Seizures are a very common manifestation of autoimmune encephalitis (AE), ranging from 33% to 100% depending on the antigen, most often accompanied by other clinical features such as behavioral changes, movement disorders, memory deficits, autoimmune disturbances, and altered levels of consciousness. Unusual seizure frequency, resistance to antiepileptic treatment, and often, definitive response to immunotherapy emphasize the importance for neurologists to consider the probable etiology of immune disorders. Studies on pathogenic mechanisms of autoantibodies have improved the understanding of different pathophysiologies and clinical characteristics of different AE groups. In encephalitis with antibodies to neuronal extracellular antigens, autoantibodies play a direct role in disease pathogenesis. They have access to target antigens and can potentially alter the structure and function of antigens but induce relatively little neuronal death. Prompt immunotherapy is usually very effective, and long-term antiepileptic treatment may not be needed. In contrast, in encephalitis with antibodies against intracellular antigens, autoantibodies may not be directly pathogenic but serve as tumor markers. These autoantibodies cannot reach intracellular target antigens and are considered to result from a T-cell-mediated immune response against antigens released by apoptotic tumor cells, which contain nerve tissue or express neuronal proteins. Neuronal loss is frequently described and predominantly induced through cytotoxic T-cell mechanisms. They often exhibit an inadequate response to immunotherapy and require early tumor treatment. Long-term antiepileptic treatment is usually needed. In conclusion, each neural autoantibody can specifically precipitate seizures. Early proper management of these cases may help prevent neurological deterioration and manage the occurrence of seizures. Consequently, confirmation of the presence of neuronal autoantibodies is strongly recommended even in patients with confirmed AE, as they are not only essential in achieving a good outcome but also may provide evidence for underlying neoplasia.

© 2022 S. Karger AG, Basel

Introduction

Seizures are a very common manifestation of autoimmune encephalitis (AE), ranging from 33% to 100% depending on the antigen [1, 2], most often accompanied by other clinical features such as autoimmune disturbance, movement disorders, memory deficits, behavioral changes, and altered levels of consciousness. Patients with AE often exhibit unusual seizure frequencies and mostly respond well to immunotherapy, emphasizing the importance for neurologists to consider the probable etiology of immune disorders [3, 4]. Immunotherapies include pulsed intravenous methylprednisolone, intravenous immunoglobulins (IVIg), or plasma exchange taken alone or in combination as first-line therapies and rituximab, cyclophosphamide, azathioprine, methotrexate, or mycophenolate mofetil (MMF) as second-line treatments adopted when first-line immunotherapy fails [2, 5, 6]. Accordingly, in 2017, the International League Against Epilepsy introduced “immune etiology” as one of the etiologies of epilepsy [7].

With the progress in detecting neuronal autoantibodies, the recognition of AE diagnosis has been greatly raised. AE may be roughly divided into three groups according to target antigens: the first group with autoantibodies to neuronal extracellular antigens, the second group with antibodies to intracellular antigens, and the third group without definite antibodies. The distinction among these three categories is important because some of the triggers are similar, but their clinical profiles, pathogenic mechanisms, and outcomes are different [5]. Viral encephalitis is a potential trigger of AE. Antigens released by virus-induced neuronal cell destruction may migrate out of the central nervous system (CNS) through lymphatic vessels and are loaded into dendritic cells and transported to regional lymph nodes [8]. In the lymph nodes, naïve B cells recognize the processed antigens and present them through major histocompatibility complex II to T-cell receptors on CD4+ T cells. The cognate “T-B conjugate” activates B cells to become memory B cells or antibody-producing plasma cells [3]. Tumors are another potential trigger of AE. It has been postulated that genetic alterations in tumor cells or abnormal expression of neuronal proteins by tumors could trigger immune tolerance breakdown, leading to extensive tumor infiltration by T and B cells and the initiation of autoimmune response [9, 10]. Similarly, tumor antigens, which are also extracellularly or intracellularly expressed by neurons, activate naïve B cells to become memory B or plasma cells. Very little IgG can cross a fully intact blood-brain barrier from the periphery unless there is a very high systemic antibody titer or a disrupted blood-brain barrier resulting from infections, inflammation, injury, or strokes [11]. In contrast, memory B cells could migrate into the brain through the choroid plexus [12], recognize the same neural-specific antigens in the brain, differentiate into antibody-producing plasma cells, and promote the intrathecal synthesis of antibodies [8]. Autoantibodies against neuronal extracellular antigens are thought to be directly pathogenic. They reach the target antigens and reversibly influence the antigen function or cause antigen internalization but with relatively little neuronal death [13, 14]. In contrast, autoantibodies against neuronal intracellular antigens are not directly pathogenic but are often useful tumor markers [15]. Moreover, autoantibodies against neuronal intracellular antigens cannot access intracellular antigens and are considered to result from immune response to tumor antigens [16]. The pathogenicity of these autoantibodies is generally accepted to be mediated by cytotoxic T cells, and neuronal loss is frequently described [5]. This review described the different pathophysiologies and clinical characteristics of each group of disorders, aiming to provide evidence on future optimum seizure management involved in AE.

Autoantibodies against Neuronal Extracellular Antigens

The antibodies in this group of AE are thought to be directly pathogenic, reversibly influencing the antigen function or causing antigen internalization but with relatively little neuronal death, and prompt immunotherapy is usually very effective [13, 14]. There are also important tumor associations in this group of diseases, although the associations are variable.

Early diagnosis and immunotherapy may lead to a marked reduction or elimination of seizures, in parallel with the resolution of other symptoms of AE in the majority of this group of patients within the next 4–6 weeks [17]. However, in patients with an underlying tumor, immunotherapy may show good effectiveness only after removing the tumor [18, 19]. Also, antiepileptic drugs (AEDs) should be considered as an add-on therapy to immunotherapy. Although seizures in AE are often drug-resistant, they still play a crucial role in symptomatic treatment [20]. Once seizure control is achieved, AEDs can be gradually tapered. However, relapse can occur and has been described in 15%–35% of the patients with autoantibodies against extracellular antigens. Subsequently, long-term maintenance of immunotherapy and AEDs may be considered [21-24].

Autoantibodies against Ionotropic Glutamate ReceptorsAntibodies against N-Methyl-D-Aspartate Receptors

Glutamate is the major neurotransmitter for excitatory function in the CNS [25]. N-methyl-D-aspartate receptors (NMDARs) are among the most well-studied ionotropic glutamate receptors, mainly existing in the postsynaptic membrane compartment, and are formed by two GluN1 and two GluN2 or GluN3 subunits [26]. GluN1 and GluN3 bind glycine, and GluN2 binds glutamate. NMDARs are widely expressed throughout the CNS and play a pivotal role in forming neuronal connections and the experience-dependent modification of neural circuitry by regulating the formation, modification, and elimination of synapses [27]. Autoantibodies against NMDARs have been described in multiple neurological disorders, especially in autoimmune-associated seizures. The pathogenesis of anti-NMDAR encephalitis is neither a cytotoxic T-cell attack nor complement-mediated neuronal damage [28], but the internalization of surface NMDARs, which leads to a decreased receptor density on the cellular surface [29, 30], results in an excitatory and inhibitory imbalance, and finally elicits seizures [31]. Anti-NMDAR encephalitis predominantly affects young individuals (median age of 22 years), with a female sex predominance (80% of women) [4]. Tumors, mostly teratomas of the ovary, are the very common trigger of NMDAR AE in women >18 years but are rarely seen in children <12 years or in men. Another potential trigger is herpes simplex virus encephalitis, described in ∼20% of the patients [32, 33]. Triggers may also be unidentifiable in ∼55%–60% of the patients [33, 34].

Headache or fever presents as a prodromal symptom in 70% of the patients with anti-NMDAR encephalitis, followed by psychiatric manifestations, including anxiety, insomnia, aggression, fear, panic attacks, compulsive behaviors, delusional thinking, or hallucinations [4, 18]. Memory deficits are also a common initial finding in patients. Most of them rapidly progress to speech dysfunction, altered level of consciousness, abnormal movements (orofacial, limb, or trunk dyskinesias), rigidity, and autonomic instability [35, 36]. Seizures seen in ∼75% of the patients can occur during the disease, which are often focal but can be secondarily generalized [36]. The frequency of an underlying tumor, usually an ovarian teratoma, varies with age and sex, ranging from 0% to 5% in children (male and female) <12 years to 58% in female patients of reproductive age (18–45 years) [4]. In patients >45 years, the tumor association is ∼23%, which are predominantly carcinomas instead of teratomas [18]. When tumors are not found, tumor screening is recommended to be continued every 6 months for some years even in children, although tumor association is extremely rare in children; however, this is based on the phenomenon that tumor is often occult, and neurological disorders typically precede the tumor diagnosis for many years [37].

Cerebrospinal fluid (CSF) pleocytosis is found in approximately two-thirds of the patients with anti-NMDAR encephalitis, and oligoclonal bands are also commonly seen. They are important evidence of CNS inflammation but are not specific to autoimmune etiologies [38]. Therefore, their absence in CSF tests does not rule out the diagnosis of anti-NMDAR encephalitis. Antibody tests for NMDAR are more sensitive and specific with CSF than with serum. Serum may offer a lower false-positive rate and a higher false-negative rate as compared to that of CSF. In an observational cohort study, anti-NMDAR encephalitis was seronegative but CSF-positive in 17% of the cases [4]. Electrographic features such as generalized slowing, excess θ and α frequencies in nonrapid eye movement sleep, preservation of background rhythm in the awake state with focal or unilateral slowing, and rarely epileptic discharges are often seen in anti-NMDAR encephalitis [39], which are usually not specific. However, extreme delta brush, as a specific pattern, has been described in patients with anti-NMDAR encephalitis [40], which is most often observed during the comatose period. The brain looks normal on magnetic resonance imaging (MRI) fluid-attenuated inversion recovery (FLAIR) and T2 sequences in the majority of patients [18, 19, 41]. MRI abnormalities such as T2 hyperintensity and swelling involving the medial temporal lobe (MTL) or cortex, elsewhere [42, 43], transient-associated contrast enhancement seen within the cortex, meninges, or basal ganglia [43, 44], and hippocampal atrophy [45] have also been described in anti-NMDAR encephalitis, which, however, are potentially reversible. On follow-up MRI imaging after recovery, there may be a complete resolution of previous MRI abnormalities, focal cortical atrophy at prior lesions, or global volume loss [4, 19, 43, 44]. When correlative with an MRI, 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) will typically demonstrate focal hypermetabolism in acute inflammation sites [46-49]. However, during the recovery phase, those findings often get improved or reversed and finally may lead to nearly normal PET images [49].

The responses of AE to immunotherapy are generally good, particularly if more effective treatments are used promptly. First-line immunotherapies include pulsed intravenous corticosteroids, human IVIg, and plasma exchange, which should be used in sequence or combination [50]. Once first-line immunotherapies fail, searching for an underlying tumor and getting the tumor removed are strongly recommended; second-line immunotherapies such as rituximab, cyclophosphamide, azathioprine, methotrexate, and MMF should be applied and may still be effective [51-54]. If complete remission has been induced, the patient will usually not need maintenance immunotherapy to prevent relapses; otherwise, a maintenance immunosuppressant will be required. No randomized trial data supported one AED over another to manage acute symptomatic seizures; however, ketamine should be avoided in NMDAR encephalitis [55]. After the full resolution of encephalitis, AEDs can successfully be tapered off [56]. Only a few patients require long-term AEDs for chronic mesial temporal atrophy secondary to the initial immune-mediated process.

Antibodies against α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), which are also one of the most well-studied ionotropic glutamate receptors, are tetramers composed of four core subunits designated as GluR1 to GluR4, predominantly expressed in the postsynaptic neuronal membrane, and mediate most of the excitatory fast synaptic transmission in the brain network [57]. Unlike NMDARs, which have a slow and prolonged activation, AMPAR turnover at synapses is considered continuous and fast. AMPAR antibodies might bind to an extracellular region on the receptor and eliminate the surface amount and synaptic localization of AMPAR [58], leading to the decrease of homeostatic plasticity in inhibitory synaptic transmission and finally AE occurrence.

Most patients with anti-AMPAR encephalitis develop a typical syndrome of limbic encephalitis (LE), which includes short-term memory deficits, behavioral changes (such as repetitive or stereotypical behaviors, delusions, hallucinations, irritability, hyperactivity, hypersexuality, or insomnia), anxiety, depression, psychosis, and seizures [59-61]. Forty percent of them show additional symptoms beyond the limbic system, and only a few patients present with a different syndrome such as rapidly progressive dementia or psychosis [58, 62]. Antibodies against AMPAR appear mildly epileptogenic. About 30%–40% of the patients with acute LE will have acute symptomatic seizures, with <5% of them developing epilepsy and who will need long-term AEDs [1]. Anti-AMPARs are commonly paraneoplastic, and ∼60% of the patients have an underlying tumor, including small cell lung cancer (SCLC), thymoma, and, less frequently, ovarian or breast cancer or teratoma [62, 63].

Antibodies may be detected in serum or CSF tests. MRI abnormalities of T2 hyperintensity and swelling of one or both MTLs have been described in most patients with anti-AMPAR encephalitis [64-66]. Abnormalities of the anterior septal nuclei, extratemporal cortex, and cerebellum have also been reported, although less commonly [58]. 18F-FDG-PET shows focal hypermetabolism in temporal lobes.

Approximately 70% of the patients tend to respond well to immunotherapy and/or tumor therapy; however, ∼16% of the patients are prone to relapse after treatment. There is no significant difference among AEDs in the management of seizures involved in AE, except for perampanel, as an AMPA antagonist, and the safety of which has not yet been studied in anti-AMPAR encephalitis [67].

Antibodies against Voltage-Gated Potassium Channel Complexes

Voltage-gated potassium channel complexes are widely present on the membrane of neurons in the CNS and peripheral nervous system. They are transmembrane channels specific for potassium and sensitive to voltage changes. Associated autoantibodies have been detected by radioimmunoassay, which employs VGKC complexes derived from the mammalian brain and labeled with 125I-α-dendrotoxin. Although patient serum was positive for VGKC antibodies using radioimmunoassay, all attempts failed to show reactivity in VGKC-transfected cells [14]. This contradiction has led to the discovery that these antibodies actually are not against the VGKC itself but the VGKC complex proteins included in the substrate used in the test. These VGKC-associated proteins include leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein 2 (CASPR2), and other still unknown elements [5]. LGI1 and CASPR2 are identified with well-defined clinical syndromes, which share a favorable response to immunotherapy. Others, positive for the VGKC complex but double-negative for LGI1 and CASPR2, presented with a wide variety of clinical syndromes, for which the implementation of immunotherapy is questionable [21].

Antibodies against LGI1

LGI1 is an extracellularly synaptic protein secreted from axonal presynapses and dendritic postsynapses [68]. By binding to presynaptic ADAM23 and postsynaptic ADAM22, LGI1 forms a transsynaptic protein complex that interacts with the KV1 subunit of the VGKC through ADAM23 at the presynaptic terminal and interacts with AMPARs via PSD95 through ADAM22 [14, 67, 69, 70]. This complex of LGI1, ADAM23, ADAM22, and PSD95 is involved in the fast synaptic transmission of neuronal excitability and is necessary for hippocampal long-term synaptic plasticity [14]. Consequently, the lack of LGI1 or the existence of antibodies against LGI1 increases the excitability of a neural network and leads to epileptic disorders through the downregulation of synaptic AMPAR function [71].

LGI1 antibodies are the second most common cause of AE and preferentially occur in older patients (between ages 50 and 70), with a slight male predominance [21, 23, 51]. The typical initial presentations of anti-LGI1 autoimmunity include seizures (53%) and cognitive disorders (42%) (almost all would evolve to develop memory impairment or behavioral changes) [21]. Spatial disorientation (52%), insomnia (65%), and autonomic dysfunction (47%) may also occur in some patients. Ninety percent of the patients will eventually develop seizures [23, 72], including faciobrachial dystonic seizures (FBDS), focal seizures, and tonic-clonic seizures. FBDS comprises briefly (usually <30 s) and frequently (10–100 times a day) occurring dystonic contractions of the face, arms, and legs, and only a minority of them respond to AEDs alone [73-75]. They are unique to anti-LGI1 encephalitis and occur in ∼40% of the patients, which often start a few weeks before the onset of cognitive symptoms [21, 76]. Focal seizures usually occur in 67% of the patients, early in the disease course, and most often have cognitive or autonomic features, with a median frequency of 12 times per day. Tonic-clonic seizures also occur in 60% of the patients but usually present only a few times during the severe stage of the disease [21, 72]. Still, classically described Morvan’s syndrome, which comprises LE, peripheral nerve hyperexcitability, insomnia, and dysautonomia, occurs infrequently (<10%) in anti-LGI1 autoimmunity [20, 21].

LGI1 antibodies can be detected in the serum and CSF using a cell-based assay, but unlike NMDAR antibodies, serum analyses for LGI1 antibodies may be more sensitive and reliable than CSF analyses, with few exceptions reported [77]. Hyponatremia is present in 60% of the patients due to inappropriate antidiuretic hormone secretion [61]. CSF tests usually are normal or show a slightly increased cell count. About 10% of the patients have varied cancer associations (thymoma, lung tumor, endocrine tumors, ovarian teratoma, mesothelioma, rectal, renal cell, and thyroid tumor) [14]. Electroencephalogram (EEG) shows epileptic activity developing in the frontal cortical and hippocampal regions in around half of the patients with anti-LGI1 encephalitis [72]. Brain MRI is often normal during the early stages of the disease, especially when only FBDS is present. However, in LGI1-related LE, abnormalities of T2/FLAIR hyperintensity and enlargement of one or both MTLs on MRI may be found in ∼70% of the cases [78, 79]. MRI abnormalities also include signal changes in the basal ganglia and cortically on diffusion-weighted imaging and FLAIR sequences [14, 67]. About 29% of MRI exams, which initially demonstrated normal or unilateral MTL findings, progress to bilateral MTL involvement during follow-up [21]. Further radiologic progression to mesial temporal sclerosis and even hippocampal atrophy has been frequently reported [80], which could at least partially be attributed to delayed immunotherapy [53]. Consequently, serial MRIs are needed to detect the delayed development of radiological abnormalities in these groups of patients. 18F-FDG-PET scans reveal hypermetabolism in MTLs and/or basal ganglia unilaterally or bilaterally even when the patients have normal MRI exams [54], suggesting that 18F-FDG-PET may have an early diagnostic value in anti-LGI1 encephalitis, and the lack of MTL hypermetabolism in 18F-FDG-PET correlates with a better outcome.

LGI1 antibodies may induce the loss of hippocampal neurons unless immunotherapy treatment is initiated as soon as possible, and earlier initiation of immunotherapy may also guarantee faster recovery [81]. Cessation of FBDS was observed in 51% of 85 patients after 30 days and in 88% after 90 days of administration with immunotherapy [81]. Also, in another study, the addition of corticosteroids was associated with the cessation of FBDS in two-thirds of the patients within 2 months [74]. Still, treatment with steroids and IVIg in LGI1-AE patients showed a better outcome and a higher rate of complete recovery than that of treatment with only steroids [54]. However, for patients who failed with first-line immunotherapies, second-line treatment (e.g., rituximab or cyclophosphamide) should be considered and might produce some benefit. As discussed in another recent study, anti-LGI1 encephalitis showed a rapid clinical improvement with rituximab; however, this group of patients had a higher relapse rate and lower seizure freedom rates than those of patients who showed a positive response to first-line immunotherapy [48]. Levetiracetam, lacosamide, perampanel, zonisamide, or pregabalin may be considered as an add-on treatment to immunotherapies, with levetiracetam mostly used [56, 82], whereas aromatic AEDs should be avoided in LGI1-antibody encephalitis, considering their side effects of high risk of idiosyncratic cutaneous reactions and hyponatremia [55].

Antibodies against CASPR2

CASPR2 is a transmembrane axonal protein and a cell adhesion molecule located at the juxtaparanodes of myelinated axons. Linked presynaptically to contactin-2 and postsynaptically to gephyrin, CASPR2 forms a transmembrane axonal complex present in the CNS and peripheral nervous system. It is believed to play a crucial role in the localization and modulation of VGKC for proper nerve impulse conduction and normal axonal excitability regulation [5]. CASPR2 antibodies are directed to the CASPR2-extracellular domain, which is widely expressed by inhibitory interneurons in the hippocampus, disrupting the interaction of CASPR2 with contactin-2 and indirectly disturbing gephyrin clustering in the postsynaptic terminal [83]. CASPR2 antibodies are of the IgG4 subtype [23, 24]; therefore, they might exert their pathogenicity by blocking the function of CASPR2 rather than through complement-mediated toxicity.

Anti-CASPR2 encephalitis is a rare disease that often occurs in older patients, with a strong predominance in men (90%). LE and Morvan’s syndrome are the two major clinical syndromes described in patients with anti-CASPR2 antibodies. Eighty percent of the patients show cognitive deficits and memory loss; 60% have neuropathic or burning pain in the extremities, weight loss, and/or insomnia; 55% have peripheral nerve hyperexcitability (also known as neuromyotonia); 50% develop seizures (which appear related to CSF-positive for CASPR2 antibodies) [84]; 45% show autonomic dysfunction, such as hyperhidrosis, diarrhea, urinary dysfunction, hypertension, hypotension, asystole, QT-interval prolongation, bradycardia, and sudden cardiac death [85, 86]; and 35% have cerebellar symptoms [14]. Tumors are found in 20% of the patients, especially those with isolated neuromyotonia, or neuromyotonia as part of Morvan’s syndrome, suggesting a detailed screening for thymoma [24]. Most cases often progress for a few months; however, ∼30% of the cases show progression over 1 year, which can mimic a neurodegenerative disease [24].

The CSF test may show mildly raised cell count or protein levels but may also be unremarkable in 75% of the patients with anti-CASPR2 encephalitis. As anti-CASPR2 encephalitis is rare, tests for antibodies against CASPR2 in serum and CSF should be encouraged. EEG results are usually nonspecific. Brain MRI is often normal, but patients with LE may have typical imaging findings of T2/FLAIR hyperintensity of one or both the MTLs on MRI [87, 88]. As the value of ancillary testing is often limited, disease diagnosis should be based on clinical features.

Seventy-nine percent to 90% of patients respond well to immunotherapy and/or tumor treatment. Long-term AEDs may not be needed because the disease mostly tends to follow a monophasic course. However, relapse may still occur in 25% of the patients, especially those with an underlying tumor. Tumor removal and gradual corticosteroid taper over ∼18 months may help to negate relapses [89].

Antibodies against γ-Aminobutyric Acid Receptor

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the CNS. Through binding to GABA-AR or GABA-BR, GABA causes the opening of ion channels specific for chloride or potassium ions, resulting in a decrease in the transmembrane potential [90], and therefore, controls the oscillation and synchronization of neural activities [91]. High-titer autoantibodies to either GABA-AR or GABA-BR convey a very high risk of severe seizures and intractable status [92, 93].

Antibodies against GABA-AR

GABA-ARs, as ligand-gated ion channels, react on a millisecond timescale to GABA binding. They are pharmacological targets of many clinically important drugs [94]. Antibodies against GABA-ARs cause a selective reduction of synaptic GABA-ARs, possibly through the crosslinking and internalization of antibody-receptor complexes [95], resulting in epilepsy, anxiety, insomnia, and other neurological and mental illnesses [96-98].

The frequency of anti-GABA-AR encephalitis is uncommon; however, alongside NMDAR, MOG, and glutamic acid decarboxylase (GAD) 65 antibodies, GABA-AR antibody is one of the most common autoantibodies identified in children with AE. Seizures are the most commonly encountered manifestations seen in 88% of the patients with anti-GABA-AR encephalitis, which are characteristically severe and rapidly develop into drug-refractory seizures, epilepsia partialis continua, and status epilepticus, requiring pharmacologically induced coma [93, 99]. Patients also display a broader array of symptoms that are suggestive of coexisting encephalopathy, including impaired cognition, altered behavior, decreased consciousness, and movement disorders [20, 100]. Tumors are found in ∼30%–40% of the patients, mainly a thymoma, especially in older patients [99, 101].

Most patients have leukocytosis, elevated protein concentration, or oligoclonal bands in CSF. Some patients often coexist with other autoantibodies such as thyroid peroxidase, GAD65, or GABA-BR autoantibodies [93]. MRI lesions are most likely present in patients with antibodies against GABA-ARs, including multifocal T2/FLAIR hyperintensities in various cortical and subcortical areas, which are rarely present in other AE and should raise suspicion of anti-GABA-A encephalitis [79].

Although treatment with AEDs is frequently ineffective in patients with GABA-A encephalitis, GABA-promoting AEDs such as benzodiazepines and barbiturates could still be considered as an add-on treatment [55]. The majority of the patients respond well to immunotherapy and tumor ablation, at least partially; however, ∼14% die of status epilepticus or secondary medical complications [20, 99].

Antibodies against GABA-BR

GABA-BR is a G protein-coupled and inhibitory metabotropic transmembrane receptor, most highly concentrated in the hippocampus, thalamus, and cerebellum [79]. The receptors are heterodimers composed of two subunits, GABA-B1 and GABA-B2, which are both necessary for limiting excessive neuronal activity [102]. Presynaptic GABA-BRs suppress neurotransmitter release by decreasing presynaptic calcium influx, and postsynaptic GABA-BRs cause hyperpolarization by activating G protein-activated inward-rectified potassium channels. Autoantibodies target the GABA-B1 subunit and may directly block the function without internalization [67].

Anti-GABA-BR encephalitis is characterized by clinical syndromes, including seizures (90%–95%) or status epilepticus (usually temporal lobe onset) [92], mixed movement disorders, prominent early psychiatric manifestations, memory loss and confusion, cerebellar ataxia (CA), and opsoclonus myoclonus [64, 103]. Antibodies against GABA-BRs have a close association with SCLC, detected in ∼50% of the patients with anti-GABA-B encephalitis and neuroendocrine tumors, especially in older patients [59, 92].

Ninety percent of the patients have abnormal CSF tests, with lymphocytic pleocytosis. Although the CSF test for GABA-BR antibodies appears to be more sensitive than the serum test, paired CSF and serum tests for antibodies are suggested to avoid false-negative results [59]. MRI abnormalities have been described in most patients, with increased T2/FLAIR signal and swelling in unilateral or bilateral MTLs [104]. Although information about 18F-FDG-PET findings in patients with anti-GABA-BR encephalitis is limited, marked MTL hypermetabolism with diffuse cortical hypometabolism on 18F-FDG-PET has been described in patients with either a normal brain MRI or concomitant T2/FLAIR hyperintensity [105], implying that 18F-FDG-PET may be helpful for the early diagnosis of anti-GABA-BR encephalitis.

Most patients with anti-GABA-BR encephalitis respond well to immunotherapy and/or tumor removal, although acute symptomatic treatments such as benzodiazepines, barbiturates, and even induced coma may be required to control severe seizures or status epilepticus [59, 92]. The prognosis is generally favorable, except in patients with SCLC, whose long-term prognosis is dictated by tumor progression or complications of chemotherapy [20].

Autoantibodies against Neuronal Intracellular Antigens

Antibodies targeting neuronal intracellular antigens such as GAD65 and onconeural antigens are considered to result from the immune recognition of tissue destruction and involve an invariably strong tumor association [16]. Unlike antibodies against extracellular targets, the pathogenicity of these antibodies is generally accepted to be mediated by cytotoxic T cells rather than by antibodies themselves [5]. Consequently, they often exhibit an inadequate response to immunotherapy and require tumor removal.

Antibodies against GAD

GAD is an intracellular and rate-limiting enzyme that catalyzes glutamate to GABA. It is highly expressed on neurons and the β-cells of pancreatic islets [106]. GAD exists in two isoforms, GAD67 and GAD65. GAD67 is expressed early during embryogenesis and takes responsibility for developing neural and nonneural tissues such as the palate and abdominal wall [107, 108]. However, in mature neurons, GAD67 is mainly expressed in the cell body and dendrites, responsible for the synthesis of the basal level of GABA [109]. GAD65, generally expressed at the postnatal stage, is largely inactively present but, when needed, can be transiently activated to rapidly catalyze GABA synthesis [90, 110]. Unlike other autoantibodies against neuronal intracellular antigens, antibodies against GAD might directly interact with their target antigen, as GAD65 could surface to the extracellular space and anchor to the plasma membrane during the exocytosis of synaptic vesicles [108]. GAD65 antibodies target the key enzyme, block its activation, and impair the prompt GABA production on demand, disrupting GABAergic synaptic transmission [111, 112]. In clinical practice, autoantibodies against GAD65 isoforms are commonly detected in the serum and CSF of patients, whereas GAD67 antibodies have seldomly been detected in the absence of GAD65 antibodies; thus, the latter is considered clinically nonrelevant [113, 114].

GAD65 antibodies have been uncommonly associated with multiple immune-mediated neurological disorders, including stiff-person syndrome (SPS), CA, and AE, with a sharp female prevalence (>80%) [115, 116]. Approximately half of the patients have a history of type 1 diabetes mellitus (T1DM), which usually precedes neurological presentations for many years [117]. The typical age of onset is 50–60 years for SPS and CA and 25–45 years for AE [118, 119]. SPS caused by the simultaneous contraction of agonist and antagonist muscles is documented with a spectrum of phenotypic presentations [109]. The classical phenotype includes axial rigidity, which predominates in the trunk and proximal lower limbs, and painful muscle spasms, which might cause falls or respiratory difficulties by interfering with normal muscle contraction [117]. The focal phenotype includes rigidity and painful spasms limited to the trunk or one limb, comprising about one-third of all SPS patients [106]. Approximately 10%–15% of the patients with SPS develop epilepsy. GAD-associated AE is characterized by the subacute new-onset of seizures, memory impairment, and behavioral changes (repetitive or stereotypical behaviors, delusions, hallucinations, irritability, hyperactivity, hypersexuality, or insomnia) [120]. Although seizures will eventually be present in all patients at some point, status epilepticus rarely happens [121]. Combinations of SPS, CA, or AE are commonly observed in patients with GAD-related disorders during follow-up, with the prevalence of 10%–20% in patients with SPS [117, 122], 14%–36% in patients with CA [114, 123], and 10%–25% in patients with AE [118, 119]. Tumor association in GAD-positive SPS is unusual, with only 4%–6% of the patients with coexisting malignant tumors, mostly thymomas and less often breast, thyroid, renal, and colon cancers [117]. Also, ∼9% of GAD-positive CA and 26% of GAD antibody-related AE have underlying tumors but mostly non-small cell lung carcinoma and pancreatic neuroendocrine tumors [108].

GAD65 antibodies are present in 60%–80% of the patients with SPS and 80% of the patients with T1DM, with serum levels in the former being >100-fold greater than those in the latter [106]. High GAD65 antibodies are also present in the serum of 14% of patients with CA [124, 125], ∼17% of the patients with AE [118], and 2.1%–5.4% of the patients with unexplained chronic pharmacoresistant epilepsy [116, 126]. Low serum levels of GAD antibodies lack specificity and could occur in 0.4%–1.7% of healthy people. GAD antibody is not necessarily needed for SPS diagnosis; however, for patients who do not fulfill the criteria, the presence of GAD antibodies in the CSF is sufficient to confirm the diagnosis. However, to establish a GAD autoimmune etiology for CA and LE, GAD65 antibodies should not only be detected in the CSF but also be demonstrated to be synthesized intrathecally, after alternative diagnoses are excluded. The CSF test can display pleocytosis and mildly elevated protein concentrations [118]. Most patients (63%–100%) have oligoclonal bands in the CSF [120]. EEG often shows slow or epileptic anomalies over the temporal lobes, with ictal and interictal discharges evident in most patients with anti-GAD-associated seizures [110]. In patients with anti-GAD-associated LE, brain MRI typically reveals hyperintensity and enlargement of the amygdala and hippocampi on T2/FLAIR, characteristically without contrast enhancement [120]. These signal abnormalities may be either transient or further progressed to mediotemporal cortical atrophy within 6–12 months [28, 110]. 18F-FDG-PET studies show hypermetabolism of early enlargement (inflammation) of the mediotemporal cortex and hypometabolism of subsequently later neuronal loss or dysfunction (atrophy) [118].

Anti-GAD-associated epilepsy is difficult to control, and early immunotherapy can produce improvement but transiently as, in the long-term, most patients continue to develop pharmacoresistant epilepsy and progressive cognitive impairment [110, 120, 127]. IVIg is often the initial treatment, considering that T1DM commonly coexists in this group of patients, discouraging corticosteroid use [128]. Rituximab or cyclophosphamide should be proposed when patients respond poorly to first-line immunotherapy, and immune suppressants such as azathioprine or MMF may be considered for maintenance treatment [106]. AEDs that inhibit GABA catabolism were reportedly inefficacious in seizures and should be avoided. In rare GAD65-related paraneoplastic cases, tumor removal combined with immunotherapy is essential to improve clinical outcomes.

Antibodies against Onconeural Antigens

These antibodies include anti-Hu (also known as ANNA1), anti-Ri (ANNA2), anti-ANNA3, anti-Yo (PCA1), anti-Ma2 (PNMA-2), and anti-collapsin response mediator protein 5 (CRMP5). They are not directly pathogenic but are often useful tumor markers, mostly targeting antigens expressed by tumor tissue, and are associated with paraneoplastic neurological disorders induced by remote immune-mediated mechanisms [15]. The risk of epilepsy is high in this group of disorders, which are often T-cell-mediated, and patients usually do not show satisfactory responses to AEDs and immunotherapy.

Antibodies frequently described in paraneoplastic LE are anti-Hu, anti-Ma2, and anti-CRMP5 [129]. Anti-Hu is usually more commonly described in cancer patients, especially in SCLC patients, than in patients with AE [130]. Anti-Ma2 is most often associated with testicular germ cell tumors in young men and may accompany neurological symptoms, among which LE may be the most common type [131]. Anti-CRMP5 targets a group of five intracellular phosphoproteins that are essential for axon development and are associated with a wider spectrum of syndromes, including cognitive impairment, cerebellar syndromes, abnormal movements, cranial neuropathies, and seizures [132, 133]. The most commonly associated malignancies are SCLC and thymoma [20].

Anti-Hu, anti-Ma2, and anti-CRMP5 are all well-characterized onconeural antibodies. Both CSF and serum are suggested to be tested for this group of antibodies; however, serum tests may be more sensitive than CSF tests. Their presence strongly favors a careful evaluation of tumors, and those who have an inconclusive initial investigation are recommended to be closely monitored every 6 months for at least 5 years after disease onset [134]. In patients with suspected LE, brain MRI usually shows T2/FLAIR hyperintensity in one or both mesial temporal lobes with enhancement and the nonlimbic cortex or brainstem with occasional enhancement. 18F-FDG-PET may also show hypermetabolism in regions that appear abnormal or even normal on MRI in acute settings [60], which might be due to increased glucose consumption from the underlying T-cell-mediated inflammatory response [135]. EEG may show a nonspecific pattern such as epileptic discharges in the unilateral or bilateral temporal lobe, slow background activity, and periodic lateralized epileptiform discharges [136].

Complete recovery is rare, and the prognosis is poor in this group of diseases. As the cellular immune response such as cytotoxic T-cell-mediated cytolysis and complement activation is the main process in AE with intracellular antibodies, high-dose corticosteroids and IVIg, which induce immune responses broadly, should be initiated first. Cyclophosphamide and rituximab could be considered second-line immunotherapy. However, associated seizures usually show little or no response to immunotherapy and most often are resistant to antiepileptic treatment [55]. Cancer treatment, including ablating tumors, may be the most effective treatment and should be instituted as quickly as possible [60].

AE without Definite Antibodies

This group of patients meets the diagnostic criteria for AE but does not have well-defined neural autoantibodies [129], accounting for more than half of the total AE patients. It is speculated that neuronal damage might be produced either through a novel antibody with unknown pathogenesis or other types of immune reaction such as innate immunity or T-cell activation, rather than by B cells [55]. Subsequently, empirical immunotherapy should be initiated as early as possible.

Brain MRI findings can be further divided into two categories: one with T2/FLAIR hyperintensity or contrast-enhanced lesions on brain MRI and the other with normal or atypical MRI findings. Immunotherapies inducing immune responses broadly, such as high-dose corticosteroids, IVIg, cyclophosphamide, or methotrexate, can be an optional treatment for the former group. For the latter group, immunotherapies similar to AE with neuronal extracellular antibodies can be attempted [55].

Conclusion

The early diagnosis of AE is suggested to be based on the conventional clinical history and supportive diagnostic tests (Table 1), which include but should not be dependent on the antibody test, so immunotherapy can be applied promptly to improve the prognosis [129]. However, investigation of CSF and serum for neuronal autoantibodies is strongly recommended even when AE diagnosis is confirmed because the presence of a well-characterized antibody is not only an important factor to consider when choosing from various immunotherapy options but also a clue for underlying malignancy. Still, further studies to clarify the pathogenic mechanisms of novel neuronal antibodies on AE are needed to widen the understanding of the pathophysiology of AE.

Table 1.

General clinical features and outcomes of antibody-associated AE

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions

Shaofang Zhu: conceptualization, writing – original draft. Jiabin Yu: resources and writing – original draft. Youliang Wu: resources. Ju Peng, Xuemin Xie, and Xiaojing Zhang: data curation. Haitao Xie: writing – review and editing. Lisen Sui: writing – review and editing, supervision, project administration.

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