Neuro-Ophthalmic Features of Autoimmune Encephalitides

Background: Over the past decade, there has been a remarkable advancement in the understanding of autoimmune etiologies of encephalitis. The first identified generation of paraneoplastic encephalitis tends to occur in older populations, responds poorly to immunotherapy, and is mediated by T-cell damage with antibodies directed toward intracellular antigens. A new generation of autoimmune encephalitides has been described, which are mediated by antibodies to cell-surface proteins, tend to occur in younger individuals, are less frequently associated with malignancy, and often respond better to treatment compared to their intracellular antigen-related paraneoplastic counterparts. This review will focus on several specific antibody-mediated autoimmune encephalitides with neuro-ophthalmic pertinence. Evidence acquisition: Literature review and personal clinical experience. Results: Several of the antibody-mediated encephalitides, specifically N-methyl-D-aspartate receptor, dipeptidyl-peptidase-like protein 6, glial fibrillary acidic protein, metabotropic glutamate receptor 1 (mGluR1), gamma-aminobutyric acid receptor, glutamic acid decarboxylase 65 (GAD65), collapsing response mediator protein 5 (CRMP5), and kelch-like protein 11 (KLHL11), contain features of neuro-ophthalmic interest. Conclusions: The novel cell-surface protein-directed autoimmune encephalitis group can present with a wide range of afferent and efferent neuro-ophthalmic manifestations. Neuro-ophthalmologists should be familiar with these antibody-associated syndromes, which are treatable and often require a high index of suspicion for diagnosis.

State-of-the-Art Review Neuro-Ophthalmic Features of Autoimmune Encephalitides Parker E. Bohm, MD, John J. Chen, MD, PhD, Tariq M. Bhatti, MD, Eric R. Eggenberger, DO Background: Over the past decade, there has been a remarkable advancement in the understanding of autoimmune etiologies of encephalitis. The first identified generation of paraneoplastic encephalitis tends to occur in older populations, responds poorly to immunotherapy, and is mediated by T-cell damage with antibodies directed toward intracellular antigens. A new generation of autoimmune encephalitides has been described, which are mediated by antibodies to cell-surface proteins, tend to occur in younger individuals, are less frequently associated with malignancy, and often respond better to treatment compared to their intracellular antigen-related paraneoplastic counterparts. This review will focus on several specific antibody-mediated autoimmune encephalitides with neuroophthalmic pertinence. Evidence Acquisition: Literature review and personal clinical experience. Results: Several of the antibody-mediated encephalitides, specifically N-methyl-D-aspartate receptor, dipeptidyl-peptidaselike protein 6, glial fibrillary acidic protein, metabotropic glutamate receptor 1 (mGluR1), gamma-aminobutyric acid receptor, glutamic acid decarboxylase 65 (GAD65), collapsing response mediator protein 5 (CRMP5), and kelch-like protein 11 (KLHL11), contain features of neuro-ophthalmic interest. Conclusions: The novel cell-surface protein-directed autoimmune encephalitis group can present with a wide range of afferent and efferent neuro-ophthalmic manifestations. Neuro-ophthalmologists should be familiar with these antibody-associated syndromes, which are treatable and often require a high index of suspicion for diagnosis. Journal of Neuro-Ophthalmology 2020;40:385-397 doi: 10.1097/WNO.0000000000001005 © 2020 by North American Neuro-Ophthalmology Society Department of Neurology (PEB, ERE), Mayo Clinic, Jacksonville, Florida; Department of Neurology (JJC, TMB), Mayo Clinic, Rochester, Minnesota; Department of Ophthalmology (JJC, TMB), Mayo Clinic, Rochester, Minnesota; Department of Ophthalmology (ERE), Mayo Clinic, Jacksonville, Florida; and Neurosurgery (ERE), Mayo Clinic, Jacksonville, Florida. The authors report no conflicts of interest. Address correspondence to Eric R. Eggenberger, DO, Departments of Ophthalmology, Neurology, and Neurosurgery, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL 32224; E-mail: Eggenberger.eric@ mayo.edu Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 O ver the past decade, there has been a remarkable advancement in the understanding of autoimmune etiologies of encephalitis. The existence of paraneoplastic causes of encephalitis had been suspected as early as 1888 by German neurologist Hermann Oppenheim in his essay with the translated title of "On Brain Symptoms Associated with Carcinomatosis without Detectable Changes in the Brain." (1). Throughout the mid-20th century, there were increasing reports of neurologic symptoms associated with malignancy without obvious laboratory correlate until 1985 and the discovery of what is now known as the Anti-Hu (ANNA-1) antibody that was thought to be a "remote effect" of cancer and found to be associated with "oat cell" (small cell) carcinoma of the lung (2). At this time, the foundation was set for the paraneoplastic encephalitides, the initial group of antibodyassociated autoimmune central nervous system (CNS) syndromes. The first generation of identified paraneoplastic antibodies associated with encephalitis were directed toward intracellular antigens, mediated by T-cell damage, occurring in older populations, and typically responding poorly to immunotherapy (3). In 2007, Dalmau et al (4) described a new category of autoimmune encephalitides mediated by antibodies to cell-surface proteins. Autoimmune encephalitis due to cell-surface antibodies tends to occur in younger individuals, is less frequently associated with malignancy, and often responds better to treatment compared to the intracellular antigen-related paraneoplastic encephalitides (5). The literature pertaining to autoimmune encephalitis has grown exponentially over the past decade, with reported incidence similar to that of infectious encephalitis (incidence of autoimmune encephalitis is approximately 1 per 100,000 person-years with a prevalence of 13.7/100,000) (6). Although neuroophthalmologic features of traditional autoimmune/ paraneoplastic syndromes have been reviewed (7), the literature lacks a review of relevant findings in these more recently described cell-surface antibody-mediated syndromes and other newer antibody-mediated encephalitides. These syndromes may present with protean manifestations affecting the afferent or efferent visual pathways and are extremely important to the 385 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review neuro-ophthalmologist due to the treatable nature of many of these conditions. Herein, we review several specific antibodymediated autoimmune encephalitides with a focus on neuroophthalmic pertinence as well as provide an overview on pathophysiology, diagnosis, and treatment. SPECIFIC SYNDROMES N-Methyl-D-aspartate Receptor Encephalitis The first cell-surface antibody-mediated autoimmune encephalitis to be described was N-methyl-D-aspartate receptor (NMDAR) encephalitis, which remains the prototype and best studied of these new encephalitides. It often presents with subacute neuropsychiatric symptoms such as psychosis, behavioral change, and cognitive decline; these may be preceded by a nonspecific prodrome of headache, nausea, upper respiratory symptoms, and fever. The syndrome progresses to include seizures, autonomic instability, alternating agitation and catatonia, and a constellation of movement disorders; the latter frequently consists of choreoathetosis and oral-facial dyskinesias, described as semirhythmic ocular, facial, jaw, and extremity movements (8,9). Some authors have commented on the similarities between eye movement disorders in NMDAR encephalitis and those found in status dissociatus (the most extreme state dissociation, when there is no clear electrophysiologic evidence of either wakefulness, nonrapid eye movement sleep, or rapid eye movement sleep), which is particularly interesting, given the often observed oscillations between agitation and catatonia noted in NMDAR encephalitis (10,11). Although the exact pathomechanism of this complex movement in NMDAR is not known, it has been postulated to be the result of a breakdown of the corticolimbic control system, which would explain its persistence during sleep. There may be occasional fixed upgaze and opisthotonus through periods of unresponsiveness (12). In terms of demographics, approximately 1/ 3 of patients have an underlying tumor, with ovarian teratoma being the most common (Fig. 1) and 2/3 of patients are young women with a median age of 20 years (5). There have been numerous published reports of NMDAR encephalitis causing afferent, efferent, and pupil abnormalities. These have included several reports of optic FIG. 1. Coronal PET-CT documents left ovarian "cyst" (A); resection demonstrates teratoma with hair and teeth components evident (B). 386 neuritis, which may be the first sign of the disease (13-18). In one case, a 30-year-old woman first presented with suspected optic neuritis of the left eye; MRI of the brain and orbits revealed enhancement and enlargement of the left optic nerve at the orbital apex. In addition, there were T2 hyperintensities in the thalamus, internal capsule, and periventricular white matter (14). She clinically improved after a course of intravenous methylprednisolone, but within weeks, she developed hypersexual behavior, agitation, and depressed mood, with the eventual diagnosis of NMDAR encephalitis. Cases of simultaneous bilateral optic neuritis in association with NMDAR encephalitis have also been reported with disc edema and MRI revealing enhancement and thickening of the entire intraorbital optic nerves (15). In another case of bilateral optic neuritis, a 52-year-old woman developed painless visual loss, which progressed over 3 months to no light perception in the left eye in the setting of recent criminal activity, paranoid schizophrenia, and memory deficits (13). Over the course of the next 3 months, she developed both left and right optic neuritis with a partial response to steroids. MRI of the brain revealed enhancement in the prechiasmatic and canalicular portions of the right optic nerve as well as leptomeningeal enhancement of the frontotemporal meninges, prompting further evaluation and the subsequent diagnosis of NMDAR encephalitis. It is important to note that some cases of NMDAR encephalitis have also revealed antibodies to myelin oligodendrocyte glycoprotein (MOG) or aquaporin 4 (AQP4) (19-22). Although AQP4 testing was negative in the previously noted cases of NMDAR-associated optic neuritis, MOG testing was only reported to be tested in one patient (15). This raises the possibility of concurrent pathologic MOG antibodies in the other cases, explaining some aspects of the symptomatology. In addition to optic neuritis, Brandt et al (23) postulated that the afferent visual system may be affected in NMDAR encephalitis due to the presence of NMDA receptors expressed by retinal cells, which may influence the synaptic connections within the retina. Even among patients without visual symptoms, they found that patients with NMDA encephalitis had worse highcontrast and low-contrast visual acuities than age-matched controls (logMAR 0.02 vs 20.09, P , 0.001). However, these differences are unlikely to be clinically significant, and no differences were noted on optical coherence tomography (OCT), including the peripapillary retinal nerve fiber layer or ganglion cell layer analysis. Furthermore, Brandt et al postulated that aspects of visual dysfunction in NMDA encephalitis may be related to cortical processing. Higher visual function deficits with NMDAR encephalitis have also been reported elsewhere. For example, a 20-year-old woman developed prosopagnosia, dyschromatopsia, loss of stereopsis, and difficulty recognizing objects visually in the setting of NMDA encephalitis (24). MRI of the brain only demonstrated a white matter T2 hyperintensity in the left Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review insular region, but positron emission tomography (PET) revealed evidence of hypometabolism in both occipital lobes. Her deficits resolved over a period of 4 months with immunosuppressive treatment and removal of a mature cystic ovarian teratoma. Efferent neuro-ophthalmic findings have also been reported in NMDAR encephalitis. There may be occasional oculogyric crisis and opisthotonus through periods of unresponsiveness, divergent strabismus, and semirhythmic facial movements with elevation of the eyebrows and flaring of the nares (12). Others have reported cases of transient inverse ocular bobbing with skew deviation (25) and increased blink rate (9). Bilateral miosis and sluggish pupil response to light was the initial presentation of herpes simplex virus (HSV)-1 encephalitis in an 11-month-old girl (26). Within 2 weeks, she developed fever, aggressive behavior, and orofacial choreoathetosis. At that time, she was noted to have bilateral complete ptosis. Subsequently, NMDA antibodies were found in the cerebrospinal fluid (CSF) leading to treatment with corticosteroids and complete recovery of the ptosis. No associated tumor was found. There have also been reports of the opsoclonus-myoclonus syndrome occurring in 2 patients with NMDAR encephalitis aged 4 and 23 years, neither of which was found to have a malignancy (27,28). Dipeptidyl-Peptidase-Like Protein 6 AntibodyAssociated Encephalitis Dipeptidyl-peptidase-like protein 6 (DPPX)-antibody encephalitis is typically associated with prodromal weight loss and diarrhea, with the average peak of the neurologic symptoms at 8 months from onset (29). DPPX is expressed in the myenteric plexus of the gastrointestinal tract, explaining the high incidence of comorbid diarrhea and weight loss (30). Neurologic symptoms often reflect CNS hyperexcitability and manifest as agitation, myoclonus, hyperekplexia (exaggerated startle response), and seizures; cognitive dysfunction or memory loss is also often a primary feature (31). Some patients harbor an underlying malignancy, frequently B-cell lymphoma (29). Occasionally, patients with DPPX antibodies can have neuro-ophthalmic manifestations. Simultagnosia and apraxia of eyelid opening were noted in a 52-year-old man who had developed weight loss, diarrhea, and abdominal pain, which was followed by cognitive decline, delusions, and hallucinations (32). After a long course of illness that was responsive to immunotherapy, he declined when tapered off prednisone and subsequently died from pneumonia; pathologic examination of his brain revealed patchy neuronal loss in the amygdala, cingulum, and temporo-occipital cortex with reactive gliosis and scattered T and B cells suggestive of encephalitis. Postmortem CSF analysis revealed the presence of DPPX antibodies. Various types of ocular motor abnormalities have been noted in patients with DPPX antibody-associated enceph- Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 alitis (29-31,33,34). In one case, a patient with several months of agitation and diarrhea developed left-beating, upbeat, and torsional nystagmus with diplopia from skew deviation (33). Whole-body 18-fluoro-deoxyglucose PET computed tomography (CT) revealed markedly asymmetric avidity of the left medial rectus, right lateral rectus, and bilateral inferior recti, correlating with the slow phase of the nystagmus and specific muscle hyperactivity. The authors theorized involvement of the perihypoglossal nuclei, paramedian tract cell groups, or connections with the vestibulocerebellum were responsible for these findings. In addition, a series of 20 patients with DPPX antibodies revealed that 8 (40%) patients had either diplopia, oscillopsia, or blurred vision, although details of these ocular manifestations were limited (31). A syndrome resembling progressive encephalomyelitis with rigidity and myoclonus has been observed in some patients with DPPX, accompanied by reports of saccadic pursuit, impaired vestibulo-ocular reflex suppression, dysmetric saccades, and nystagmus (including downbeat, gaze-evoked, and upbeat) (34). Finally, opsoclonus has been documented accompanied by saccadic pursuit and limited excursion of saccades (35). Glial Fibrillary Acidic Protein AntibodyAssociated Encephalitis Antibodies against glial fibrillary acidic protein (GFAP), a cytoplasmic intermediate filament protein found in astrocytes, have been found to be a biomarker in patients with a steroid-responsive meningoencephalomyelitis characterized by prominent headache, optic papillitis, encephalopathy, postural tremor, and cerebellar ataxia. This entity was originally reported by Fang et al (36) in 2016 and has a known lethal canine equivalent known as necrotizing meningoencephalitis. Underlying malignancies are found in 14%-38% of patients, and MRI often features a unique appearance of perivascular radial enhancement extending from the ventricles or cerebellum (Fig. 2) (36-38). Approximately 25%-50% of patients with GFAP-associated meningoencephalitis have some degree of ophthalmic involvement, which often presents with bilateral optic disc edema with relatively preserved central visual acuity (36,38,39). Chen et al (39) detailed the eye findings of 10 patients with GFAP antibody-associated meningoencephalitis who presented with bilateral disc edema. Visual acuity was generally preserved, but some patients had arcuate visual field defects and developed optic disc pallor after resolution of the optic disc edema (Fig. 2). The opening pressure on lumbar puncture was normal in most patients and therefore the cause of the optic disc edema does not seem to be from raised intracranial pressure. It was speculated that the optic disc edema is from an inflammatory etiology primarily affecting the veins. Fluorescein angiography was available in one patient, which revealed selective leakage from the venules (39). Most patients do not 387 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 2. Fifty-one-year-old man with glial fibrillary acidic protein (GFAP) autoantibody-positive meningoencephalitis. The patient presented with headache, confusion, and transient visual obscurations. Visual acuity was 20/20 in both eyes. Fundus photographs at initial presentation show bilateral symmetric optic disc edema (A). Goldmann visual fields and Tangent screen are full in both eyes (B). Magnetic resonance images demonstrate perivascular radial enhancement in the cortex bilaterally (arrow), which is characteristic for GFAP autoantibody-positive meningoencephalitis (C). The disc edema and symptoms resolved with prednisone but relapsed with the steroid taper. The patient is currently on mycophenolate mofetil with no further relapses. No malignancy was identified. demonstrate enhancement of the optic nerve on MRI to suggest a retrobulbar optic neuritis, although a single case of unilateral optic neuritis with "blurred vision" was reported in a series of 22 patients (37). Clinical manifestations are typically steroid responsive with good recovery but can leave permanent neurologic sequelae. Some cases are monophasic, whereas others will relapse and may need chronic immunotherapy. Metabotropic Glutamate Receptor 1 (mGluR1) Antibody-Associated Encephalitis MGluR1 is a G-protein-coupled cell-surface receptor that is, ubiquitously found in the cerebellar cortex. The literature concerning mGluR1 antibody-associated encephalitis comprises 18 cases with presentations often including cerebellar dysfunction, in addition to more unique symptoms such as dysgeusia, head titubation, and isolated progressive dysarthria (40-42). The syndrome shares some features with mGluR5 encephalitis, which is associated with Ophelia syndrome (encephalitis with prominent memory compromise) (5). Mutations in the mGluR1 gene are associated with spinocerebellar ataxia (SCA), specifically auto388 somal recessive SCA 13 and SCA44 (40). Approximately 50% of reported cases are associated with an underlying tumor. In a review of the 18 reported cases, all patients exhibited cerebellar ataxia and nearly 50% of patients had ocular involvement, including oscillopsia, vertical nystagmus, gaze-evoked nystagmus, diplopia, and saccadic pursuits. In a Mayo Clinic series of 9 patients, 3 reported diplopia (41). Six of 18 cases were associated with T2 cerebellar hyperintensities or cerebellar atrophy on MRI. Gamma-Aminobutyric Acid Receptor Encephalitis GABA chloride channels are responsible for fast inhibitory synaptic transmission in the CNS. GABA receptor antibody encephalitis encompasses antibodies to both GABAA and GABAB and is typically characterized by signs of limbic encephalitis and early, refractory seizures often leading to status epilepticus (43,44). Nearly half of patients with GABAA encephalitis have underlying tumors, with thymoma most commonly reported. In comparison, GABAB antibodies are highly associated with malignancy including smallcell lung cancer (5,44). Rarely, there have been reports of Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review neuro-ophthalmic manifestations, including 3 reports of opsoclonus-myoclonus syndrome, with one concerning a three-year-old boy who developed opsoclonus, ataxia, and chorea (43,45,46). In addition, there have been 2 reported cases of "pathologic nystagmus" in the setting of "gait and stance ataxia" but additional details were not provided (47). GABAB encephalitis is often associated with T2 hyperintensities in the medial temporal lobes, whereas GABAA encephalitis tends to show multiple T2 hyperintensities spread throughout the cortical and subcortical regions (5). Glutamic Acid Decarboxylase 65 (GAD65) Antibody-Associated Encephalitis GAD65 is an intraneuronal protein responsible for enzymatic production of GABA from glutamate. Despite its classification as an encephalitis caused by antibodies to an intracellular antigen, the syndrome deserves review, given the variety of neuro-ophthalmic manifestations (48). AntiGAD65 antibody syndrome is associated with multiple phenotypes, which most commonly include stiff person syndrome, cerebellar ataxia, epilepsy, and encephalitis. The frequency of cancer detection is approximately 15%, which is roughly the same percentage found among samples sent to the Mayo Clinic neuroimmunology laboratory for paraneoplastic antibody testing that test seronegative for all known antibodies (49). In addition, low titers of GAD65 may be seen in healthy individuals or those with Type 1 diabetes mellitus. There are sparse data on afferent neuro-ophthalmic involvement in GAD65 antibody syndrome, but retinopathy and optic neuropathy were described in a 35-year-old man with latent autoimmune diabetes in adults and bilateral painless progressive visual loss over 4 years (50). Visual acuity was 20/30 in the right eye and 20/100 in the left eye. After exhaustive testing, a paraneoplastic test was ordered, which revealed high titers of anti-GAD65 antibodies. MRI of the brain revealed asymmetric atrophy and increased signal in the left optic nerve. A variety of efferent neuro-ophthalmic manifestations has been reported in association with GAD65 antibodies. Nystagmus is a common finding in GAD65 neurologic disease. In a study of 14 patients with cerebellar ataxia due to anti-GAD65 antibodies, 12 were noted to have "nystagmus" as a part of their presentation, although further details were not provided (51). Saiz et al (52) reported nystagmus in 11 of 61 patients with neurologic symptoms in the setting of high titers of anti-GAD65 antibodies. Downbeat nystagmus is the most commonly reported form of nystagmus associated with anti-GAD65 antibodies, but other forms of nystagmus can be seen as well, such as gazeevoked and upbeat nystagmus (52-56). In keeping with cerebellar involvement in patients with GAD65 antibodies, an alternating hypertropia from skew deviation can be seen Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 (57). Quantitative documentation of ocular movement abnormalities in patients with GAD65-associated stiff person syndrome has been documented by Zivotofsky et al (58), who reported a single case of rare multicomponent single saccades with atypical velocity profiles. The direction of the saccades was always toward the target, but they found variable acceleration during the saccadic movements, reminiscent of findings seen in adult-onset Tay Sachs disease (59). There have also been several reports of an opsoclonus-myoclonus ataxia syndrome, which consists of the typical multidirectional saccadic eye movements in combination with appendicular or truncal ataxia with or without underlying encephalitis (60-62). A progressive supranuclear palsy (PSP)-like phenotype has also been reported in association with GAD65 antibody syndrome. A 45-year-old woman developed 18 months of progressive gait difficulty characterized by frequent falls, supranuclear vertical gaze palsy, vertical saccade hypometria, delayed saccadic initiation, startle-induced spasms, and hypomimia/bradykinesia (63). After extensive evaluation, titers to GAD65 were found to be elevated, and the patient underwent treatment with monthly intravenous immunoglobulin (IVIG) with good clinical response. The authors felt that diagnostic clues pointing away from PSP included the increased saccadic latency, prominent early upgaze palsy, and startle-induced spasms. Overall, establishing a typical phenotype of GAD65 antibody syndrome is difficult. This may be secondary to the relative ubiquity of positive GAD65 antibody titers, which may or may not be pathologic in each reported case. Collapsin Response Mediator Protein 5 (CRMP5) Paraneoplastic Encephalitis Discovery of antibodies directed against CRMP5 (also known as anti-CV2) led to the recognition of a wide spectrum of disease including cognitive dysfunction, memory loss, asymmetric and painful sensorimotor axonal neuropathy, hypokinetic and hyperkinetic movement disorders, and cerebellar symptoms. The antibodies in CRMP5 encephalitis are directed toward an intracellular antigen. The syndrome is often associated with underlying malignancy, especially small-cell lung cancer, but has also been reported in association with thymoma, uterine sarcoma, and thyroid papillary carcinoma (64). Other neural antibodies may be present in association with CRMP5, including antibodies directed toward voltage-gated potassium, calcium channels, and Purkinje cells. Several neuroophthalmic associations have been described as CRMP5 associated syndrome but often present with visual loss as a prominent feature (Fig. 3) (7,64-68). In 2003, 16 cases of CRMP5-associated optic neuropathy were reported (69). Subsequently, in a series of 105 cases with CRMP5-associated peripheral neuropathy, optic neuropathy or retinitis was present in 11% of patients (70). Most 389 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 3. Sixty-five-year-old woman with collapsin response-mediator protein-5 (CRMP-5) autoimmunity with disc edema, vitritis, and retinitis. The patient presented with chorea and vision loss. Visual acuity was 20/40 in the right eye and hand motion in the left eye. Fundus photographs demonstrate bilateral optic disc edema and arteriolar attenuation in the left eye. The hazy view is due to vitreous cells. Goldmann visual fields show mild constriction in the right eye and severe constriction in the left eye (C). OCT of the macula shows mild ellipsoid zone mottling in the right eye (A) and almost complete loss of the ellipsoid zone in the left eye (B), which corresponds to the photoreceptors. Full-field ERG shows a fairly normal response in the right eye and no response in the left eye (D). The patient was found to have smallcell lung carcinoma. patients with optic neuropathy present with optic disc edema at onset without retrobulbar enhancement of the optic nerve on MRI. Coexisting vitritis and/or retinitis is common and sometimes patients can have vitritis/retinitis without optic nerve involvement (64,69). Rarely, optic neuropathy and vitritis may be present without other typical neurologic symptoms (71). Opsoclonus has also been described in CRMP5 encephalitis (72). Furthermore, approximately 4% of patients with CRMP5 autoimmunity can have concurrent myasthenia gravis (70). The visual outcomes after immunotherapy and treatment of the underlying malignancy are variable (71). In one case, resolution of papilledema and dramatic improvement of cerebellar ataxia was noted after removal of a small cell lung carcinoma (67). Intravitreal triamcinolone acetonide has also been effective as an adjunctive therapy in decreasing ocular inflammation and improving visual acuity in 2 patients with optic neuritis and vitritis associated with CRMP5 antibodies (66). Kelch-like Protein 11 (KLHL11) SeminomaAssociated Paraneoplastic Encephalitis Mandel-Brehm et al (73) recently reported 11 cases of seminoma-associated paraneoplastic encephalitis with antibodies directed toward KLHL11, an intracellular protein with a role in cell death and ubiquitination. All patients 390 were male with median age of onset of 41 years with a prevalence of 1.4 cases per 100,000 people in Olmstead County, MN. Patients presented with rhomboencephalitis (symptoms referable to inflammation of the brainstem and cerebellum), most commonly with ataxia, vertigo, hearing loss, and diplopia. Seminoma was discovered in 11 cases (8 testicular and 3 extratesticular), and the antibody testing led to the diagnosis of seminoma in 8 of the patients. The 2 patients without seminoma had microlithiasis and fibrosis of the testes (considered to be a premalignant condition) and underwent orchiectomy. Approximately 50% of patients presented with diplopia. Three patients exhibited nystagmus, which was only described specifically in one case as "horizontal and vertical nystagmus with a rotatory component." An additional patient with seminoma-associated KLHL11 encephalitis examined by the authors (PB, E2) demonstrated periodic alternating nystagmus, although the full case is currently unpublished. With immunotherapy and treatment of the underlying seminoma, 9 of 13 patients achieved stabilization or improvement. Other Neuro-Ophthalmic Associations in Autoimmune Encephalitides In addition to the specific antibodies reviewed above, there are other neuronal antibodies with varied neuro-ophthalmic Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review manifestations. There is an extensive body of literature devoted to 2 specific cell-surface antibodies which cause associated neurologic disease: AQP4 positive neuromyelitis optica spectrum disorder (NMOSD and MOG-IgGassociated disorder [MOGAD]). These 2 disorders are often associated with optic neuritis, often bilateral and recurrent, and have their own imaging characteristics (74). Neuromyelitis optica classically prevents with optic neuritis and longitudinally extensive transverse myelitis, but can have other CNS manifestations, including symptomatic cerebral syndrome. In comparison to AQP4-IgG-positive NMOSD, MOGAD more commonly presents with encephalitis acute disseminated encephalomyelitis, especially in children. Details of these disorders are beyond the scope of this review. Myasthenia gravis has also been reported in tandem with limbic encephalitis caused by the cell-surface antibodies directed toward a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor (AMPA), which is also associated with thymoma (3,75). Given the relatively frequent finding of thymoma in association with autoimmune encephalitides, further reports of associated myasthenia gravis are expected. The true prevalence of neuro-ophthalmic manifestations in autoimmune encephalitis is likely underestimated by the current literature because other neurologic symptoms are often severe, which can lead to neuro-ophthalmic symptoms being ignored or missed. A prospective cohort study of patients with autoimmune encephalitis began enrollment in 2019, which will systematically characterize further neuro-ophthalmic involvement in the autoimmune encephalitides (76). AUTOIMMUNE ENCEPHALITIS PATHOGENESIS A postinfectious pathogenesis has been suspected in autoimmune encephalitis with supportive data of a viral prodrome in 50% of patients with NMDAR encephalitis (3). Recently, the Spanish Herpes Simplex Encephalitis Study Group reported a strong association between HSV encephalitis and subsequent antibody-mediated autoimmune encephalitis (77). In a prospective observational study, 51 patients with HSV encephalitis were followed clinically, and 27% of the cohort developed autoimmune encephalitis during the study period (range of 7-61 days). Interestingly, an additional 22% of patients developed neuronal antibodies without clinical evidence of encephalitis. The authors suggested molecular mimicry as the cause of disease may be less likely, given that a variety of different neuronal antibodies were detected during monitoring postHSV rather than just one specific antibody. However a case-control study found that patients with NMDA encephalitis had significantly higher percentage of HSV IgG antibodies than controls (78). One of the 18 reported MGLUR1 encephalitis cases occurred after infection with herpes zoster virus (41). There have also been 2 cases of Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 reported neurosyphilis coexisting with NMDA seropositivity. One patient had chronic, progressive, bilateral visual loss, which improved after penicillin G, and the other patient had anisocoria without pupillary light response as well as neuropsychiatric symptoms (19). These associations do not imply causality and, in some instances, the autoantibodies may be "innocent bystanders." In fact, most diagnoses of autoimmune encephalitis are not associated with a recognized preceding insult to the immune system, raising concern for a genetic predisposition (79). One study detailed a significant correlation between LGI1 encephalitis and certain HLA genotypes, although NMDAR encephalitis did not seem to have an obvious HLA genotype association (80). Several studies have investigated the relationship between autoimmune encephalitis and other entities such NMOSD or MOGAD (19,20,22,81). One study retrospectively examined 691 clinical cases of NMDAR encephalitis and identified 12 cases of NMOSD that distinctly preceded or followed an episode of NMDAR encephalitis (81). Eleven cases of concurrent NMOSD and NMDAR encephalitis were also identified. In another series, Wang et al (21) reported that 5/18 (27.7%) patients with MOGAD had concurrent NMDA antibodies. The pathologic roles and relationship between these antibodies is unclear at this time, but NMDA receptor is known to play a role in the differentiation of oligodendrocytes and remyelination (82). It is conceivable that myelin damage through one process could then activate a separate autoimmune process directed against the damaged remnant myelin. Alternatively, reports of coexisting GFAP, NMDAR, and anti-aquaporin 4 have led some authors to suggest that the initiation of the autoimmune response may be due to a primitive neural-type cell (36). GENERAL PRINCIPLES OF DIAGNOSIS AND MANAGEMENT Diagnostic Considerations Although a full review on diagnosis and management of autoimmune encephalitides is beyond the scope of this review, some specific considerations are pertinent. In an effort to avoid delay of immunomodulatory treatment, criteria for diagnosing possible autoimmune encephalitis were recently revised (83). These new criteria, outlined in a 2016 consensus statement, remove reliance on antibody positivity and require 3 main features for possible autoimmune encephalitis: 1. Subacute onset of cognitive deficit (working memory, altered mental status, or psychiatric symptoms) 2. Concordant diagnostic finding (either focal CNS findings, unexplained seizures, CSF pleocytosis, or typical MRI findings) 3. Reasonable exclusion of other causes. 391 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Other diagnostic clues for autoimmune encephalitis include history of malignancy or malignancy risk factors and personal or family history of autoimmunity (84). A predictive scoring system has been developed to identify cases of autoimmune epilepsy, which commonly occurs in the autoimmune encephalitides (85). Consisting of 9 domains (e.g., autonomic dysfunction, neuropsychiatric symptoms, viral prodrome, specific CSF findings), the antibody prevalence in epilepsy of unknown etiology score (APE) showed sensitivity and specificity of 97.7% and 77.9%, respectively, for predicting the presence of a specific neural antibody. For the neuro-ophthalmologist, these syndromes may present with a wide variety of manifestations of the afferent or efferent visual pathways and are likely underdiagnosed. A high index of suspicion is required to order appropriate testing, which facilitate diagnosis. Practically, the patient's clinical history may offer diagnostic clues such as a subacute onset, cognitive deficits, or seizures may suggest the autoimmune encephalitides as a diagnostic group. Moreover, specific clues may implicate specific antibody-associated syndromes such as neuropsychiatric symptoms with NMDAR encephalitis, severe diarrhea, and weight loss with DPPX antibody-associated encephalitis, or dysgeusia with mGluR1 encephalitis (Table 1). Specific objective findings may incriminate certain autoimmune syndromes, such as bilateral optic disc edema without increased intracranial pressure in GFAP encephalitis or optic neuropathy, vitritis, and painful axonal neuropathy in CRMP5 encephalitis. Finally, given the ever-expanding phenotypes of neurologic autoimmunity, neuro-ophthalmologists should strongly consider testing for autoantibodies in any case in which the causative etiology is unclear or the clinical condition is out of proportion to findings on neuroimaging. Like most diagnostic tests, false positives can occur with antibody testing. Thus, accurate diagnosis relies on appropriate patient selection and clinical correlation, balancing the sensitivity and specificity of ancillary testing. Ancillary Testing MRI of the brain and electroencephalogram (EEG) are often obligatory components of the evaluation, given their diagnostic utility in these cases (3). EEG may capture subclinical seizures (autoimmune encephalitis is often accompanied by multiple seizure types). A unique association has also been made between NMDAR encephalitis and an EEG pattern termed "extreme delta brush," which bears resemblance to EEG waveforms seen in premature infants (86,87). MRI is often normal despite significant clinical deterioration; when abnormalities are present, they may consist of T2-FLAIR hyperintensities in the diencephalon and striatum with mild contrast enhancement, whereas some diseases have more pathognomonic radiologic findings, such as the perivenular enhancement seen in GFAP 392 antibody-associated meningoencephalomyelitis (88). Recent studies have reported that PET CT is useful for early diagnosis of autoimmune encephalitis even when compared to MRI, CSF evaluation, and EEG (89,90). CSF investigation including nucleated cells, protein, oligoclonal bands, and IgG index, and thorough search for autoimmune antibodies is mandatory. Some antibodies are more likely to be found in either serum or CSF. For instance, evaluation of NMDAR antibodies in CSF increases sensitivity by approximately 15% (91). Conversely, sensitivity of DPPX antibodies seems equivalent in serum and CSF to date (31). For most autoimmune encephalitides, the sensitivity of testing serum vs CSF is not well defined. At this juncture, testing both serum and CSF is generally recommended. In addition, one must exercise caution in the interpretation of testing during immunotherapy, which can affect sensitivity of antibody detection by either antibody suppression or antibody removal (i.e., through plasma exchange) (84). Because autoimmune neurology is a growing, dynamic field, clinicians should review the specific antibodies contained within their ordered antibody panels to assure all syndromes of interest are interrogated (Table 2). Malignancy Screening Before initiating long-term treatment for the neurologic syndrome, one must be cognizant to search for an underlying neoplasm. Many of the newly described autoimmune encephalitides have association with underlying malignancy (Table 1), albeit typically much less frequent than classic paraneoplastic encephalitides. Malignancy screening typically involves CT evaluation of the chest, abdomen, and pelvis as well as sex-specific screening (e.g., ovarian or testicular ultrasound). In many cases, the autoantibody has an association with a specific malignancy, which should be thoroughly investigated (e.g., NMDA antibodies with ovarian teratoma, CRMP5 antibodies with small-cell lung cancer, or KLHL11 antibodies with seminoma). We prefer PET CT as a malignancy screening tool, especially in cases of high suspicion for underlying malignancy (risk factors, comorbid weight loss, antibody with high oncologic association, etc.), given its increased sensitivity compared to CT alone (84,92). Treatment of the Neurologic Syndrome Immunotherapy is often used acutely in the form of corticosteroids and either IVIG or plasma exchange (5,84). Given the significant time delay for antibody confirmation, immunotherapy should be initiated before the antibody results return if there is high clinical suspicion for autoimmune encephalitis. A typical regimen for acute treatment of autoimmune encephalitis may consist of 3-5 days of high-dose intravenous corticosteroids followed by a taper of corticosteroids over a period of months. Corticosteroid administration thereafter has typically been through the oral route; however, Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 1. Selected antibodies associated with neuro-ophthalmic manifestations* Antibody Age (Median; Range, yr) Sex Ratio (Male:Female) Antigen Notable Associated Clinical Characteristics Associated Malignancy (%) Reported Neuro-ophthalmic Associations NMDAR 21; 2-85 mo 1:4 Cell surface Neuropsychiatric symptoms, movement disorders, extreme delta brush on EEG Age-dependent, 10%-58%; ovarian teratoma Optic neuritis, higher cortical visual deficits, oculogyric crisis, inverse ocular bobbing, increased blink rate, complete bilateral ptosis, opsoclonusmyoclonus Simultagnosia, apraxia of eyelid opening, nystagmus, skew deviation, saccadic pursuit, impaired vestibulo-ocular reflex suppression, dysmetric saccades, opsoclonus Bilateral disc edema (optic papillitis), arcuate visual field defect, single case of optic neuritis DPPX 52; 13-76 2.3:1 Cell surface Diarrhea, weight loss, agitation, myoclonus, hyperekplexia GFAP 45; 6-103 1:1.2 Cytoplasm 14%-38% mGluR1 57; 19-81 0.8:1 Cell surface Meningoencephalomyelitis, optic papillitis, MRI with characteristic perivascular radial enhancement Cerebellar ataxia, head titubation, dysgeusia GABAB 61; 16-77 1.5:1 Cell surface GAD65 51; 5-70 1:2.3 Cytoplasm Refractory seizures with status epilepticus Stiff-person syndrome, ataxia, seizures, type 1 diabetes mellitus, autoimmune thyroid disease, pernicious anemia 50%, small-cell lung cancer 15% CRMP5 69; 20-88 1:1.2 Cytoplasm Painful axonal polyradiculoneuropathy, ataxia 69%, small cell lung cancer, thymoma KLHL11 41; 27-68 All cases male Cytoplasm Ataxia, vertigo, diplopia, hearing loss ,10% 42% 100%, seminoma or premalignant testicular microlithiasis Vertical nystagmus, gazeevoked nystagmus, oscillopsia, diplopia Opsoclonus-myoclonus, nystagmus Autoimmune-related retinopathy and optic neuropathy, nystagmus (most commonly downbeat), skew deviation, opsoclonusmyoclonus, supranuclear vertical gaze palsy with syndrome mimicking progressive supranuclear palsy Optic neuropathy, retinitis, vitritis, opsoclonus, myasthenia gravis (approximately 4% of cases) Diplopia, vertical/rotary and periodic alternating nystagmus *Information derived from a variety of sources (3,5,37,38,40,48,49,70,79). CRMP5, collapsin response mediator protein 5; DPPX, dipeptidyl-peptidase-like protein 6; EEG, electroencephalogram; GABAB, gammaaminobutyric acid receptor; GAD65, glutamic acid decarboxylase 65; GFAP, glial fibrillary acidic protein; KLHL11, kelch-like protein 11; mGluR1, metabotropic glutamate receptor 1; NMDAR, n-methyl- d-aspartate receptor. an alternative dosing option uses weekly intravenous highdose corticosteroids, which can then be gradually reduced in frequency. This alternative dosing regimen offers the theoretical benefit of less constant exposure to corticosteroids, which are well known for diverse adverse effects. Optimal prevention of these side effects includes simultaneous medical prophylaxis with antibiotics for Pneumocystis infection, calcium and vitamin D for prevention osteopenia/osteoporosis, and consideration of a gastroprotective agent such as a proton pump inhibitor. If there is a poor clinical response to corticosteroids or relative contraindications (poor tolerance in the Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 past, uncontrolled hyperglycemia, recent or planned surgical procedure), IVIG or plasma exchange represent alternate forms of immunomodulatory treatments. Although often effective, these forms of treatment are expensive and accompanied by additional risks such as aseptic meningitis, hypercoagulable state, infection, and central line placement. Additional acute therapy may be necessary if there is poor response to first-line therapy, which often consists of either rituximab or cyclophosphamide. Chronic immunotherapy, such as corticosteroids, mycophenolate mofetil, azathioprine, rituximab, or regular infusions of IVIG may be necessary to 393 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 2. Mayo clinic autoimmune encephalitis panel Test ID AEESI NMDCS VGKC LG1CS CS2CS GD65S GABCS AMPCS ANN1S ANN2S ANN3S AGN1S PCABP PCAB2 PCATR AMPHS CCN CCPQ ARBI GANG CRMS Reflex Tests WBN CRMWS ABLOT NMOFS NMOTS AMPIS GABIS NMDIS Reporting Name Available Separately Always Performed Encephalopathy, interpretation, S NMDA-R Ab CBA, S Neuronal (V-G) K+ Channel Ab, S LGI1-IgG CBA, S CASPR2-IgG CBA, S GAD65 Ab Assay, S GABA-B-R Ab CBA, S AMPA-R Ab CBA, S Anti-Neuronal Nuclear Ab, Type 1 Anti-Neuronal Nuclear Ab, Type 2 Anti-Neuronal Nuclear Ab, Type 3 Anti-Glial Nuclear Ab, Type 1 Purkinje Cell Cytoplasmic Ab Type 1 Purkinje Cell Cytoplasmic Ab Type 2 Purkinje Cell Cytoplasmic Ab Type Amphiphysin Ab, S N-Type Calcium Channel Ab P/Q-Type Calcium Channel Ab ACh Receptor (Muscle) Binding Ab AChR Ganglionic Neuronal Ab, S CRMP-5-IgG, S No No No No No Yes No No No No No No No No No No No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Paraneoplastic Autoantibody WBlot, S CRMP-5-IgG Western Blot, S Amphiphysin Western Blot, S NMO/AQP4 FACS, S NMO/AQP4 FACS Titer, S AMPA-R Ab IF Titer Assay, S GABA-B-R Ab IF Titer Assay, S NMDA-R Ab IF Titer Assay, S No Yes No Yes No No No No No No No No No No No No prevent recurrent disease in some cases and is well described elsewhere (5,84). Unfortunately, there are limited data regarding comparative efficacy of acute or maintenance treatments at this time. In these circumstances, expert opinion and case series currently provide the foundation on which treatment decisions are made. Chronic immunomodulatory treatments are typically continued for a matter of years if clinically effective and well tolerated before attempting to taper and withdraw treatment. CONCLUSIONS Research efforts over the past decade have dramatically expanded the field of autoimmune neurology in terms of diagnosis, prognostication, and treatment. The identification and classification of autoimmune encephalitides is an evolving science, but a wide variety of neuro-ophthalmic manifestations have been identified. Although there are overlapping features of many of autoimmune encephalitides not only between syndromes but other CNS disorders, some unique clinical features and paraclinical findings can suggest a particular diagnosis. For the neuroophthalmologist involved in the evaluation of these patients, 394 an awareness and high clinical suspicion is paramount for early recognition and treatment. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: P. E. Bohm, T. M. Bhatti, J. J. Chen, and E. R. Eggenberger; b. Acquisition of data: P. E. Bohm, T. M. Bhatti, J. J. Chen, and E. R. Eggenberger; c. Analysis and interpretation of data: P. E. Bohm, T. M. Bhatti, J. J. Chen, and E. R. Eggenberger. Category 2: a. Drafting the manuscript: P. E. Bohm, T. M. Bhatti, J. J. Chen, and E. R. Eggenberger; b. Revising it for intellectual content: P. E. Bohm, T. M. Bhatti, J. J. Chen, and E. R. Eggenberger. Category 3: a. Final approval of the completed manuscript: P. E. Bohm, T. M. Bhatti, J. J. Chen, and E. R. Eggenberger. REFERENCES 1. Schulz P, Pruss H. Hirnsymptome bei Carcinomatose- Hermann Oppenheim and an Early Description of a Paraneoplastic Neurological Syndrome. J Hist Neurosci. 2015;24:371-377. 2. Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology. 1985;35:538-543. 3. Bradshaw MJ, Linnoila JJ. An overview of autoimmune and paraneoplastic encephalitides. Semin Neurol. 2018;38:330-343. Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review 4. Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, Baehring JM, Shimazaki H, Koide R, King D, Mason W, Sansing LH, Dichter MA, Rosenfeld MR, Lynch DR. Paraneoplastic antiN-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61:25-36. 5. Hermetter C, Fazekas F, Hochmeister S. Systematic review: syndromes, early diagnosis, and treatment in autoimmune encephalitis. Front Neurol. 2018;9:706. 6. Dubey D, Pittock SJ, Kelly CR, McKeon A, Lopez-Chiriboga AS, Lennon VA, Gadoth A, Smith CY, Bryant SC, Klein CJ, Aksamit AJ, Toledano M, Boeve BF, Tillema JM, Flanagan EP. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018;83:166-177. 7. Bataller L, Dalmau J. Neuro-ophthalmology and paraneoplastic syndromes. Curr Opin Neurol. 2004;17:3-8. 8. Baizabal-Carvallo JF, Stocco A, Muscal E, Jankovic J. The spectrum of movement disorders in children with anti-NMDA receptor encephalitis. Mov Disord. 2013;28:543-547. 9. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63-74. 10. Stamelou M, Plazzi G, Lugaresi E, Edwards MJ, Bhatia KP. The distinct movement disorder in anti-NMDA receptor encephalitis may be related to Status Dissociatus: a hypothesis. Mov Disord. 2012;27:1360-1363. 11. Mahowald MW, Schenck CH. Status dissociatus-a perspective on states of being. Sleep. 1991;14:69-79. 12. Kleinig TJ, Thompson PD, Matar W, Duggins A, Kimber TE, Morris JG, Kneebone CS, Blumbergs PC. The distinctive movement disorder of ovarian teratoma-associated encephalitis. Mov Disord. 2008;23:1256-1261. 13. Mugavin M, Mueller BH, Desai M, Golnik KC. Optic neuropathy as the initial presenting sign of N-methyl-d-aspartate (NMDA) encephalitis. Neuroophthalmology. 2017;41:90-93. 14. Colley S, Smith J. Sore eyes and psychosis. BMJ Case Rep BMJ Case Rep. 2014;2014:bcr2013201956. 15. Yang HK, Kim JH, Park YH, Park KS, Kim JS, Hwang JM. AntiNMDA-receptor optic neuritis in a patient with a history of encephalitis. Can J Ophthalmol. 2017;52:e216-e218. 16. Motoyama R, Shiraishi K, Tanaka K, Kinoshita M, Tanaka M. Anti-NMDA receptor antibody encephalitis with recurrent optic neuritis and epilepsy. Rinsho Shinkeigaku. 2010;50:585- 588. 17. Kruer MC, Koch TK, Bourdette DN, Chabas D, Waubant E, Mueller S, Moscarello MA, Dalmau J, Woltjer RL, Adamus G. NMDA receptor encephalitis mimicking seronegative neuromyelitis optica. Neurology. 2010;74:1473-1475. 18. Ishikawa N, Tajima G, Hyodo S, Takahashi Y, Kobayashi M. Detection of autoantibodies against NMDA-type glutamate receptor in a patient with recurrent optic neuritis and transient cerebral lesions. Neuropediatrics. 2007;38:257-260. 19. Qin K, Wu W, Huang Y, Xu D, Zhang L, Zheng B, Jiang M, Kou C, Gao J, Li W, Zhang J, Wang S, Luan Y, Yan C, Xu D, Zheng X. Anti-N-methyl-D-aspartate receptor(NMDAR) antibody encephalitis presents in atypical types and coexists with neuromyelitis optica spectrum disorder or neurosyphilis. BMC Neurol. 2017;17:1. 20. Zoccarato M, Saddi MV, Serra G, Pelizza MF, Rosellini I, Peddone L, Ticca A, Giometto B, Zuliani L. Aquaporin-4 antibody neuromyelitis optica following anti-NMDA receptor encephalitis. J Neurol. 2013;260:3185-3187. 21. Wang L, ZhangBao J, Zhou L, Zhang Y, Li H, Li Y, Huang Y, Wang M, Lu C, Lu J, Zhao C, Quan C. Encephalitis is an important clinical component of myelin oligodendrocyte glycoprotein antibody associated demyelination: a singlecenter cohort study in Shanghai, China. Eur J Neurol. 2019;26:168-174. 22. Zhou L, ZhangBao J, Li H, Li X, Huang Y, Wang M, Zhao C, Lu J, Lu C, Li Y, Quan C. Cerebral cortical encephalitis followed by recurrent CNS demyelination in a patient with concomitant antiMOG and anti-NMDA receptor antibodies. Mult Scler Relat Disord. 2017;18:90-92. Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 23. Brandt AU, Oberwahrenbrock T, Mikolajczak J, Zimmermann H, Prüss H, Paul F, Finke C. Visual dysfunction, but not retinal thinning, following anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflamm. 2016;3:e198. 24. Sawamura H, Yamamoto T, Ohtomo R, Bannai T, Wakakura M, Tsuji S. Anti-NMDA receptor encephalitis associated with transient cerebral dyschromatopsia, prosopagnosia, and lack of stereopsis. J Neuroophthalmol. 2014;34:144-148. 25. Shimazaki H, Morita M, Nakano I, Dalmau J. Inverse ocular bobbing in a patient with encephalitis associated with antibodies to the N-methyl-D-aspartate receptor. Arch Neurol. 2008;65:1251. 26. Hellgren K, Fowler Å, Rydberg A, Wickström R. Ophthalmological findings in children with encephalitis. Acta Ophthalmol. 2017;95:66-73. 27. Kurian M, Lalive PH, Dalmau JO, Horvath J. Opsoclonusmyoclonus syndrome in anti-N-methyl-D-aspartate receptor encephalitis. Arch Neurol. 2010;67:118-121. 28. Player B, Harmelink M, Bordini B, Weisgerber M, Girolami M, Croix M. Pediatric opsoclonus-myoclonus-ataxia syndrome associated with anti-N-methyl-D-aspartate receptor encephalitis. Pediatr Neurol. 2015;53:456-458. 29. Hara M, Ariño H, Petit-Pedrol M, Sabater L, Titulaer MJ, Martinez-Hernandez E, Schreurs MW, Rosenfeld MR, Graus F, Dalmau J. DPPX antibody-associated encephalitis: main syndrome and antibody effects. Neurology. 2017;88:1340- 1348. 30. Boronat A, Gelfand JM, Gresa-Arribas N, Jeong HY, Walsh M, Roberts K, Martinez-Hernandez E, Rosenfeld MR, BaliceGordon R, Graus F, Rudy B, Dalmau J. Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol. 2013;73:120-128. 31. Tobin WO, Lennon VA, Komorowski L, Probst C, Clardy SL, Aksamit AJ, Appendino JP, Lucchinetti CF, Matsumoto JY, Pittock SJ, Sandroni P, Tippmann-Peikert M, Wirrell EC, McKeon A. DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. Neurology. 2014;83:1797-1803. 32. Stokin GB, Popovi c M, Gelpi E, Kogoj A, Dalmau J, Graus F. Neuropathologic features of anti-dipeptidyl-peptidase-like protein-6 antibody encephalitis. Neurology. 2015;84:430- 432. 33. Doherty L, Gold D, Solnes L, Probasco J, Venkatesan A. AntiDPPX encephalitis: prominent nystagmus reflected by extraocular muscle FDG-PET avidity. Neurol Neuroimmunol Neuroinflamm. 2017;4:e361. 34. Balint B, Jarius S, Nagel S, Haberkorn U, Probst C, Blöcker IM, Bahtz R, Komorowski L, Stöcker W, Kastrup A, Kuthe M, Meinck HM. Progressive encephalomyelitis with rigidity and myoclonus: a new variant with DPPX antibodies. Neurology. 2014;82:1521-1528. 35. Micieli JA, Newman NJ, Kase CS, Biousse V. Teaching video NeuroImages: opsoclonus in anti-DPPX encephalitis. Neurology. 2019;92:e2298. 36. Fang B, McKeon A, Hinson SR, Kryzer TJ, Pittock SJ, Aksamit AJ, Lennon VA. Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis. JAMA Neurol. 2016;73:1297-1307. 37. Iorio R, Damato V, Evoli A, Gessi M, Gaudino S, Di Lazzaro V, Spagni G, Sluijs JA, Hol EM. Clinical and immunological characteristics of the spectrum of GFAP autoimmunity: a case series of 22 patients. J Neurol Neurosurg Psychiatry. 2018;89:138-146. 38. Flanagan EP, Hinson SR, Lennon VA, Fang B, Aksamit AJ, Morris PP, Basal E, Honorat JA, Alfugham NB, Linnoila JJ, Weinshenker BG, Pittock SJ, McKeon A. Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: analysis of 102 patients. Ann Neurol. 2017;81:298-309. 39. Chen JJ, Aksamit AJ, McKeon A, Pittock SJ, Weinshenker BG, Leavitt JA, Morris PP, Flanagan EP. Optic disc edema in glial fibrillary acidic protein autoantibody-positive meningoencephalitis. J Neuroophthalmol. 2018;38:276-281. 395 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review 40. Christ M, Müller T, Bien C, Hagen T, Naumann M, Bayas A. Autoimmune encephalitis associated with antibodies against the metabotropic glutamate receptor type 1: case report and review of the literature. Ther Adv Neurol Disord. 2019;12:1756286419847418. 41. Lopez-Chiriboga AS, Komorowski L, Kümpfel T, Probst C, Hinson SR, Pittock SJ, McKeon A. Metabotropic glutamate receptor type 1 autoimmunity: clinical features and treatment outcomes. Neurology. 2016;86:1009-1013. 42. Pedroso JL, Dutra LA, Espay AJ, Höftberger R, Barsottini OGP. Video neuroImages: head titubation in anti-mGluR1 autoantibody-associated cerebellitis. Neurology. 2018;90:746-747. 43. Hoftberger R, Titulaer MJ, Sabater L, Dome B, Rózsás A, Hegedus B, Hoda MA, Laszlo V, Ankersmit HJ, Harms L, Boyero S, de Felipe A, Saiz A, Dalmau J, Graus F. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology. 2013;81:1500-1506. 44. Spatola M, Petit-Pedrol M, Simabukuro MM, Armangue T, Castro FJ, Barcelo Artigues MI, Julià Benique MR, Benson L, Gorman M, Felipe A, Caparó Oblitas RL, Rosenfeld MR, Graus F, Dalmau J. Investigations in GABAA receptor antibodyassociated encephalitis. Neurology. 2017;88:1012-1020. 45. DeFelipe-Mimbrera A, Masjuan J, Corral Í, Villar LM, Graus F, García-Barragán N. Opsoclonus-myoclonus syndrome and limbic encephalitis associated with GABAB receptor antibodies in CSF. J Neuroimmunol. 2014;272:91-93. 46. Kruer MC, Hoeftberger R, Lim KY, Coryell JC, Svoboda MD, Woltjer RL, Dalmau J. Aggressive course in encephalitis with opsoclonus, ataxia, chorea, and seizures: the first pediatric case of gamma-aminobutyric acid type B receptor autoimmunity. JAMA Neurol. 2014;71:620-623. 47. Dogan Onugoren M, Deuretzbacher D, Haensch CA, Hagedorn HJ, Halve S, Isenmann S, Kramme C, Lohner H, Melzer N, Monotti R, Presslauer S, Schäbitz WR, Steffanoni S, Stoeck K, Strittmatter M, Stögbauer F, Trinka E, von Oertzen TJ, Wiendl H, Woermann FG, Bien CG. Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series. J Neurol Neurosurg Psychiatry. 2015;86:965-972. 48. Pittock SJ, Yoshikawa H, Ahlskog JE, Tisch SH, Benarroch EE, Kryzer TJ, Lennon VA. Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin Proc. 2006;81:1207-1214. 49. McKeon A, Tracy JA. GAD65 neurological autoimmunity. Muscle Nerve. 2017;56:15-27. 50. Almarzouqi SJ, Morgan ML, Carvounis PE, Lee AG. Autoimmune-related retinopathy and optic neuropathy accompanied by anti-GAD antibodies. Neuroophthalmology. 2015;39:195-200. 51. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, de Andres C, Maestre J, Fabien N, Vighetto A, Casamitjana R, Thivolet C, Tavolato B, Antoine J, Trouillas P, Graus F. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58:225-230. 52. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R, Ramió-Torrentà L, Graus F. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131:2553-2563. 53. Antonini G, Nemni R, Giubilei F, Gragnani F, Ceschin V, Morino S, Bucci E, Accornero N. Autoantibodies to glutamic acid decarboxylase in downbeat nystagmus. J Neurol Neurosurg Psychiatry. 2003;74:998-999. 54. Ances BM, Dalmau JO, Tsai J, Hasbani MJ, Galetta SL. Downbeating nystagmus and muscle spasms in a patient with glutamic-acid decarboxylase antibodies. Am J Ophthalmol. 2005;140:142-144. 55. Georgieva Z, Parton M. Cerebellar ataxia and epilepsy with anti-GAD antibodies: treatment with IVIG and plasmapheresis. BMJ Case Rep. 2014;2014:bcr2013202314. 56. Martins AI, Carvalho JN, Amorim AM, Geraldo A, Eggenberger E, Lemos J. Disabling central paroxysmal positioning upbeat nystagmus and vertigo associated with the presence of anti- 396 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. glutamic acid decarboxylase antibodies. J Neuroophthalmol. 2018;38:32-35. Farooq AV, Soin K, Moss HE. Alternating skew deviation in association with anti-glutamic acid decarboxylase antibodies. Neuroophthalmology. 2015;39:140-143. Zivotofsky AZ, Siman-Tov T, Gadoth N, Gordon CR. A rare saccade velocity profile in Stiff-Person Syndrome with cerebellar degeneration. Brain Res. 2006;1093:135-140. Rucker JC, Shapiro BE, Han YH, Kumar AN, Garbutt S, Keller EL, Leigh RJ. Neuro-ophthalmology of late-onset Tay-Sachs disease (LOTS). Neurology. 2004;63:1918-1926. Laroumagne S, Elharrar X, Coiffard B, Plojoux J, Dutau H, Breen D, Astoul P. Dancing eye syndrome secondary to opsoclonusmyoclonus syndrome in small-cell lung cancer. Case Rep Med. 2014;2014:545490. Bhandari HS. Presentation of opsoclonus myoclonus ataxia syndrome with glutamic acid decarboxylase antibodies. BMJ Case Rep. 2012;2012:bcr2012006339. Markakis I, Alexiou E, Xifaras M, Gekas G, Rombos A. Opsoclonus-myoclonus-ataxia syndrome with autoantibodies to glutamic acid decarboxylase. Clin Neurol Neurosurg. 2008;110:619-621. Oskarsson B, Pelak V, Quan D, Hall D, Foster C, Galetta S. Stiff eyes in stiff-person syndrome. Neurology. 2008;71:378-380. Moss HE, Liu GT, Dalmau J. Glazed (vision) and confused. Surv Ophthalmol. 2010;55:169-173. Thambisetty MR, Scherzer CR, Yu Z, Lennon VA, Newman NJ. Paraneoplastic optic neuropathy and cerebellar ataxia with small cell carcinoma of the lung. J Neuroophthalmol. 2001;21:164-167. Pulido J, Cross SA, Lennon VA, Pulido J, Swanson D, Muench M, Lachance DH. Bilateral autoimmune optic neuritis and vitreitis related to CRMP-5-IgG: intravitreal triamcinolone acetonide therapy of four eyes. Eye (Lond). 2008;22:1191- 1193. de la Sayette V, Bertran F, Honnorat J, Schaeffer S, Iglesias S, Defer G. Paraneoplastic cerebellar syndrome and optic neuritis with anti-CV2 antibodies: clinical response to excision of the primary tumor. Arch Neurol. 1998;55:405-408. Gordon LK. Paraneoplastic syndromes in neuro-ophthalmology. J Neuroophthalmol. 2015;35:306-314. Cross SA, Salomao DR, Parisi JE, Kryzer TJ, Bradley EA, Mines JA, Lam BL, Lennon VA. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol. 2003;54:38-50. Dubey D, Lennon VA, Gadoth A, Pittock SJ, Flanagan EP, Schmeling JE, McKeon A, Klein CJ. Autoimmune CRMP5 neuropathy phenotype and outcome defined from 105 cases. Neurology. 2018;90:e103-e110. Igarashi N, Sawamura H, Kaburaki T, Aihara M. Anti-collapsing response-mediating protein-5 antibody-positive paraneoplastic perioptic neuritis without typical neurological symptoms. Neuroophthalmology. 2017;41:24-29. Nakajima M, Uchibori A, Ogawa Y, Miyazaki T, Ichikawa Y, Kaneko K, Takahashi T, Nakashima I, Shiraishi H, Motomura M, Chiba A. CV2/CRMP5-antibody-related paraneoplastic optic neuropathy associated with small-cell lung cancer. Intern Med. 2018;57:1645-1649. Mandel-Brehm C, Dubey D, Kryzer TJ, O'Donovan BD, Tran B, Vazquez SE, Sample HA, Zorn KC, Khan LM, Bledsoe IO, McKeon A, Pleasure SJ, Lennon VA, DeRisi JL, Wilson MR, Pittock SJ. Kelch-like protein 11 antibodies in seminomaassociated paraneoplastic encephalitis. N Engl J Med. 2019;381:47-54. Flanagan EP. Neuromyelitis optica spectrum disorder and other non-multiple sclerosis central nervous system inflammatory diseases. Continuum. 2019;25:815-844. Li X, Mao YT, Wu JJ, Li LX, Chen XJ. Anti-AMPA receptor encephalitis associated with thymomatous myasthenia gravis. J Neuroimmunol. 2015;281:35-37. Neuro-ophthalmology and Autoimmune Encephalitis (NODE) (NODE). ClinicTrials.Gov. Available at: https://clinicaltrials. gov/ct2/show/NCT03872284. Accessed date June 7, 2019. Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review 77. Armangue T, Spatola M, Vlagea A, Mattozzi S, Cárceles-Cordon M, Martinez-Heras E, Llufriu S, Muchart J, Erro ME, Abraira L, Moris G, Monros-Giménez L, Corral-Corral Í, Montejo C, Toledo M, Bataller L, Secondi G, Ariño H, Martínez-Hernández E, Juan M, Marcos MA, Alsina L, Saiz A, Rosenfeld MR, Graus F, Dalmau J. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018;17:760-772. 78. Salovin A, Glanzman J, Roslin K, Armangue T, Lynch DR, Panzer JA. Anti-NMDA receptor encephalitis and nonencephalitic HSV-1 infection. Neurol Neuroimmunol Neuroinflamm. 2018;5:e458. 79. Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med. 2018;378:840-851. 80. Kim TJ, Lee ST, Moon J, Sunwoo JS, Byun JI, Lim JA, Shin YW, Jun JS, Lee HS, Lee WJ, Yang AR, Choi Y, Park KI, Jung KH, Jung KY, Kim M, Lee SK, Chu K. Anti-LGI1 encephalitis is associated with unique HLA subtypes. Ann Neurol. 2017;81:183-192. 81. Titulaer MJ, Höftberger R, Iizuka T, Leypoldt F, McCracken L, Cellucci T, Benson LA, Shu H, Irioka T, Hirano M, Singh G, Cobo Calvo A, Kaida K, Morales PS, Wirtz PW, Yamamoto T, Reindl M, Rosenfeld MR, Graus F, Saiz A, Dalmau J. Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2014;75:411-428. 82. Li C, Xiao L, Liu X, Yang W, Shen W, Hu C, Yang G, He C. A functional role of NMDA receptor in regulating the differentiation of oligodendrocyte precursor cells and remyelination. Glia. 2013;61:732-749. 83. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15:391-404. Bohm et al: J Neuro-Ophthalmol 2020; 40: 385-397 84. Lopez-Chiriboga AS, Flanagan EP. Diagnostic and therapeutic approach to autoimmune neurologic disorders. Semin Neurol. 2018;38:392-402. 85. Dubey D, Singh J, Britton JW, Pittock SJ, Flanagan EP, Lennon VA, Tillema JM, Wirrell E, Shin C, So E, Cascino GD, Wingerchuk DM, Hoerth MT, Shih JJ, Nickels KC, McKeon A. Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia. 2017;58:1181-1189. 86. Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79:1094-1100. 87. Toledano M, Pittock SJ. Autoimmune epilepsy. Semin Neurol. 2015;35:245-258. 88. Kelley BP, Patel SC, Marin HL, Corrigan JJ, Mitsias PD, Griffith B. Autoimmune encephalitis: pathophysiology and imaging review of an overlooked diagnosis. AJNR Am J Neuroradiol. 2017;38:1070-1078. 89. Solnes LB, Jones KM, Rowe SP, Pattanayak P, Nalluri A, Venkatesan A, Probasco JC, Javadi MS. Diagnostic value of (18)F-FDG PET/CT versus MRI in the setting of antibodyspecific autoimmune encephalitis. J Nucl Med. 2017;58:1307-1313. 90. Probasco JC, Solnes L, Nalluri A, Cohen J, Jones KM, Zan E, Javadi MS, Venkatesan A. Abnormal brain metabolism on FDGPET/CT is a common early finding in autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm. 2017;4:e352. 91. Gresa-Arribas N, Titulaer MJ, Torrents A, Aguilar E, McCracken L, Leypoldt F, Gleichman AJ, Balice-Gordon R, Rosenfeld MR, Lynch D, Graus F, Dalmau J. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13:167-177. 92. McKeon A, Apiwattanakul M, Lachance DH, Lennon VA, Mandrekar JN, Boeve BF, Mullan B, Mokri B, Britton JW, Drubach DA, Pittock SJ. Positron emission tomography-computed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol. 2010;67:322-329. 397 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.