-cell mediated neuronal destruction and may also involve neural autoantibody uptake as well, with further work needed to fully understand the pathophysiology of cell death in these classic syndromes. 6,7 Classic paraneoplastic syndromes ascribed to these antibodies are protean (e.g., paraneoplastic chorea, cerebellar degeneration, limbic encephalitis [with seizures], and opsoclonus myoclonus). Identification of these antibodies, particularly if clustered, can direct the search for solid-organ or occult cancers. 8,9 Treatment of the underlying cancer, in addition to T-cell directed immunotherapy, improves the likelihood of neurologic stability, even though outcomes of these patients are generally poor and likely related to a combination of the underlying pathophysiological process and the often prolonged time to diagnosis. Antibodies targeting extracellular neuronal synaptic and cell membrane proteins are pathogenically implicated in epileptogenesis. Antibody binding leads to functional modifications of synaptic neurotransmitter receptors and ion channels that are potentially reversible by antibody removal. 6 Some of the more extensively studied antigens include N-methyl-D-aspartate receptor (NMDAR), voltagegated potassium channel (VGKC) complex with leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein-like (CASPR) specificities, α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid receptor (AMPAR), and γ-aminobutyric acid type B and A receptor (GABA B Rand GABA A R). These neural autoantibodies result in a myriad of clinical phenotypes (e.g., epilepsy 3,5,10,11 and encephalitis) and are associated with occult and solid-organ cancers at variable rates. Patients with these antibodies could respond favorably to antibody-depleting treatments, frequently with a time-to-treatment correlation in the extent and rapidity of improvement. 6 Seizure Characteristics Autoimmune seizures often occur in limbic encephalitis with associated neurologic symptoms (e.g., confusion, memory difficulties, behavioral change, psychiatric symptoms, sleep disruption and decreased consciousness) in the setting of temporal lobe abnormalities on magnetic resonance imaging (MRI) and electroencephalogram (EEG) and inflammatory serum and cerebrospinal fluid (CSF) findings. Seizures frequently manifest early during the clinical course of disease, but the clinical phenotype and EEG abnormalities may be subtle or atypical. Alternatively, and probably less commonly, an isolated seizure phenotype (in the absence of other limbic features) can present as a forme fruste of limbic encephalitis. These clinical scenarios can pose a diagnostic challenge as these patients may present with focal-onset seizures or seizures that are refractory to antiepileptic drugs (AEDs). 3 Notably, up to two-thirds of patients may have other neurologic symptoms reminiscent of limbic encephalitis (e.g., cognitive and personality changes). 3,5 In practical terms, attributing these latter features to autoimmune epilepsy, a mild limbic encephalitis, or the use of multiple AEDs is often inconsequential, as immune-suppressing treatment remains the mainstay of treatment. The more frequently identified antibodies associated with autoimmune epilepsy are directed against the VGKC complex (specifically LGI1 and CASPR), glutamic acid decarboxylase 65 (GAD65), and NMDAR antigens. 3,10,11 GABA A R, GABA B R, glycine receptor, and AMPAR antibodies are less frequent but also likely underdiagnosed given the current lack of universally available testing. Rarely, nuclear or cytoplasmic paraneoplastic antibodies have been identified in patients with autoimmune epilepsy (ANNA-1, ANNA-, amphiphysin, CRMP-5, and Ma/Ta antibodies). 3,10,11 Data on the prevalence of autoimmune epilepsy among general epilepsy populations are limited. Early studies observed VGKC complex and GAD65 antibodies in approximately 3 to 10% of epilepsy patients These studies were performed before the antibody specificities for VKGC complex (LGI1, CASPR) were discovered. More recent studies reported neural autoantibody detection rates of 10 to 0% in epilepsy cohorts. However, the high detection rates are likely because of selection of patients with predominantly drugrefractory seizures a subtype of epilepsy that is increasingly recognized to be associated with autoimmune epilepsy.

3 9 Autoimmune Epilepsy Quek, O Toole Although these data may reflect epilepsy specialty practice, these estimates may not be generalized to a communitybased general practice. 10,16 18 In the following sections, selected antibodies that are frequently encountered in autoimmune epilepsy are discussed. Table 1 describes several common extracellular/ synaptic antibodies and their known clinical characteristics, whereas Table expands the description to include intracellular (nuclear or cytoplasmic) antibodies. NMDAR Antibodies Anti-NMDA receptor antibodies targeting the NR1 and NR subunits of the NMDAR, a glutamate-gated cation channel essential for synaptic transmission and plasticity, are most commonly encountered in autoimmune encephalitis Epilepsy can present in isolation or as a predominant clinical feature. 3,10,11, NMDAR antibodies have been reported to result in a selective (but reversible) decrease in NMDAR surface density, synaptic localization, and synaptic NMDAR-mediated currents through antibody-mediated receptor internalization, resulting in a decrease in glutamatergic synaptic function. 19,3,4 Encephalitis associated with anti-nmdar antibodies has a strong preponderance for young women (80% of all patients) and is associated with a tumor in 58% of patients (almost invariably females with ovarian teratoma). 19 The clinical illness is less commonly Table 1 Neural autoantibodies targeting extracellular synaptic and cell membrane proteins associated with autoimmune epilepsy Antibody Frequency of Ab Isolated seizures described Associated features Tumor association Relapses AMPAR þþ Yes Limbic encephalitis, cognitive and psychiatric disorders, confusion CASPR þþ Yes Limbic encephalitis, Morvan s syndrome, peripheral nerve hyperexcitability, cognitive, psychiatric and sleep disorders DPPX þ No Myoclonus, tremor, dysautonomia, cognitive and psychiatric disorders, brainstem disorders, sleep disturbance, diarrhea, weight loss GABA A R þ Yes Cognitive and behavioral disorders, movement disorders, decreased consciousness Multifocal cortical subcortical MRI T/FLAIR changes GABA B R þþ No Limbic encephalitis, cognitive and behavioral disorders, ataxia, opsoclonus myoclonus Ganglionic AchR þ Yes Dysautonomia, peripheral neuropathy, cognitive and psychiatric disorders GFAP þ Yes Encephalitis, meningitis, myelitis (meningoencephalomyelitis), encephalopathy, psychiatric disorders, headache, blurred vision, ataxia Glycine þ Yes Axial/ limb spasms, stiff person syndrome, progressive encephalomyelitis with rigidity and myoclonus, cognitive disorders, dysautonomia LGI1 þþþ Yes Limbic encephalitis, FBDS, cognitive disorder, dementia, behavioral changes, insomnia, autonomic, hyponatremia Breast, small cell lung, thymoma, Thymoma B-cell neoplasms Mostly thymoma SCLC Adenocarcinoma Varied (ovarian teratoma) Breast, lymphoma, leukemia, small cell lung, thymoma Varied, e.g., thymoma, endocrine tumor (10%) Yes (frequent) Yes Yes Unclear Infrequent Unclear mglur5 þ No Ataxia, Ophelia s syndrome Hodgkin s lymphoma Unclear NMDAR þþþ Yes Cognitive and psychiatric symptoms, movement disorders (orolingual dyskinesias), ataxia, autonomic dysfunction, encephalopathy, reduced consciousness/coma ExtremedeltabrushonEEG VGCC (P/Q and Ntypes) þ Yes Encephalopathy, ataxia, Lambert Eaton syndrome Mostly ovarian teratoma in females (40%) Small cell lung, breast Yes Yes Yes Yes Unclear Abbreviations: þ, rare;þþ, less common; þþþ, very common; AchR, acetylcholine receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR, contactin-associated protein ; DPPX, dipeptidyl-peptidase-like protein 6; EEG, electroencephalogram; FBDS, faciobrachial dystonic seizures; FLAIR, fluid-attenuated inversion recovery; GABA A R, γ aminobutyric acid A receptor; GABA B R, γ aminobutyric acid B receptor; GFAP, glial fibrillary acid protein; LGI1, leucine-rich glioma inactivated 1; mglur5, metabotropic glutamate receptor 5; MRI, magnetic resonance imaging; NMDAR, N-methyl-D-aspartate receptor; VGCC, voltage-gated calcium channel.

4 Autoimmune Epilepsy Quek, O Toole 93 Table Neural autoantibodies targeting intracellular antigens associated with autoimmune epilepsy Antibody Frequency of Ab Isolated seizures described Associated features Amphiphysin þþ No Limbic encephalitis, myelopathy, stiff person syndrome ANNA-1(Hu) þþþ Yes Limbic/brainstem encephalitis, sensory neuronopathy CRMP-5 þþþ Yes Ataxia, myelopathy, chorea, cognitive disorders, encephalopathy, neuropathy GAD65 þþþ Yes Stiff person syndrome, ataxia, limbic encephalitis, brainstem symptoms, anxiety Ma/Ta þþþ Yes Limbic/brainstem encephalitis, encephalopathy, hypothalamic dysfunction Tumor association Breast, small cell lung Bladder,smallcelllung NHL,smallcelllung,thymoma,tonsillar Breast cancer, colon cancer, lymphoma, renalcellcancer,thymoma Testicular, Ma; breast, colon, testicular, Ma1 Abbreviations: þþ, less common; þþþ, very common; ANNA-1, antineuronal nuclear type 1; CRMP-5, collapsin response mediator protein 5; GAD65, glutamic acid decarboxylase 65: NHL, non-hodgkin s lymphoma. paraneoplastic if NMDAR antibodies are detected in men and children. 5,6 Anti-NMDAR encephalitis has a stereotypical clinical evolution comprising an octad of psychiatric symptoms, memory loss, seizures, movement disorders, speech disorder, decreased consciousness, autonomic dysfunction, and central hypoventilation. 7 Psychiatric and behavioral features are common presenting symptoms in adults (65%); 7 seizures as the first presentation of anti-nmdar encephalitis are more commonly encountered in children. 7 Most patients typically evolve toward a similar anti-nmdar encephalitis syndrome within 4 weeks of symptom onset, with 90% manifesting at least four of the symptom octad during this stage of disease. 7 Only 1% of anti-nmdar encephalitis patients remain monosymptomatic; 7 they may present with either an isolated newonset epilepsyor complex partial status epilepticus. 3,10,11,,8 Although seizures in anti-nmdar encephalitis are typically focal motor and complex partial seizures, 6 refractory complex partial and generalized status epilepticus may occur. 19,8 Associated psychiatric symptoms and movement disorders can provide helpful clinical clues, particularly in the presence of orofacial lingual dyskinesias, chorea, and dystonic and opisthotonic posturing. 6,8 Frank mutism has been described. At disease nadir, patients could develop decreased consciousness, catatonia, and even coma. 6,8 EEG may distinguish seizures from complex repetitive movement disorders when their clinical features are clinically indistinguishable. 8 A unique EEG pattern characterized by rhythmic delta activity at 1 to 3 Hz with superimposed bursts of rhythmic 0- to 30-Hz β activity riding on each delta wave may occur in anti-nmdar encephalitis. Also known as the extreme delta brush pattern, this EEG pattern is associated with a more severe and prolonged disease course. 9 Neuroimaging may show limbic or extralimbic changes, but a normal MRI can be seen in approximately 50%. 6 CSF shows a lymphocytic pleocytosis in 80%, and the antibody is better detected in CSF than serum. 6 In patients with paraneoplastic autoimmune epilepsy, immunotherapy (when combined with tumor removal) could result in a substantial clinical improvement in approximately 80% patients. 7 VGKC-Complex Antibodies, LGI1, and CASPR VGKC-complex antibodies are the most commonly identified antibodies associated with autoimmune epilepsy and seizure-predominant limbic encephalitis. 4,10,15,16,30,31 Since 010, VGKC-associated proteins LGI1 and CASPR have been identified as the predominant targets of the antibodies rather than the VGKC complex itself LGI1 is a secreted neuronal protein that binds to presynaptic disintegrin and metallopeptidase protein 3 (ADAM 3) and postsynaptic ADAM, forming part of a pathway linking presynaptic VGKC to the postsynaptic AMPAR, an interaction that is responsible for fast excitatory synaptic transmission and hippocampal long-term synaptic plasticity. 38 Furthermore, genetic mutations in LGI1 are associated with an autosomal dominant lateral temporal epilepsy. 39,40 CASPR, a membrane protein expressed in both the central and peripheral nervous systems, plays an important role in clustering of VGKC (Kv1.1/1.) at the juxtaparanodal region of myelinated axons and regulates axonal excitability. 41,4 Mutations of the gene encoding CASPR are associated with increased risk of seizures and cognitive disorders. 43,44 CASPR antibodies target hippocampal interneurons, which contribute to a disruption of inhibitory interneuron activity. 45 Caution should be exercised when VGKC-complex seropositivity occurs in the absence of antibodies to LGI1 and CASPR (termed double negatives), as their clinical significance and value of immunotherapy remain unclear. 35,46 LGI1 Antibodies Limbic encephalitis is the most common clinical feature of anti-lgi1 autoimmunity followed by Morvan s syndrome and pure autoimmune epilepsy. 3,5,10,11,3,36 Unlike other

5 94 Autoimmune Epilepsy Quek, O Toole autoimmune diseases, anti-lgi1 encephalitis is more frequently encountered in men (64%) and often manifests itself at a later age (median: years). 3,36,47 Ten percent of patients have varied cancer associations (thymoma, endocrine tumors, ovarian teratoma, mesothelioma, rectal, renal cell, and thyroid). 3,36,48 The typical initial presentations of anti-lgi1 autoimmunity include seizures (53%) and cognitive disorders (4%) 36 (almost all would evolve to develop memory impairment or behavioral changes). In some patients, spatial disorientation (5%), insomnia (65%), and autonomic dysfunction (47%) may occur. The classically described Morvan s syndrome, which comprises limbic encephalitis, peripheral nerve hyperexcitability, insomnia, and dysautonomia, occurs infrequently (<10%) in anti-lgi1 autoimmunity. 36 Faciobrachial dystonic seizures (FBDSs), unique to anti- LGI1 encephalitis, are stereotypical, brief contractions of the face, arm, and leg. 36,47 50 These dystonic seizures are usually brief (usually <3 15 seconds) and occur frequently (median: times daily). 36,47,49 Commonly triggered by emotions and movements, FBDSs are usually preceded by a sensory aura and are accompanied by ictal loss of awareness, dysphasia, vocalizations, automatisms, agitation, fear, and speech arrest Concurrent ictal epileptiform changes have been observed on scalp EEG in only a minority of patients. 4,47,48,50 The association between FBDSs and anti-lgi1 autoimmunity needs to be recognized, as they are often confused with other movement and psychogenic disorders. 48 FBDSs occur in 47% of patients with anti-lgi1 encephalitis 36 and 43% of anti-lgi1 associated autoimmune epilepsy. 3 FBDSs can precede the onset of cognitive symptoms from encephalitis by a median of 3 to 5 weeks, 36,47 and only a minority respond to AEDs alone. 47,48,50 Cutaneous reactions to AEDs in patients with anti-lgi1 are unusually high (41 50%). 47 These reactions have been reported to occur with phenytoin, carbamazepine, valproate, lamotrigine, and levetiracetam, although there is no evidence of a predilection for a specific type and class of AEDs. FBDS responds well to corticosteroids, with early seizure cessation mostly observed within months following treatment. 36,47,48 Improvement in cognitive deficits and amnesia tend to lag seizure recovery by months or even years. 36,48 Existing data suggest that initiation of immunotherapy is reasonable in patients with drug-refractory epilepsy and the presence of cognitive impairment. 36,48 Noteworthy, one in three patients progresses to develop further clinical relapses despite immunotherapy. 36,48 In addition to FBDSs, other seizure semiologies with multifocal localizations have been associated with anti- LGI1 autoimmunity. 3,36,49 Tonic clonic and focal seizures with cognitive, autonomic, sensory, motor, and even gelastic features and piloerection have been reported. 3,36,49,51 Subclinical electrographic seizures are not infrequent. 36,49,50 MRI of the brain is often normal, particularly during the early stages of the disease, when only FBDSs are present. MRI abnormalities can include signal changes in the medial temporal lobe, sometimes the basal ganglia and cortically on diffusion-weighted imaging and FLAIR (fluid-attenuated inversion recovery) sequences. 3,36,47 Serial MRIs are useful to detect delayed development of radiological abnormalities, evolution of changes, and progression to medial temporal sclerosis. 5 The CSF is often bland. 47,48 Serum hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion is another useful clue of LGI1 autoimmunity, occurring in 66% of patients, either during early or late stages of the disease. Hence, serum sodium should be repeated as initial levels may be normal. 47 CASPR Antibodies Similar to anti-lgi1 antibody, there is a male predilection (90%) in anti-caspr autoimmunity, with a median age of onset in the sixties. 34,37,53,54 The most common clinical phenotypes of CASPR autoimmunity are limbic encephalitis (4%), Morvan s syndrome (9%), and peripheral nerve hyperexcitability (13%). 37 There is also growing recognition that CASPR antibody may be associated with autoimmune epilepsy. 3,11,17,55 The disease course can be protracted, taking months to over a year to evolve. In 30%, the disease nadir was only reached 1 months after symptom onset. 37 Seizures are the presenting symptom in a quarter of patients and occur during the course of the disease in up to 50%. 37,54 Seizure types include focal seizures of temporal lobe origin, secondarily generalized seizures, and nonconvulsive status epilepticus. 17,34,55 Seizures may remain the only or predominant symptom. 3,11,17,55 Peri-ictal autonomic symptoms can include nausea, epigastric aura, palpitations, flushing, and pilomotor erection. 55 Anterograde and episodic memory disorders are reported in those with limbic encephalitis. Typical symptoms of limbic encephalitis (e.g., acute confusion or behavioral disorders) may be absent. 54 During the course of disease, other reported features can include sleep disorders (68%), neuropathic pain (61%), peripheral nerve hyperexcitability (54%), autonomic dysfunction (44%), and cerebellar symptoms (35%). 37 The multifocal involvement of the central and peripheral nervous system provides a useful clue to an underlying CASPR autoimmunity. A recent study reported that among patients with CASPR antibodies, CSF antibody positivity was predictive of autoimmune encephalitis dominated by seizures and cognitive changes. By contrast, patients with a negative CSF study but serum positivity were more likely to manifest Morvan s syndrome and peripheral nerve hyperexcitability. 54 When the central nervous system is involved in patients with anti-caspr seropositivity in the CSF, MRI and CSF evaluations are more likely to show inflammatory changes. In this group, 90% demonstrate limbic changes on MRI and 75% yield an inflammatory CSF. 54 Nineteen percent of anti- CASPR disease may be associated with tumor (e.g., thymoma, lung, and sigmoid tumors). 37 When present, thymoma occurs more commonly in patients with peripheral nerve hyperexcitability and Morvan s syndrome. 54 CASPR-antibody associated epilepsy responds poorly to AED 55 but reacts well to immunotherapy with full (39%) or

6 Autoimmune Epilepsy Quek, O Toole 95 partial recovery (5%) after treatment. 34,37 If present, surgery or chemotherapy for an underlying tumor is also helpful in improving treatment response. Relapses are not rare (5%), even among those who received initial immunotherapy, as there have been reports of relapses occurring as late as 6 years after the initial disease onset. 37 GABA B R Antibodies GABA B R antibodies bind to the B1 subunit of the GABA B Rthat exerts inhibitory regulatory effects on synaptic transmission. 56 GABA B R antibodies were first described in 15 patients with limbic encephalitis, with seizures as a predominant feature. 57 Seizures are typically focal-onset originating from the temporal lobe; secondary generalization and status epilepticus can also occur. 57,58 Related syndromes attributed to GABA B R autoimmunity include cerebellar ataxia and opsoclonus myoclonus. 59,60 The GABA B R antibody is closely associated with small-cell lung carcinoma when detected in older patients. 57,60 When testing for GABA B R antibodies, paired serum and CSF should be examined to avoid false-negative results, as CSF appears to be more sensitive than serum for antibody detection, similar to NMDAR and AMPAR antibodies. 57,60 Also, GABA B R antibody has been reported in association with GAD65 and voltage-gated calcium channel (N-type) antibodies. 57,59,60 Significantly, the coexistence of paraneoplastic neuronal nuclear and cytoplasmic antibodies is more predictive of an underlying cancer. 60 The prognosis of patients with GABA B R autoimmunity is generally favorable, especially after treatment with immunotherapy and/or cancer treatment, except in patients with small cell carcinoma. 57,60 In the latter, tumor progression or complications of chemotherapy may limit survival. 60 GABA A RAntibodies The GABA A R antibody is associated with a severe form of encephalitis characterized by recurrent seizures and MRI findings comprising multifocal and cortical subcortical MRI T/FLAIR hyperintensities a distinctive imaging finding that should immediately raise suspicion of GABA A Rantibody association GABA A R is a ligand-gated ion channel that mediates fast inhibitory transmission, and its disruption results in increased neuronal excitability and seizures. 64 These characteristics make the GABA A Rasuitable therapeutic target of AEDs (e.g., benzodiazepines, phenobarbital, and topiramate). 65 Mutations in the GABA A R gene have been associated with increased epilepsy risk. 66,67 In animal studies, GABA A R antibodies result in a decrease in GABA A R density at synaptic sites of rat hippocampal neurons. 61,63 In anti-gaba A R encephalitis, the most commonly encountered manifestations are seizures, seen in 88%. 61,6 Seizures are characteristically severe, resulting in drugrefractory status epilepticus requiring pharmacologically induced coma. 6 Frequent accompaniments to seizures associated with GABA A R autoimmunity include cognitive impairment, altered behavior, decreased consciousness, and movement disorders. 61,6,68 Patients with anti-gaba A R antibodies can present as postviral encephalitis (e.g., herpes simplex 1 and human herpesvirus 6) or coexist with other neural autoantibodies (e.g., NMDAR, LGI1, GABA B R, and GAD65 autoantibodies). 61,6 An association between anti-gaba A R antibodies and tumor (mostly thymoma) is seen in 40% of patients. 6,63 Despite the severity of this disorder, patients may still respond (at least partially) to immunotherapy and tumor treatment AMPAR Antibodies Since 009, antibodies to the AMPAR have been described in small case series and in patients with new-onset confusion, amnesia, psychiatric disturbance, and seizures AMPARs are ionotropic glutamate receptors involved in neuronal excitatory neurotransmission. In vivo application of AMPAR antibodies to neuronal cultures causes a reversible reduction in AMPAR clusters. 69 Patients with AMPAR autoimmunity may present initially with seizures or in association with other neurologic accompaniments (described earlier). In contrast to anti-nmdar encephalitis, those with anti-ampar encephalitis do not develop autonomic instability, dyskinesias, and hypoventilation. 69,71 The typical age of affected cases is 60 years (range: 38 9 years). Middle-aged women are more commonly affected. Overall, this is considered a rare disorder in comparison to anti-nmdar encephalitis 69,71 and is estimated to occur in approximately 10% of patients with limbic encephalitis. 73 Similar to GABA B and NMDA receptor antibodies, serum AMPAR antibody levels can be initially negative. 71 However, AMPAR antibodies are normally detected in the CSF in conjunction with lymphocytic pleocytosis, high protein, and/or oligoclonal bands. 69,71 EEG can vary from normal to slow background rhythms or demonstrate epileptiform changes, particularly in the temporal lobes. 69,71 MRI of the brain may also be initially normal or show increased FLAIR signal in the temporal lobes. 69,71 Patients with an associated cancer (50 70%) (mostly lung, breast, or thymus) need a definitive cancer treatment (surgery removal and chemo/radiotherapy) in conjunction with immunotherapy. 69,71 These patients generally respond well to immunotherapy (70%), but relapses may be frequent, so a prolonged second-line immunotherapy is warranted in most cases. Coexistence of another classic paraneoplastic antibody in addition to AMPAR antibodies portends a poorer prognosis. 71 Delay in diagnosis or frequent relapses can inadvertently lead to an increased long-term disability GAD65 Antibodies GAD65 is an intracellular cytoplasmic-facing synaptic vesicle moleculethat catalyzes the production of GABA from glutamate, highly expressed in the pancreas and in GABAergic neurons of the nervous system. GAD65 antibodies are frequently detected in patients with type 1 diabetes but, when present at high titers in the CSF, may also be associated with immune-mediated neurologic disorders (e.g., stiff person syndrome, cerebellar ataxia, limbic encephalitis, and autoimmune epilepsy). 3,75 78 Women are more frequently affected than men, and the typical age of onset is 0 to 40 years (range: 5 80 years). A coexistent

7 96 Autoimmune Epilepsy Quek, O Toole neural autoantibody (e.g., GABA receptor antibodies) may increase the risk of cancer. 79 Although there have been cases of GAD65 antibodyassociated epilepsy patients who improved after immunotherapy, patient responses to antibody-depleting strategies are generally poor, as the antigenic target is intracellular and the antibody is possibly a surrogate marker of a cytotoxic T-cell mediated inflammatory disorder. 5,77,80 Patients frequently continue to have poorly controlled, treatment-resistant, disabling epilepsy. Paraneoplastic Antibodies Targeting Neuronal Nuclear and Cytoplasmic Antigens ANNA-1 (Hu) Antibodies The ANNA-1 antibody targets RNA-binding proteins important for RNA regulation of neurons postmitosis. 81 Although ANNA-1 autoimmunity typically presents heterogeneously in a multifocal fashion (e.g., neuropathy, gastrointestinal dysfunction, and limbic encephalitis), previous reports have suggested an association between epilepsy and ANNA-1 antibody. 11,81,8 Seizures associated with ANNA-1 autoimmunity can be limbic or extralimbic in origin, 83 where the temporal lobes are particularly targeted by a T-cell rather than a B-cell attack. 84 ANNA-1 antibody is highly associated with small cell lung cancer, where treatment response to immunotherapy is generally poor. 81,8 Cytotoxic therapies work better once cancer, if identified, has been treated. CRMP-5 Antibodies The antigenic target of CRMP-5 antibodies is important for neuronal development. Rarely reported in association with autoimmune epilepsy, patients with CRMP-5 autoimmunity frequently manifest multifocal neurologic signs including chorea, cranial neuropathy, dementia, cerebellar ataxia, myelopathy, and peripheral neuropathy. 85 Small cell lung cancer and thymoma are the most commonly associated malignancies. Autopsy studies reveal evidence of inflammatory neuronal death similar to anti-hu disorders. 86 Ma/Ta Antibodies Ma1 and Ma proteins are nuclear neuronal proteins important to RNA transcription and cellular apoptosis. Ma1 and Ma antibodies can occur together, collectively known as Ma. This combination of antibodies occurs more commonly in women with breast, colonic, or ovarian cancers. Isolated Ma positivity, also known as Ta, occurs in males in the setting of testicular cancer. In addition to seizures, patients may also develop hypothalamic and brainstem dysfunction with a narcolepsytype syndrome, often including partial cataplexy. As testicular cancer can be highly responsive to early chemotherapy, these patients can do reasonably well if diagnosed early. Ma1 patients less often have associated seizures and usually have a poor response to immunotherapy. 87 Amphiphysin Antibodies Amphiphysin antibodies attach to a synaptic vesicle-bound protein that colocates with dynamin to collect membrane components after neurotransmitter exocytosis. 88 This antibody is classically associated with small cell lung and breast cancer, and any coexisting antibodies are highly predictive of a specific common cancer type. 89 It is associated with stiff person syndrome, encephalopathy, myelopathy, and cerebellar ataxia. 89 Clinical Approach to Autoimmune Epilepsy Establishing which patients might have an immunological cause for their epilepsy is challenging. The diagnosis of autoimmune epilepsy can be confirmed based on a triad of clinical features, neural autoantibody detection, and response to immunotherapy ( Fig. 1). 3,5,90 Subjecting epilepsy patients with low pretest likelihood of autoimmune epilepsy to detailed neural autoantibody testing is not advisable and may lead to seropositive results of uncertain significance or inappropriate use of immunotherapy. We suggest a practical approach, guided by good clinical reasoning, to identify potential patients who will benefit from neural autoantibody testing and a treatment trial of immunotherapy. Clinical Features of Autoimmune Epilepsy Early identification of patients at a high risk of autoimmune epilepsy will enable early treatment and portend better outcomes ( Fig. 1). 3,5 Suspicious features would include subacute onset (days, weeks) of epilepsy of unknown etiology, unusually high seizure frequency, and a lack of response to standard AED treatment. 3,5 Patients with a clear seizure etiology (e.g., metabolic, infectious, neoplastic, or structural causes) should be excluded. As with other autoimmune and paraneoplastic disorders, patients may have a strong personal or family history of autoimmunity or cancer. Seizures are typically focal in origin 3,10,17 with motor, sensory, and autonomic manifestations. Neural autoantibodies are detected in 30% of patients, where seizures can be accompanied by peri-ictal autonomic findings (e.g., gastrointestinal manifestations and piloerection). 55 An autoimmune etiology should also be suspected when there is variability in seizure semiology in each individual or a multifocal source of epileptiform discharges. 3 Secondarily generalized seizures, epilepsia partialis continua, and nonconvulsive and convulsive status epilepticus may also occur or coexist in these patients. 3,5,91 FBDS is the only distinctive seizure semiology that is pathognomonic of an autoimmune etiology. Because it is only present in approximately 50% of anti-lgi1 encephalitis, the diagnosis of anti-lgi1 autoimmune epilepsy cannot be excluded in the absence of FBDS. 36 When typical symptoms of limbic dysfunction are present, autoimmune encephalitis is readily identified. In patients with autoimmune epilepsy, however, seizures may be the only clinical manifestation. Subtle memory impairment and mood changes may be absent or hard to appreciate. One should be watchful for neuropsychiatric symptoms (e.g., cognitive, memory, behavioral, personality, and psychiatric) and other features of movement disorders

8 Autoimmune Epilepsy Quek, O Toole 97 EPILEPSY OF UNKNOWN ETIOLOGY NEURAL AUTOANTIBODY TESTING Exclude other metabolic, infectious and structural causes Suspect Autoimmune Epilepsy if APE score 4 (refer Table 3) Antibodies targeting intracellular antigens (paraneoplastic association) (eg. ANNA-1, CRMP-5, Ma1/Ma) Screen and treat tumor Consider cyclophosphamide Antibodies targeting cell membrane proteins Strong association (e.g. LGI1, Caspr, NMDAR, GABA A/B, AMPAR) Moderate association (e.g. VGCC, gachr) GAD65 antibodies Seronegative Tumor Screening (treat if present) TRIAL OF IMMUNOTHERAPY RITE score 7 (refer Table 3) IVMP 1g 3-5 days, then weekly for 4-6 weeks, or IVIg 0.4g/kg body weight 3-5 days, then weekly for 4-6 weeks No improvement Consider second immunotherapy trial with another agent Evaluate outcomes Seizure freedom or >50% seizure reduction and autonomic dysfunction. 3 A preceding history of a viral prodrome can occur in patients with autoimmune epilepsy. EEG is of limited value for differentiating autoimmune epilepsy from other causes, with the exception of the extreme delta brush pattern unique to anti-nmdar encephalitis. 9,9 EEG can, but does not always, provide clues to a possible autoimmune epilepsy, including multifocal seizure localizations, nonconvulsive seizures, and focal motor status epilepticus. 93 MRI and CSF evaluations are useful ancillary investigations to support an underlying inflammation affecting the central nervous system and to exclude other alternative diagnoses (e.g., structural, neoplastic and infectious seizures). T/FLAIR signal and volume changes in the medial temporal regions are typical MRI features of autoimmune limbic encephalitis. The presence of multifocal, asymmetric cortical-subcortical abnormalities (especially in the temporal and frontal regions) is a distinct feature of anti-gaba A R autoimmunity. 61,6 CSF inflammation with lymphocytic pleocytosis, elevated protein, CSF-specific oligoclonal bands, and/or a raised CSF IgG index are also supportive. Improvement Supports diagnosis of Autoimmune Epilepsy Taper IVMP or IVIg over 4-6 months Consider maintenance immunotherapy (azathioprine or mycophenolate) Fig. 1 A clinical and neural autoantibody approach to diagnosis and treatment of autoimmune epilepsy. AMPAR, α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor; ANNA-1, antineuronal nuclear type 1; APE, Antibody Prevalence in Epilepsy; CASPR, contactin-associated protein-like ; CRMP-5, collapsin response mediator protein 5; GABAAR γ-aminobutyric acid A receptor; GABABR, γ-aminobutyric acid B receptor; gachr, ganglionic acetylcholine receptor; GAD65, glutamic acid decarboxylase 65; IVIg, intravenous immunoglobulin; IVIg, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; LGI1, leucine-rich glioma inactivated 1; NMDAR, N-methyl-D-aspartate receptor; RITE, response to immunotherapy in epilepsy; VGCC, voltage-gated calcium channel. Patients with autoimmune epilepsy typically manifest a constellation of these clinical radiological features, which, in isolation, are nonspecific. Recently, a clinical risk score termed the Antibody Prevalence in Epilepsy (APE) score was proposed. The APE score is a composite of nine items that are differentially weighted to a maximum score of 15, aimed at estimating the probability of an autoimmune etiology before antibody testing. 10,11 The components of the scoring system comprise clinical, brain MRI, and CSF parameters. The APE score was derived using a cohort of patients with epilepsy of unknown etiology and subsequently externally validated as a predictive model of neural autoantibody positivity in a separate cohort of epilepsy cases. 11,94 An APE score of 4 (sensitivity: 98%; specificity: 78%) identifies patients with a high likelihood of autoimmune epilepsy and selects patients who would benefit from neural autoantibody testing. 11 Conversely, low scores would indicate a lower likelihood of autoimmune epilepsy. A method to judiciously stratify patients according to their likelihood of autoimmune epilepsy is important to select individuals for neural autoantibody tests and to divert scarce healthcare resources to

9 98 Autoimmune Epilepsy Quek, O Toole pursuing other etiologies if the likelihood for autoimmune epilepsy is low. 11 Neural Autoantibody Evaluation and Paraneoplastic Association Detection of neural autoantibodies in the appropriate context and at sufficient titer supports an immunological basis for epilepsy ( Fig. 1). 3,6,90,95 97 A detailed assessment using a panel of antibodies is preferred over a single antibody as there are significant clinical overlaps between patients with different neural autoantibodies. 6,90,96 To optimize the sensitivity of antibody tests, both serum and CSF assays should be tested concurrently. 97 Interpretation of positive or negative results must take into account the clinical presentation, type of antibody, and reliability of bioassays. 90,96,98 A seropositive result does not necessarily confirm a diagnosis of autoimmune epilepsy. NMDAR, LGI1, CASPR, AMPAR, GABA A R, and GABA B Rantibodies are particularly associated with encephalitis and seizures. 90,96 Considered arbitrarily as high-rank 96 or antibodies strongly associated with autoimmune epilepsy, 90 the presence of these neural autoantibodies is highly suspicious for autoimmune epilepsy and predicts likely response to immunotherapy. Other neural autoantibodies exist that are described less frequently in autoimmune epilepsy or that are inconsistently immunotherapy-responsive (e.g., antibodies to voltage-gated calcium channels, ganglionic acetylcholine receptors, glycine receptors, low-titers of GAD65 antibodies, and double-negative VGKC-complex antibodies). In such cases, diagnosis of autoimmunity must be strongly supported by clinical features and potentially a clear response to a limited trial of immunotherapy. Neural autoantibody seronegativity does not preclude the diagnosis when the clinical phenotype is highly suggestive. 5,90,96,98 Some of these patients respond to immunotherapy. 3,5 As the field progresses, it is likely that more neural autoantibodies will be discovered. 90,98 The ability to detect these neural autoantibodies depends heavily on assay sensitivity and is subject to assay availability in commercial laboratories outside of the major neuroimmunology centers. 98 In seronegative cases, the diagnosis is clinical with a positive trial of immunotherapy. Positive ancillary testing that objectively demonstrates a response to treatment, including MRI, CSF, and EEG, can also be useful in this regard. 5,90 A directed tumor search should be performed depending on the antibody detected. When antibodies with high cancer associations are detected, evaluation for cancer should be thorough. If initial computed tomography is negative, computed tomography positron emission tomography (CT-PET) of the body will increase the diagnostic yield of cancer by an additional 18%. 99 ( Tables 1 and ) Diagnostic and Therapeutic Immunotherapy Trial A treatment trial of immunotherapy may be a useful adjunct to aid diagnosis of autoimmune epilepsy in high-risk individuals. A positive, clinically meaningful response to immunotherapy may justify long-term immunosuppressive treatment. 3,5 The Response to Immunotherapy in Epilepsy (RITE) score, which includes early initiation of immunotherapy and detection of a plasma membrane protein antibody strongly associated with autoimmune epilepsy, is useful to predict response to a treatment trial of immunotherapy ( Table 3). 11 In the absence of randomized control trials, treatment recommendations are based largely on observational reports and clinical experience of large neuroimmunology centers in Europe and the United States. 3,5,7 The Mayo Clinic group recently compiled a series of patients with autoimmune epilepsy and evaluated their response to a treatment trial of immunotherapy. 5 In this study, patients with presumed autoimmune epilepsy received mainly intravenous methylprednisolone (IVMP), intravenous immunoglobulin (IVIg), or both treatments sequentially. Approximately half of these patients improved with the first treatment, and another 40% of the remaining nonresponders improved after a second agent was added. In total, two-thirds of treated patients responded favorably to immunotherapy, as evidenced by either seizure freedom or more than 50% reduction in seizure frequency. The majority of those who improved responded within 4 weeks. Early initiation of immunotherapy was associated with a favorable outcome. 5 A diagnostic treatment algorithm may be adapted to guide clinical management of patients with suspected autoimmune epilepsy ( Fig. 1). 5,90 In this algorithm, either IVMP or IVIg (depending on patients comorbidities) may be used as first-line treatment. For example, IVMP may be avoided in patients with poorly controlled diabetes, chronic hepatitis, and tuberculosis. There are no definitive studies supporting the superiority of one treatment over the other. After 4 to 6 weeks of a treatment trial, a detailed evaluation for treatment response is performed to decide whether treatment should be continued for an additional interval of time. In autoimmune epilepsy, a detailed assessment of clinical outcomes is objectively measured using seizure diaries and detailed clinical history. EEG, MRI, and cognitive tests are additional parameters that can be monitored. Patients who fail to show response may try another first-line agent when the suspicion for autoimmune epilepsy remains high; these patients are then reevaluated after a further 4 to 6 weeks of treatment. Second-line treatment (e.g., rituximab or cyclophosphamide) may be reserved for those who continue to show poor or incomplete response but have neural autoantibodies highly associated with autoimmune encephalitis. Seizures in autoimmune epilepsy generally improve within 4 to 6 weeks of initiating immunotherapy. 5 Conversely, cognitive impairment and amnesia, if present, recover more slowly. For patients who show a positive response, IV treatment should be tapered by gradually increasing the interinfusion intervals over 4 to 6 months, as abrupt discontinuation could lead to relapse. 90 Chronic immunosuppression for maintenance immunotherapy (e.g., azathioprine or mycophenolate mofetil) to prevent relapses may be considered and initiated while the IV treatment is tapered. The exact duration required for maintenance immunotherapy is not known, although it has been suggested that a trial of immunotherapy withdrawal may be initiated after years of treatment. 90

10 Autoimmune Epilepsy Quek, O Toole 99 Table 3 Risk stratification scores to identify patients at a high risk of autoimmune epilepsy (APE score) and those who will benefit from treatment trial of immunotherapy (RITE score) APE score Value RITE score Value New-onset seizures (within 1 y of evaluation) or new-onset, rapidly progressive mental status changes over 1 6 wk Neuropsychiatric changes, agitation, aggressiveness, emotional lability Autonomic dysfunction (sustained tachycardia or bradycardia, orthostatic hypotension, hyperhidrosis, persistently labile blood pressure, ventricular tachycardia or cardiac asystole) Viral prodrome (rhinorrhea, sore throat, low-grade fever) 1 New-onset seizures (within 1 y of evaluation) or new-onset, rapidly progressive mental status changes over 1 6 wk 1 Neuropsychiatric changes, agitation, aggressiveness, emotional lability 1 Autonomic dysfunction (sustained tachycardia or bradycardia, orthostatic hypotension, hyperhidrosis, persistently labile blood pressure, ventricular tachycardia or cardiac asystole) Viral prodrome (rhinorrhea, sore throat, low-grade fever) Facial dyskinesia or faciobrachial dystonic movements Facial dyskinesia or faciobrachial dystonic movements Seizure refractory to at least two antiepileptic medications CSF consistent with inflammation (elevated protein > 50 mg/dl and/or lymphocytic pleocytosis > 5 cells/dl, if the total RBC count is <1,000 cells/dl) a Brain MRI signal changes consistent with limbic encephalitis (medial temporal T/FLAIR signal changes) a Underlying malignancy (excluding cutaneous squamous cell carcinoma, basal cell carcinoma) Seizure refractory to at least two antiepileptic medications CSF consistent with inflammation (elevated protein > 50 mg/dl and/or lymphocytic pleocytosis > 5 cells/dl, if the total RBC count is <1,000 cells/dl) a Brain MRI signal changes consistent with limbic encephalitis (medial temporal T/FLAIR signal changes) a Underlying malignancy (excluding cutaneous squamous cell carcinoma, basal cell carcinoma) Initiation of immunotherapy within 6 mo of symptom onset Detected neural plasma membrane autoantibody (NMDAR, GABA A R, GABA B R, AMPAR, DPPX, mglur-1, mglur, mglur5, LGI1, or CASPR Ab) Total score b 15 Total score b 19 APE score 4 predicts detection of neural autoantibody in autoimmune epilepsy (sensitivity: 97.7%; specificity: 77.9%) RITE score 7 predicts response to initial immunotherapy for autoimmune epilepsy (sensitivity: 87.5%; specificity: 83.8%) Abbreviations: Ab,antibody; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; APE score, Antibody Prevalence in Epilepsy of unknown etiology score; CASPR, contactin-associated protein-like ; CSF, cerebrospinal fluid; DPPX, dipeptidyl-peptidase-like protein 6; FLAIR, fluidattenuated inversion recovery; GABA A R γ-aminobutyric acid A receptor; GABA B R, γ-aminobutyric acid B receptor; LGI1, leucine-rich glioma inactivated 1; mglur5, metabotropic glutamate receptor 5; MRI, magnetic resonance imaging; NMDAR, N-methyl-D-aspartate receptor; RITE, response to immunotherapy in epilepsy. a Patients who did not undergo MRI of the brain or CSF evaluation are scored 0. b Total APE or RITE score assigned to each patient is the sum of values of all the components. The RITE score includes all the components of the APE score and two additional variables This approach should only serve as a guide to diagnose and treat patients with autoimmune epilepsy. Patients who initially present with seizures, but subsequently deteriorate rapidly to status epilepticus or display the full syndrome of autoimmune encephalitis, should receive more rapid treatment escalation that includes plasma exchange and possibly even early second-line treatments (e.g., rituximab or cyclophosphamide). 7 Conversely, autoimmune epilepsy patients whose clinical course is benign may not require immunotherapy if AEDs alone are capable of achieving satisfactory seizure control. The presence of onconeural autoantibodies portends a more guarded prognosis. If detected, cancer should be screened. Treatment of the underlying cancer with a consideration of immunotherapy is pivotal. 6 Antiepileptic Drugs Although seizures in autoimmune epilepsy are characteristically resistant to antiepileptic treatment, AEDs continue to play a crucial role in symptomatic treatment and should be continued even in those undergoing immunotherapy treatment. In some patients with milder autoimmune epilepsy, AEDs alone may be sufficient to achieve seizure freedom. 3,91 There are no randomized trial data to support one AED over another, although there are observations from a case series favoring sodium channel blocking AEDs (carbamazepine, oxcarbamazepine, lacosamide, and phenytoin). 91 It is unclear whether the greater seizure freedom associated with sodium channel blocking AEDs is related to their inherent immunomodulatory effects, the involvement of