KEY POINTS FOR CLINICIANS
• Autoimmune encephalitis (AE) describes a group of disorders associated with neural-specific autoantibodies.
• Antibodies can target either intracellular antigens or extracellular plasma membrane proteins such as ion channels or neurotransmitter receptors.
• Antibodies targeting intracellular antigens are usually associated with malignancy and are poorly responsive to immunotherapy.
• AE associated with antibodies targeting extracellular plasma membrane proteins are immunotherapy responsive.
• AE can present with distinct clinical syndromes but presentation is heterogeneous and selective antibody testing should be avoided.
• Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis can occur as a postinfectious syndrome following herpes simplex virus encephalitis.
• Antibodies should be tested in both serum and cerebrospinal fluid (CSF).
• Prompt initiation of immunotherapy improves outcome.
Clinically, encephalitis is characterized by the subacute onset of altered mental status, focal neurologic deficits, fever, and generalized or focal seizures. Historically, encephalitis was synonymous with infection but over the last decades it has become clear that central nervous system (CNS) autoimmunity is a common cause of encephalitis (1,2). AE describes a heterogeneous group of neurologic disorders associated with neural-specific autoantibodies (3). Establishing the diagnosis can be challenging given the wide range of clinical presentations, as well as the overlap with other causes of encephalitis such as infection.
Understanding the pathophysiology of AE is helpful in guiding diagnostic testing and management (Figure 41.1). AE can be subdivided into two major groups based on the location of the antigenic target of the associated neural autoantibody. The first group includes the classic paraneoplastic disorders, which are associated with antibodies targeting intracellular antigens (nuclear and cytoplasmic enzymes, ribonucleic acid (RNA)-binding proteins, and transcription factors) (4,6). These antibodies have a strong association with neoplasms but are not considered pathogenic. Rather, it is thought that CD8+ T cell mediated inflammation is the likely responsible mechanism of tissue injury (7). Prognosis in these disorders tends to be poor and patients respond poorly to immunotherapy (8). Not all autoantibodies targeting intracellular antigens are paraneoplastic. Antibodies to glutamic acid decarboxylase 65 (GAD65), an intracellular synaptic protein, are not usually associated with malignancy. Patients harboring these antibodies tend to have more variable response to immunotherapy.
The second group is associated with antibodies targeting extracellular plasma membrane proteins (neurotransmitter receptors, ion channels, water channels, and channel-complex proteins). Tumor associations in this group are variable but unlike antibodies targeting intracellular proteins, these antibodies can access their target antigen in vivo and alter their function and number to cause disease (9). Consequently, neurologic syndromes associated with these antibodies tend to be immunotherapy responsive and have a much better prognosis.
WHEN TO SUSPECT AE
Patients with AE tend to present with subacute onset of alterations in level of consciousness, cognitive difficulties, movement abnormalities, sleep disturbances, and seizures. Psychiatric disturbances including psychosis, hallucination, and agitation are common in some types of AE, particularly NMDAR encephalitis. Distinct clinical syndromes have been described and these can help narrow the differential of AE but the clinical spectrum is wide and many patients with AE do not fit neatly into any of the described syndromes (9,10) (Table 41.1).
In cases of paraneoplastic autoimmunity, tumor-targeted immune responses are initiated by onconeural proteins expressed in the plasma membrane (red diamond) or in the cytoplasm, nucleus or nucleolus (green triangle) of certain tumors. These antigens are also expressed in neural cells and thus are coincidental targets. Although there is some evidence to support an analogous infectious-induced mimicry in nonparaneoplastic autoimmunity (e.g., anti-NMDAR encephalitis after encephalitis with certain herpes viruses) (5), the source of the antigen remains elusive in the majority of these cases. Antibodies targeting plasma membrane antigens are effectors of injury (red): antibodies (red) directed at neural cell plasma membrane antigens (e.g., leucine-rich glioma inactivated-1, NMDAR, or alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproponic acid receptor are effectors of cellular dysfunction or injury through multiple effector mechanisms. These mechanisms include receptor agonist or antagonist effects, activation of the complement cascades, activation of Fc receptors (leading to antibody-dependent cell mediated cytotoxicity), and antigen internalization (antigenic modulation), thereby altering antigen density on the cell surface. Antibodies targeting nuclear or cytoplasmic antigens are serum markers of a T cell effector mediated injury (green): intracellular antigens (green triangles) are not accessible to immune attack in situ, but peptides derived from intracellular proteins are displayed on upregulated MHC class-I molecules in a pro-inflammatory cytokine milieu after proteasomal degradation, and are then accessible to peptide-specific cytotoxic T cells. Antibodies (green e.g., antineuronal nuclear antibody type-1, or collapsin response mediator protein-5) targeting these intracellular antigens (green) are detected in both serum and in CSF but are not pathogenic. In clinical practice, these antibodies serve as diagnostic markers of a T cell predominant effector process.
CSF, cerebrospinal fluid; NMDAR, N-methyl-D-aspartate receptor.
Source: Modified with permission from Figure 1 in Toledano M, Pittock SJ. Autoimmune epilepsy. Semin Neurol. 2015;35(3):246.
Clinicians should suspect AE in patients presenting with
• Subacute onset of unexplained neuropsychiatric symptoms or the presence of a well-defined clinical syndrome such as limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus (PERM), or faciobrachial dystonic seizures
• Recent-onset cryptogenic epilepsy or new-onset refractory status epilepticus (including nonconvulsive status)
Supportive clinical features include
• Antiepileptic drug resistance
• Viral prodrome (but not persistent or periodic fevers which are suggestive of infectious encephalitis)
• Fluctuating course
• History of systemic autoimmunity
• History of smoking
• History of past or recent malignancy, particularly with a tumor known to be associated with AE
These patients should undergo evaluation for neural-specific antibodies. In addition to neural-antibody testing, patients should undergo a thorough evaluation for clinical and paraclinical markers supportive of a diagnosis of AE. Infectious, metabolic, neoplastic, and neurodegenerative causes of encephalopathy should be ruled out.
383Supportive paraclinical biomarkers include
• Evidence of CNS inflammation on:
• CSF (elevated protein [<100 mg/dL], pleocytosis [<100 cells/uL], oligoclonal bands, elevated synthesis rate or IgG index)
• MRI brain scan demonstrating mesiotempotal, mesencephalic, or parenchymal fluid-attenuated inversion-recovery (FLAIR) T2-weighted hyperintensity. T1-gadolinium (GAD) enhancement can occur but is less common in AE
• Fluorodeoxyglucose (FDG)-PET hypermetabolism or hypometabolism
• Systemic markers of autoimmunity such as antinuclear antibody (ANA) or thyroid peroxidase (TPO) antibody positivity
MRI imaging is variable and partially dependent on the underlying antibody. Many patients with AE can have normal imaging. Normal CSF parameters, although uncommon, also do not rule out AE.
AUTOANTIBODIES SPECIFIC FOR PLASMA MEMBRANE ANTIGENS ASSOCIATED WITH AE
AE associated with antibodies targeting extracellular plasma membrane antigens (Table 41.2) tend to be immunotherapy responsive, as the antibodies themselves are likely pathogenic. Epidemiologic and clinical characteristics, as well as oncologic associations, vary among different antibodies and are discussed in the following section.
Voltage-Gated Potassium Channel Complex Antibodies
Both leucine-rich glioma inactivated-1 (LGI1) and contactin-associated protein-2 (CASPR2) are components of the macromolecular complex formed by voltage-gated channels (VGKCs) on the cell surface. Antibodies to LGI1 and CASPR2 comprise a majority of antibodies previously thought to target VGKCs themselves (11,12). Patients with these antibodies are predominately men, with a median age of 60 years. The incidence of cancer detection is less than 10% in cases of LGI1 encephalitis (13), but CASPR2 antibodies can be associated with thymoma in up to 40% of cases. Malignancy is more common in patients with dual LGI1/CASPR2 positivity (13).
Anti-LGI1 encephalitis is the second most common form of AE after anti-NMDA receptor encephalitis (14). Memory disturbances, seizures, hallucinations, myoclonus, and hyponatremia are common. Seizures tend to be focal and largely mesiotemporal in origin (15). A new type of seizure called faciobrachial dystonic seizures characterized by posturing of the hemi-face and ipsilateral arm can occur during or prior to the cognitive disturbances (16). Seizures respond well to immunotherapy but patients can be left with cognitive deficits in spite of adequate immunotherapy (13,17). CASPR-2 antibodies are associated with encephalitis, Morvan syndrome (sleep disturbances, dysautonomia, and peripheral nerve hyper-excitability), and acquired neuromyotonia (Isaacs syndrome) (9).
Up to 50% of patients with LGI1 and CASPR2 encephalitis have MRI evidence of inflammation manifested as enlargement and T2 FLAIR hyperintensity of the mesial temporal lobe structures in the acute phase (18). Enhancement and restricted diffusion can occur but are less common. Basal ganglia nonenhancing T1 hyperintensity is sometimes associated with faciobrachial dystonic seizures in anti-LGI1 encephalitis (Figure 41.2) (19). Serial MRI frequently demonstrate mesial temporal sclerosis, even in patients who have been treated successfully (Figure 41.2) (18). Mesiotemporal sclerosis may account in part for the persistence of cognitive deficits in successfully treated patients, as well as the need for long-term therapy with antiepileptic drugs in these patients (13,17).
Ionotropic Glutamate Receptor Antibodies
Anti-NMDAR encephalitis was first described in young women with ovarian teratomas (20), but it can affect males, infants, and older patients as well (21). About one-third of women over 18 with this disorder have an ovarian teratoma but the likelihood of finding a tumor varies according to sex, age, and ethnicity. Ovarian teratomas are more frequent in African Americans and Asians and approximately 5% of men have testicular germ-cell tumors (21). Anti-NMDAR encephalitis can also occur as a postinfectious complication in patients with successfully treated herpes simplex virus (HSV) encephalitis (5). This phenomenon has also been described with encephalitis caused by other herpes viruses (22,23). Possible mechanisms include molecular mimicry or an immune response to neuronal damage.
Anti-NMDAR encephalitis classically presents with a viral prodrome followed by onset of psychiatric disturbances, orolingual/limb dyskinesias, and other abnormal movements. If untreated, dysautonomia, central hypoventilation, and coma can ensue (21). Children are more likely to present with abnormal movement disorders early in the course of the disease, and psychosis is less common compared with adults (21).
Seizures, including subclinical seizures, can occur early in the disorder. In a recent case series of 23 patients with anti-NMDAR encephalitis who underwent continuous EEG, 60% had electrographic seizures without clinical correlate. Up to 30% of patients in this series had a unique electrographic pattern that the investigators termed “extreme delta brush” because of similarities to waveforms seen in premature infants (24). Although the specificity of this finding is not yet established, its presence should raise suspicion for this disorder. Less than a third of patients have abnormalities on MRI brain, usually T2 FLAIR hyperintensity in cortical or subcortical regions, or in the cerebellum or brainstem (21).
Patients with antibodies to the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproponic acid receptor (AMPAR) have been associated with limbic encephalitis (25). Females appear to be more susceptible than men, with a median age of 60. In the initial case series only four of 10 had seizures and eight had MRI findings of mesiotemporal inflammation. Seventy percent had an associated malignancy (small-cell and non–small-cell lung cancer, thymoma, and breast cancer) (25). Relapses were common, occurring in about half of the patients.
FLAIR, fluid-attenuated inversion-recovery.
Gamma-amino butyric acid B receptor (GABABR) antibodies have been recently recognized as a cause of epilepsy associated with limbic encephalitis. In the initial case series, men and women were equally affected and all patients had seizures (26). MRI imaging in most revealed evidence of mesiotemporal inflammation (26). Approximately 60% of them had an associated malignancy, most often small-cell lung cancer.
High titers of GABAAR antibodies have been identified in patients presenting with seizures (frequently accompanied by status epilepticus), cognitive impairment, and movement abnormalities (more common in children) (23). MRI showed unilateral or bilateral multifocal T2 hyperintensities involving both gray and white matter (23). About 40% of patients had an associated neoplasm, mostly thymoma.
Autoantibodies to the metabotropic glutamate receptor 5 (mGluR5) were identified in the CSF of one woman and two men with Hodgkin lymphoma and limbic encephalitis (Ophelia syndrome) (27,28). Recently, a nonparaneoplastic case has been reported (29). Patients with anti-mGluR5 encephalitis display a relatively mild form of encephalitis without the dramatic psychosis, agitation, seizures, and autonomic instability seen with anti-NMDAR encephalitis.
Anti-glycine receptor (GlyR) antibodies should be considered in patients presenting with PERM (30), and stiff-person syndrome (SPS) (31). CNS hyper-excitability with increased muscle tone, a pathologically exaggerated startle response, and spasms is the defining characteristic of these syndromes. Limbic encephalitis, seizures, cerebellar ataxia, and optic neuritis have also been described in association with this antibody. Most patients do not have associated malignancy.
Anti-dipeptidyl-peptidase-like protein-6 (DPPX6) antibodies are associated with a broad clinical spectrum including encephalopathy, central hyperexcitability, myelopathy, dysautonomia, and seizures (32,33). Gastrointestinal symptoms characterized by severe diarrhea and/or constipation are common.
Both neuronal ganglionic nicotinic acetylcholine receptor (gAChR) and voltage-gated calcium channel N-type and P/Q-type (VGCC N/VGCC P/Q) antibodies have been described in patients with suspected AE in a nonparaneoplastic context (15). The pathogenic role of these antibodies in AE is uncertain, and may be secondary to coexisting autoantibodies such as anti-GABABR, which are known to co-occur with VGCC antibodies (26).
Antibodies targeting IgLON5, an immunoglobulin-like cell adhesion molecule, have been associated with a progressive CNS disorder of insidious onset characterized by bulbar symptoms, sleep disturbances, central hyperexcitability, and movement abnormalities (34). Neuropathologic features include a lack of inflammatory infiltrates and neuronal accumulation of hyperphosphorylated tau protein (both 3-repeat and 4-repeat), leading some to question whether antibodies to IgLON5 are a 386marker of autoimmunity or epiphenomena of a primarily neurodegenerative process. In a recent case series, seven out of nine treated patients responded to immunotherapy supporting an autoimmune basis for this disorder (34).
ANTIBODIES TO INTRACELLULAR ANTIGENS ASSOCIATED WITH AE
Antigenic targets of autoantibodies targeting intracellular proteins include nuclear and cytoplasmic enzymes, RNA-binding proteins, transcription factors, as well as synaptic proteins (Table 41.3). With the exception of antibodies targeting GAD65 these antibodies have a strong association with malignancy. The antibodies themselves are not pathogenic and symptoms result from cytotoxic T-cell mediated damage (7). Response to immunotherapy is poor, although response is more variable in AE associated with antibodies to intracellular synaptic antibodies, the reasons for which are discussed in the following section.
Autoantibodies to Neuronal Nuclear and Cytoplasmic Antigens
Antineuronal nuclear antibody type-1 (ANNA1, also known as anti-Hu) was the first type of onconeural antibody described (35). Most patients present with a sensory-predominant neuronopathy but may also present with limbic encephalitis, encephalomyelitis, and gastrointenstinal dysmotility. Seizures may occur in the absence of other syndromic manifestations of limbic encephalitis (36). The vast majority of cases is associated with small-cell carcinoma but can also occur with thymoma and neuroblastoma (in children).
387Antineuronal nuclear antibody type-2 (ANNA2, also known as anti-Ri) has been associated with a broad spectrum of presentations, including cerebellar degeneration, brainstem encephalitis, and encephalomyelitis (37). Most patients have associated small-cell lung carcinoma or breast adenocarcinoma. Antineuronal nuclear antibody type-3 (ANNA3) can rarely present with encephalitis and is strongly associated with small-cell lung cancer (38).
Anti-glial neuronal antibody (AGNA, also known as SOX-1) is associated with Lambert–Eaton myasthenic syndrome but can present with limbic encephalitis (39). Purkinje cell cytoplasmic antibody type-2 (PCA2) usually presents with cerebellar degeneration but can also present with brainstem or limbic encephalitis (40). Both of these antibodies are strongly associated with small-cell lung cancer.
Anti-collapsin response mediator protein-5 (CRMP5) antibodies are associated with a wide spectrum of neurologic presentations, including cerebellar degeneration, chorea (basal ganglionitis), optic neuropathy, retinopathy, myelopathy, radiculoneuropathy, encephalitis, and seizures (7). The most common associated neoplasms are small-cell lung carcinoma and thymoma (41).
Dual Ma-1/M-2 positivity (anti-Ma) is more common in females and associated with ovarian, breast, and colon cancer (42). Anti-Ma-2 (anti-Ta) is associated with testicular germ-line cancers in males (43). Patients with these antibodies usually present with brainstem encephalitis, diencephalic encephalitis, and/or limbic encephalitis (Figure 41.3). Presence of the antibody strongly suggests underlying malignancy and neoplastic workup (including biopsy) should be pursued even in cases when imaging is equivocal.