Clinical manifestations

Presentation and course

There are two major subgroups of autoimmune encephalitis according to disease physiopathology: 1) those showing antibodies against intracellular antigens where cellular immunity seems to play a relevant role, and 2) those with antibodies directed against cellular surface antigens, where the humoral response likely has a central role in the clinical manifestations. The main features of representative disorders from each group are discussed.

Autoimmune encephalitis with antibodies against intracellular antigens. These are strongly associated with malignancy. The process is T-cell mediated, which accounts for its poor response to immunotherapy. It is most commonly observed in elderly subjects.

Anti-neuronal nuclear antibody type 1 (ANNA-1) or anti-Hu. Symptoms reflect affected areas such as the cortex, cerebellum, brainstem, spinal cord, or the peripheral nervous system (dorsal root ganglia), leading to epilepsia partialis continua; cortical, limbic, brainstem encephalitis; chorea; paraneoplastic cerebellar degeneration; myelitis; subacute sensory neuronopathy; and autonomic dysfunction (44; 172).

Anti-Yo or Purkinje cell antibody type 1 (PCA-1) (119). Ninety percent of subjects develop paraneoplastic cerebellar degeneration associated with brainstem, spinal cord, and peripheral findings. Chorea, hemichorea, and hemiballism have also been described in an individual with anti-Yo antibodies, the latter associated with anti-MOG antibodies (97; 148).

Anti-neuronal nuclear antibody type 2 (ANNA-2) or anti-Ri (119). Findings include paraneoplastic cerebellar degeneration, brainstem encephalitis, opsoclonus-myoclonus, and dystonia/laryngospasm.

Anti-CV2/collapsin response mediator protein 5 (CRMP5) (119; 172). Findings include paraneoplastic encephalomyelitis, paraneoplastic cerebellar degeneration, chorea, uveitis, optic neuritis, and peripheral neuropathy. A case of small fiber neuropathy followed by choreoathetosis was described in a patient with positive serum PCA-2 and CRMP-5 autoantibodies (176).

Anti-Ma2 (34). Most patients present with the neurologic syndrome prior to the cancer diagnosis. The symptoms are frequently multisystemic (diencephalon, limbic cortex, and/or upper brainstem); however, some patients may present with isolated syndromes. Common symptoms include cognitive deficits (short-term memory deficits, confusion), psychiatric symptoms (anxiety, depression, paranoia, hallucinations), sleep disturbance (excessive daytime sleepiness, narcolepsy, REM sleep behavior disorder), dysthermia, endocrine dysfunction (weight gain; diabetes insipidus; hypothyroidism; FSH, LH, ACTH levels), dysarthria, dysphagia, oculomotor abnormalities (vertical gaze palsy that can progress to complete extraocular ophthalmoplegia), seizures, parkinsonism, oromandibular dystonia, and cerebellar ataxia (34; 96). There is a case report of a Huntington disease-like presentation (49). Some patients may also present anti-Ma1 antibodies and are usually more likely to develop a cerebellar syndrome. The main findings in those anti-Ma1/Ma2 positive subjects are brainstem dysfunction, ataxia, limbic encephalopathy, and hypothalamic deficits. Testicular germ-cell tumors are the most frequent tumor, followed by lung cancer.

Anti-Ta. Presentation includes limbic encephalitis, cerebellar syndrome, and polyneuropathy (77).

Anti-amphiphysin. Presentation includes stiff-person syndrome, paraneoplastic encephalomyelitis, limbic encephalitis, myelopathy, and ataxia (15; 75).

Microtubule-associated protein (MAP) 1B or Purkinje cell cytoplasmic antibody type 2 (PCA-2). Roughly 50% of patients present with peripheral neuropathy, followed by a cerebellar syndrome (38%) and encephalopathy (27%) (56).

Anti-ITPR1/anti-Sj (inositol1,4,5-triphosphate receptor type 1). These patients commonly present with encephalopathy, psychosis, seizures, myelopathy, radiculopathy, and peripheral or autonomic neuropathy. An underlying tumor is observed in 45% of cases (85).

Autoimmune encephalitis with antibodies to cell surface or synaptic proteins. These may occur in any age group and may not be associated with malignancy.

Basal ganglia encephalitis. This disorder predominates in children 15 years of age and younger and has equal gender distribution. Patients present with emotional lability, attention deficit, or frank psychosis. The most common movement disorders are dystonia, dystonic tremor, and parkinsonism, whereas chorea is less frequently observed. Most cases occur following an infection implicating a beta-hemolytic streptococcus, mycoplasma, or enterovirus (32). Antibodies against the dopamine D2 receptor have been detected in some individuals but their pathogenic role is yet to be elucidated. Lesions in the basal ganglia are observed in roughly 50% of cases (32). A similar clinical presentation with positive oligoclonal bands, improvement with steroids, and lack of the influenza virus RNA in pathological samples has led to the theory that at least some patients diagnosed with encephalitis lethargica actually had a form of autoimmune basal ganglia encephalitis (31).

Anti-N-methyl-D-aspartate receptor (NMDAR) (33; 105; 140). The syndrome is usually characterized by a crescendo course, and movement disorders are frequently observed. Prodromal syndromes are reported in at least 70% of subjects and include headaches or fever, followed by insomnia, psychomotor agitation, hallucinations, delusions, paranoia, disinhibition, and catatonia. Movement disorders commonly follow, and the three most common ones are dystonia, chorea, and stereotypies followed by clonic perseveration, ballism, myoclonus, tonic perseveration, and tremor (171). In children, usually more than one movement disorder is observed (17). Bradykinesia has been observed in a subset of patients, particularly those older than 10 years of age (45). Lastly, subjects develop dysautonomia, hypoventilation, and decreased level of consciousness that may evolve into coma. Seizures may occur at any point during the disease course, and they are usually more common as a presenting symptom in males. Movement disorders or seizures are more frequently observed as the initial symptom in children, which are present in approximately 67% of subjects. However, neuropsychiatric symptoms and behavioral abnormalities that may resemble schizophrenia or autism spectrum disorder are reported in up to 90% of cases (61). Otherwise, the syndrome is similar to that of adults, but children present with partial syndromes more often (178). The most commonly associated tumor is ovarian teratoma, occurring in 46% of females (black women > white women), but ovarian carcinomas may be detected in older women. Malignancies are rarely observed in males, and the frequency of a paraneoplastic presentation increases with age (35). Prognosis varies, but up to 45% of children report cognitive and academic difficulties in the long-term follow-up despite apparent recovery (54).

Postherpes simplex virus encephalitis. This disorder usually presents one to two weeks following an episode of herpes simplex virus encephalitis. Patients are usually between 24 and 79 years of age with equal gender distribution. The disorder is more commonly associated to the presence of anti-NMDAR antibodies of various isotypes (IgG, IgA, or IgM) that are produced between one to four weeks following the initial infection. Other antibodies include anti-D2 dopamine receptor and anti-GABAa receptor antibodies (126). Choreoathetosis sometimes with facial movements is a common presentation in children whereas adults more commonly present with psychosis (142; 06; 68). Movement disorders are useful to differentiate clinically an episode of herpes virus encephalitis induced anti-NMDAR encephalitis from a relapse of herpes simplex encephalitis; 75% versus 2.5%, respectively (137). These patients seem to have a more pronounced inflammatory response than those with anti-NMDAR encephalitis (94).

Voltage‐gated potassium channel (VGKC)‐complex autoimmunity. The two main antigenic targets are LGI1 (leucine‐rich glioma‐inactivated 1) and CASPR2 (contactin‐associated protein‐like 2). In a published study of 3910 patients tested for neural autoantibody, 196 were LGI1-IgG positive, 51 were CASPR2-IgG positive, and nine presented both antibodies. Central and peripheral symptoms, including dysautonomia, have been described with both antibodies, and advanced age is the only predictor of central involvement compared to peripheral involvement. Four out of nine patients positive for both antibodies had cancer (57).

Leucine-rich glioma inactivated 1 (LGI1) antibodies (150). Onset of frequent “faciobrachial dystonic seizures” in an adult should signal the possibility of this disorder. The term “faciobrachial dystonic seizures” refers to a syndrome of frequent dystonic posturing of the arm, which is frequently associated with facial contraction, lasts less than 30 seconds, without impairment of consciousness. It is poorly responsive to antiepileptic treatment (82; 60). Faciobrachial dystonic seizures are present in roughly 50% of subjects and may appear before the onset of overt limbic encephalitis with amnesia and confusion (60; 170). Paroxysmal dizziness spells are usually described as “floating" or “out of body” sensation, occurring multiple times a day without changes in level of consciousness is a more recently described feature (57). Other symptoms are hyponatremia, REM-sleep behavior disorder, and tonic seizures (81). Other presentations include parkinsonism associated with faciobrachial spasms and cognitive deficits and generalized and isolated chorea (167; 146; 100). There is an association with tumors in less than 15% of cases.

Anti-contactin-associated protein-like 2 (Caspr2). A systematic review showed that limbic encephalitis is the most common presentation in patients with anti-CASPR2 antibodies (38.7%), followed by peripheral nerve hyperexcitability (37.7%), Morvan syndrome (22.7%), and cerebellar syndrome (14.7%) (21). About half of patients show positive antibodies in the CSF and abnormal MRI findings, whereas an associated thymoma is reported in 22% of cases (21). There is a frequent association to tumor (81; 57). Isolated paraneoplastic hemichorea in association to anti-Caspr2 has been reported (175). Parkinsonism associated with tonic-clonic seizures and hyponatremia has been identified in few cases with this disorder (144). Caspr2 encephalitis has been identified in 40 children—25 males and 15 females—with a mean age of 9.2 years (24). Psychiatric symptoms were the most common presenting symptom in 72.5% of cases, followed by sleep disturbances (62.5%) and movement disorders (60%). No underlying cancer was detected in these patients who had a good recovery following immunotherapy (24).

VGKC-positive, LGI1/Caspr2-negative. It has an unclear clinical spectrum, with cases of limbic encephalitis, neuromyotonia, pain, and sleep disorders. Nonetheless, those antibodies have also been found in other disorders, including neurodegenerative ones, and its clinical relevance is still under study (169).

Anti-glycine receptor (anti-GlyR). Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subacute disorder characterized by muscular rigidity and painful muscle spasms, generalized myoclonus, hyperekplexia, diplopia, cerebellar ataxia, and autonomic dysfunction (sweating, tachycardia, urinary retention) (28). Other less common features include breathing and swallowing difficulties and psychiatric features (163). Although the name implies a progressive evolution, most patients show a relapsing-remitting course with episodic fluctuations (10).

Glutamic acid decarboxylase antibody (GAD-ab) (154; 02). The spectrum of neurologic disorders in the presence of high GAD-ab includes stiff-person syndrome, cerebellar ataxia, refractory epilepsy, limbic and extralimbic encephalitis, PERM, and oculomotor dysfunction (10). In large series of patients with limbic encephalitis, anti-GAD antibodies were observed in between 7% and 17% of cases (116; 20). Patients with positive anti-GAD antibodies were younger, had a higher frequency of seizures and oligoclonal bands on the CSF, as well as had intrathecal production of anti-GAD antibodies (116). Some patients with anti-GAD associated limbic encephalitis may have an underlying neoplasia, which was more frequently observed in patients older than 50 years of age with positive anti-GABAB receptor antibodies (20; 04). Pathological samples have revealed acute necrosis affecting hippocampal neurons; it is believed that such changes may evolve to hippocampal atrophy (99). Extralimbic encephalitis may also be observed in patients with anti-GAD antibodies, sometimes coexisting with limbic inflammation (10). Such areas of inflammation are usually cortical/subcortical without contrast enhancement (109; 128). Histological samples of the lesions show microglial proliferation with perivascular lymphohistiocytic infiltrates (132).

• Stiff-person syndrome. Patients with stiff-person syndrome present with progressive muscle stiffness, mainly in the axial and proximal leg muscles, leading to changes in gait and posture (usually hyperlordosis). Stiff-person syndrome may be focal in approximately 20% of patients. Superimposed painful spasm is a characteristic feature (15). Associated symptoms include painful muscle spasms, anxiety, and phobias. Symptoms may be precipitated by emotional distress and unexpected sounds. Paroxysmal dysautonomic symptoms may coincide with muscle spasms (124). The continuous firing of motor neurons, involving agonist and antagonist muscles, causes muscle stiffness in stiff-person syndrome. Electromyography (EMG) shows continuous motor-unit activity in agonists and antagonist muscles, despite attempted relaxation. The presence of anti-GAD antibodies supports but it is not mandatory for the diagnosis (10).

• Cerebellar ataxia. Cerebellar ataxia is the second most common syndrome associated with high GAD-ab levels and has the same demographic, clinical, and immunological aspects as stiff-person syndrome. The most important cerebellar finding is gait ataxia, but appendicular ataxia, dysarthria, nystagmus, and oculomotor findings are common (154). Patients with ataxia usually have associated DM1 or an autoimmune polyendocrine syndrome, which is an important clue for the diagnosis (11).

Dopamine-2 receptor (D2R) antibodies (32; 108). This disorder has not been reported in adults. The most common presentation is basal ganglia encephalitis characterized by movement disorders (parkinsonism, dystonia, chorea), somnolence, and psychiatric symptoms (attention deficit, emotional lability, psychosis, and obsessive-compulsive disorder) (32). Patients commonly report an infection prior to onset of symptoms. The movement disorder phenotype varies with gender. In females, chorea is the most frequent movement disorder followed by dystonia-parkinsonism and tics; in males, the order is dystonia-parkinsonism, tics, and chorea. Oculogyric crisis was described in subjects with dystonia or parkinsonism, and ocular flutter was described in a child with chorea and ataxia. These antibodies have been found in subjects with Sydenham chorea and Tourette syndrome.

Anti-gamma-aminobutyric acid A receptor (GABAAR). Core symptoms include seizures (including refractory status epilepticus), cognitive impairment, changes in behavior, altered consciousness, and movement disorders, which is observed in approximately one third of patients. Movement disorders described in pediatric subjects were orofacial dyskinesias, dystonia, and choreoathetosis, whereas adults had facial movements and cramps. Forty percent of patients have neoplasia. Cases of anti-GABAAR encephalitis after viral encephalitis (HSV1 and HSV6), mostly in children, have also been identified (162).

Anti-gamma-aminobutyric acid B (GABAB). GABAB usually presents as a limbic encephalitis. There is a pediatric case reported with opsoclonus, chorea, ataxia, and refractory seizures (98).

Anti-dipeptidyl-peptidase-like protein-6 (Anti-DPPX). Presentation includes agitation, hallucinations, myoclonus, and seizures and is associated with diarrhea and weight loss; not paraneoplastic (37).

Antibodies against metabotropic glutamate receptor 1 (mGluR1). Presentation includes idiopathic or paraneoplastic cerebellar ataxia associated with Hodgkin lymphoma (37).

Glial fibrillar acidic protein (GFAP) autoantibodies. An identified glial antigen, GFAP-IgG, has been associated with autoimmune central nervous system disorders, both paraneoplastic and nonparaneoplastic. Clinical manifestations include headaches, optic neuritis, meningoencephalomyelitis or encephalitis, choreoathetosis, myoclonus, cerebellar ataxia, AED-resistant epilepsy, dysautonomia, and dementia (50; 53; 80).

Anti-IgLON 5. This is a disorder characterized by sleep disorders, brainstem, and hypothalamic manifestations. Patients have a median age at onset of 64 years, with males and females affected equally (58). They typically present either with a complex sleep disorder, severe gait instability, or chorea affecting the limbs and orofacial muscles in some instances (151). Cognitive decline with or without chorea was the predominant presentation a series (58). Isolated progressive hemichorea has been described in selected patients, remarkably without sleep disturbances (66). Periodic leg movements during wakefulness present frequently and may continue during sleep; obstructive sleep apnea, abnormal non-REM, and REM sleep are common; other patients present with stridor, dysphagia, dysarthria, hypoventilation, dysautonomia, and altered ocular movements (151; 58).

Anti-Myelin Oligodendrocyte Glycoprotein (MOG). This is the most common antibody associated with autoimmune demyelinating disease. Patients with these are more likely to exhibit large globular lesions and long segment myelitis without oligoclonal bands. The spectrum of disorders associated with anti-MOG has broadened and includes acute disseminated encephalomyelitis, cortical encephalitis with seizures, meningoencephalitis, brainstem encephalitis, and mimics of vasculitis. Few cases with hemichorea have been reported (148). The evolution is typically monophasic, but anti-MOG antibodies remain positive in relapsing cases.

Neurexin-3α. The disorder presents with prodromal headache, fever, and gastrointestinal symptoms, followed by an encephalitis-like syndrome with seizures and increased level of consciousness. Mild orofacial dyskinesia is observed in less than 50% of patients (65). Some patients require respiratory support; these features make this disorder similar to anti-NMDAR encephalitis, although the mean age at onset (44 years) is older than the former (112).

Anti-Kelch-like protein 11. Patients affected with this syndrome are usually male with a testicular seminoma, although a smaller proportion may have microlithiasis, and negative anti-Ma2 antibodies. Clinical manifestations usually include rhombencephalitis with vertigo, tinnitus, hearing loss, and ataxia (117). Severe weight loss seems to be present in two thirds of patients, whereas hypersomnia and seizures are less common (174). Cerebellar ataxia may be isolated or combined with other neurologic manifestations. Atypical phenotypes resembling progressive supranuclear palsy and flail arm syndrome have also been identified in these patients (174). A new score (MATCH: male, ataxia, testicular cancer, hearing alterations) can successfully identify patients with Kelch-like protein 11 antibodies with a sensitivity of 78% and specificity of 99% (174). Mean age at presentation is 41 years. A prevalence of 2.79 cases per 100 000 men has been estimated (117). Orchiectomy and immunotherapy seem to provide benefit. Antigen discovery by programmable phage display was used to identify this novel antibody target.

Autoimmune encephalitis of unclear pathophysiology. In this group usually more than a single antibody has been recognized but their relative role in the pathogenesis is unclear.

Acute disseminated encephalomyelitis. This is a monophasic disease of the CNS occurring in children and young adults. Patients have variable degrees of encephalopathy, which is mandatory for the diagnosis, as well as other neurologic manifestations such as cranial nerve palsies, ataxia, hemiparesis, myelopathy, or optic neuritis (64); other manifestations include headache, fever, meningismus, and psychosis. Brain MRI shows multiple, large (greater than 2 cm) abnormalities on T2W or FLAIR in the supratentorial white matter, basal ganglia, brainstem, cerebellum, and spinal cord that may show contrast enhancement without new and clinical and MRI findings 3 months after symptom onset. CSF shows mild pleocytosis and uncommon oligoclonal bands (less than 7% of cases) (64). Some cases may follow infection with group A beta hemolytic streptococcal infection along with antibasal ganglia antibodies (30). Movement disorders may be observed in patients with acute disseminated encephalomyelitis; cerebellar ataxia is more common but dystonia and segmental myoclonus have also been reported in few cases (30; 88; 70; 83). Among 116 patients with anti-MOG antibodies, 49% were female with a median age of 6.2 years; besides acute disseminated encephalomyelitis (68% of cases), these patients had other forms of encephalitis (19%), optic neuritis (17%), myelitis (11%), neuromyelitis optica spectrum disorder (5%), and other disorders (8%) (07).

Hashimoto encephalopathy (also known as steroid responsive encephalopathy associated with autoimmune thyroiditis: SREAT). This is disorder is defined by the combination of neuropsychiatric symptoms, movement disorders, and positive antithyroid antibodies with prominent clinical improvement following treatment with steroids and lack of evidence of other causes of the encephalopathy (16). Onset is usually between 45 and 55 years of age and females are up to five times more commonly affected. Movement disorders are observed in up to 80% of patients with Hashimoto encephalopathy, with myoclonus, tremor, and gait ataxia being the most prominent (16), although chorea and palatal myoclonus are also reported. Some patients may present with a clinical picture of limbic encephalitis (131). The myoclonus is reported to have a subcortical origin (51). Patients have high titers of antithyroid peroxidase antibodies, although most patients are euthyroid or have subclinical hypothyroidism, whereas overt hypothyroidism is observed only 20% of cases (51). Antithyroid peroxidase antibodies do not seem to be pathogenic. However, antibodies directed against α-enolase are detected in about half of cases; this is a cytoplasmic glycolytic enzyme, but it is also present in the cell surface where it acts as plasminogen receptor in some cell types (43). Perivascular lymphocytic infiltration of small vessels can be demonstrated in pathological samples and hypoperfusion has been documented with SPECT with normal MRI (125). Patients usually respond to steroids within four to six weeks, supporting an autoimmune origin of the disorder.

Systemic lupus erythematosus and the antiphospholipid syndrome. Systemic lupus erythematosus is an autoimmune multisystemic disorder with positive antinuclear and anti-DNA antibodies. Women represent more than 90% of cases, with a median age at onset between 15 and 26 years. Between 1% and 3% of cases may develop chorea. This movement disorder is frequently present with abnormal behavior or psychosis, suggesting an encephalopathy state (12). 18F-deoxyglucose PET reveals increased metabolism in the contralateral striatum. Some of these patients have positive antiphospholipid antibodies from which a pathogenic role has been proposed (13). Moreover, some patients with positive antiphospholipid antibodies without lupus may develop chorea. These patients may or may not fulfill the diagnostic criteria for primary antiphospholipid syndrome. Chorea in this case has similar features to lupus chorea. Other movement disorders identified in these cases include parkinsonism, cerebellar ataxia, tremor, dystonia, tics, paroxysmal nonkinesigenic dyskinesia, and corticobasal syndrome (13); however, it is unclear whether there is causal relationship between the autoimmune response and the abnormal movements.

Opsoclonus-myoclonus syndrome. This disorder is characterized by multidirectional saccades (opsoclonus) along with myoclonus, predominantly in the limbs or axial muscles. Patients may also have gait ataxia or tremor. The disorder has a bimodal presentation. In children, it is commonly associated with a neuroblastoma; however, it may be seen in association with a wide number of neoplasia in adults, such as breast or lung cancer or in the context of an infectious disease (91). In a large series of 114 patients, 61% had idiopathic whereas in 39% had paraneoplastic opsoclonus myoclonus syndrome (08). It is unclear the pathogenesis is unclear; ANNA-2/anti-Ri antibodies may be present in patients with underlying cancer whereas neuronal surface antibodies were identified in 11% of cases including anti-GlyR antibodies; antibodies against HNK-1 have been identified in a small proportion of cases (08).

Seronegative autoimmune encephalitis. Some patients with presumed autoimmune process affecting the central nervous system do not show positive serum titers of any known antibody. These patients are further subcategorized as antibody-negative probable autoimmune encephalitis, autoimmune limbic encephalitis, and acute disseminated encephalomyelitis (102). A good outcome is achieved in 56.5% of these cases following immunotherapy, although cerebellar atrophy on MRI is considered an indicator of poor outcome (102).

Table 1. Movement Disorders and Other Motor Phenomena in Diverse Autoimmune Encephalitis

	Main movement/motor disorder	Main encephalitis type or antibodies
	Catatonia	Anti-NMDAR, anti-GABAA
	Cerebellar ataxia	ANNA1 (anti-Hu), ANNA2 (Anti-Ri), PCA1 (anti-Yo), PCA2, anti-Tr, anti-GABAB, anti-AMPA, anti-IgLON5, Hashimoto encephalitis, lupus
	Chorea	Anti-NMDAR, anti-CRMP5, anti-IgLON-5, lupus
	Dystonia	Anti-NMDAR, basal ganglia encephalitis
	Faciobrachial dystonic seizures	Anti-LGI limbic encephalitis
	Myoclonus	Anti-NMDAR, Hashimoto encephalitis, opsoclonus-myoclonus syndrome
	Myorhythmia	Anti-NMDAR
	Neuromyotonia	Anti-CASPR2, anti-LGI1
	Opsoclonus	Anti-Ri, anti-GABAA, anti-GABAB
	Parkinsonism	Anti-Ma1, Anti-Ma2, basal ganglia encephalitis, lupus
	Periodic leg movements	Anti-IgLON-5
	Stiff-person syndrome phenomenon	Anti-amphiphysin, anti-GlyR, anti-AMPAR, anti-GABAA
	Stereotypies	Anti-NMDAR
	Tremor	Hashimoto encephalitis

Prognosis and complications

A systematic review of cognitive outcomes in patients with anti-NMDA encephalitis showed that although roughly 70% of patients have substantial cognitive improvement, but with residual impairment in executive functioning, processing speed and episodic memory was observed. Delay in immunotherapy seemed to carry a worse prognosis for cognitive function (120). Mortality in anti-NMDA encephalitis is associated with a Glasgow Coma Scale Score below 8 at presentation, admission to intensive care unit, and a number of clinical complications (25). A cross-sectional study in Germany comparing 27 successfully treated patients with anti-LGI encephalitis to age-matched controls demonstrated considerable verbal and spatial memory deficits as well as working memory, executive function, and attention impairment (52). Cognitive impairment was more likely in those with delayed immunotherapy.

Clinical vignette

GBS, a two-year-old boy with an uneventful delivery and normal development, presented to the hospital with one week of intermittent involuntary jerky movements of the right leg, impairing gait and present at rest and on voluntary movement. His mother stated that the movements were rhythmic and would last approximately 30 minutes, four to five times per day. His mother also noticed that he was having trouble picking up objects, such as toys, and that he had involuntary tilting movements of his head that would last for only a few seconds but would recur throughout the day. The child had a low-grade fever at the onset of the movements, but it subsided in the three days prior to admission. His mother also observed severe constipation in the three weeks prior to evaluation. On initial examination, the patient had generalized chorea and hypotonia. Just after admission, he had alternating periods of extreme agitation and drowsiness. His CSF examination showed a protein of 21, glucose of 64 (blood sugar 83), and white cell count of 6 (100% lymphocytes); anti-streptolysin O was 306 (normal < 201). Other laboratory testing was unremarkable, and the brain MRI was normal. At this point, he received the diagnosis of Sydenham chorea and was started on penicillin and risperidone. In the next few days, he became increasingly sleepy and developed EEG-documented status epilepticus. This was treated successfully. A second brain MRI was normal. At this point, the possibility of encephalitis was entertained and studies to rule out viral or autoimmune encephalitis were sent. Anti-NMDAR was positive, and he received IVIG. There was some improvement of his alertness and of his movements, and two more IVIG cycles were performed within three months. The patient slowly recovered over the course of a year. Work-up for malignancy was negative. His last follow-up was four years after the initial event. He had a mild speech abnormality, and he had received speech therapy since his release from the hospital. He had no seizures after his admission and his neurologic examination was otherwise normal.

Biological basis

Etiology and pathogenesis

Autoimmune encephalitis can be broadly classified in paraneoplastic and nonparaneoplastic based on the presence or not of an underlying tumor, respectively. Paraneoplastic autoimmune encephalitis seems to originate from shared antigens of the tumor and CNS. Most common tumors include small-cell lung cancer, breast cancer, thymoma, Hodgkin lymphoma, neuroblastoma, germ cell tumor of the testes, and ovarian teratomas. More importantly, the location of the antigen (intracellular vs. extracellular) seems to be the most important element in the pathogenesis of these autoimmune disorders.

In autoimmune encephalitis with antibodies targeting intracellular neuronal antigens, the mechanism of damage is mediated by cytotoxic T-cells; these patients usually have poor clinical outcomes even with optimal immunosuppressive therapy with high frequency of irreversible neuronal damage and the antibodies are less specific for particular autoimmune encephalitis.

In autoimmune encephalitis with extracellular antibodies, on the other hand, the humoral immune mechanism is directly implicated with neurologic dysfunction; these patients respond better to immunomodulatory therapy and the antibodies show higher specificity for autoimmune encephalitis. Table 2 summarizes the most common neurologic presentations in specific cancer and antibodies.

Table 2. Antibodies, Associated Neoplasia, and Type of Neurologic Syndrome in Diverse Autoimmune Encephalitis

	Antibody	Most common associated neoplasia	Most common neurologic presentations
	Anti-HU	Small-cell lung cancer (75%)	Encephalomyelitis Sub-acute sensory neuropathy Cerebellar degeneration
	Anti-Ri	Small-cell lung cancer Breast cancer	Diffuse and brainstem encephalitis
	Anti-Ma/Ta	Testicular tumors	Combined limbic, diencephalic, and brainstem encephalitis (most patients) Limbic encephalitis
	Anti-CV2/CRMP5	Small-cell lung cancer Malignant thymoma	Diffuse and basal ganglia encephalitis
	Anti-GAD	Various types	Stiff-person syndrome, limbic encephalitis, extra-limbic encephalitis, cerebellar ataxia
	Anti-amphiphysin	Breast cancer	Stiff-person syndrome, encephalomyelitis, myelitis
	Anti-Gly1R	Thymoma
	Anti-Yo (PCA1)	Breast cancer Ovarian cancer	Cerebellar degeneration Encephalitis
	Anti-NMDAR	Ovarian teratoma Ovarian carcinoma	Diffuse encephalitis
	Anti-VGKC LGI1 CSPR2	Thymoma Thymoma	Limbic encephalitis Morvan syndrome
	Anti-GABAA	Thymoma (rare)	Limbic with extralimbic encephalitis
	Anti-GABAB	Small-cell lung cancer Neuroendocrine lung tumors	Limbic encephalitis
	Anti-AMPA	Breast cancer Lung cancer	Diffuse encephalitis
	Anti-IgLON5	None	Diffuse encephalitis with prominent brainstem involvement

Autoimmune encephalitis with antibodies against intracellular antigens (150). Peptides derived from intracellular proteins are presented by upregulated MHC class-I molecules after proteasomal degradation to peptide-specific cytotoxic T cells. The antibodies are not pathogenic but are rather useful for diagnostic purposes (62; 119).

Autoimmune encephalitis with antibodies to cell surface or synaptic proteins. The antibodies produce cellular dysfunction or injury through receptor agonist or antagonist action, activation of the complement cascades, antibody-dependent cell-mediated cytotoxicity, and antigen internalization (38).

Anti-NMDAR. Antibodies lead to selective internalization of NMDARs, resulting in interruption of NMDAR currents, long-term potentiation, and increasing extracellular levels of glutamate (87). Effects are reversible after removing the antibodies (105). Ovarian teratoma and previous herpes simplex virus encephalitis are two known factors leading to the development of the encephalitis (38).

Anti-VGKC. Anti-VGKC present on the membrane of neurons in the central and peripheral nervous system, acting on cell repolarization (169).

Anti-LGI1. LGI1 is protein that interacts with the presynaptic and postsynaptic receptors, organizing a transsynaptic complex. Antibodies seem to interfere in this interaction leading to decreased levels of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) (105).

Anti-Caspr2. Anti-Caspr2 is a cell adhesion molecule that participates in the transmembrane complex at the juxtaparanodes of myelinated axons as well as expressed in inhibitory cells in the central nervous system. Evidence suggests that the antibodies target the extracellular domain, interfering with its proper function (169).

GlyR antibodies. Antibody-mediated internalization of the receptor (108).

Anti-D2R. Antibody-mediated internalization of the receptor (108).

Anti-GAD/anti-amphiphysin. Multiple in vivo and in vitro studies failed to elucidate the pathological mechanism of anti-GAD-ab in stiff-person syndrome and cerebellar ataxia. Possibly, anti-GAD-ab interferes with the inhibitory GABAergic circuits. Autoantibody levels are not related to disease severity and treatment response. In stiff-person syndrome, autoantigens may be present in the presynaptic (anti-GAD, anti-amphiphysin) and postsynaptic neurons (GABAA receptor-associated protein; glycine and gephyrin) (02).

Anti-DPPX. DPPX participates in the regulation of voltage-gate potassium channels and is expressed in the myenteric plexus (37).

The physiopathology of movement disorders in autoimmune encephalitis depends on the underlying disease. In paraneoplastic cerebellar degeneration, the ataxic syndrome probably results from the extensive loss of Purkinje cells in the cerebellar cortex, deep cerebellar nuclei, and the inferior olivary nuclei (36). The NMDA receptors are fundamental for basal ganglia function as they integrate different neurotransmitter systems (147). In anti-NMDAR encephalitis, the resulting imbalance between those neurotransmitters within the basal ganglia might account for the movement disorders observed (133). The activation of D2-like receptors suppresses the activity of the indirect pathway medium spiny neurons (59). In stiff-person syndrome, there is concurrent contraction of agonist and antagonist muscles suggesting lack of reciprocal inhibition (02).

Certain cytokines have been found elevated in the CSF of patients with anti-LGI1 and anti-CASPR2 encephalitis, but they did not show marked changes in concentration after treatment (93). Patients with anti-CASPR2 antibodies may present with peripheral nerve hyperexcitability or limbic encephalitis, the latter, associated more frequently with HLA-DRB1*11:01, had higher serum titers of higher rates of CSF positivity than patients with peripheral nerve hyperexcitability (130). On the other hand, patients with anti-LGI1 encephalitis showed DRB1*03:01 or DQB1*02:01 allele haplotypes more frequently in a Chinese Han population (78).

A subset of autoimmune encephalitis does not have a specific humoral marker or an antibody with clear pathogenic implications; these disorders mainly include systemic lupus erythematosus, Hashimoto encephalitis, and opsoclonus-myoclonus. The response to immunomodulatory therapy in a background of autoimmunity supports an immune-mediated mechanism of the encephalopathy and underlying movements.

Autoimmune encephalitis associated with an immune check point inhibitors. A number of autoimmune encephalitis syndromes have been observed in patients being treated with immune checkpoint inhibitors (ICI). These medications improve survival in an increased number of cancer types, but an emerging number of immune-related adverse effects are recognized. Nivolumab pembrolizumab, ipilimumab, durvalumab, and atezolumab have been related to three main neurologic syndromes, including: meningoencephalitis, limbic encephalitis and cerebellitis, and to various antibodies such as anti-Hu, anti-Ma2, or anti-CASPR2 (173). Nivolumab (a monoclonal antibody inhibitor of programmed cell death protein) has been associated with antiglial fibrillary acidic protein (GFAP) antibodies causing meningoencephalitis (89). A female patient with renal cell carcinoma treated with nivolumab developed anti-Ma antibodies and limbic encephalitis (114). Immunotherapy usually provides benefit and should be started early.

COVID-19 infections. Increased incidence of autoimmune encephalitis has been observed in recent years during the COVID-19 pandemic, increasing the possibility of a causal association. The frequency of autoimmune encephalitis in neurocritical care practice raised in downtown Los Angeles (152). GAD and VGKC antibodies were the most frequently observed. An analysis of the literature showed 88 cases of autoimmune encephalitis associated with COVID-19, 14 of these cases were vaccine-associated (153). Anti-NMDAR encephalitis was the most common cause. Altered mental status was the most common manifestation, followed by several types of movement disorders in 39.4% of cases and seizures (153). Several other autoimmune disorders affecting the nervous system, such as Guillain-Barre syndrome, Miller-Fisher syndrome, systemic lupus erythematosus, demyelinating encephalomyelitis, and CNS vasculitis have been related to COVID-19 infections (143). Vaccination against SARS-CoV2 has been associated with GABA-B receptor antibody encephalitis presenting with seizures, cognitive decline, and gait disturbances (01). It is unclear the mechanism for development of these disorders; however, loss of tolerance during the period of immunosuppression induced by SARS-CoV2 has been postulated as a possible mechanism (143).

Epidemiology

Two large epidemiological studies, one in the United Kingdom and another in California, showed that the frequency of autoimmune encephalitis exceeds the frequency of any single viral encephalitis (55; 69). Anti-NMDAR encephalitis in subjects younger than 30 years old was over four times more frequent than herpes simplex virus type 1, varicella-zoster virus, and West Nile virus, and it was the leading cause of encephalitis in the Californian cohort (55). In the same cohort, 65% of anti-NMDAR encephalitis occurred in subjects aged 18 years or younger, and it was more frequent in females (55). A prospective study in Thailand involving 103 patients with encephalitis found an infectious etiology in 25 subjects (24%), whereas the same figure had an immune-mediated mechanism (155).

In a series of 70,000 subjects evaluated for neural antibodies in 2015, detection rate was 0.026% for MAP 1B and amphiphysin IgG, 0.016% for ANNA-2, and 0.006% for PCA-Tr (56).

The D2R antibody basal ganglia encephalitis is more common in non-Caucasian children, whereas GlyR antibodies are rare in children and may present as an epileptic encephalopathy or encephalopathy associated with demyelination (32; 108).

Prevention

Although removal of underlying cancer prevents the development of paraneoplastic syndromes, there is no know way to prevent these autoimmune disorders.

Differential diagnosis

Confusing conditions

The main differential diagnoses include the following (150):

Infectious encephalitis

There are no clinical pathognomonic findings that can reliably differentiate infectious from autoimmune encephalitis (155). The most common pathogens are herpes simplex virus, human herpes virus 6, Treponema pallidum, prion diseases, and rabies (150). Autoimmune encephalitis seems to occur more frequently in immunocompetent than immunocompromised patients. Fever is common in infectious encephalitis; however, half of subjects with autoimmune encephalitis present with or develop fever. Prodromal symptoms may appear in both, whereas skin lesions, if present, may assist in the diagnosis of an infectious cause. Cerebrospinal fluid examination is somewhat similar in autoimmune and viral encephalitis with normal glucose levels, mildly elevated protein, and lymphocytic pleocytosis (05). Human herpes virus 6 is observed in the context of post-transplantation acute limbic encephalitis. A study assessed the metabolites of the kynurenine pathway and tryptophan in the CSF of patients with autoimmune neuroinflammatory disorders, mostly anti-NMDAR encephalitis, and herpesvirus encephalitis (113). The study showed a statistically significant increase in kynurenine concentration and the kynurenine/tryptophan ratio in patients with viral infection, whereas patients with autoimmune disorders had low levels of such markers.

Another study showed that patients with anti-NMDAR or anti-LGI/CARPR2 encephalitis had elevated biomarkers for neuroaxonal injury (neurofilament light chain) and neuroinflammation (YKL-40) in the CSF; however, total tau protein was stable, whereas VILIP-1 and markers of synaptic dysfunction (SNAP25 and neurogranin) were decreased (40). These biomarkers may mirror the synaptic changes, with internalization of cell-surface receptors and some level of preservation of neurons (40). Neopterin levels have been shown to be higher in patients with viral or bacterial meningitis compared with patients with noninfectious inflammatory conditions (127). Further studies should define the diagnostic accuracy of these markers and their discriminatory efficiency compared with specific autoimmune encephalitis.

Toxic-metabolic
	• Wernicke-Korsakoff encephalopathy • Metabolic encephalopathy • Exogenous intoxication (alcohol, illicit drugs, medications) • Alcohol withdrawal syndrome
Other autoimmune disorders
	• Acute demyelinating encephalomyelitis • Primary vasculitis of the central nervous system • Systemic autoimmune disorders (14) • Nonconvulsive status epilepticus

Catatonia

This disorder is characterized by several neuropsychiatric manifestations, including mutism, catalepsy, stereotypy, agitation, negativism, and lack of mobility, among others. Catatonia may be observed in patients with schizophrenia, bipolar disorder, or major depressive disorder. Some patients with anti-NMDAR encephalitis may present with catatonia. Mannerism (odd behaviors), waxy flexibility (resisting being moved), and impulsivity seem more frequent in patients with catatonia associated with another medical disorder (48).

Stroke

Malignancy (primary or metastatic CNS disease

Degenerative disorders

Creutzfeldt-Jakob disease (115)

In a series of 346 patients with rapid neurologic degeneration suggestive of Creutzfeldt-Jakob disease, six subjects were found to have neuronal surface antibodies, none of which fulfilled clinical criteria for probable or possible Creutzfeldt-Jakob disease (63). The presence of focal neurologic findings is suggestive of Creutzfeldt-Jakob disease, whereas dysautonomia, epilepsy, and hyponatremia point towards autoimmune encephalitis (23). Moreover, patients with anti-NMDAR encephalitis may have positive protein 14-3-3 in CSF, which can be confused with sporadic Creutzfeldt-Jakob disease when combined with rapidly progressive cognitive decline, movement disorders, and neuropsychiatric manifestations (110).

Transient global amnesia

A number of nonautoimmune disorders may mimic the MRI findings of limbic encephalitis such as hypoglycemia, Whipple disease, and 4-aminopyridine toxicity (09).

Associated or underlying disorders

Patients with autoimmune movement disorders may present with cognitive impairment, particularly those with limbic encephalitis or anti-NMDAR encephalitis. A study included patients 45 years or older with dementia criteria and no prominent seizures early in the disease but with anti-LGI1, anti-NMDAR, anti-GABA-B-R, and anti-CARPR2 encephalitis (18). Most patients had anti-LGI1 and anti-NMDAR antibodies. Red flags for an autoimmune underlying disorder were rapidly progressive cognitive decline, subtle seizures, and biomarkers atypical for dementia. On the other hand, isolated first episodes of psychosis seem rare in patients with anti-NMDAR encephalitis, as most patients with the disorder also have other signs consistent with CNS autoimmunity directed against NMDA receptors (67).

Diagnostic workup

Leading experts in the field of autoimmune encephalitis have published clinical criteria to expedite diagnosis and treatment, even in the absence of confirmatory antibodies. The criteria proposed that the initial clinical assessment for patients with suspected autoimmune encephalitis should: (a) characterize the presence of working memory deficits, altered metal status, or psychiatric symptoms with onset and progression in less than three months; (b) use at least one confirmatory clinical or diagnostic workup (presence of focal findings on neurologic exam; presence of new-onset seizures; CSF pleocytosis; MRI findings compatible with encephalitis); and (c) exclude plausible alternative causes (64). The diagnosis criteria for autoimmune limbic encephalitis and ADEM have also been proposed (Tables 3 and 4, respectively).

Table 3. Diagnostic Criteria for Definite Autoimmune Limbic Encephalitis

	Diagnosis can be made when all four of the following are met (if one is not met a diagnosis can be made with detection of cell-surface, synaptic, or onconeural antibodies):
	(1) Subacute onset (rapid progression less than 3 months) of working memory deficits, seizures, or psychiatric symptoms that suggest involvement of the limbic system
	(2) Bilateral abnormal T2-weighted fluid-attenuated inversion recovery MRI highly restricted to the medial temporal lobes (18F-FDG PET can be used to fulfill this criterion)
	(3) At least one of the following: • CSF pleocytosis (white blood cell count of greater than 5 cell/mm3) • EEG with epileptic or slow-wave activity involving the temporal lobes
	(4) Reasonable exclusion of alternative causes

Table 4. Diagnostic Criteria for Definite Acute Disseminated Encephalomyelitis

	Diagnosis can be made when all five of the following are met:
	(1) A first multifocal, clinical CNS event with a presumed inflammatory demyelinating cause
	(2) Encephalopathy that cannot be explained by fever
	(3) Abnormal brain MRI, defined by: • Diffuse, poorly demarcated, large (greater than 1 to 2 cm) lesions, predominantly involving the cerebral white matter • T1-weighted hypointense lesions in the white matter in rare cases • Deep grey matter abnormalities (eg, thalamus or basal ganglia) can be present
	(4) No new clinical or MRI findings after 3 months of symptom onset
	(5) Reasonable exclusion of alternative causes

The diagnosis of definite anti-NMDAR encephalitis is based on the presence of IgG anti-GluN1 antibodies in the serum but more importantly in the CSF (64) (Table 5). In a retrospective analysis in children, these criteria showed a sensitivity of 90% (95% confidence interval 73 to 98) and specificity of 96% (95% confidence interval 89 to 99) (76).

Table 5. Diagnostic Criteria for Anti-NMDAR Receptor Encephalitis

	Probable anti-NMDA receptor encephalitis Diagnosis can be made when all three of the following criteria have been met:
	(1) Rapid onset (less than 3 months) of at least four of the six following major groups of symptoms (or three of these symptoms in the presence of ovarian teratoma): • Abnormal (psychiatric) behavior or cognitive dysfunction • Speech dysfunction (pressured speech, verbal reduction, mutism) • Seizures • Movement disorders, dyskinesia, or rigidity/abnormal postures • Decreased level of consciousness • Autonomic dysfunction or central hypoventilation
	(2) At least one of the laboratory study results: • Abnormal EEG (focal or diffuse slow or disorganized activity, epileptic activity, or extreme delta brush) • CSF with pleocytosis or oligoclonal bands
	(3) Reasonable exclusion of alternative causes
	Definite anti-NMDA receptor encephalitis Presence of one or more of the six major groups of symptoms and IgG anti-GluN1 antibodies, after exclusion of other disorders: • Antibody testing should include CSF • If only serum testing is performed, confirmatory tests should be included such as live neurons or tissue immunohistochemistry, in addition to cell-based assay

For patients with negative antibodies but who still have suspicion of an autoimmune CNS disorder, the diagnostic criteria of Hashimoto encephalitis or autoantibody negative encephalitis should be considered (Tables 6 and 7, respectively) (64).

Table 6. Diagnostic Criteria for Hashimoto Encephalopathy

Diagnosis can be made when all six criteria are met:

(1) Encephalopathy with seizures, myoclonus, hallucinations, or stroke-like episodes (2) Subclinical or mild overt thyroid disease (usually hypothyroidism) (3) Brain MRI normal or with nonspecific abnormalities (4) Presence of serum thyroid antibodies (thyroid peroxidase, thyroglobulin) antibodies (5) Absence of well characterized neuronal antibodies in serum and CSF (6) Reasonable exclusion of alternative causes

In case of patients with Hashimoto encephalitis, current pretreatment diagnostic criteria were associated with improvement only in 31% of 24 cases, suggesting that such criteria do not predict clinical improvement (118).

Table 7. Diagnostic Criteria for Autoantibody-Negative but Probable Autoimmune Encephalitis

	Diagnosis can be made when all four criteria have been met:
	(1) Rapid progression (less than 3 months) of working memory deficits (short-term memory loss), altered mental status, or psychiatric symptoms
	(2) Exclusion of well-defined syndromes of autoimmune encephalitis (typical limbic encephalitis, etc.)
	(3) Absence of well characterized autoantibodies in serum and CSF, and at least two of the following criteria: • MRI abnormalities suggestive of autoimmune encephalitis • CSF pleocytosis, CSF-specific oligoclonal bands or elevated CSF IgG index, or both • Brain biopsy showing inflammatory infiltrates and excluding other disorders (tumor)
	(4) Reasonable exclusion of alternative causes

In a series of 115 patients aged 60 years or older, at least 20% of those with positive antibodies against neuronal surface antigens had no evidence of inflammation on MRI or CSF analysis. Hence, those with well-defined neurologic syndromes such as faciobrachial dystonic seizure, gait instability associated to brainstem dysfunction and sleep disorder, autoimmune encephalitis, and rapidly progressive cognitive dysfunction should still be tested for neuronal surface antigens (47).

Routine laboratory work-up

Work-up includes complete blood cell count, electrolytes, renal and hepatic function, thyroid function tests, and serologies.

CSF examination (including viral serologies)

CSF lymphocytic pleocytosis ± oligoclonal bands

Brain MRI

Anti-MA2. Three-quarters of the subjects have brain MRI abnormalities, visible on T2 and FLAIR. Those are more common in limbic or diencephalic syndromes. Some subjects may present with a normal initial MRI, developing abnormalities in later studies. Contrast enhancement is observed in a third of cases, and lesions may resemble a mass (34).

Anti-NMDAR encephalitis (72). Abnormalities that are typically discrete and nonspecific are present in 23% to 50% of patients. Subjects with superimposed demyelinating syndromes have T2/FLAIR hyperintense lesions with mild contrast enhancement.

Anti-LGI1 (72). In earlier stages (faciobrachial dystonia seizures), it is typically unremarkable. In the presence of limbic encephalitis, most subjects present T2/FLAIR hyperintensities in the medial temporal lobes, either unilateral or bilateral (60; 22) and, less frequently, basal ganglia signal changes.

Anti-GlyR (72). Abnormalities are present in only 30% of the subjects and include T2/FLAIR hyperintense white matter lesions, temporal lobe signal changes, and atrophy as well as spinal cord lesions.

Anti-GABAAR encephalitis. Anti-GABAAR encephalitis is multifocal cortical and subcortical T2/FLAIR abnormalities, without diffusion restriction or contrast enhancement (162).

Anti-GAD (72). Subjects present with cerebellar atrophy and have T2/FLAIR hyperintensities in the medial temporal lobes; focal or multifocal extralimbic lesions are observed in some patients, sometimes coexisting with limbic hyperintensities (10).

D2R antibody-positive basal ganglia encephalitis. Inflammatory changes in the basal ganglia and brainstem structures are present in 50% of the patients (32).

GFAP-IgG. MRI demonstrated diffuse T2 abnormalities in periventricular white matter, prominent linear perivascular enhancement radially oriented to the ventricles, and leptomeningeal enhancement. Patients with myelitis had T2-hyperintense lesions of the spinal cord with longitudinal extension over more than three contiguous vertebral segments. Some with ataxia had cerebellar atrophy without T2-hyperintense lesion (50; 53; 80).

FDG-PET

Cases with normal initial brain MRI can present a positive FDG-PET (135). A widespread decrease in the cortex/striatum ratio was identified in a cohort of 56 patients with autoimmune encephalitis compared with healthy controls (42). A ratio threshold of 1.23 highly discriminated patients with autoimmune encephalitis compared with controls.

Anti-NMDAR encephalitis. Frontotemporal-to-occipital gradient is increased (106). There are reports of altered metabolism in the brainstem, cerebellum, basal ganglia, and frontal, temporal, and occipital lobes (72).

Anti-LGI1 LGI1 and CASPR2. PET is a sensitive method to demonstrate abnormalities in the CNS in patients with autoimmune encephalitis. In the early stages, there are isolated case reports of hypo/hyperperfusion of the temporal lobes (72). In a series of 16 patients with anti-LGI1, nine had FDG-PET: seven showed hippocampal hypermetabolism (bilateral or unilateral), one had unilateral hippocampal hypometabolism, and another had no abnormalities (22). One study showed abnormalities in 18F-FDG-PET scan in 91% of patients with LGI1, compared with 59% of patients showing abnormalities in the MRI (111). These patients exhibit hypermetabolism in the basal ganglia (80%) and medial temporal lobe (70%); isolated basal ganglia hypermetabolism seems to predominate in patients with fasciobraquial dystonic seizures. The abnormalities observed with 18F-FDG-PET scan in the anti-LGI1 patients frequently reverses with treatment (111). In the case of anti-CASPR-2, temporomesial hypometabolism is the most common finding, reported in 85.7% of patients (21).

Systemic lupus erythematosus. Hypermetabolism of basal ganglia may be observed in patients with lupus chorea (13).

SPECT

Anti-LGI1. In a series of 10 patients, two showed decreased glucose metabolism in the basal ganglia, whereas one showed increased metabolism in the same area (60).

EEG

Anti-NMDAR encephalitis. EEG usually shows nonspecific, slow, and disorganized activity, sometimes with electrographic seizures. Generalized rhythmic delta frequency activity with superimposed rhythmic beta frequency activity and “extreme delta brush” was described in about 30% of subjects in a series, and its presence is associated with a longer hospitalization (158).

D2R antibody-positive basal ganglia encephalitis. EEG shows either normal or nonspecific slowing compatible with encephalopathy.

Anti-LGI1. Interictal EEG shows generalized background slowing, at times associated with temporal sharp waves and slow wave (60). In a case series of 16 patients, 12 had the following abnormalities: temporal (7) or frontal (2) interictal epileptiform discharges, focal temporal slowing (6), frontal intermittent rhythmic delta activity (1), and diffuse slowing (6) (22).

Anti-GABAAR encephalitis. The most common EEG abnormality was unilateral or bilateral periodic epileptiform discharges involving the temporal lobes, followed by slow activity (162).

Anti-DPPX encephalitis. Extreme delta brushes, similar to those found in anti-NMDAR encephalitis, have been identified in selected cases (74).

Screening for malignancy (166)

The nature of the antibody and the clinical syndrome should guide clinicians on the most likely malignancy. Testing for several paraneoplastic antibodies simultaneously is recommended as no particular symptomatology is specific for any antibody, whereas positive antibodies may point to a specific tumor or at least narrow the focus (Table 2) (62). Patients with a negative initial screening should have repeated screening after 3 to 6 months, followed by regular screening every 6 months for 5 years. However, it should be pointed out that antibody testing can be extremely expensive and may not be covered by insurance.

Antibody testing

Antibodies against neuronal cell-surface antigens are present in CSF or serum, and both should be tested whenever possible as serum antibodies are not 100% specific (145; 161). Because GAD-ab may be present in concomitant DM1 or endocrine autoimmune disorders, the demonstration of intrathecal synthesis of GAD-ab in the setting of a neurologic disorder is required (154).

Management

Most studies are retrospective cohorts in autoimmune encephalitis (paraneoplastic and nonparaneoplastic). The recommendations below are based on disease physiopathology, clinical experience, published clinical cases, and expert guidelines. Most studies include different syndromes, subjects with and without associated neoplasia and subjects with negative antibodies in the same cohorts. The first-line therapy is variable between studies (IVIG ± steroids ± plasma exchange ± immunoadsorption), as well as the second- and third-line. The endpoint is usually the modified Rankin Scale (mRS) score, and only a few address relapse rate, cognitive improvement, seizure control, and improvement in movement disorders. The stepwise approach, although recommended, has no evidence to substantiate it.

A double-blind, placebo-controlled trial of rituximab in patients with stiff-person syndrome failed to show drug superiority over placebo, though GAD titers clearly decreased in the rituximab arm. Limitations of the study were the relatively small sample size (n=24, 12 in each arm), significant clinical variability, and long standing stiff-person syndrome, which may explain the clinical irreversibility (29). Nonetheless, a systematic review suggested that treated subjects with autoimmune encephalitis associated with antibodies to cell surface antigens have better outcomes and less relapses than those who do not receive treatment (138). The earlier the immune therapy is provided the better, and, lastly, if a patient fails the first-line therapies, the second-line ones also lead to better clinical response and fewer relapses.

Acute phase of the disease (37; 145; 46)

If associated with malignancy. Appropriate treatment of the tumor

First-line therapy. First-line therapy is as follows.

	• Methylprednisolone: usually 1000 mg intravenously daily for 5 days followed by high-dose prednisone (1-2 mg/kg/day)
	• Intravenous immunoglobulin (IVIG): 2 g/kg administered over two to five doses. Some studies recommend the simultaneous use of methylprednisolone and IVIG (32; 145).
	• Plasma exchange (PE) or immunoadsorption (IA): in a prospective observational case control study of 21 patients with autoimmune encephalitis (NMDAR, LGI1, CASPR2, GAD, mGluR5, and Hu antibodies), both plasma exchange and immunoadsorption led to a clinical improvement in at least 60% of subjects. Adverse events were rare and only observed in the plasma exchange group (71). In another small series of 12 patients with antibody confirmed encephalitis (NMDAR, GAD, GABA, LGI1), tryptophan immunoadsorption, alone or combined with either IVIG or steroids, improved in at least 1 point the modified Rankin scale score (92).

Failure to respond in one to two weeks, should lead to second-line therapy.

Second-line therapy. Encephalitis secondary to antibodies against intracellular antigens usually does not respond to immune therapy. However, there is some evidence of improvement with rituximab and cyclophosphamide (168). In a retrospective evaluation of 80 subjects who received rituximab as a second-line therapy, regardless of autoantibodies, rituximab was safe and effective. Patients with partial response to first-line therapy had a better prognosis when rituximab was used than those without it (103). Rituximab provided a good functional outcome in 72.2% of patients with autoimmune encephalitis in a meta-analysis (134); although relapses presented in 14.2% of patients. Infusion-related reactions, pneumonia, and severe sepsis are the most common side effects, occurring in nearly 16% of patients (134).

Further therapies. Small series and case reports in subjects refractory to rituximab demonstrated the potential use of tocilizumab (104), bortezomib (157; 164), and low-dose IL-2 (107). Bortezomib is a plasma-cell-depleting proteasome 26S inhibitor that has shown benefit in patients with anti-NMDAR encephalitis with delayed response or resistance to standard immunotherapy with a dose of 1.3 mg/m2 in one to six cycles and minor side effects (157). Bortezomib seems useful in adults and children with anti-NMDAR encephalitis (157; 101). Most patients show a decrease in antibody titer (26). A double-blinded study is underway to assess the effect of bortezomib in patients with autoimmune encephalitis (177). Daratumumab 16 mg/kg, an anti-CD38 antibody, showed benefit in a patient with anti-CASPR2 encephalitis (156).

Maintenance. There is no consensus on the use of steroid-sparing therapy, and most reports are anecdotal (145). Maintenance includes use of steroids, azathioprine, mycophenolate, and monthly rituximab (103).

Treatment. Movement disorders in autoimmune encephalitis are symptoms and part of a larger array of neurologic presentations. Treatment should be directed at the encephalitis. The abnormal movements usually improve when the provoking cause is eliminated. However, at times, symptomatic relief of the movements may be desirable. Therapies should, then, be aimed towards the specific movement, and drug choice should always take into consideration the presence of associated symptoms, such as psychosis and seizures.

Myoclonus (84; 122). The opsoclonus-myoclonus syndrome usually improves with the treatment of the neoplasia in the paraneoplastic cases or immunotherapy in the idiopathic ones. Clonazepam may be used for symptomatic treatment.

Dystonia. The most commonly studied/used drugs are anticholinergic, such as trihexyphenidyl and baclofen, a GABA-B autoreceptor agonist. Trihexyphenidyl should be started at 1 mg twice daily and increased slowly over the course of several weeks as needed and tolerated. Baclofen dosages range from 60 to 120 mg/day in divided doses. It should also be started slowly (83). A child with anti-NMDA and a combination of dystonia, stereotypies, and chorea improved with tetrabenazine (17).

Ataxia. There is no available treatment for ataxia (79). However, removal of autoimmune triggering factors and immunotherapy in certain cases may lead to improvement (123). A study conducted at the Mayo Clinic included 118 patients with ataxia who presented with at least one neural autoantibody (63 had paraneoplastic ataxia and 58 nonparaneoplastic) and who received immunotherapy or treatment for cancer. Of those, 54 had significant improvement. Good prognostic factors were nonparaneoplastic ataxia and plasma membrane protein antibody positivity rather than neuronal nuclear or cytoplasmatic antibody positivity (86).

Parkinsonism. In anti-MA2 encephalitis, parkinsonism responded to levodopa, but not in a subject with LGI1 antibody encephalitis (34; 95; 100).

Chorea. Symptomatic treatment usually involves decreasing dopamine activity, either with atypical antipsychotics or presynaptic depletion (tetrabenazine, valbenazine, deutetrabenazine, reserpine) (172; 17; 175). Other options include anticonvulsants such as valproic acid, levetiracetam, and carbamazepine, although their mechanisms of action in chorea are not understood (73).

Stiff-person syndrome. The first therapeutic option is diazepam, followed by clonazepam, alprazolam, lorazepam, and temazepam. Second-line therapies include baclofen, tizanidine, and dantrolene. Both benzodiazepines and the later drugs may require high doses not tolerated by some patients. Vigabatrin, tiagabine, pregabalin, gabapentin, and levetiracetam may be used either alone or in combination to enhance GABAergic transmission (02; 15).

Outcomes

In a study of 577 subjects with anti-NMDAR encephalitis (211 children), immunotherapy and tumor treatment, when required, resulted in significant improvement in 81% of patients after a median follow-up of 24 months (165). Second-line immunotherapy (rituximab, cyclophosphamide, or both) for those who did not respond after a 4-week course of immunotherapy led to clinical improvement and decreased relapses. Early treatment and no admission to the intensive care unit (ICU) were predictors of good outcome. Another study suggested that altered consciousness and central hypoventilation were predictors of poor outcome (P < 0.05) (141). Some patients continue to show clinical improvement up to 18 months after the onset. Relapses occurred in 12% of subjects, and 30% of these had multiple relapses. They were more frequently mono-symptomatic and less severe than the initial presentation, with fewer subjects requiring ICU admission. Fatigue and cognitive problems in children may be present into adolescence, however, with deficits in sustained attention and decreased quality of life (41). A metanalysis reported the functional outcomes and relapsing frequency in 1550 patients with anti-NMDAR encephalitis (136). Good functional outcome was related to adolescent age and first-line treatment with therapeutic apheresis, corticosteroids plus intravenous immunoglobulin, or use of all three. Poor outcomes were related to onset before 2 years and after 65 years of age, admission to the intensive care unit, extreme delta brush pattern on EEG, lack of immunotherapy within the first 30 days from onset, and long maintenance use of intravenous immunoglobulin. Nonrelapsing disease was associated with rituximab use or maintenance therapy with intravenous immunoglobulin for 6 or more months, whereas relapsing disease was related to adolescent age at onset. A composed score was related to poor outcome at 1 year.

In a 2-year follow-up study of 38 subjects with anti-LGI1, 86% had persistent amnesia for the disease period, 35% had relapses up to eight years after initial disease, and the 2-year case fatality rate was 19% (170). First-line treatment was thought effective in 80% of the patients, and the median time to start of improvement was 2 weeks, usually with a decrease in seizures followed by improving cognitive function. Memory deficits, apathy, and difficulties with spatial orientation were common residual symptoms.

In a United Kingdom study involving 31 children, 18 out of 23 subjects treated early (< six months of disease presentation) showed a full recovery compared to only one of eight with a late diagnosis. There were seven relapses (23%). Children treated with plasmapheresis had a full recovery in eight out of nine cases; this was significantly better than those who received initial steroids or IVIG. There was, unfortunately, confounding in this analysis due to early treatment and second-line immunotherapy in seven cases.

Case series have reported occasional spontaneous recovery (32).

The prognosis for autoimmune encephalitis with antibodies against intracellular antigens is much worse because the antibodies are nonpathogenic and there is no response to immunotherapy.

Anti-Hu (ANNA-1). Early reports generally had poor outcomes, but uncontrolled trials and case reports suggest occasional improvement, long-lasting in one case, with the use of rituximab (159; 27).

Anti-Ma2. Prognostic factors for improvement or stabilization are male gender; age younger than 45 years, testicular tumor with response to treatment (over 50% of cases), absence of anti-Ma1 antibodies, and limited involvement of the central nervous system. The presence of anti-Ma1 antibodies increased mortality (34).

Anti-Yo. The type of associated tumor predicted survival. Whereas the median survival for breast cancer was 100 months, those with gynecologic cancer had a 22-month median survival (149).

Special considerations

Pregnancy

In a retrospective review of 13 published cases of anti-NMDA encephalitis during pregnancy (eight in the first trimester and five in the second trimester), the authors reported five cases of associated ovarian teratoma; seven patients responded to first-line therapy and two more to second-line therapy, one patient died from a secondary infection, and one had spasticity and dystonia as sequela. Three fetuses were miscarried or aborted; one newborn presented global developmental delay and another cervical dystonia and strabismus (160).

Ninety-six consecutive patients with postpartum psychosis were screened for autoimmune encephalitis. Two women had anti-NMDA receptor antibody. Both women developed movement disorders with low-dose haloperidol (19).

Anesthesia

Inhaled anesthetics intensify GlyR activity. However, a patient with PERM and GlyR antibodies had an uneventful induction of general anesthesia with sevoflurane and maintenance of anesthesia using sevoflurane and nitrous oxide (139).