Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis

INTRODUCTION — Encephalitis is an inflammatory condition of the brain with many etiologies. There are several types of encephalitis that are immune mediated (autoimmune), including the encephalitis syndromes associated with antibodies against neuronal cell-surface/synaptic proteins and those associated with antibodies against intracellular neuronal proteins.

Although both categories of autoimmune encephalitis can occur as paraneoplastic manifestations of an underlying cancer, the frequency of cancer association varies depending on the autoantibodies (table 1). Most neuronal antibodies typically associated with paraneoplastic encephalitis (eg, >70 percent of cases occur with a cancer association) are directed against intracellular neuronal proteins (onconeuronal proteins).

Thus, many autoimmune encephalitides associated with antibodies against neuronal cell-surface proteins can occur in the presence or absence of cancer, and a few encephalitides associated with antibodies against intracellular neuronal proteins (eg, glutamic-acid decarboxylase 65 kilodalton isoform [GAD65] or adenylate kinase 5 [AK5]) rarely or almost never occur with cancer.

Clinical features, diagnosis, and natural history of autoimmune encephalitis, including paraneoplastic encephalitis, will be reviewed here. Initial and long-term management are reviewed separately. (See "Autoimmune (including paraneoplastic) encephalitis: Management".)

An overview of paraneoplastic syndromes and other paraneoplastic disorders are discussed separately. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle" and "Paraneoplastic cerebellar degeneration" and "Opsoclonus-myoclonus-ataxia syndrome".)

Other inflammatory disorders of the central nervous system (CNS) covered in separate topics include:

●Acute disseminated encephalomyelitis (ADEM) (see "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis" and "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis" and "Acute disseminated encephalomyelitis (ADEM) in adults")

●Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (see "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis" and "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Treatment and prognosis")

●Neuromyelitis optica spectrum disorders (NMOSD) (see "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis" and "Neuromyelitis optica spectrum disorder (NMOSD): Treatment and prognosis")

●Hashimoto encephalopathy/steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) (see "Hashimoto encephalopathy")

●Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) (see "Evaluation and diagnosis of multiple sclerosis in adults", section on 'CLIPPERS')

NEURONAL CELL-SURFACE PROTEIN ANTIBODY SYNDROMES — These syndromes occur in patients of all ages, some with a preferential age distribution, and may or may be associated with cancer. For many syndromes, the antibodies have been shown to be pathogenic. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Pathogenic effects of antibodies'.)

Anti-NMDA receptor encephalitis

Clinical features — Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a disorder that usually affects young adults and children, with a female predominance in young adults and a less strong female predominance in children and patients older than 45 years of age. The disorder is associated with a predictable set of symptoms that combine to make up a characteristic syndrome [1-5].

Many patients present with prodromal headache, fever, or a viral-like process, followed in a few days by a multistage progression of symptoms that include:

●Prominent psychiatric manifestations (anxiety, agitation, bizarre behavior, hallucinations, delusions, disorganized thinking, psychosis). In very rare instances the disease can be monosymptomatic (eg, manifesting as isolated psychosis), or psychiatric symptoms can be the only manifestation of a recurrence [6,7].

●Sleep disorders, including sleep reduction at disease onset and hypersomnia during recovery [8].

●Memory deficits.

●Seizures.

●Decreased level of consciousness, stupor with catatonic features.

●Frequent dyskinesias: orofacial, choreoathetoid movements, dystonia, rigidity, opisthotonic postures.

●Autonomic instability: hyperthermia, fluctuations of blood pressure, tachycardia, bradycardia, cardiac pauses, and sometimes hypoventilation requiring mechanical ventilation.

●Language dysfunction: diminished language output, mutism, echolalia.

Children as young as eight months have been reported with this syndrome [3,9-12]; in the authors' experience, children as young as two months may be affected. In children, the symptoms are similar to those of the adults, with prominent early behavioral or psychiatric symptoms in most patients; dysautonomia and hypoventilation are less frequent and severe. Presenting symptoms usually include acute behavioral change, seizures, language dysfunction, and prominent dyskinesias, including dystonia and chorea [13-15]. Although rare, approximately 5 percent of patients are >45 years of age. In this group, the disease is less severe but outcomes tend to be worse, possibly due to delay in diagnosis and treatment [16].

Diagnosis and differential diagnosis — The disorder should be suspected in adults or children that develop the above clinical symptoms, usually accompanied by:

●Cerebrospinal fluid (CSF) lymphocytic pleocytosis or oligoclonal bands (although basic CSF parameters can be normal initially).

●Electroencephalography (EEG) with infrequent epileptic activity but frequent slow, disorganized activity that does not correlate with most abnormal movements. An infrequent (<30 percent of cases; less frequent in children) unique electrographic pattern called extreme delta brush can assist in the diagnosis and is associated with a more prolonged illness [17].

●Brain magnetic resonance imaging (MRI) that is often normal or shows transient fluid-attenuated inversion recovery (FLAIR) or contrast-enhancing abnormalities in cortical (brain, cerebellum) or subcortical (hippocampus, basal ganglia, white matter) regions [2,18]. While not routinely performed, positron emission tomography (PET) reportedly shows a characteristic increase in the frontal-occipital gradient of cerebral glucose metabolism, which correlates with disease severity [19].

The diagnosis of anti-NMDA receptor encephalitis is confirmed by the detection of immune globulin G (IgG) antibodies against the GluN1 (also known as NR1) subunit of the NMDA receptor (table 2) [20]. Initial antibody studies should be done in CSF since CSF antibodies are always present at the time of presentation; most patients have intrathecal synthesis of antibodies [21]. False-positive and -negative results may occur when testing only serum [22]. However, results of antibody testing can be delayed.

A set of criteria based on the clinical examination and commonly available diagnostic tests (eg, MRI, EEG, and routine CSF studies) has been proposed to support the diagnosis of probable anti-NMDA encephalitis [23]. Patients meeting these criteria should initiate treatment. The diagnosis and treatment approach can then be re-evaluated when antibody testing results are available. A critical caveat to the use of these criteria is that they are not applicable to patients in the very early stages of the disease when they may have few symptoms or an isolated symptom (eg, only seizures), as the differential diagnosis is too broad.

Immune globulin M (IgM) and immune globulin A (IgA) antibodies against the NMDA receptor, which have been described in some patients with chronic schizophrenia and many other chronic neurologic or psychiatric disorders, are nonspecific and have no additional value in the diagnosis of NMDA receptor encephalitis [24,25].

After treatment or in advanced stages of the disease, the CSF antibodies usually remain elevated if there is no clinical improvement, while serum antibodies may be substantially decreased by treatments [18,26,27]. The titer of CSF antibodies appears to correlate more closely with the clinical outcome than serum titers [2,18,22,26].

The differential diagnosis includes primary psychiatric disorders (acute psychosis or schizophrenia), malignant catatonia, neuroleptic malignant syndrome [28], viral encephalitis [29], and encephalitis lethargica [30], among others [31]. There have been several case reports of anti-NMDA receptor encephalitis in patients with current or recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [32-34]; the pathogenic link between both diseases is unclear. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Other acute neurologic manifestations'.)

Association with ovarian teratoma and other tumors — The detection of an ovarian teratoma is age dependent; approximately 45 percent of female patients older than 18 years have uni- or bilateral ovarian teratomas, while less than 9 percent of females younger than 14 years have a teratoma [5]. A review of 400 cases showed that African American patients have a mild predominance to have ovarian teratomas compared with patients from other ethnic groups [4]. Ovarian teratomas are often revealed by MRI and computed tomography (CT) of the abdomen and pelvis, along with abdominal or transvaginal ultrasound (table 3) [18]. (See "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis", section on 'Teratomas'.)

In male patients, the detection of a tumor is rare. Cases with associated tumors other than ovarian teratoma include testicular germ cell tumor [35], teratoma of the mediastinum, small cell lung cancer (SCLC) [2], Hodgkin lymphoma [36], ovarian cystadenofibroma [37], and neuroblastoma [38]. The frequency of underlying tumors in older patients (>45 years) is low, and when present, tumors are more often carcinomas instead of teratomas [16]. Anti-NMDA receptor encephalitis has been described in a few patients with metastatic cancer treated with checkpoint inhibitor immunotherapy [39]. (See "Toxicities associated with immune checkpoint inhibitors".)

Association with HSVE — Although preceding infections have been suspected to play a role in triggering autoimmune encephalitis, to date this has only been demonstrated for herpes simplex viral encephalitis (HSVE). Studies have shown that approximately 25 percent of patients who are NMDA receptor antibody-negative in serum and CSF at the time of HSVE infection seroconvert to positive NMDA receptor antibodies (or less commonly other neuronal antibodies) in the setting of relapsing symptoms not attributable to HSVE relapse [40-43]. A smaller proportion develops NMDA receptor or other antibodies in the absence of clinical symptoms [43].

Symptoms of anti-NMDA receptor encephalitis in these cases begin at a median of four to six weeks after initial viral infection and may occur in contiguity with or after recovery from the HSVE [41,43-47]. In a series of 58 patients with antibody-confirmed autoimmune encephalitis after HSVE (74 percent with NMDA receptor antibodies), the most common symptoms were change of behavior (93 percent), decreased level of consciousness (57 percent), choreoathetosis (47 percent, all in children four years of age or younger), seizures (38 percent), and dysautonomia (27 percent) [43]. In most pediatric cases, symptoms have included choreoathetosis and/or orofacial dyskinesias [41]; teenagers and young adults are more likely to develop behavioral and psychiatric symptoms [42]. Prompt diagnosis and treatment with immunomodulatory therapy improve symptoms and outcome despite persistence of deficits from the HSVE, especially in older children and adults [41,43].

In addition to NMDA receptor antibodies, antibodies to gamma-aminobutyric acid A (GABA-A), dopamine 2 receptor, and unknown neuronal cell-surface antigens have been reported in patients with autoimmune encephalitis after HSVE [42,43].

Treatment — Treatment of anti-NMDA receptor encephalitis consists of immunomodulatory therapy and tumor resection, when appropriate (algorithm 1). Progressive neurologic deterioration and death can occur without treatment, and early initiation of immunomodulatory therapy is associated with improved outcomes. Treatment is reviewed in detail separately. (See "Autoimmune (including paraneoplastic) encephalitis: Management".)

Long-term outcomes — After recovery of the acute phase, when patients are able to return home, they continue to have residual cognitive, behavioral and psychiatric alterations that can last more than one year [48]. In a study that included 28 patients with anti-NMDA receptor encephalitis, 89 percent of patients at visit 1 (median 4 months from disease onset) had deficits in at least one cognitive domain (most commonly executive function), including 54 percent with deficits in one to two domains, 18 percent with deficits in three to four domains, and 18 percent with deficits in five to six domains [49]. Only 11 percent of patients had normal cognitive function. Features of this postacute stage resemble the alterations found in patients with stable symptoms of schizophrenia spectrum disorders.

The strongest risk factors for poor one-year functional outcomes are lack of clinical improvement within the first four weeks of treatment, requirement for intensive care unit admission, treatment delay >4 weeks, abnormal MRI, and CSF white blood cell count >20 cells/microL [50]. Additional risk factors include extremes of age (≤2 or ≥65 years of age) and extreme delta brush pattern on EEG [51]. In children, an abnormal brain MRI and sensorimotor deficits at presentation have also been associated with worse outcomes [52].

Patients with anti-NMDA receptor encephalitis are at risk for relapse. Relapse occurs in 15 to 24 percent of patients, sometimes after several years [2,18,53]. Relapse may occur in the absence of a tumor or in association with an occult or recurrent teratoma. In several series, relapses were more common among those who did not receive immunomodulatory therapy with the initial presentation [5,53]. Adolescent presentation has also been associated with increased risk for relapse [51]. Relapses are typically treated similarly to the approach in newly diagnosed patients, with a lower threshold to initiate second-line therapies early in the course of the relapse. (See "Autoimmune (including paraneoplastic) encephalitis: Management", section on 'Relapsed disease'.)

Pregnancy and fetal effects — Transplacental transfer of IgG anti-NMDA receptor antibodies has been documented in serum of babies born to mothers with anti-NMDA receptor encephalitis. However, newborn outcomes appear to be good in most cases.

In a review of 21 previously published cases and 11 new cases of females who either developed anti-NMDA receptor encephalitis while pregnant or became pregnant while recovering from the encephalitis, the majority of newborns were healthy and had no evidence of neurodevelopmental delay with follow-up ranging from 6 to 36 months [54-60]. Transient respiratory distress or neuromuscular deficits at delivery rarely occurred. Such complications spontaneously recovered and were considered secondary to antiseizure and sedative medications given to the mothers. Adverse outcomes included one infant with cortical dysplasia, developmental disorder, and seizures who was the result of a complicated pregnancy with uteroplacental insufficiency [55]. There was one neonatal death reported [54]. In this case, the mother had recovered from anti-NMDA receptor encephalitis 18 months before delivery and presented with eclampsia without prior knowledge of the pregnancy or prenatal care.

Obstetric complications were reported in approximately one-third of the females who developed anti-NMDA receptor encephalitis during pregnancy, mostly due to pathologic pregnancy or spontaneous miscarriage, supporting close monitoring in intensive care units focused on high-risk pregnancies [60].

Anti-LGI1 encephalitis — Patients with anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis develop memory disturbances, confusion, and seizures [61-64]. Memory and cognitive deficits may be preceded by short faciobrachial dystonic seizures that can be mistaken for myoclonus or dystonia and are often poorly responsive to antiseizure medication therapy. Patients may develop hyponatremia and rapid eye movement (REM) sleep behavior disorder. Some patients present with rapidly progressive cognitive decline without signs of encephalitis in CSF or on MRI [65].

MRI usually shows findings typical of limbic encephalitis (eg, medial temporal lobe hyperintensity) (image 1) [66]. CSF may show pleocytosis but is often normal or only shows oligoclonal bands [67]. Approximately 5 percent of cases are associated with tumors; the most common associated tumor is thymoma. The association with other tumors may be coincidental [65].

The associated antibodies target the LGI1 protein, a secreted neuronal protein that functions as a ligand for two epilepsy-related proteins, ADAM22 and ADAM23 [68]. The binding of the antibodies to LGI1 disrupts pre- and postsynaptic LGI1 signaling, resulting in neuronal hyperexcitability [69].

Treatment with immunomodulatory therapy results in substantial clinical improvement in 70 to 80 percent of patients [61,70-73]. Observational data suggest that early initiation of immunomodulatory therapy in patients with faciobrachial dystonic seizures may prevent the development of cognitive impairment and improve long-term outcomes [63]. (See "Autoimmune (including paraneoplastic) encephalitis: Management".)

Relapses occur in up to one-third of patients, often but not exclusively during the first six months of the disease, and are associated with worse outcome. In one study, the median time to relapse after initial presentation was 35 months [74]. Despite substantial recovery, cognitive deficits and disability persist in many patients, along with evidence of hippocampal atrophy on MRI [65,75]. The risk of long-term epilepsy appears to be low in the absence of disease relapse [76,77].

Anti-Caspr2-associated encephalitis — Anti-contactin-associated protein-like 2 (Caspr2)-associated encephalitis can manifest as limbic encephalitis, as Morvan syndrome (neuromyotonia, memory loss and confusion, sleep disturbances, autonomic instability), and in a small number of patients with isolated neuromyotonia [67,78-80]. The target antigen is Caspr2, which plays a role in maintaining the normal function of voltage-gated potassium channels (VGKC) [78]. Caspr2 autoantibodies inhibit cell adhesion interactions between Caspr2 and contactin-2, reduce levels of Caspr2 and related proteins, and cause reversible memory impairment in mice [81,82].

This disorder predominantly affects older males with a median age of 65 years, although rare pediatric cases have been described in children as young as two years old [64,80,83,84]. Most patients do not have cancer. Patients with a tumor (usually thymoma) are more likely to develop Morvan syndrome than isolated central or peripheral symptoms.

Although the clinical syndrome is varied, almost 80 percent of patients develop three or more of the following core symptoms: cognitive changes, cerebellar symptoms, peripheral nerve hyperexcitability, autonomic dysfunction, insomnia, neuropathic pain, and weight loss [83]. Seizures occur in approximately one-third of patients, mostly focal nonmotor seizures with impaired awareness [85]. Approximately one-third of patients have one or more movement disorders, including ataxia, myoclonus, and tremor [86]. Rare but unusual manifestations include continuous segmental spinal myoclonus, orthostatic myoclonus of the legs, and paroxysmal cerebellar ataxia [86,87].

The presentation and disease course are slower than those of other autoimmune encephalitis syndromes. In one study, the median time to disease nadir was four months, but in 30 percent of cases it was >12 months. Most patients have responses to immunomodulatory therapy, and approximately 25 percent will have relapses.

Anti-AMPA receptor encephalitis — Encephalitis associated with antibodies against the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor affects predominantly females, with a median age of onset of 50 to 60 years [88-92]. In a case series of 22 patients with anti-AMPA receptor antibodies, limbic encephalitis with or without seizures was the most common clinical presentation (55 percent); other presentations included limbic dysfunction along with multifocal or diffuse encephalopathy (36 percent), motor deficits followed by limbic encephalitis (one patient), and psychosis with bipolar features (one patient) [91].

An underlying neoplasm is identified in approximately two-thirds of the patients, most commonly lung, thymus, or breast [88,91,93]. A lymphocytic pleocytosis in the CSF has been reported in 50 to 90 percent of patients (range 5 to 164 cells) [88,91]. MRI is usually abnormal, with FLAIR signal abnormality in the medial temporal lobes.

In one series, 9 of 10 patients responded to treatment of the underlying neoplasm and/or immunomodulatory therapy, but subsequent relapses occurred in five (in the absence of tumor recurrence) and were associated with an incomplete treatment response and death from status epilepticus in one patient [88]. In another series, 15 of 21 patients had a full or partial response to treatment of the underlying neoplasm and/or immunomodulatory therapy [91].

The binding of patients' antibodies to AMPA receptors causes a reversible decrease of these receptors. In an animal model of passive transfer of patients' antibodies, these caused a reorganization of AMPA receptor subunits and memory dysfunction [94,95].

Anti-GABA-A receptor encephalitis — Patients with encephalitis due to antibodies against the GABA-A receptor develop a rapidly progressive encephalitis with refractory seizures, status epilepticus, and/or epilepsia partialis continua [96]. Nearly half of reported cases are children [97]. In these patients, the development of dyskinesias can suggest the diagnosis of anti-NMDA receptor encephalitis.

The CSF often shows lymphocytic pleocytosis with increased protein concentration. Unlike other causes of autoimmune encephalitis, in which the MRI is normal or shows abnormalities limited to the limbic system, the MRI in anti-GABA-A receptor encephalitis often shows multifocal cortical/subcortical and widespread FLAIR and T2 signal abnormalities [97]. Tumors (mostly thymoma) occur in 40 percent of patients, almost all adults; isolated cases with other tumors have been reported [96,97]. In children, anti-GABA-A receptor encephalitis may develop as a postviral encephalitis and coexist with NMDA receptor antibodies. (See 'Association with HSVE' above.)

Patients respond to immunomodulatory therapy but often require pharmacologic-induced coma for prolonged seizures. (See "Autoimmune (including paraneoplastic) encephalitis: Management", section on 'Intensive care management'.)

Anti-GABA-B receptor encephalitis — Encephalitis due to antibodies against the B1 subunit of the gamma-aminobutyric acid B (GABA-B) receptor has been described primarily in adults presenting with limbic encephalitis, although presentations may vary and include limbic encephalitis with seizures, rapidly progressive dementia, status epilepticus, ataxia, or opsoclonus-myoclonus-ataxia syndrome (OMAS) [98,99]. In one report, anti-GABA-B antibodies were the most common antibodies found in limbic encephalitis syndromes associated with SCLC that were previously considered seronegative [100]. One pediatric case was characterized by encephalopathy, refractory seizures, and a mixed movement disorder (opsoclonus, ataxia, and chorea) [101].

Approximately 50 percent of cases are paraneoplastic and are almost always associated with SCLC [98,102]. Co-occurring antibodies against potassium channel tetramerization domain-containing 16 (KCTD16) increase the likelihood of a paraneoplastic etiology [99]. MRI shows FLAIR and T2 signal abnormalities consistent with limbic encephalitis in approximately one-half of patients, and over one-half of patients have CSF pleocytosis and/or elevated protein levels [98].

Most patients have substantial improvement with treatment (ie, immunomodulatory therapy and tumor treatment when indicated). However, the outcome is dictated by the presence of a tumor [98,103].

Anti-IgLON5 disease — Patients with antibodies against IgLON family member 5 (IgLON5), a neuronal cell adhesion protein, manifest a neurologic disease with shared features of autoimmunity and neurodegeneration. Although REM and non-REM sleep parasomnias were highlighted in early case descriptions, subsequent studies have shown that abnormal movements and gait and balance problems are usually present in addition to sleep problems [104-108].

In a series of 72 patients with anti-IgLON5 disease, the median age at symptom onset was 62 years (range 42 to 91 years) [108]. In approximately three-quarters of patients, symptoms progressed over months to years leading up to diagnosis. In the remaining quarter, the presentation was more rapid, with progression over weeks to a few months.

Five main clinical syndromes have been described at diagnosis: a sleep disorder with REM and non-REM parasomnias and sleep-disordered breathing; movement disorders, which in some cases resemble progressive supranuclear palsy (PSP); a bulbar syndrome including dysarthria, dysphagia, vocal cord paralysis (stridor), or acute respiratory insufficiency; cognitive decline with or without chorea; and neuromuscular manifestations with muscle weakness, atrophy, or fasciculations [107-109]. Almost all patients eventually develop both abnormal movements and sleep problems, such as parasomnias, sleep apnea, insomnia, or excessive daytime sleepiness.

Video-polysomnography is essential to define the complex sleep disorder and identify characteristic features of the disorder [110] (see "Polysomnography in the evaluation of parasomnias and epilepsy"). CSF and imaging studies tend to be normal aside from the presence of anti-IgLON5 antibodies in CSF and serum. There appears to be a strong association with the human leucocyte antigen (HLA) DRB1*10:01 allele [107]. Prognosis is poor, with few patients responding to immunomodulatory therapy and a high mortality rate [107,108]. Early initiation of immunomodulatory therapy prior to advanced symptoms may be associated with disease stabilization and better outcomes [109].

Neuropathologic evaluation of some patients at autopsy revealed neuronal loss and extensive deposits of hyperphosphorylated tau, mainly involving the brainstem tegmentum and hypothalamus. Neuropathologic criteria of anti-IgLON5-related tauopathy have been proposed [111].

Anti-DPPX encephalitis — Patients with antibodies against dipeptidyl-peptidase-like protein-6 (DPPX) develop severe prodromal symptoms of loss of weight, diarrhea, or other gastrointestinal symptoms followed within a few months (average four months) by the development of encephalitis with central hyperexcitability such as hyperekplexia, agitation, myoclonus, tremor, and seizures [112,113]. Some patients have symptoms suggestive of progressive encephalomyelitis with rigidity and myoclonus (PERM) [113,114]. Most patients have a protracted course, although subacute presentations have been reported [112,115]. Tumors are rare, and when they do occur, most are B cell neoplasms [115].

Other common features included CSF lymphocytic pleocytosis, but studies may be normal; the MRI is usually not specific. Patients usually have an initial benefit from immunomodulatory therapy but often relapse when therapy is tapered.

Anti-GlyR encephalopathy — Antibodies to the alpha-1 subunit of the glycine receptor (GlyR) have been associated with a syndrome of PERM, acquired hyperekplexia, and stiff-person syndrome in some patients without glutamic acid decarboxylase (GAD) antibodies [116-119]. A few patients have been reported with limbic or other encephalitis without brainstem or spinal cord features. In a series of 45 patients, five had a past history and successful treatment of a tumor, and in four patients, the tumor diagnosis was concurrent with the neurologic disease [120]. Most patients have responses to immunomodulatory therapy. Antibodies to alpha-1 GlyR have also been reported in serum (and at low titers) of some patients with isolated seizures, optic neuritis, multiple sclerosis, OMAS, and cerebellar ataxia without stiff-person syndrome or PERM [121-124].

Anti-mGluR5 encephalitis — Antibodies against the metabotropic glutamate receptor 5 (mGluR 5) have been associated with encephalitis, often including movement disorders, sleep dysfunction, and seizures [125-128]. The clinical spectrum includes prominent neuropsychiatric features (eg, progressive mood and personality changes, anterograde amnesia, disorientation), prosopagnosia, headaches, involuntary movements, and seizures. The CSF often shows pleocytosis, and in approximately half of the cases, the MRI shows FLAIR abnormalities in limbic or extralimbic regions [128].

The syndrome is most commonly associated with Hodgkin lymphoma (Ophelia syndrome) or SCLC but can also occur in the absence of a tumor. The disorder is highly responsive to immunomodulatory therapy and treatment of the tumor, but relapses can occur.

Anti-mGluR1 encephalitis — Patients with antibodies against the mGluR1 develop cerebellar ataxia that remains isolated in less than 15 percent of patients [129]. In the majority, the ataxia is accompanied by cognitive changes, seizures, or psychiatric symptoms [129-131]. Both sexes are affected, with a slight predominance of males and a median age of 55 years [129].

The CSF is abnormal is approximately 75 percent of patients, including pleocytosis, oligoclonal bands, or increased IgG index. Brain MRI is normal in most patients but can show cerebellar T2 hyperintensities or, less frequently, leptomeningeal enhancement. Cerebellar atrophy may develop over time.

The disorder is usually not associated with cancer; reported associations have involved a history of Hodgkin lymphoma or other hematologic malignancy and one patient with a concurrent cutaneous T cell lymphoma. The disorder can improve with early immunomodulatory therapy. Relapses can occur, usually in the context of immunomodulatory therapy discontinuation.

Anti-neurexin-3 alpha encephalitis — Antibodies to neurexin-3 alpha have been described in a series of five patients who developed a severe encephalitis with rapid decline in consciousness, orofacial dyskinesias, and central hypoventilation that in some patients resembled anti-NMDA receptor encephalitis [132]; however, NMDA receptor antibodies were absent in all cases. Patients were relatively young (median age 44 years) and all had prodromal symptoms before the rapid decline. The CSF was abnormal in all (four with pleocytosis and one with elevated IgG index); brain MRI was normal in four and showed FLAIR abnormalities in the temporal lobes in one. All five patients received immunomodulatory therapy, and three had partial recovery. One patient died from the disease and the other from sepsis. Four of the patients had evidence of systemic autoimmunity, but none had a cancer history. A more complete clinical spectrum of this syndrome remains to be described.

Encephalopathy with antibodies against GFAP — Antibodies against glial fibrillary acidic protein (GFAP, an astrocytic intracellular protein) have been described as a marker for a relapsing autoimmune meningoencephalitis or encephalitis, with or without myelitis [133,134]. Although these antibodies do not target a neuronal protein, they are included in this section because many of the reported patients had other relevant autoimmune responses (eg, anti-NMDA receptor antibodies, anti-GAD antibodies, and aquaporin-4 [AQP4] antibodies, among others) that may have driven the clinical syndrome. The patients had a range of clinical symptoms including headache, optic disc edema and optic papillitis, encephalopathy, myelopathy, tremor, autonomic dysfunction, and psychiatric disturbances [133-135]. Approximately one-third of the patients had a past or current systemic tumor. The CSF often showed a leukocytic pleocytosis. A variety of MRI features have been described including diffuse T2 abnormalities in periventricular white matter, leptomeningeal or perivascular enhancement (sometimes in a radial distribution), and longitudinally extensive T2 hyperintensity in the spinal cord [136]. Most of the patients responded to glucocorticoids [133,134]. GFAP-antibody-associated neurologic disorders can also occur as adverse events of checkpoint inhibitor immunotherapy.

Other encephalitides

●Anti-mGluR2 encephalitis – Antibodies against mGluR2 were described in two patients with paraneoplastic cerebellar ataxia [137]. One patient was 78 years of age with SCLC who had a relapsing-remitting course and the other was three years old with an alveolar rhabdomyosarcoma who improved with corticosteroids. In both cases, the tumor was shown to express mGluR2.

●Anti-SEZ6L2 encephalitis – Antibodies against seizure-related 6 homolog like 2 (SEZ6L2) were initially described in two patients who developed subacute cerebellar ataxia with retinopathy [138]. In a study of four additional patients, median age was 62 years, half were females, and the cerebellar syndrome was associated with extrapyramidal symptoms in three [139]. None of the reported patients had cancer.

●Anti-GluK2 encephalitis – Antibodies against the glutamate kainate receptor subunit 2 (GluK2) have been described in eight patients with encephalitis and prominent cerebellar involvement [140]. The median age was 28 years (range 14 to 75), and five were males. The most common clinical presentation was rapidly progressive cerebellitis or encephalitis with cerebellar ataxia often accompanied by alterations of cognition and memory, decreased level of consciousness, myoclonus, or movement disorders. There was a remote history of Hodgkin lymphoma in one patient. Immunotherapy resulted in improvement in three of four patients with assessable follow-up.

INTRACELLULAR NEURONAL PROTEIN ANTIBODY SYNDROMES

High-risk antibodies (>70 percent cancer association) — These syndromes are almost always paraneoplastic and usually occur in older patients. The associated antibodies target intracellular neuronal proteins, and the pathogenic mechanisms are mediated by cytotoxic T cells that lead to irreversible neuronal degeneration and a poor response to treatment. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Immunologic mechanisms'.)

Anti-Hu encephalomyelitis — Anti-Hu paraneoplastic syndromes are often multifocal, resulting from involvement of cortical gray matter, temporal lobes, brainstem, cerebellum, dorsal root ganglia, and/or autonomic nervous system [141-144]. In many patients, symptoms begin with, and may remain restricted to, the dorsal root ganglia, causing a subacute sensory neuronopathy [142,143] (see "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Subacute motor neuronopathy'). Other patients with anti-Hu antibodies present with a more restricted brainstem or limbic encephalitis [142,145].

Small cell lung cancer (SCLC) is found in most patients with anti-Hu encephalitis [141,143,144]. Some patients have other cancer types; no cancer is found in approximately 15 percent of patients [143,144]. Some children with anti-Hu antibodies have opsoclonus-myoclonus-ataxia syndrome (OMAS) and neuroblastoma, but more commonly, the encephalitis is not paraneoplastic. In one referral-based cohort, six of eight children with anti-Hu encephalitis were cancer free compared with none of 243 adults [146].

Early recognition of anti-Hu encephalomyelitis and prompt antitumor treatment are important in stabilizing or sometimes improving the neurologic symptoms. In one series of 200 patients with paraneoplastic encephalomyelitis and anti-Hu antibodies, antitumor treatment was associated with a significantly greater likelihood of neurologic improvement or stabilization (odds ratio [OR] 4.6) and a lower mortality rate (relative risk of death with no antitumor treatment 2.6) [143].

Immunomodulatory therapy (eg, glucocorticoids, immune globulin, therapeutic plasma exchange), either given with antitumor treatment or alone, has also been associated with stabilization in a smaller proportion of patients [144,147]. One report describes improvement with rituximab in two patients with paraneoplastic encephalomyelitis associated with the anti-Hu antibody [148]. In children, the syndrome appears to be more treatment resistant and associated with long-term sequelae of intractable epilepsy and cognitive impairment [146].

Neurologic dysfunction is a frequent cause of death, particularly when there is brainstem and autonomic dysfunction [142]. However, prolonged survival can occur in association with regression of the tumor [143,149].

Ma2-associated encephalitis — Ma2-associated encephalitis (also called anti-Ta) is usually associated with testicular germ-cell tumors, mainly seminoma [150]. The Ma2 antigen is selectively expressed in neurons and the testicular tumor. Ma2 shares homology with Ma1, a protein that is associated with other paraneoplastic neurologic syndromes, particularly brainstem and cerebellar dysfunction (table 1) [151,152].

The clinical presentation of anti-Ma2-associated encephalitis differs from classic paraneoplastic limbic encephalitis. In a series of 38 patients with anti-Ma2 encephalitis, 34 (89 percent) developed isolated or combined limbic (n = 27), diencephalic (n = 13), or brainstem encephalopathy (n = 25) [151]. MRI abnormalities were frequent in these brain regions, and inflammatory changes were typically present in the cerebrospinal fluid (CSF). Four patients developed other syndromes, including two with a predominant cerebellar ataxia that remained stable for several years and two with myelopathy.

Other prominent neurologic features included excessive daytime sleepiness and eye movement abnormalities, particularly a vertical gaze paresis (mainly upward gaze) that sometimes evolved to total external ophthalmoplegia. Three patients developed atypical parkinsonism, and two developed a severe hypokinetic syndrome. An additional case report describes an individual whose syndrome included amyotrophy of the upper extremities with an associated cervical cord lesion [153].

Testicular germ cell tumors are the most common associated neoplasms, identified in 18 of 34 patients found to have cancer in the above described series [151]. Orchiectomy may be required to reveal microscopic testicular germ cell neoplasia, as occurred in six males (age 26 to 40 years) with Ma2-associated encephalitis and no evidence of other cancer by rigorous testing [154]. All six males were identified to be at risk for testicular cancer because of new testicular enlargement, testicular microcalcifications, and/or cryptorchidism. Extragonadal germ cell tumors have also been described in association with this syndrome [155,156]. The diagnosis of testicular germ cell tumors is discussed separately. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors".)

Coexisting antibodies to Ma1 were identified in 15 of 34 patients with anti-Ma2 encephalitis and were significantly more common in patients with tumors other than testicular cancer (usually lung cancer) [151]. Compared with patients with antibodies only to Ma2, these patients are also more likely to develop ataxia and to have a worse prognosis.

Anti-Ma2-associated encephalitis is more responsive to oncologic and immunomodulatory therapy than other types of paraneoplastic encephalomyelitis [155]. In the series cited above, neurologic improvement or stabilization occurred in 18 of 33 patients with outcome information [151]. Features significantly associated with improvement or stabilization included male sex, age 45 years or less, testicular tumor with complete response to treatment, absence of anti-Ma1 antibodies, and limited central nervous system (CNS) involvement. However, a positive treatment response can occur in other patients as well [157].

Anti-CRMP5 encephalomyelitis — Antibodies to collapsin-responsive mediator protein 5 (CRMP5) have been associated with paraneoplastic encephalitis. Cortical symptoms are often not confined to the limbic system; distinctive symptoms including cerebellar ataxia, chorea, optic neuropathy, cranial neuropathies, and loss of olfaction and taste have been described [158-162]. Other paraneoplastic syndromes associated with these antibodies include axonal sensorimotor neuropathy, uveitis, and optic neuritis.

The most common associated cancers are SCLC and thymoma. Improvement with anticancer therapy and glucocorticoids has been described.

Others

●Stiff-person syndrome – Stiff-person syndrome may occur in isolation or as part of encephalomyelitis. Paraneoplastic stiff-person syndrome is associated with antiamphiphysin antibodies and rarely with antibodies to glutamic acid decarboxylase 65 kilodalton isoform (GAD65) or glycine receptor (GlyR) that are more commonly associated with the nonparaneoplastic syndrome [121,163-165]. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Stiff-person syndrome'.)

●Anti-Ri encephalitis – Antibodies to Ri are found in patients with paraneoplastic OMAS. These antibodies have also been described in some patients with paraneoplastic brainstem encephalitis with eye movement disorders, dysphagia, ptosis, laryngospasm, and/or jaw dystonia [166]. While most patients do not respond to therapy, as with other paraneoplastic neurologic disorders, there are reports of responses to early initiation of immunomodulatory therapy and tumor-directed treatment. (See "Opsoclonus-myoclonus-ataxia syndrome", section on 'Pathogenesis'.)

●Anti-KLHL11 encephalitis – Antibodies to Kelch-like protein 11 (KLHL11) have been described in patients with a predominant brainstem/cerebellar encephalitis, often with sensorineural hearing loss, and are frequently but not invariably associated with tumors, most commonly benign teratoma or a testicular tumor [167-169]. Other symptoms may include limbic encephalitis, myelitis, hypersomnia, and seizures [170]. Both males and females can be affected, and patients ranging in age from 9 to 76 years have been reported. These antibodies have also been described in patients with other types of autoimmune encephalitis, including anti-N-methyl-D-aspartate (NMDA) receptor and anti-Ma2 encephalitis [169]. In these patients, the presence of KLHL11 antibodies did not confer distinct clinical features.

Low-risk antibodies (<30 percent cancer association)

●Anti-GAD65 encephalitis – High-titer antibodies against GAD65 can be associated with three distinct syndromes, sometimes with overlapping symptoms: stiff-person syndrome and variants, cerebellar ataxia, and encephalitis with pharmacoresistent temporal lobe seizures [171]. Patients with GAD65 antibody-associated neurologic syndromes always have high-titer GAD65 antibodies in CSF, and more than 80 percent have evidence of intrathecal antibody synthesis. Since low titers of GAD65 antibodies can be found in the serum of patients with type 1 diabetes mellitus, healthy subjects, and patients with a variety of nonimmunologic neurologic disorders [172], the determination that a neurologic syndrome is GAD antibody-associated should be based in CSF antibody testing and determination of intrathecal GAD65 antibody synthesis [173]. To date, there is no clear evidence that GAD antibodies are pathogenic.

●Anti-AK5 encephalitis – Antibodies to adenylate kinase 5 (AK5) were initially described in two patients with the subacute onset of a severe limbic encephalitis refractory to therapy [174], and additional patients have been encountered [175-177]. In a review of 26 patients, the median age of onset was 66 years, and 77 percent of patients were male [177]. Predominant symptoms were severe episodic amnesia, depression, anorexia, and weight loss. MRI demonstrated bilateral medial temporal T2-weighted signal abnormalities in most patients, which evolved to severe atrophy. AK5 is an intracellular protein, and the pathogenesis of anti-AK5 encephalitis appears to be related to T cell-mediated cytotoxicity resulting in extensive neuronal loss. The response to immunomodulatory therapy is generally poor.

DIAGNOSTIC APPROACH — The diagnosis of autoimmune encephalitis is established by detection of specific antineuronal antibodies in patients with a characteristic clinical syndrome. However, not all patients with autoimmune encephalitis have antibodies. For these patients, the suspicion of an autoimmune etiology is based on [178]:

●Acute or subacute presentation

●Clinical features, which in some cases are highly suggestive of a specific autoimmune encephalitis syndrome

●Clinical history, including cancer risk factors

●Supportive laboratory and radiologic findings

In all patients, it is critical to consider alternative etiologies for the encephalitis syndrome (table 4), as initial treatment decisions are often made before confirmatory antibody test results are available, and infectious etiologies in particular should be excluded before embarking on immunomodulatory therapies.

Differential diagnosis — The differential diagnosis of autoimmune (including paraneoplastic) encephalitis includes a variety of alternative causes of encephalitis and encephalopathy. Broad categories include infection, toxic and metabolic disturbances, vascular disorders, neoplastic disorders, demyelinating and inflammatory disorders, psychiatric disease, neurodegenerative dementias, and rare heritable or metabolic disorders (table 4).

Syndromes such as anti-N-methyl-D-aspartate (NMDA) receptor encephalitis have a characteristic pattern of symptoms that are easily recognizable. By contrast, other syndromes such as limbic encephalitis may initially have a wide differential diagnosis. For example, metastatic disease affecting the brain or leptomeninges, viral encephalitis, Creutzfeldt-Jakob disease, ischemic and hemorrhagic cerebrovascular disease, Whipple disease, psychiatric disease, toxic-metabolic encephalopathy, Wernicke encephalopathy, and primary degenerative dementia have all been reported to cause a clinical syndrome for which the diagnosis of autoimmune limbic encephalitis was considered [20,31,141,179-181]. The differential diagnosis in patients with predominant brainstem encephalitis also includes certain additional disorders with a predilection for the brainstem, such as multiple sclerosis, Behçet syndrome, Listeria infection, enterovirus, and tuberculosis infection [182]. Some of the autoimmune encephalitides have early and prominent psychiatric manifestations that overlap with primary psychiatric diseases and substance use disorders. Careful examination may reveal subtle neurologic deficits at this stage, findings that should lead to the consideration of autoimmune encephalitis. Most patients develop additional features of the syndrome within days or a few weeks [5,183].

Clinical evaluation and imaging — Patients with suspected autoimmune encephalitis (table 5) should have neuroimaging, EEG, lumbar puncture, and serologic testing for appropriate biomarkers to confirm the diagnosis and exclude alternative etiologies.

●Neuroimaging – A brain MRI is helpful in this clinical setting to exclude a cerebrovascular event or metastatic disease, among others. Characteristic MRI findings in patients with autoimmune encephalitis include signal hyperintensities on fluid-attenuated inversion recovery (FLAIR) or T2-weighted images in affected brain regions (eg, medial temporal lobes and/or brainstem); subcortical regions and the cerebellum are sometimes affected as well. Contrast enhancement is variable. Although MRI findings are neither sensitive nor specific for these disorders, in the appropriate clinical setting they can be highly suggestive of specific syndromes (eg, multifocal FLAIR and T2 signal abnormalities in gamma-aminobutyric acid A [GABA-A] receptor encephalitis) [96]. (See 'Anti-GABA-A receptor encephalitis' above.)

●EEG – An EEG should be performed in most cases to exclude nonconvulsive seizures. In patients with autoimmune encephalitis, nonspecific EEG abnormalities are common and include focal or generalized slowing, epileptiform activity, and periodic lateralized epileptiform discharges (PLEDs) [184]. Less than one-third of patients with NMDA receptor encephalitis have an EEG pattern called extreme delta brush that is considered characteristic for the disorder [17].

●Lumbar puncture – Cerebrospinal fluid (CSF) examination should be performed and should include cell count, protein, and glucose concentrations; inflammatory markers (immune globulin G [IgG] index, oligoclonal bands); cell-surface and/or intracellular neuronal antibodies; broad viral studies including herpes simplex virus (HSV) 1/2 and varicella zoster virus (VZV) polymerase chain reaction (PCR), and bacterial and fungal cultures when appropriate (see "Viral encephalitis in adults", section on 'Diagnosis'); and cytology to exclude leptomeningeal metastasis [185]. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors", section on 'Diagnostic evaluation'.)

Patients with autoimmune encephalitis may have normal or abnormal CSF findings. Abnormalities include modest elevation of protein (<100 mg/dL), mild to moderate lymphocytic pleocytosis, elevated IgG index, and/or the presence of oligoclonal bands [184,186]. However, these findings are variable, and some syndromes, such as anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis, often have only mildly abnormal or normal CSF studies [187]. A lack of inflammatory findings on CSF and MRI may be particularly common in older adults [188].

●Oncologic evaluation – If the patient does not have a known cancer diagnosis, evaluation for occult malignancy should also ensue, with the syndrome often providing a clue as to the tumor location (table 1 and table 3). For example, as small cell lung cancer (SCLC) comprises the majority of underlying neoplasms in older patients with limbic encephalitis, chest imaging and 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) should have a high priority in patients with this syndrome, whereas young females with anti-NMDA receptor encephalitis should be thoroughly investigated for an ovarian teratoma. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Search for occult malignancy'.)

Antibody testing — Autoimmune encephalitis antibody testing should initially always include CSF and serum (table 1) [20]. Not all biomarkers have commercially available testing, and some antigens remain to be characterized. Thus, negative results do not exclude an autoimmune disorder [186]. A sample of a patient's CSF and serum can be sent to a research laboratory for examination in these cases. Other caveats regarding antibody testing are discussed separately. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Antibody screening'.)

Of note, some forms of autoimmune cortical encephalitis are associated with myelin oligodendrocyte glycoprotein (MOG) antibodies; for MOG antibodies, the optimal sample is serum. MOG antibody-associated cases predominantly involving cortical gray matter can occur in adults and children; however, serum MOG antibody testing should be considered in most children with suspected autoimmune encephalitis. Studies suggest that in children with autoimmune encephalitis, MOG and NMDA receptor antibodies are by far the most frequent autoantibodies [189]. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)

General principles to follow when assessing and interpreting neuronal antibody testing in a patient with symptoms suggesting autoimmune encephalitis include the following:

●Test for antibodies in CSF and serum. The approach of first testing serum and then, if negative, testing CSF is not recommended, as it delays diagnosis and may lead to false-positive results.

●If serum antibody testing is positive but the CSF is negative, consider that the serum result may be a false-positive diagnosis. Contact the laboratory and request retesting of the samples.

●If the clinical picture does not fit with the antibody identified, the antibody may be a false-positive result [190], particularly if only serum has been examined, or if the antibodies were only identified in serum. In this case, contact the clinical laboratory for retesting or a research laboratory for guidance.

●Clinical decisions should be based on clinical assessment rather than on antibody titers. Although the antibody titers may correlate with the clinical course, this correlation is imperfect, and antibody titers often remain detectable even after recovery.

Among over 100 patients referred to tertiary care centers with a diagnosis of autoimmune encephalitis who were ultimately diagnosed with an alternative disorder, the most common misdiagnoses were functional neurological symptom disorder (conversion disorder), neurodegenerative disease, primary psychiatric disease, cognitive deficits from comorbidities, and cerebral neoplasm [191]. In retrospect, approximately half of the misdiagnoses were caused by overinterpretation of nonspecific positive serum antibody testing. Misdiagnosis based on CSF testing was much less common. These results emphasize the primacy of clinical judgment and the importance of careful consideration of the differential diagnosis, understanding of the nuances of antibody testing, and, in particular when CSF is not investigated for antibodies, adherence to diagnostic criteria [192].

Diagnostic criteria — A clinical approach to the diagnosis of autoimmune encephalitis has been developed by expert panels [23,193]. Because autoantibody test results (table 1) and response to antitumor and immunomodulatory therapy are not available at disease onset, these criteria rely on neurologic assessment and conventional neuroimaging and CSF testing reviewed above [23]. Misdiagnosis of autoimmune encephalitis and probable antibody-negative autoimmune encephalitis can be mitigated by adherence to these criteria and comprehensive antibody testing [178].

Diagnostic criteria for definite autoimmune limbic encephalitis require all four of the following (table 6):

●Subacute onset (rapid progression of <3 months) of working memory deficits (short-term memory loss), seizures, or psychiatric symptoms suggesting involvement of the limbic system

●Bilateral brain abnormalities on T2-weighted FLAIR MRI highly restricted to the medial temporal lobes

●At least one of the following:

•CSF pleocytosis (>5 white blood cells per mm³)

•EEG with epileptic or slow-wave activity involving the temporal lobes

●Reasonable exclusion of alternative causes

If one of the first three criteria is not met, a diagnosis of definite limbic encephalitis can be made only with the detection of antibodies against cell-surface or onconeuronal proteins [23]. In addition to limbic encephalitis, specific criteria for probable and definite anti-NMDA receptor encephalitis are also available (table 2). (See 'Anti-NMDA receptor encephalitis' above.)

Proposed criteria for probable antibody-negative autoimmune encephalitis require the following [178]:

●Rapid progression (<3 months) of working memory deficit (short-term memory loss), altered mental status, or psychiatric symptoms

●Exclusion of well-defined syndromes of autoimmune encephalitis (limbic encephalitis, acute disseminated encephalomyelitis, Bickerstaff brainstem encephalitis, among others)

●Absence of well-characterized autoantibodies in serum and CSF, and at least two of the following:

•MRI abnormalities suggesting autoimmune encephalitis

•CSF pleocytosis, CSF-specific oligoclonal bands, or elevated CSF IgG index

•Brain biopsy showing inflammatory infiltrates and excluding other disorders (eg, vasculitis or tumor)

●Reasonable exclusion of alternative causes (table 4)

Diagnostic criteria for paraneoplastic neurologic syndromes are reviewed separately [193]. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Diagnostic criteria'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Paraneoplastic neurologic disorders".)

SUMMARY AND RECOMMENDATIONS

●Terminology – Autoimmune encephalitis includes the encephalitis syndromes associated with antibodies against neuronal cell-surface proteins and the paraneoplastic encephalitis syndromes that are usually associated with antibodies against intracellular neuronal (onconeuronal) proteins. (See 'Introduction' above.)

●Clinical syndromes

•Associated with antibodies against neuronal cell-surface proteins – A large number of autoimmune encephalitis syndromes have been identified in association with antibodies against neuronal cell-surface or synaptic proteins (table 1). The most common is anti-N-methyl-D-aspartate (NMDA) receptor encephalitis (table 2). (See 'Anti-NMDA receptor encephalitis' above.)

These syndromes occur in patients of all ages, some with a preferential age distribution, and may or may not be associated with the presence of a cancer. For many syndromes, the antibodies have been shown to be pathogenic via antibody-mediated effects. (See 'Neuronal cell-surface protein antibody syndromes' above.)

•Associated with antibodies against intracellular neuronal proteins (onconeural proteins), high cancer association – These disorders are almost always paraneoplastic and can involve the limbic system (limbic encephalitis), brainstem (brainstem encephalitis), spinal cord (myelitis), or the entire neuraxis (encephalomyelitis). In most cases, symptoms have an acute to subacute onset and are accompanied by evidence of inflammation in the cerebrospinal fluid (CSF). Pathogenesis is mediated by cytotoxic T cells and neuronal degeneration. (See 'High-risk antibodies (>70 percent cancer association)' above.)

Examples of classic paraneoplastic encephalitis syndromes include anti-Hu encephalomyelitis, often associated with small cell lung cancer (SCLC), Ma2-associated encephalitis related to testicular cancer, and anti-collapsin-responsive mediator protein 5 (CRMP5) encephalomyelitis related to SCLC or thymoma (table 1).

•Associated with antibodies against intracellular neuronal proteins, low cancer association – These antibody-associated disorders are rarely associated with cancer, but they appear to be mediated by cytotoxic T cell mechanisms rather than direct antibody-mediated effects. Examples include anti-glutamic acid decarboxylase 65 kilodalton isoform (GAD65) and anti-adenylate kinase 5 (AK5) encephalitis. (See 'Low-risk antibodies (<30 percent cancer association)' above.)

●Diagnostic approach – Patients with suspected autoimmune encephalitis (table 5) should have neuroimaging (image 1), EEG, lumbar puncture, and CSF and serum neuronal antibody testing (table 1). Detection of specific antineuronal antibodies establishes the diagnosis of autoimmune encephalitis in patients with a characteristic clinical syndrome. (See 'Diagnostic approach' above and 'Diagnostic criteria' above.)

However, initial treatment decisions are often required while antibody results are pending. A provisional diagnosis of autoimmune encephalitis can be made based on the medical history and clinical features, laboratory and radiologic evidence of central nervous system (CNS) inflammation, and exclusion of infection and other alternative etiologies. (See 'Clinical evaluation and imaging' above.)

●Differential diagnosis – In all patients, it is critical to consider alternative etiologies for the encephalitis syndrome (table 4). The differential diagnosis includes a variety of alternative causes of encephalitis and encephalopathy. Broad categories include infection, toxic and metabolic disturbances, vascular disorders, neoplastic disorders, demyelinating and inflammatory disorders, psychiatric disease, neurodegenerative dementias, and rare heritable or metabolic disorders. (See 'Differential diagnosis' above.)