antibodies in epilepsy

EPILEPSY (CW BAZIL, SECTION EDITOR)

Antibodies in Epilepsy

Cynthia M. Correll

Published online: 24 March 2013# Springer Science+Business Media New York 2013

Abstract Antibody mediated limbic encephalitis is an in-creasingly recognized cause of seizures in cryptogenic epi-lepsy. Autoimmune encephalitis and epilepsy have beenlinked to both neuronal intracellular antibodies (GAD65,ANNA-1, and Ma) and neuronal cell surface antibodies(VGKC complex, NMDAR, AMPA, GABA-B, andGluR5). This article outlines the latest data on these variousantibodies with a focus on their association with acuteseizures in limbic encephalitis and likely increased risk forchronic epilepsy. There is mounting evidence that theseantibodies may play a role in acute onset and chronic sei-zures in the general epilepsy population without manifestingtypical limbic encephalitis symptoms. This review will dis-cuss the data supporting early recognition and treatmentoptions, beyond typical antiepileptic medications, necessaryto improve outcomes in this epilepsy subgroup.

Keywords Epilepsy . Antibodies . Autoimmune . Limbicencephalitis . NMDA . Voltage-gated potassium channel .

AMPA . GABA-B . GAD . ANNA-1 .Ma

Introduction

Despite our expanding treatment options for epilepsy, up toone-third of patients remain medically intractable [1]. Thiscan be partly attributed to the cryptogenic nature of manyepilepsy cases forcing us to treat the symptoms withantiepileptic medications rather than the underlying etiologyof the seizure disorder. Over the past 30 years, there has

been growing evidence that antibodies associated autoim-mune epilepsy, most commonly presenting as limbic en-cephalitis with seizures but also in chronic or acute onsetepilepsy, is an increasingly recognized cause of cryptogenicepilepsy [2–9]. Initial reports demonstrated encephalitiswith seizures in paraneoplastic syndromes associated withneuronal intracellular antibodies such as anti-neuronal nu-clear antibodies-1 (ANNA-1) and Ma antibodies [10–15] aswell as nonparaneoplastic syndromes associated withglutamic acid decarboxylase (GAD65) antibodies [16–18].We now recognize seizures and epilepsy may be even morecommon in syndromes associated with neuronal cell surfaceantibodies such as voltage gated potassium channel(VGKC) complex antibodies, N-methyl-d-aspartate receptor(NMDAR) antibodies, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptor antibodies,gamma-amino butyric acid (GABA-B) receptor antibodies,and metabotropic glutamate receptor 5 (mGluR5) antibodies[19, 20, 21••, 22–27, 28••, 29, 30, 31•, 32, 33]. This articlewill review the clinical characteristics of these antibodysyndromes, with a focus on seizures and epilepsy; the grow-ing evidence for these antibodies in the general epilepsypopulation; and the literature supporting oncologic and im-munosuppressive therapy.

Neuronal Cell Surface Antibodies

Voltage-Gated Potassium Channel Antibodies

Autoantibodies to voltage-gated potassium channels (VGKC),specifically theKv1 channels, were first recognized in disordersof the peripheral nervous system such as neuromyotonia, adisorder of peripheral nerve hyperexcitability marked clinicallyby cramps and stiffness, and Morvan’s Syndrome, defined asneuromyotonia associated with autonomic instability, CNS

This article is part of the Topical Collection on Epilepsy

C. M. Correll (*)Columbia Comprehensive Epilepsy Center, New YorkPresbyterian Medical Center, 710 W. 168th Street,New York, NY 10032, USAe-mail: [email protected]

Curr Neurol Neurosci Rep (2013) 13:348DOI 10.1007/s11910-013-0348-1

dysfunction, and insomnia [2, 20]. The VGKC antibodies werelater recognized as a common cause of limbic encephalitis andseizures (Table 1). More recently, it was discovered that theactual antigen target of these antibodies are proteins associatedwith the VGKC complex, specifically leucine-rich gliomainactivated 1 protein (Lgi1) and contactin-associated protein 2(CASPR2) [21••, 22].

The characteristics of the limbic encephalitis associatedwith VGKC complex antibodies include impaired episodicmemory, confusion and disorientation, behavioral changessuch as aggression and agitation, psychotic symptoms suchas hallucinations, seizures (complex partial and generalizedtonic-clonic), and low sodium secondary to SIADH [20].Studies have reported seizures frequencies as high as 80 %–90 % in these patients, with mesial temporal or hippocampalfoci more common than extratemporal, and about half ofpatients showing temporal lobe hyperintensity on magneticresonance imaging (MRI), a typical finding in limbic en-cephalitis [21••, 22, 34••].

Irani et al. [22] looked more closely at the clinical char-acteristics of the VGKC complex antibodies in a cohort of74 patients, dividing them into those directed against Lgi1vs CASPR2. They found that the 55 patients with Lgi1antibodies were more likely to have limbic encephalitiswhile the 19 with CASPR2 antibodies were more likely tohave neuromyotonia or Morvan’s syndrome. Lgi1 antibodypatients were also significantly more like to have seizurescompared with CASPR2 antibody patients, with 49 of 55patients vs 10 of 19 patients developing seizures respective-ly. A new seizure type termed faciobrachial dystonic sei-zures has been recognized in VGKC complex antibodyencephalitis, with 89 % of the patients found to have the

Lgi1 antibody [34••]. Irani et al. [34••] reviewed 29 patientswith brief dystonic seizures of the arm and less frequentlyipsilateral face and leg, capturing an ictal EEG correlate in24 % of the patients. Seventy-seven percent of these patientsdeveloped the fasciobrachial dystonic seizures prior to anycognitive symptoms suggestive of limbic encephalitis. The-se seizures were exceptionally hard to control with only 4patients achieving good response to antiepileptic medica-tions. The patients did eventually go on to develop typicallimbic encephalitis with 70 % developing further seizurestypes, including simple partial, complex partial, and gener-alized tonic-clonic seizures.

N-methyl-d-aspartate (NMDA) Receptor Antibodies

An encephalitic entity associated with autoantibodies to theNR1/NR2 subunits of the NMDA receptor, an ionotropicglutamate channel, was first identified by Dalmau and col-leagues in young women with ovarian teratomas [23–25].Since this initial discovery, the disease is now recognized inmen and patients without tumors as well, although about80 % of patients with NMDAR antibody encephalitis arewomen with 60 % of these women presenting with ovarianteratomas [27, 28••]. Compared with VGKC complex antibodyencephalitis, NMDAR antibody encephalitis tends to be a morediffuse CNS syndrome with MRI findings more commonlyextending beyond the temporal region. The encephalitis typi-cally presents in 2 stages. The first stage presents with psychi-atric symptoms including hallucinations, psychosis, depression,and anxiety; confusion; memory deficits and amnesia; aphasia;and seizures. During the second stage, patients typically developreduced consciousness, movement disorders characterized by

Table 1 Antibody specific seizure significance, general epilepsy population prevalence, and response to treatment

Antibody Seizure predominance in encephalitis Prevalence inepilepsy population

Response to treatment

Cell surface

VGKC Major feature (present in up to80 %–90 % of cases) [21••, 22, 33]

6.5 %–11.5 %[19, 49, 51]

Good response to immunotherapy and tumor therapy if present[8, 20, 22, 53, 55, 56]

NMDAR Major feature (present in up to70 %–80 % of cases) [25, 26]

2.5 %–7 % [50] Good response to immunotherapy and tumor therapyif present (75 %–81 % good outcomes) [25, 26, 28••]

AMPA Minor feature (40 % in 1 case series)[29]

Good response to immunotherapy and tumor therapy ifpresent [29, 30]

GABA-B Major feature (80 % and 100 % in 2case series) [31•, 32]

Moderate response to immunotherapy + tumor therapy if present(56 % and 50 % good outcomes in 2 case series) [31•, 32]

mGluR5 Minor feature (present in 1 of 2patients) [33]

Good response to tumor therapy ± immunotherapy [33]

Intracellular

GAD65 Major feature [16–18] 1.6 %–8.7 %[40–44, 45•, 51]

Mixed responses to immunotherapy [16–18, 40]

ANNA-1 Major feature [10–13, 46, 47] Poor response to tumor therapy ± immunotherapy [13, 52]

Ma1/2 Minor feature [14, 15] Moderate response to immunotherapy and tumor therapy(44 % and 33 % good outcomes in 2 case series) [4, 15]

348, of 8 Curr Neurol Neurosci Rep (2013) 13:348

oro-lingual-facial dyskinesias and choreoathetoid movements,dysautonomia including tachycardia/brachycardia and labileblood pressure, and central hypoventilation. It has beensuggested that the initial stage represents cortical involvementof the disease and later stages progression to subcortical dys-function [35].

Seizures have been reported in 70 %–80 % of patients incase series of patients with NMDAR antibody encephalitis[25, 26, 28••]. Reported seizure subtypes include simple par-tial, complex partial, and generalized tonic-clonic, which canbe localized temporally, extratemporally, or multifocally.Schmitt et al. [36] published a case series of continuousEEG recording of 23 patients with NMDAR antibody enceph-alitis. Seventy-eight percent of patients displayed clinical sei-zures before or during the hospitalization. Sixty percent ofpatients were noted to have electrographic seizures withoutclinical correlate, and 60 % of patients exhibited clinicalseizures with EEG correlate. A recent review of NMDARantibody encephalitis in over 400 patients noted that seizurefrequency tends to decrease with disease progression but cancommonly recur spontaneously or as sedation is weaned,which can lead to status epilepticus [27, 37].

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionicAcid (AMPA) Receptor Antibodies

More recently, autoantibodies directed toward theGluR1/GluR2 subunits of the AMPA receptors, anotherionotropic glutamate channel, were established as a less com-mon cause of limbic encephalitis and seizures. The initial reportby Lai et al. [29] identified 10 patients with limbic encephalitisof unknown etiology found to have AMPAR antibodies in theirCSF. Eight patients had MRI findings of temporal lobehyperintensity. Patients displayed symptoms typical of limbicencephalitis including short term memory loss, confusion, be-havioral changes, agitation/aggression, and hypersomnolenceor decreased consciousness. Four of the 10 patients had recog-nized seizures, making seizures in this initial cohort of AMPARencephalitis less common than in encephalitis associated withVGKC complex or NMDAR antibodies. EEG recordings re-vealed temporal lobe epileptiform activity, defined as seizuresor interictal discharges, in 3 of the 4 patients noted to haveclinical seizures. Further case reports and series since the initialpaper have noted cognitive and psychiatric symptoms as theprominent features and not seizures, although some EEG re-cordings in these patients displayed sharp waves [30, 38].

Gamma-amino Butyric Acid (GABA-B) ReceptorAntibodies

Autoantibodies to the metabotropic GABA-B receptor havealso been recently recognized as a cause of epilepsy associ-atedwith limbic encephalitis. Lancaster et al. [31•] published a

case series of 15 patients with serum or CSF reactive toneuronal cell surface antigens determined to be GABA-Breceptors. Patients clinically presented with symptoms typicalof limbic encephalitis including confusion, memory deficits,behavioral changes, sleep disturbances, psychosis, and apha-sia. Of note, all 15 patients had seizures with 13 of the patientsexhibiting seizures as their presenting symptom. Furthermore,3 patients were noted to develop status epilepticus. The ma-jority of seizures were determined to be temporal lobe inorigin often with secondary generalization. This is consistentwith the fact that 10 out of 15 patients displayed unilateral orbilateral MRI hyperintensities in the temporal lobes.

Another 11 patients with GABA-B antibodies were iden-tified by Boronat et al. [32]. These patients were identifiedby screening the serum and CSF of 70 patients with limbicencephalitis and 77 patients with syndromes associated withglutamic acid decarboxylase (GAD) antibodies. Ten of the11 patients found to have GABA-B antibodies presentedwith typical limbic encephalitis, and nine of these patientsdeveloped seizures.

Metabotropic Glutamate Receptor 5 (mGluR5) Antibodies

Antibodies to mGluR5, a metabotropic glutamate receptor,have been reported in 2 patients with autoimmune enceph-alitis and Hodgkin lymphoma, termed Ophelia syndrome[33]. Their presentation was characterized by confusion,short term memory loss, emotional lability, hallucinations,and delusions. One of the patients was noted to have sei-zures and myoclonic jerks as well as right temporal lobehyperintensity on MRI while the other patient did not haveany recognized seizures with MRI hyperintensities in theparieto-occipital regions.

Neuronal Intracellular Antibodies

Glutamic Acid Decarboxylase (GAD65) Antibodies

Antibodies to GAD65, a cytoplasmic enzyme that catalyzesthe conversion of L-glutamate to GABA, have been contro-versial in the historical literature as a cause of encephalitisand epilepsy due to their prevalence in other systemic andneurological disorders. GAD65 antibodies are expressed inthe pancreatic beta cells and can be found in patients withdiabetes mellitus type 1. They are also seen in a variety ofneurological disorders including stiff person syndrome, cer-ebellar ataxia, and palatal myoclonus [39]. Over time, theliterature has expanded to include many examples ofGAD65 antibodies in limbic encephalitis and to suggest thatthese antibodies may also be causal in cases of chronicepilepsy without significant limbic symptoms or cognitivedeficits.

Curr Neurol Neurosci Rep (2013) 13:348 of 8, 348

There are now a number of case reports and series asso-ciating acute or subacute typical limbic encephalitis withhigh titers of GAD65 antibody [16–18]. The clinical pre-sentation is characterized by short term memory loss, be-havioral changes such as anxiety, and temporal lobeseizures. Reported imaging studies, both MRI and PET,have typically demonstrated temporal abnormalities withEEG reports also supporting temporal lobe seizure foci. Astudy of 53 patients diagnosed with limbic encephalitis viasymptoms and MRI findings revealed 9 patients with highGAD65 antibody titers [18]. Compared with the 10 patientswith VGKC complex antibodies, the GAD65 antibody pa-tients tended to be younger, median age 55 vs 23 respec-tively. Patients with GAD65 antibodies also tended topresent with seizures, specifically of temporal lobe localiza-tion, as their prominent sign.

A number of studies have also explored the presence ofGAD65 antibodies in patients with chronic or new onsetmedically intractable temporal lobe epilepsy [40–44, 45•].An early study compared GAD65 antibody positivity in 51patients with localization related epilepsy, 49 patients withgeneralized epilepsy syndromes, and 48 healthy controlswith results demonstrating 8 patients with GAD65 anti-bodies found exclusively in the localization related epilepsygroup [41]. Two larger studies composed of 253 and 233epilepsy patients found prevalence rates of GAD65 anti-bodies to be 5.9 % (2.8 % very high titers) and 2.6 %,respectively [42, 44]. One of the larger studies also includeda 200 patient healthy control group and noted a 1.5 %prevalence of GAD65 antibodies among controls. Lastly, amore recent study of patients with temporal lobe epilepsy ofknown etiology (19 patients) or cryptogenic etiology (23patients) found 5 patients in the cryptogenic group withGAD65 antibody positivity.

Anti-Neuronal Nuclear Antibody (ANNA-1)

ANNA-1, also termed anti-Hu antibody, is a nuclear anti-body, which targets RNA-binding proteins and has beenassociated with a variety of autoimmune neurological syn-dromes including peripheral neuropathy (sensory and/ormotor), cerebellar ataxia, brainstem encephalitis, autonomicdysfunction, gastrointestinal dysmotility, and limbic en-cephalitis. In the largest case series of patients withANNA-1, Graus et al. [11] described the presenting featuresof 200 patients. Cortical encephalitis was the primary pre-sentation in 20 of the patients, and 17 of these cases weremore specifically labeled as limbic encephalitis. Seizureswere a common symptom. Other studies have also describedseizures as a common manifestation in this patient popula-tion [10, 12] including examples of status epilepticus [13]and epilepsia partialis continua [46, 47]. A more recentstudy confirmed that cortical findings and epilepsy in

ANNA-1 encephalitis are not just confined to the limbicregion [48]. This study of 28 patients with ANNA-1 andclinical symptoms of new onset seizures, memory loss, andpsychiatric disturbance included EEG data from 12 patientswith epileptiform discharges in the temporal region (33 %),extratemporal region (25 %), or both (42 %). Four patientsdemonstrated seizures on EEG with 2 of temporal localiza-tion and 2 with epilepsia partialis continua of the precentralgyrus.

Ma1 and Ma2 Antibodies

The Ma1 and Ma2 antibodies target nuclear antigensthought to be involved in RNA transcription and apoptosis[2]. Ma antibodies were initially recognized in cases ofbrainstem encephalitis characterized by gaze palsies, ptosis,opsoclonus, dysarthria, and facial weakness [15]. Later stud-ies of Ma antibody syndromes confirmed that cases oflimbic encephalitis and seizures were also associated withthis antibody [14, 15]. One case series of 27 patients withlimbic encephalitis reported 12 of these patients developedseizures [15]. EEG performed in 10 of these patients dem-onstrated mostly temporal lobe epileptiform activity.

Chronic or New Onset Epilepsy and Autoantibodies

As previously discussed, a number of studies havesuggested that elevated levels of GAD65 antibodies areassociated with chronic or new onset medically intractableepilepsy without limbic encephalitis [40–44, 45•]. The sig-nificance of this is unclear but it has been suggested thatthese cases may represent a less severe form of limbicencephalitis or a more chronic epilepsy resultant from aprevious acute inflammatory limbic encephalitis state. Overtime, the literature has incorporated further examples ofelevated levels of various antibodies in patients with epilep-sy presenting without other typical limbic encephalitissymptoms. These examples include ANNA-1 [10],NMDAR antibodies [5, 26], and VGKC complex antibodies[22] (Table 1).

In an attempt to determine the significance of theseantibodies in the general epilepsy population, a number ofgroups have now studied the prevalence of these antibodiesamong patients with chronic or new onset epilepsy.McKnight et al. [49] performed 1 of the first studies of thistype comparing 139 epilepsy patients, composed of 26patients with definite concomitant autoimmune disorders(systemic lupus erythematosus, Hashimoto’s encephalopa-thy, antiphospholipid syndrome, etc), 46 patients withsuspected concomitant autoimmune disorders, and 67 pa-tients with solely drug resistant epilepsy, to a control groupof 150 patients. They reported VGKC complex antibodies in


11.5 % of the patients with epilepsy, spread across all 3patient populations, vs 0.5 % of the control subjects as well asGAD65 antibodies in 3.6 % of the epilepsy patients and noneof the controls. Another study of 106 female patients withchronic epilepsy found VGKC complex antibodies in 6.5% ofthe subjects [19]. Niehusmann et al. [50] found 5 NMDARantibody positive patients and 3 GAD65 antibody positivepatients in a group of 19 female patients with new onsetunexplained epilepsy between the ages of 15 and 45. In areview article in 2011, Lang [51] reported the prevalence ofVGKC complex, NMDAR, and GAD65 antibodies in a largecohort of 236 chronic epilepsy patients and 185 new diag-nosed epilepsy patients. VGKC complex antibodies werefound in 10 % of the epilepsy patients compared with 0.5 %of controls. NMDAR antibodies were found in 7 % of newdiagnosed epilepsy patients as well as 2.5 % of the chronicepilepsy patients. GAD65 antibodies were found in 1.6 %–1.7 % of the epilepsy patients. Overall, this data suggests thatthese antibodies are present in increased numbers in the gen-eral epilepsy population, even when these patients do notpresent as typical limbic encephalitis.

Treatment Outcomes in Antibody Mediated LimbicEncephalitis and Epilepsy

Early studies looking at the outcomes of intracellularonconeuronal antibody mediated limbic encephalitis and sei-zures were not promising. Two studies of 15 patients and 10patients, respectively, with ANNA-1 mediated encephalitisshowed no improvement to a combination of tumor therapyand immunotherapy [13, 52]. Later studies examining 50patients with paraneoplastic limbic encephalitis and 28 pa-tients with Ma antibody encephalitis reported improvementrates of 44 % and 33 %, respectively, in response to treatmentof the tumor and immunosuppressive agents [4, 15]. Thesestudies also suggested that treatment of the underlying tumorwas essential as patients receiving only immunotherapy did notshow improvement. Treatment outcomes in nonparaneoplasticintracellular GAD65 antibody limbic encephalitis and epilepsyhas also been mixed [16–18, 40].

As our knowledge of neuronal cell surface antibodies hasexpanded, there have been increasing reports of improvedoutcomes in a variety of cell surface antibodies mediatedencephalitis and seizures cases (Table 1). Battaler et al. [53]reported a series of 39 patients with a variety of antibodiestreated with a combination of oncologic therapy and immu-notherapy showing that patients with antibodies to cell surfaceantigens (VGKC complex and unidentified neuronal cellmembrane) had better response rates than patients with intra-cellular antigens (Ma2 and Hu). In NMDAR antibody enceph-alitis cases, 75 %–81 % of patients show improvement with acombination of immunotherapy and tumor therapy [25, 28••].

Studies also suggested better outcomes if therapy was initiatedearlier [26, 28••]. Notably, relapses can be seen in up to 25 %of patients with NMDAR encephalitis, commonly with sei-zures during the relapses, and are more common if the initialtreatment regimen did not include immunosuppression [54].Recently, an observational study of 501 patients withNMDAR encephalitis found initiation of second line therapy(rituximab, cyclophosphamide) following first line therapy(steroids, IVIG, plasmapheresis) was a predictor of improvedoutcomes [28••].

Further studies have reported good response of limbic en-cephalitis symptoms, and specifically improved seizure control,to immunotherapy and tumor treatment as needed in patientswith VGKC complex antibodies [8, 20, 22, 55, 56], AMPAantibodies [30], GABA-B [31•, 32], and mGluR5 antibodies[33]. Seizures in VGKC complex antibody encephalitis werereported to have much better response to immunotherapy thanantiepileptic medications [8, 55]. A recent study of 32 patientswith antibody mediated seizures, including patients withVGCK complex, GAD65, Ma2, and NMDA antibodies, found81 % had improvement in seizure frequency in response toimmunotherapy (IV steroids, IVIG, or a combination of IVsteroids, IVIG, plasmapheresis, and cyclophosphamide), with18 patients seizure free [57••]. They also found that outcomeswere better with earlier initiation of therapy.

In fact, early initiation of treatment may prove to be essen-tial in improving therapeutic response and preventing thedevelopment of epilepsy. Multiple studies following serialMRI and PET imaging of patients with limbic encephalitisand seizures have demonstrated mesial temporalhyperintensity or swelling and hypermetabolism during theacute or subacute disease process [58–62]. A number of theseimages later evolved into mesial temporal atrophy andhypometabolism [58, 61, 62]. The development of hippocam-pal atrophy and MRI hyperintensity consistent with mesialtemporal sclerosis suggests acute limbic encephalitis has thepotential to lead to more chronic temporal lobe epilepsy.Perhaps, early treatment initiation to prevent further inflam-mation and damage may improve seizure outcomes.

Approach to Treatment

There are currently no head to head trials of treatmentmodalities for autoimmune encephalitis and seizures. Out-come data is limited to observational case series relying onthe clinician to determine the treatment regimen. Overall,there appears to be agreement that treatment should startwith steroids, IVIG, plasmapheresis, or a combination ofthese interventions [20, 27, 35, 43, 51, 56, 57••]. Steroidsare usually administered as methylprednisolone 500–1,000 mg IV daily for 5 days. This can be combined withIVIG (2G/kg divided over 3–5 days) or plasmapheresis,


though some authors caution against plasmapheresis as firstline given the increased risk of complications [27, 56]. Afterthe initial 5 day treatment period, some have suggestedcontinuation of high dose oral prednisone with a taper overmany months. Others have suggested continued IVIG orplasmapheresis ranging from weekly to every 6–8 weeks.Second line therapy with long-term immunosuppressants,such as rituximab or cyclophosphamide, should be initiatedif there is no subsequent improvement. Dalmau et al. [27]suggested initiation of second line therapy in NMDA en-cephalitis as early as 10 days into treatment if no improve-ment is observed.

First line therapy also includes treatment of an underlyingtumor if present. All patients with suspected autoimmuneencephalitis should undergo at least a CT scan of the chestand abdomen with contrast enhancement to assess for aneoplasm [51, 63]. If there is a defined antibody, highsuspicion for autoimmune disease, or other systemic signsor risk factors for a neoplasm, an FDG-PET scan is alsoindicated. Women should undergo a gynecological examand mammogram. For NMDAR encephalitis, a transvaginalultrasound is standard screening protocol. Men should un-dergo urological examination to assess for testicular cancerand prostate cancer, with serum PSA screening in men over50 years of age. Evidence of neoplasm should lead toprompt treatment with chemotherapy and/or resection.

Conclusions

Both paraneoplastic and nonparaneoplastic autoimmune an-tibodies can cause encephalitis and epilepsy, most common-ly localized to the temporal regions [2–9]. Initial reportsfocused on paraneoplastic antibodies targeting neuronal in-tracellular antigens, such as ANNA-1 and Ma antibodies [4,11–15]. While these antibodies are often associated withneurological syndromes of the peripheral nerves, brainstem,or diffuse cerebral structures, they are also, though lesscommonly, seen in limbic encephalitis with accompanyingseizures. Nonparaneoplastic GAD65 antibodies also targetneuronal intracellular antigens but are more commonly as-sociated with limbic encephalitis or chronic epilepsy. In thegeneral epilepsy population, GAD65 antibodies were foundin 1.6 %–8.7 % of patients [40–44, 45•, 52]. Outcomes incases of neuronal intracellular antibody syndromes weregenerally disappointing despite treatment of underlying tu-mor and immunosuppression [4, 13, 15–18, 52].

Later, neuronal cell surface antibodies were recognized ascommon causes of autoimmune encephalitis and epilepsy[19, 20, 21••, 22–27, 28••, 29, 30, 31•, 32, 33]. Seizures incell surface antibody syndromes were even more commonlyreported than in intracellular antibody syndromes withgreater than 70 % of reported patients developing seizures

in studies of VGKC Ab complex and NMDAR encephalitis[21••, 22, 25, 26, 28••, 33]. Seizures were also reported inpatients with AMPA, GABA-B, and GluR5 antibodysyndromes [29, 31•, 32, 33]. Prevalence rates of 6.5 %–11.5 % and 7 %, for VGKC complex and NMDARantibodies respectively, were found in the general epilepsypopulation [19, 49–51]. Outcome studies were much morepromising with up to 80 % of patients showing improvementwith immunotherapy and oncologic therapy as needed[8, 20, 22, 28••, 30, 31•, 32, 33, 55, 56, 57••].

Recent studies have demonstrated that acute inflamma-tion of the mesial temporal regions during limbic encepha-litis can lead to hippocampal atrophy [58–62] consistentwith mesial temporal sclerosis on magnetic resonance im-aging. Outcomes, including reduction in seizure frequency,are consistently superior if treatment regimens include im-munotherapy, plus oncologic therapy if a tumor is present[8, 20, 22, 30, 31•, 32, 33, 55, 56]. Furthermore, earlierinitiation of immunotherapy also improves outcomes [28••,57••]. This data highlights the importance of early recogni-tion and initiation of immunosuppressive treatment in pa-tients with antibody mediated limbic encephalitis in order toboth treat the acute symptoms and potentially reduce the riskof developing chronic epilepsy.

There is also mounting evidence that autoantibodies,specifically GAD65, VGCK complex, and NMDAR anti-bodies, are present in a modest number of patients withchronic or acute onset epilepsy, mostly localized to thetemporal lobe [5, 22, 26, 40–44, 45•]. At this point, it isunclear whether immunosuppressive therapy will be as ef-fective in these patients. There are no guidelines to suggesttesting for antibodies in all focal epilepsy patients of un-known etiology, but it may be considered in those with acuteonset temporal lobe epilepsy that are severe or medicallyintractable. Overall, further research is needed to clarify theefficacy of antibody testing in the general epilepsy popula-tion as well as the utility of immunotherapy in these epilepsypatients.

Conflict of Interest CynthiaM. Correll declares no conflict of interest.

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