Continuing Education Activity

Autoimmune encephalitis is an immune-mediated cause of central nervous system inflammation that may present with nonspecific neuropsychiatric symptoms, seizures, movement disorders, autonomic dysfunction, or altered consciousness. Delayed recognition can lead to missed opportunities for early immunotherapy, tumor screening, relapse prevention, and complication reduction. Current practice may not consistently distinguish autoimmune encephalitis from infectious, toxic, metabolic, neurodegenerative, or psychiatric conditions, particularly when antibody testing is delayed or initially unavailable. This continuing medical education activity addresses that gap by reviewing clinical syndromes, consensus diagnostic criteria, appropriate serum and cerebrospinal fluid testing, neuroimaging and electroencephalography findings, malignancy screening, and stepwise immunotherapy. Participants will gain actionable strategies to improve diagnostic accuracy, initiate timely treatment, monitor for relapse and cognitive sequelae, and coordinate interdisciplinary care among neurology, rheumatology, oncology, internal medicine, pharmacy, and surgical specialists.

Objectives:

• Identify clinical features that raise suspicion for autoimmune encephalitis in patients with acute to subacute neuropsychiatric or neurologic symptoms.
• Differentiate autoimmune encephalitis from infectious, toxic, metabolic, neurodegenerative, oncologic, and primary psychiatric mimics.
• Interpret neuroimaging, cerebrospinal fluid, and electroencephalography findings in the diagnostic evaluation of autoimmune encephalitis.
• Collaborate with neurology, rheumatology, oncology, internal medicine, pharmacy, and surgical specialists to support timely diagnosis, treatment, surveillance, and patient education.

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Introduction

Autoimmune encephalitis is an immune-mediated condition that causes central nervous system (CNS) inflammation and is one of the most common causes of noninfectious encephalitis. In the past decade, autoimmune encephalitis has emerged as a differential diagnosis when a classic infection cannot explain focal neurological symptoms. Although the exact mechanism of autoimmune encephalitis is unknown, results from studies suggest that autoimmune antibodies target CNS proteins, leading to widespread inflammation.[1]

Autoimmune encephalitis commonly presents with new-onset acute to subacute neurologic symptoms, including encephalopathy, behavioral changes, psychosis, and seizures. Clinical symptoms develop over a few weeks to 3 months. Autoimmune encephalitis involves several parts of the nervous system, including the limbic system, the spinal cord, and the entire neuraxis. Autoimmune encephalitis can be confirmed by multiple modalities, including laboratory testing (antibody detection in serum and cerebrospinal fluid [CSF]), neuroimaging, and electroencephalography. Antibody-negative autoimmune encephalititis can occur when the patient's clinical presentation is consistent with autoimmune encephalititis, but no identifiable autoantibodies are found.

Autoimmune encephalitis can also be associated with underlying malignant neoplasms. Therefore, once the diagnosis is established, patients should undergo cancer screening because of the high degree of association with underlying malignant neoplasms. Clinicians should initiate treatment early when clinical suspicion for autoimmune encephalitis is high because patients often respond and achieve significantly improved outcomes. The current review describes the current state of knowledge on various types of autoimmune encephalititis and provides a concise, up-to-date summary.

Etiology

Although the exact mechanism remains under investigation, autoimmune encephalitis is thought to involve an exaggerated immune response to neuronal self-antigens. Unlike paraneoplastic encephalitis, which is a T-cell-mediated response, antibodies in autoimmune encephalitis are intrinsically pathogenic. These antibodies induce inflammation by targeting specific neuronal proteins. When bound to target proteins, these antibodies induce conformational changes that lead to an inflammatory response. Forms of autoimmune encephalitis associated with cell-surface antigens respond to immunotherapy and tend to affect the limbic system. Conversely, forms of autoimmune encephalitis associated with intracellular antigens respond poorly to immunosuppression and tend to cause widespread inflammation.[1]

Epidemiology

Results from a population-based study from Olmsted County, Minnesota, found the incidence of autoimmune encephalitis to be approximately 0.8 to 1.2 per 100,000 person-years, with a prevalence of 13.7 per 100,000, comparable with infectious encephalitis (11.6 per 100,000). The incidence has increased over time (from 0.4 per 100,000 in 1995 to 2005 to 1.2 per 100,000 in 2006 to 2015), attributable to improved detection.[2] Anti–N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis now surpasses any individual viral cause of encephalitis in young persons. Anti–NMDAR and anti–leucine-rich glioma-inactivated 1 encephalitis (anti-LGI-1) are the 2 most common forms of autoimmune encephalitis.

Pathophysiology

To date, the exact mechanism of immune tolerance collapse in autoimmune encephalitis remains largely unknown. Patients with autoimmune encephalitis often have an infection as a preceding event, causing inflammation that leads to neurological symptoms. Results from case reports and observational studies suggest that herpes simplex virus encephalitis triggers an immune response, causing anti-NMDAR encephalitis.[3] Additionally, genetic factors such as human leukocyte antigen (HLA) were strongly associated with certain antibody production, causing autoimmune responses, eg, immunoglobulin-like cell adhesion molecule 5 antibody encephalitis.[4] Table 1 summarizes the most commonly reported forms of autoimmune encephalitis.[5]

Table

Table 1. Commonly Reported Autoimmune Encephalitis.

Abbreviations: ADAM23, ADAM metallopeptidase domain 23; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR2, contactin-associated protein-like 2; CLL, chronic lymphocytic leukemia; CSF, cerebrospinal fluid; DPPX, dipeptidyl-peptidase-like protein 6; FLAIR, fluid-attenuated inversion recovery; FLAMES, FLAIR-hyperintense lesions in anti-MOG-associated encephalitis with seizures; GABA, γ-aminobutyric acid; GFAP, glial fibrillary acidic protein; GluK2, glutamate kainate receptor 2; HLA, human leukocyte antigen; HSE, herpes simplex virus encephalitis; IgG, immunoglobulin G; IgLON5, immunoglobulin-like cell adhesion molecule 5; IVIG, intravenous immunoglobulin; LGI1, leucine-rich glioma-inactivated 1; MOG, myelin oligodendrocyte glycoprotein; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; NMDAR, N-methyl-D-aspartate receptor; PERM, progressive encephalopathy with rigidity and myoclonus; PSP, progressive supranuclear palsy; REM, rapid eye movement.

History and Physical

The initial clinical presentation is often vague and nonspecific. Thus, if the clinician has a sufficient index of suspicion, the diagnostic evaluation should be initiated, including multiple modalities such as imaging, serology, CSF analysis, and electroencephalography (EEG). The presentation varies from typical limbic system involvement to syndromes with complex neuropsychiatric manifestations. Certain forms of autoimmune encephalitis have specific clinical syndromes.

Approximately 70% of patients have prodromal manifestations, including headache, fever, and viral-illness–like symptoms. Clinical presentation involves an acute to subacute onset of memory deficits, altered mental status, behavior changes, psychosis, orofacial dyskinesia, hallucinations, agitation, delusions, catatonia, seizures, or abnormal movements. Patients with autoimmune encephalitis may have a fluctuating clinical course with interval improvement.[29] Psychiatric manifestations can make diagnosis difficult.

Patients might develop a decreased level of consciousness or central hypoventilation requiring mechanical ventilation. Review of systems should include questions about fever, weight loss, night sweats (B symptoms), and oncologic history. A complete neurological examination is vital to evaluate for focal neurological deficits and rule out other possible causes of encephalitis.

Evaluation

Diagnosing autoimmune encephalitis can be difficult because the average time from symptom onset to diagnosis often takes a few weeks to 3 months. Infectious encephalitis can be fatal and should always be excluded from the differential diagnosis before considering autoimmune encephalitis. Even after eliminating other potential causes, diagnosing autoimmune encephalitis can be difficult. Diagnosing autoimmune encephalitis requires multiple diagnostic tools and clinical judgment, including assessment for various neuropsychiatric symptoms, laboratory tests, neuroimaging, and electroencephalography. Therefore, a group of experts generated consensus diagnostic criteria to help clinicians diagnose autoimmune encephalitis. The following criteria were adopted for the evaluation of a possible diagnosis of autoimmune encephalitis:

• Subacute onset (usually within a few weeks but less than 3 months) with a change in the level of consciousness or personality; limbic system involvement, including working memory deficits, lethargy, or psychiatric manifestations. At least 1 of the following:

  • New focal clinical central nervous system findings
  • Seizures not explained by a previously diagnosed seizure disorder
  • Cerebrospinal fluid pleocytosis (> 5 white blood cells per mm³)
  • Brain MRI findings suggestive of encephalitis
•       Reasonable exclusion of possible alternative causes*[30]

All 3 criteria must be met. Brain MRI findings include increased signal on T2-weighted fluid-attenuated inversion recovery (FLAIR) sequence images seen in one or both medial temporal lobes (limbic encephalitis) or multifocal areas involving gray or white matter compatible with demyelination or inflammation.

Definite Diagnosis of Autoimmune Limbic Encephalitis

Subacute onset of symptoms (< 3 months) involving the limbic system (memory deficits, neuropsychiatric symptoms, or seizures)

• MRI brain findings are suggestive of an abnormality highly restricted to the bilateral medial temporal lobes on T2-weighted FLAIR images
• One of the following is present:

  • CSF pleocytosis (> 5 white blood cells per mm³)
  • Electroencephalography findings are suggestive of slow-wave or epileptic activity corresponding to the temporal lobes
• Reasonable exclusion of alternative causes*

*Possible causes include infectious meningoencephalitis, septic encephalopathy, metabolic encephalopathy, toxins, cerebrovascular disease, neoplasms, Creutzfeldt-Jakob disease, epileptic disorders, Hashimoto encephalopathy, autoimmune disorders, mitochondrial or metabolic storage disorders.

Both serum and cerebrospinal fluid testing are recommended. In general, cerebrospinal fluid testing is more sensitive and specific for most neuronal cell-surface antibodies, except for anti–leucine-rich glioma-inactivated 1 (LGI1) and anti–contactin-associated protein-like 2 (CASPR2), which are more sensitive in the serum. If initial testing for both serum and cerebrospinal fluid is not feasible, experts recommend testing for the following in serum: leucine-rich glioma-inactivated 1 (LGI1), glutamic acid decarboxylase 65 (GAD65), immunoglobulin-like cell adhesion molecule 5 (IgLON5), glycine receptor (GlyR), voltage-gated calcium channel (VGCC); the following in cerebrospinal fluid: N-methyl-D-aspartate receptor (NMDAR), glial fibrillary acidic protein (GFAP), Kelch-like protein 11 (KLHL11); and the following in both serum and cerebrospinal fluid: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), dipeptidyl-peptidase-like protein 6 (DPPX), contactin-associated protein-like 2 (CASPR2), and γ-aminobutyric acid B receptor (GABA-B).[31]

If all 4 criteria are met, a definitive diagnosis can be made. If 1 of the first 3 criteria does not match, a diagnosis of definite limbic encephalitis can be made only in the presence of antibodies against cell-surface, synaptic, or onconeural proteins. Antibodies should be detected both in serum and CSF for diagnosis.

Antibody testing methods also affect the accuracy of results. Complementary assays (eg, live- or fixed-cell-based assays with adjunctive immunohistochemical tissue-based assays) have lower false-positive rates than single-assay methods. Live cell-based assays use native antigen and therefore are more likely to yield meaningful results than fixed assays.[5] Following diagnosis, screening for malignant neoplasms is necessary. Coexisting malignant neoplasms correlate with the clinical subtype of autoimmune encephalitis. The best initial step is to perform a CT scan of the chest, abdomen, and pelvis to look for pulmonary, abdominal, or urogenital malignant neoplasms. Women should undergo gynecological examinations with breast and ovarian ultrasonography or MRI based on sensitivity and clinical judgment. Similarly, men should undergo testicular ultrasonography as part of the urological evaluation. If the above imaging does not yield any findings, a whole-body 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) should be considered.

Treatment / Management

The treatment options for autoimmune encephalitis include immunosuppression and, if applicable, tumor resection. The treatment regimen is based on principles of autoimmune disease treatment, with the aim of depleting pathogenic antibodies. Clinicians should not delay treatment until antibody detection because early initiation is associated with improved outcomes. An interdisciplinary team, including autoimmune neurologists, rheumatologists, and oncologists, should be involved in treating autoimmune encephalitis.

Results from expert consensus data showed that 84% of specialists select corticosteroids alone or in combination with intravenous immunoglobulin (IVIG) or plasmapheresis as first-line therapy. Dosing for corticosteroids is 1 g of intravenous methylprednisolone for 3 to 5 days, IVIG at 0.4 g/kg/d for 5 days, and plasmapheresis alone or in combination.[32] Corticosteroids are often the initial treatment, are frequently combined with either IVIG or plasma exchange, and are considered first-line therapies.[5] Plasmapheresis should be considered when patients have severe dysautonomia, refractory seizures, or central hypoventilation syndrome.

Second-line immunotherapy can be initiated with or after first-line therapy when patients do not improve with first-line regimens. Rituximab is now the preferred second-line agent, chosen by 80% of experts, compared with cyclophosphamide (10%). Results from a survival analysis demonstrated that rituximab use was associated with a 71% lower hazard of time to first relapse (HR, 0.29; 95% CI, 0.09-0.85).[33]. Rituximab (375 mg/m² for 4 weeks) is also the most popular maintenance therapy (46% of experts).[34] Cyclophosphamide (750 mg/m² for 6 months) may be used alone or combined in the adult population. In anti-NMDAR receptor encephalitis, combining first- and second-line therapies reduces morbidity and mortality, but second-line agents are rarely needed in anti-LRG1 autoimmune encephalitis.[35][36]

Third-Line and Refractory Therapy

Approximately 10% of patients are refractory to first- and second-line therapies.[37] Options for refractory cases include:

• Tocilizumab (IL-6 receptor antagonist): Results from small retrospective studies suggested better outcomes at 24 months compared with continued rituximab in treatment-refractory cases
• Bortezomib (proteasome inhibitor): Plasma cell–depleting agent with mixed evidence
• Daratumumab (anti-CD38): Emerging plasma cell–depleting agent
• Other emerging therapies: Intrathecal methotrexate, natalizumab, low-dose IL-2, anakinra, and tofacitinib [38][39]

However, if an underlying malignant neoplasm is found, the patient should undergo tumor resection or chemotherapy because treatment accelerates improvement and prevents relapses.[7]

Differential Diagnosis

Because of its variable presentation, autoimmune encephalitis can mimic other conditions. Most patients develop additional syndromic features within days or weeks. Because of the initial prodrome of fever and headache, infectious causes of meningoencephalitis must be ruled out. Cognitive and behavioral changes should prompt a diagnostic evaluation for toxic, metabolic, oncologic, and neurodegenerative causes, including rapidly progressive dementia. Focal neurological deficits should prompt evaluation for stroke and seizures. Patients must undergo a thorough physical examination, along with neuroimaging and laboratory testing, for diagnosis.[40]

Some autoimmune encephalitides have early and prominent psychiatric manifestations (eg, anti-NMDA receptor encephalititis), leading to admission to an inpatient psychiatric unit. Clinicians should focus on the disease's clinical progression, as these patients develop additional features of the syndrome within days to a few weeks. Careful examination may reveal subtle neurologic deficits that serve as clues to autoimmune encephalitis. Patients may present with a demyelinating disorder (eg, multiple sclerosis) or autoimmune disease (eg, lupus or neurosarcoidosis) that has multisystem involvement and should be appropriately evaluated with cerebrospinal fluid studies and neuroimaging. Neurodegenerative diseases such as Alzheimer disease usually have a chronic course and should be further evaluated with neuroimaging, although they rarely can present as rapidly progressive dementia. Rarely, inherited and metabolic disorders can cause neuropsychiatric manifestations with a positive family history that require further study.

Prognosis

As noted above, autoimmune encephalitis usually responds to immunosuppression and tumor removal, although staging of the cancer is independently associated with adverse outcomes. Results from an observational cohort study showed that 94% of patients received first-line therapy with immunosuppression or tumor removal, resulting in improvement within 4 weeks (53%), with most patients having good outcomes in the first 24 months. Outcomes continue to improve up to 18 months from symptom onset. Predictors of good outcomes included early treatment and no requirement for intensive care unit admission.[7] 

Long-Term Outcomes 

Cognitive recovery may continue for up to 3 years after diagnosis, with the most improvement in the first 6 months.[41] However, beyond 36 months:

• 34% of patients have persistent cognitive impairment (z-score of −1.5 standard deviations), and 65% score below average in at least 1 cognitive domain, despite favorable modified Rankin Scale (mRS) scores (≤ 2) in 91% of patients. [41]
• Memory and language are the most affected domains in the long term.[42]
• The mRS does not fully capture outcomes because cognitive deficits, emotional well-being, social functioning, and energy levels can be impaired even with favorable scores.[43][44]
• 30% of patients do not resume school or work, and 18% require accommodations.[42]
• Predictors of poor cognitive outcome include delayed treatment, higher disease severity, and longer duration of the acute phase.[42]

Patients need to be monitored closely after recovery to evaluate for relapse. Recommendations suggest surveillance imaging at 4- to 6-month intervals for at least 4 years. Overall, cell-surface antibodies are associated with a better prognosis than intracellular antibodies.

Complications

Although autoimmune encephalitis is often responsive to treatment, delayed or absent treatment can lead to serious complications. Complications include cognitive impairment, sleep disorders, hyperkinesia, autonomic dysfunction, persistent amnesia (anti–leucine-rich glioma-inactivated 1 encephalitis), coma, and status epilepticus. Results from a retrospective study by Xu et al found that central hypoventilation syndrome is a key risk factor for mechanical ventilation during hospitalization in patients with anti–NMDAR encephalitis and requires close monitoring.[45]

Deterrence and Patient Education

Patient education is necessary to understand the condition's etiology, onset, and progression; its strong association with underlying malignant neoplasms; treatment; and prognosis. Patients should be educated about the variable course of the disease, which may lead to a delay in diagnosis. Furthermore, patients should be encouraged to follow up with their neurologist or oncologist after hospital discharge due to concerns about relapse and screening for malignant neoplasms.

Patients with autoimmune encephalitis should undergo imaging every 6 months for at least 4 years to look for any tumor growth or metastasis, which might not be evident early and can lead to neurological manifestations. Families should be involved in clinical interviews whenever possible, because they may notice unusual changes in the patient's behavior or possible seizures. Moreover, patients should be educated about the adverse effects of chronic therapy with corticosteroids and the role of immunosuppressive treatment, which may put them at risk of infection or systemic adverse effects.

Enhancing Healthcare Team Outcomes

A variable clinical presentation encompasses autoimmune encephalitis with varying disease progression levels that require the expertise of multiple specialists. Clinicians involved in the treatment of autoimmune encephalitis need to be well informed about the condition to ensure the patient receives the most appropriate care. The treatment of autoimmune encephalitis is complex and requires expert opinion from a neurologist, rheumatologist, internist, an oncologist, surgical oncologist, and pharmacist, all functioning as a cohesive, interprofessional team. Long-term follow-up is essential, even after full recovery, because of the potential for relapse, adverse effects of immunotherapy, and tumor screening secondary to autoimmune encephalitis. With proper treatment, the patient should be able to make a full recovery and maintain remission.

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Disclosure: Amritpal Anand declares no relevant financial relationships with ineligible companies.

Disclosure: Chichun Sun declares no relevant financial relationships with ineligible companies.