Autoimmune (including paraneoplastic) encephalitis: Management

INTRODUCTION — Autoimmune encephalitis is a heterogeneous entity that includes paraneoplastic, idiopathic, drug-induced, and postviral causes, often but not always in association with antibodies against either intracellular or cell-surface neuronal antigens. Patients can have severe and wide-ranging manifestations that include mental status changes, psychiatric symptoms, seizures, movement disorders, sleep disruption, dysautonomia, and hypoventilation.

The mainstay of treatment is immunomodulatory therapy to stop the immune-mediated attack and ameliorate brain inflammation. Admission to the intensive care unit is needed in a substantial number of patients to manage severe dysautonomia, central hypoventilation, and/or status epilepticus.

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

Other inflammatory disorders of the central nervous system 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')

PRETREATMENT EVALUATION

Pathogenic mechanism — Autoimmune encephalitis is a heterogeneous entity that includes paraneoplastic, idiopathic, drug-induced, and postviral causes. Pathogenesis is thought to be mediated by one of two mechanisms: antibody-mediated (humoral) effects, largely involving B cells, or cell-mediated effects, largely involving T cells. The distinction is important for selecting appropriate immunomodulatory therapy.

●Antibody-mediated – An antibody-mediated mechanism is suspected in many cases of idiopathic autoimmune encephalitis, especially those associated with antibodies against neuronal cell-surface or synaptic proteins (eg, anti-N-methyl-D-aspartate [NMDA] receptor, anti-leucine-rich glioma inactivated 1 [LGI1] protein). In the three-tier classification system of antibodies associated with autoimmune encephalitis syndromes, all of the intermediate and most of the lower-risk antibodies target cell-surface antigens and are thought to be directly pathogenic via antibody-mediated effects (table 1).

●T cell-mediated – A T cell-mediated mechanism is likely in cases of classic paraneoplastic encephalitis associated with antibodies against intracellular neuronal proteins (eg, anti-Hu, anti-Ri). Such high-risk onconeuronal antibodies (table 1) are not considered to be directly pathogenic. Rather, damage is mediated by cytotoxic T cells and can result in irreversible neuronal degeneration. Most cases of iatrogenic autoimmune encephalitis in the setting of immune checkpoint inhibitors (ICIs) are likely T cell-mediated as well. (See 'Triggers (tumor, infection, drugs)' below.)

●Unknown – The pathogenesis of antibody-negative autoimmune encephalitis (no associated cancer or detectable antibody) is unknown, and the relative contribution of antibody- versus T cell-mediated pathology is therefore unclear.

In most cases, initiation of immunomodulatory therapy takes place before the results of the neuronal antibody panel are known. In this setting, clinicians should use indirect clues to a suspected pathogenic mechanism. As an example, antibody-mediated pathology can be presumed in patients with faciobrachial dystonic seizures (suggestive of anti-LGI1 encephalitis) [1] and in patients with a clinical picture typical of anti-NMDA receptor encephalitis (table 2) [2]. Clinical features of these and other antibody-mediated encephalitides are reviewed separately. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Neuronal cell-surface protein antibody syndromes'.)

T cell-mediated pathology can be presumed in patients with known cancer or who have high cancer risk, since most of the classic paraneoplastic syndromes are T cell-mediated. There are exceptions, however, most notably among the intermediate-risk and low-risk antibody syndromes (table 1), which are thought to be antibody-mediated whether or not an associated cancer is present (eg, anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] receptor, and anti-gamma-aminobutyric acid B [GABA-B] receptor).

Triggers (tumor, infection, drugs) — Potential triggers of autoimmune encephalitis should be treated promptly to hasten neurologic recovery. These include treatment of the associated tumor in paraneoplastic cases, treatment of active infections in parainfectious cases (eg, herpes simplex virus encephalitis) (see "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Association with HSVE'), and removal of any potential iatrogenic triggers (eg, ICIs). (See "Toxicities associated with immune checkpoint inhibitors", section on 'Neurologic'.)

In patients with acute and severe presentations of encephalitis, empiric antimicrobial therapy is appropriate to cover herpes simplex virus (HSV)-1 infection and other major pathogens. Antibiotics and acyclovir can generally be discontinued if cerebrospinal fluid (CSF) bacterial cultures and HSV polymerase chain reaction (PCR) studies return negative. (See "Viral encephalitis in adults", section on 'Empiric therapy'.)

Severity and care setting — Most patients with autoimmune encephalitis are acutely ill, and initial immunomodulatory therapy is delivered in the inpatient setting. Symptomatic treatment is often needed for symptoms including psychosis, agitation, seizures, involuntary movements, and sleep dysfunction. Patients with severe complications, including dysautonomia, central hypoventilation, and/or status epilepticus, require admission to the intensive care unit. (See 'Supportive care' below.)

ANTITUMOR THERAPY — Prompt and adequate treatment of the underlying tumor is fundamental in paraneoplastic neurologic syndromes, as it removes the origin of the aberrant immune response.

Tumor present — In many patients with paraneoplastic encephalitis, neurologic symptoms are resistant to immunomodulatory therapy alone, especially when a classic onconeuronal antibody is present (table 1) [3]. Multidisciplinary care is critical to identify the most appropriate antitumor treatment based on tumor type, stage, and patient characteristics.

Improvement or stabilization has been described after tumor treatment in patients with paraneoplastic encephalitis or encephalomyelitis [3,4] as well as those with other paraneoplastic neurologic syndromes, such as opsoclonus-myoclonus-ataxia syndrome [5]. While outcomes are generally poor in paraneoplastic cerebellar degeneration (especially those associated with anti-Yo antibodies) [6,7], individual patients have shown benefit.

For patients with metastatic disease, debulking surgery or palliative radiation therapy or chemotherapy may reduce the inappropriate immune drive, resulting in neurologic improvement [8]. Of note, the performance status (eg, Karnofsky Performance Status [KPS] (table 3)) is often poor based on the paraneoplastic neurologic symptoms rather than direct effects of the cancer. Low KPS scores in this setting should not be used to postpone or withhold aggressive oncologic management until neurologic symptoms improve. On the contrary, especially in patients with classic onconeuronal antibodies, immunomodulatory therapy without concomitant tumor treatment is rarely effective.

For patients with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, resection of an associated ovarian or testicular teratoma is essential to accelerate remission, in combination with immunomodulatory therapy [9]. Similar principles likely apply to other antibody-mediated syndromes with an associated tumor, although data are limited by their rarity.

Tumor absent on initial screening — Repeat cancer screening is warranted in patients with a paraneoplastic syndrome who do not have a malignancy detected at the time of initial presentation. The extent and frequency of repeat screening are dictated by the clinical phenotype and antibody identified (table 4) [10,11]. This evaluation is reviewed separately. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Search for occult malignancy'.)

In highly selected scenarios when the suspicion for a paraneoplastic origin is very high and the clinical course is severe but screening investigations are nonspecific or unrevealing, explorative surgery can be considered. The main examples are as follows:

●Males <50 years of age with Ma2 antibodies – In male patients younger than 50 years of age, there is a very strong association between anti-Ma2 antibodies and testicular tumors, most commonly germ cell tumors. This has led some clinicians to advocate ‘blind’ orchiectomy for suspected microscopic tumor in carefully selected patients with Ma2 antibodies and a paraneoplastic neurologic syndrome in whom no tumor is found after initial screening. In a retrospective study of six such patients with risk factors for a testicular malignancy (new testicular enlargement or risk factors for a germ cell tumor, such as cryptorchidism or microcalcifications on testicular ultrasound) but no overt evidence of cancer on initial screening, pathologic examination showed intratubular germ cell neoplasms in all six [12]. Four of these six patients showed partial neurologic improvement and prolonged stabilization.

●Females with anti-NMDA receptor encephalitis – In females of reproductive age, half of anti-NMDA receptor encephalitis cases are associated with an ovarian teratoma [13], which can be microscopic [14]. Therefore, every imaging abnormality should be considered carefully in these patients. For those with negative initial screening who are extremely refractory to immunomodulatory therapy, pelvic/abdominal imaging should be repeated to search for subtle abnormalities that may indicate a small or microscopic teratoma. In such cases with subtle potential abnormalities, exploratory laparotomy may be considered.

By contrast, blind bilateral oophorectomy despite negative pelvic imaging for teratoma is generally not useful and should only be considered in exceptional patients with extremely severe and refractory clinical picture and after exhausting every effort to identify one affected ovary. This necessitates extensive discussion of the potential benefits and risks, including sterilization, with the family and caregivers [14]. Often, patients who continue to be symptomatic after unilateral oophorectomy and sufficient immunomodulatory therapy simply need longer to recover. Assumption of a microscopic teratoma in the remaining normal ovary is often speculative and may cost a young patient her fertility if an unnecessary resection of a normal ovary is undertaken.

Several female patients have been reported with anti-NMDA receptor encephalitis and immunomodulatory therapy-refractory disease who have had good outcomes after empiric oophorectomy despite pelvic imaging that was considered negative [14]. However, natural history and late response to immunomodulatory therapies could have confounded the apparent response after oophorectomy. Nevertheless, microscopic teratomas were identified in at least some of these patients, which suggested a direct paraneoplastic association.

INITIAL IMMUNOMODULATORY THERAPY

Timing — Immunomodulatory therapy should be started as soon as possible. Delayed treatment is one of the factors most consistently associated with poor outcomes after autoimmune encephalitis [15,16].

It is unnecessary and potentially harmful to wait for results of the neuronal antibody panel before starting treatment. In patients meeting criteria for definite autoimmune limbic encephalitis (table 5), probable anti-N-methyl-D-aspartate(NMDA) receptor encephalitis (table 2), or probable anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis, immunomodulatory therapy can be started once infectious causes have been ruled out based on preliminary cerebrospinal fluid (CSF) results (table 6) [17]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Diagnostic approach'.)

In patients not meeting these criteria, a thorough evaluation for alternative causes or consultation with a neuroimmunologist is advisable before starting empiric immunomodulatory therapy.

Goals and response assessment — The goal of acute immunomodulatory therapy is to achieve maximal clinical response by suppressing the pathogenic immune response. Response should be assessed clinically by history and neurologic examination at regular intervals based on clinical acuity (eg, daily during initial immunomodulatory therapy, weekly if rituximab is being administered, every one to three months during a taper). Patients with baseline neuroimaging abnormalities should have repeat imaging within the first three months, although radiologic improvement may lag behind clinical recovery. Electroencephalography (EEG) improvement may also indicate a favorable response to immunomodulatory therapy.

An adequate clinical response to first-line immunomodulatory therapy is not formally defined and varies based not only on the symptom complex but also on the antibody syndrome. Some symptoms take longer than others to improve. Examples of an adequate clinical response may include improvement in mental state, cessation of status epilepticus or decreased frequency of seizures, achievement of autonomic stability, resolution of dangerous hyperkinetic movements, or resolution of agitation and psychosis.

Serial antibody testing is not generally helpful in assessing response. While some laboratories may provide quantification of antibody levels, antibody burden has not been validated as an indicator of treatment response. It may be reasonable to repeat antibody levels when a patient has reached clinical remission so that a baseline is available for comparison if the patient relapses or otherwise worsens clinically. Antibodies may also be useful to help interpret the significance of ongoing symptoms after initial therapy. (See 'Patients with refractory disease' below.)

Selection of initial therapy — Based on clinical experience, case series, and indirect evidence from other autoimmune disorders, high-dose glucocorticoids, intravenous immune globulin (IVIG), and therapeutic plasma exchange (TPE) are all considered first-line immunomodulatory therapies for confirmed or suspected autoimmune encephalitis, and rituximab and cyclophosphamide are the most common second-line therapies [18]. Absent randomized trials, selection of a specific regimen is based on mechanism of disease and clinical severity (algorithm 1).

Antibody-mediated mechanism — For all patients with a known or suspected antibody-mediated mechanism of autoimmune encephalitis (table 1), we suggest initial treatment with high-dose glucocorticoids. In addition, we suggest concurrent use of IVIG or TPE in patients with any of the following risk factors for worse outcomes:

●Severe disease (eg, respiratory failure, severe dysautonomia, refractory status epilepticus)

●Definite or probable anti-NMDA receptor encephalitis (table 2)

The choice between IVIG and TPE in combination with steroids is individualized and may vary by center. IVIG is often favored because it is more readily available and does not require a central line. TPE is an alternative to IVIG when there are relative contraindications to IVIG, such as high thromboembolic risk or severe hyponatremia. Administration and outcomes are reviewed below. (See 'Glucocorticoids' below and 'Intravenous immune globulin' below and 'Therapeutic plasma exchange' below.)

For patients selected for glucocorticoids alone who do not improve by 14 days from the start of the steroid course or do not tolerate high-dose steroids, we start IVIG or TPE. For those who have received concurrent high-dose steroids and IVIG/TPE initially and do not respond adequately by 14 days, we suggest starting a second-line therapy (eg, rituximab) rather than administering a second round of the first-line therapy [18]. A minority of experts (15 percent) favor use of rituximab initially in combination with steroids and/or IVIG/TPE, rather than stepwise escalation [18]. Before each escalation step, it is important to review the diagnosis and reconsider alternative diagnoses.

If there is no improvement following rituximab (eg, four weeks after first dose), we begin cyclophosphamide. In severe cases, cyclophosphamide may be started at the same time as rituximab. In children, tocilizumab may be an alternative third-line agent; in adults, we prefer cyclophosphamide because it has more evidence to support its use than tocilizumab and other investigational therapies. (See 'Cyclophosphamide' below and 'Patients with refractory disease' below.)

T cell-mediated mechanism — For most patients with a known or suspected T cell-mediated mechanism, including those with immune checkpoint inhibitor (ICI)-associated encephalitis, we suggest high-dose glucocorticoids alone as first-line therapy. We do not use IVIG or TPE initially in most of these patients, as long as a T cell-mediated mechanism is likely based on clinical clues. However, some experts favor combination therapy in all patients with severe presentations for whom a mechanism has not yet been confirmed by antibody testing results, in order to address both antibody-mediated and T cell-mediated mechanisms [18]. (See 'Pathogenic mechanism' above.)

For patients with a poor response to high-dose glucocorticoids, the likelihood of T cell- versus antibody-mediated pathology should be reassessed based on additional testing results. If a classic onconeuronal antibody syndrome has been confirmed, our preferred second-line therapy is cyclophosphamide (see 'Cyclophosphamide' below). For severely affected patients whose antibody results remain pending, a course of IVIG or TPE is reasonable before considering cyclophosphamide. If an antibody against a cell-surface antigen such as gamma-aminobutyric acid B (GABA-B) receptor or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor has been identified, preferred therapies for escalation are IVIG, TPE, and/or rituximab. (See 'Antibody-mediated mechanism' above.)

Checkpoint inhibitor-associated — In the subset of patients with ICI-associated autoimmune encephalitis, cancer immunotherapy (table 7) should be stopped. Most patients respond well to high-dose glucocorticoids [19,20]. For those with an inadequate response to steroids, or for those with a particularly severe syndrome at presentation, IVIG or TPE is reasonable to add (table 8), even if an antibody-mediated mechanism has not been confirmed. Rituximab may be considered in refractory cases or when a neuronal antibody has been detected.

Encephalitis is usually considered to be a moderate to severe (grade 3 or 4) immune-related adverse event, which warrants permanent discontinuation of ICI therapy [21,22]. Rechallenge with an ICI may be carefully considered in selected cases but would require extensive counseling and consideration of risks and benefits of tumor progression versus recurrence of neurologic symptoms. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Retreatment after prior toxicity'.)

Antibody-negative (unknown) — For patients with antibody-negative autoimmune encephalitis (ie, no neuronal antibody detected and no cancer), we use the same approach as outlined above for antibody-mediated encephalitis (see 'Antibody-mediated mechanism' above). If there is no response to stepwise therapy including rituximab, or if a cancer is diagnosed subsequently, we consider cyclophosphamide.

In regions where neuronal antibody testing is not available but autoimmune encephalitis is highly suspected, first-line agents can be used, but only after a thorough exclusion of alternative diagnoses. It should be noted that the likelihood of autoimmune encephalitis in such regions is unknown and is probably different from the likelihood reported in the published literature from centers with access to testing [23]. If the patient is refractory to first-line therapy, we advise consultation with reference laboratories and neuroimmunology experts before starting second-line therapy.

Administration of specific therapies

Glucocorticoids — A typical high-dose steroid regimen used for known or suspected autoimmune encephalitis in adults is intravenous methylprednisolone (IVMP) 1000 mg daily for 3 to 7 days [16-18]. The recommended weight-based dose of IVMP for children is 20 to 30 mg/kg/day (maximum 1000 mg per day) for 3 to 5 days [16].

We prefer pulsed IVMP over daily oral glucocorticoids for acute therapy because it allows for a clearer determination of clinical response and helps to avoid the side effects and interactions of long-term daily steroids in patients who are not deriving benefit. Shorter courses (eg, 1000 mg daily for 1 to 3 days) are often used for subsequent pulses in the setting of an extended taper. There are no data to inform superiority of one dosing schedule or formulation over another.

Clinicians should be aware that steroid psychosis may mask treatment response in encephalitis patients with psychiatric presentations. We do not consider psychosis to be a contraindication to use of high-dose glucocorticoids with appropriate monitoring and supportive care; in some cases, psychosis improves dramatically with steroids. Uncontrolled diabetes or hypertension are relative contraindications to use. Additional side effects and safety monitoring are reviewed separately. (See "Major adverse effects of systemic glucocorticoids".)

High-dose glucocorticoids have long been used to treat suspected autoimmune encephalitis based on their broad and rapid immunosuppressive effects. In a survey of 68 members of the Autoimmune Encephalitis Alliance Clinicians Network, glucocorticoid therapy alone or combined with other first-line agents was the most frequently selected option (selected by 84 percent of network members) for initial treatment of patients with an unspecified autoimmune encephalitis presentation [18]. Glucocorticoid therapy was also the most frequently selected option for patients with anti-NMDA receptor, anti-LGI1, and paraneoplastic encephalitis presentations.

Some subtypes of autoimmune encephalitis tend to be highly responsive to glucocorticoids as monotherapy. These include anti-LGI1 encephalitis [24], anti-glial fibrillary acidic protein (GFAP) encephalomyelitis [25], and ICI-associated encephalitis [21,26].

Intravenous immune globulin — Dosing of IVIG for autoimmune encephalitis is not standardized. A common approach is to administer a dose of 2 g/kg divided over two to five days [13,18]. The dose is the same whether IVIG is being used in combination with high-dose glucocorticoids for severe presentations or, uncommonly, as initial monotherapy in patients with a contraindication to glucocorticoids (for example, anti-glutamic acid decarboxylase [GAD65] encephalitis with concomitant poorly controlled type 1 diabetes mellitus [27]).

The increased risk of thromboembolism might complicate the use of IVIG in patients with paraneoplastic encephalitis, in whom the thromboembolic risk is already increased because of underlying cancer. Aggressive mechanical and chemical prophylaxis against deep vein thrombosis can reduce this risk when the use of IVIG is necessary in such patients. New or worsening hyponatremia is a potential concern with IVIG, especially in patients with anti-LGI1 encephalitis who may present with hyponatremia [1]. However, this complication is rare in our experience. Administration and toxicities of IVIG are reviewed in detail separately. (See "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects".)

Most of the evidence supporting use of IVIG comes from studies in patients with autoimmune encephalitis due to specific antibodies such as anti-NMDA receptor or anti-LGI1, and the timing of administration varies. Data on IVIG as monotherapy include results of a small randomized placebo-controlled trial of IVIG in 17 patients with anti-LGI1 or anti-contactin-associated protein-like 2 (CASPR2) encephalitis and seizures who enrolled within a year of symptom onset [28]. At five-week follow-up, the IVIG group was more likely to experience a ≥50 percent reduction in seizure frequency over baseline (75 versus 22 percent) [28]. By contrast, in a retrospective study of 118 patients with anti-LGI1 encephalitis, analysis of the 70 patients who received initial monotherapy with glucocorticoids (n = 49) or IVIG (n = 21) suggested that glucocorticoid monotherapy might be more effective than IVIG in this patient group in the acute phase [24].

Evidence on the role of IVIG in combination with glucocorticoids is largely retrospective [13]. A 2021 meta-analysis collected patient-level data on 1550 patients with anti-NMDA receptor encephalitis that were reported in the literature across 652 mostly retrospective studies [16]. In a multivariable analysis of 582 patients with functional outcome data available (poor outcome defined as a score of ≥3 on the modified Rankin scale), initial treatment factors associated with improved functional outcome at 12 months included use of glucocorticoids plus IVIG (odds ratio [OR] 0.37, 95% CI 0.15-0.91) and use of all three first-line agents together (OR 0.36, 95% CI 0.13-0.97).

Therapeutic plasma exchange — TPE can provide rapid removal of pathologic antibodies in the acute setting. A common regimen consists of 5 to 10 every-other-day sessions. In centers with established pathways for use, plasma exchange is a reasonable alternative to IVIG in combination with high-dose glucocorticoids or as an alternative to high-dose glucocorticoids in patients with contraindications.

The main safety considerations relate to increased risk of bleeding and line-related complications, including thromboembolism and infection. Plasma exchange can also have a negative effect on blood pressure, which can be problematic in dysautonomic patients. It is also less suitable for agitated patients, children, or those with poorly controlled hyperkinetic movement disorders. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)

Retrospective studies in anti-NMDA receptor and mixed-cause autoimmune encephalitis suggest that TPE combined with glucocorticoids is superior to glucocorticoid monotherapy [29,30]. A 2021 meta-analysis of therapeutic regimens in anti-NMDA receptor encephalitis also found that TPE alone or combined with glucocorticoids and IVIG was associated with better functional outcome at one year after presentation [16]. Anti-NMDA receptor encephalitis is considered a category I disorder based on low-quality evidence by the American Society for Apheresis, indicating that TPE is accepted as a first-line therapy alone or in conjunction with other therapeutic modalities [31]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

Rituximab — Common rituximab dosing regimens for autoimmune encephalitis include 375 mg/m² weekly for four weeks or two doses of 1000 mg given two weeks apart. Rituximab is preferred over cyclophosphamide as escalation therapy in children given its relative safety [32].

In studies of anti-NMDA receptor and mixed-type autoimmune encephalitis, the use of rituximab was associated with better functional outcomes in patients refractory to first-line agents [13,33]. This positive effect seems most pronounced in anti-NMDA receptor and anti-CASPR2 serotypes and is less robust in anti-LGI1 and anti-GAD65 serotypes [33]. The use of rituximab as a rescue therapy in the acute setting has also been associated with decreased relapse rates in patients with anti-NMDA receptor encephalitis [13,16,33].

Cyclophosphamide — Cyclophosphamide is anecdotally preferred in patients with presumed T cell-mediated pathology, including patients with confirmed or highly suspected paraneoplastic encephalitis (high-risk paraneoplastic antibody against intracellular antigens and/or cancer consistent with the clinical phenotype (table 1)) [10]. It is also used as a second- or third-line therapy in patients with known or presumed antibody-mediated pathology who do not respond adequately to first-line immunomodulatory therapy. (See 'T cell-mediated mechanism' above and 'Antibody-mediated mechanism' above.)

Dosing is mostly derived from studies in lupus cerebritis [34]. The usual dose is 600 to 750 mg/m² monthly for an average of six months. Another dosing regimen based on studies from antineutrophil cytoplasmic antibody (ANCA)-related vasculitis includes three induction courses of 15 mg/kg (minus potential dose reduction for age, leucocyte count, and kidney function) every 14 days followed by consolidation with 500 mg every two weeks or 1000 mg every four weeks for two to six months depending on recovery [35]. Since cyclophosphamide toxicity is related to its cumulative dose [36], clinicians should avoid high or extended doses of cyclophosphamide. For patients who show significant clinical improvement and have also received rituximab, only a few courses of cyclophosphamide may be needed, thus limiting toxicity.

Supporting evidence for cyclophosphamide consists mainly of clinical experience, expert opinion, and observational studies. In a prospective cohort study of over 500 patients with anti-NMDA receptor encephalitis, treatment responses were similar for cyclophosphamide, rituximab, or the combination [13].

SUBSEQUENT IMMUNOMODULATORY THERAPY

Patients with clinical response — Rapid interruption of immune suppression can result in early recurrence of autoimmune encephalitis, possibly due to incomplete clearance of the pathologic antibody [13,16]. Therefore, we suggest use of a tapering strategy once patients have achieved maximal clinical response to initial immunomodulatory therapy.

The most common tapering strategies are an oral prednisone taper, monthly intravenous methylprednisolone (IVMP), monthly intravenous immune globulin (IVIG), and rituximab. Duration is individualized but typically extends over a two- to six-month period [18]. Choice of a specific strategy is largely determined by the first-line therapy:

●Patients treated with IVMP alone – For patients who achieve clinical remission with IVMP alone, a transition to an oral prednisone taper is reasonable, starting with 0.5 to 1 mg/kg and tapering slowly over three to six months. An alternative is to repeat IVMP pulses at four-week intervals for two to six months, or with gradually spaced-out infusions over up to six months. Nonsteroid strategies (eg, IVIG, rituximab) are also an option for patients with poor tolerance for glucocorticoids.

●Patients treated with IVMP plus IVIG or therapeutic plasma exchange (TPE) – For patients who achieve clinical remission after multiple first-line agents, any of the initial agents can be selected as a tapering strategy. Monthly IVIG for up to six months (or more in patients with a history of relapse) is a strategy that avoids additional glucocorticoid exposure and toxicities, although prolonged courses of IVIG also carry risks and burdens, and the amount of data for steroids are much more extensive than for IVIG in this setting. In a meta-analysis of over 500 patients with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, monthly IVIG for six months or more was also associated with decreased risk of relapse, although the number of patients treated in this manner was small [16]. A single course of rituximab is yet another option.

●Patients treated with rituximab – Patients who receive rituximab as a second-line therapy are expected to have B cell depletion for nearly six months or longer. In this sense, rituximab acts as both a second-line therapy and a tapering strategy. In patients with anti-NMDA receptor encephalitis, large observational studies have found that patients who received rituximab as a second-line agent were less likely to relapse than those who did not receive rituximab [13,16].

●Patients treated with cyclophosphamide – Similar to rituximab, cyclophosphamide achieves more prolonged immune suppression than the first-line therapies, and a bridging strategy beyond the planned initial course of cyclophosphamide may not be needed for patients who have achieved clinical remission unless they have relapsed with prior attempts to discontinue therapy.

Patients with refractory disease — A wide range of alternative immunomodulatory agents are being explored in patients with refractory autoimmune encephalitis who have not responded to standard therapies including rituximab and/or cyclophosphamide. Among these, the interleukin-6 (IL-6) inhibitor tocilizumab has received the most attention. Participation in clinical trials is encouraged.

Of note, in patients with considerable deficits who reach a plateau, repeat antibody levels may be considered. High residual antibodies in cerebrospinal fluid (CSF) have been associated with poorer outcomes in anti-NMDA receptor encephalitis [37], suggesting a rationale for repeating or escalating immunomodulatory therapy, whereas absent antibodies would not support escalation in this context.

●Interleukin-6 (IL-6) inhibitors – IL-6 is implicated in the maturation of B cells into plasmablasts and plasma cells. It also acts as a proinflammatory cytokine and inhibits T-regulatory cells. Tocilizumab, satralizumab, and other IL-6 inhibitors could therefore be useful in the treatment of autoimmune encephalitis with antibody-mediated or T cell-mediated mechanisms.

International consensus recommendations for pediatric anti-NMDA receptor encephalitis include tocilizumab as an option for rituximab-refractory patients, based on its overall safety profile compared with cyclophosphamide [32]. Increased infection risk and neutropenia are complications of special concern, however, since IL-6 inhibition may prevent the febrile reaction and mask signs of infection. Additional safety considerations are reviewed separately. (See "Interleukin 6 inhibitors: Biology, principles of use, and adverse effects".)

Supporting data include a retrospective study of 91 patients with mixed-type autoimmune encephalitis refractory to rituximab, in which 30 patients who received tocilizumab had improved functional outcome scores at two months compared with those treated with additional rituximab or observation [38]. Another study showed that a treatment regimen consisting of teratoma removal, glucocorticoids, IVIG, rituximab, and tocilizumab (T-SIRT) in anti-NMDA receptor encephalitis might add some benefit to all other treatment combinations not including tocilizumab [39]. The T-SIRT regimen was most beneficial when completed within one month from symptom onset. However, a major limitation of both studies is that treatments were administered sequentially, and the potential benefit of tocilizumab was strongly confounded by delayed effects of earlier therapies, especially rituximab.

Satralizumab is a longer-acting IL-6 inhibitor that has regulatory approval in the United States (US) for treatment of neuromyelitis optica spectrum disorder (NMOSD). Based on its utility in NMOSD [40,41], satralizumab is being studied in an ongoing clinical trial in patients with anti-NMDA receptor or anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis (NCT05503264).

●B cell-depleting therapies – B cell-depleting therapies other than rituximab are also under investigation.

Inebilizumab is an anti-CD19 monoclonal antibody that depletes B cells as well as antibody-producing CD19-positive plasmablasts [42], which could offer an advantage over rituximab and other anti-CD20 agents. Inebilizumab has shown efficacy against early relapses in NMOSD and has regulatory approval in the US for aquaporin-4 (AQP4) antibody-positive disease [43]. A trial of inebilizumab in patients with anti-NMDA receptor encephalitis is in progress (NCT04372615).

A single-center clinical trial of ocrelizumab, a humanized anti-CD20 monoclonal antibody, as a second-line therapy for autoimmune encephalitis was aborted due to low recruitment [44].

●Bortezomib – The proteasome inhibitor bortezomib inhibits differentiation and survival of immune cells, especially plasma cells [45]. It is approved for treatment of multiple myeloma. A small retrospective study showed improvement in four out of five patients with anti-NMDA receptor encephalitis who failed to respond to conventional first- and second-line therapies [46]. A meta-analysis of 29 published cases concluded that bortezomib was associated with a favorable outcome in 55 percent of patients with refractory anti-NMDA receptor encephalitis [47]. Based on this preliminary data, a clinical trial of bortezomib in autoimmune encephalitis is recruiting (NCT03993262).

●Neonatal Fc receptor antagonists – A trial of rozanolixizumab, a monoclonal antibody against the neonatal Fc receptor, is in progress in patients with anti-LGI1 encephalitis (NCT04875975). The rationale is based on the efficacy of the human immune globulin G 1 (IgG1) Fc-fragment efgartigimod in myasthenia gravis [48]. Both agents share a similar mechanism of action targeting the neonatal Fc receptor, which leads to increased degradation of IgG including pathologic antibodies.

●Others – Other agents for which more data are needed before clinical use in autoimmune encephalitis include:

•Low-dose interleukin-2 (IL-2) – In a small retrospective case series without a comparator group, low-dose IL-2 was associated with clinical improvement in 6 out of 10 patients with autoimmune encephalitis refractory to second-line therapy [49]. Neutropenia was seen in one patient.

•Tofacitinib – In an uncontrolled retrospective case series of patients with refractory autoimmune encephalitis, the Janus kinase inhibitor tofacitinib was associated with a good response in two out of eight patients, partial response in three, and no response in three [50]. Both patients with good response had anti-myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), a demyelinating inflammatory central nervous system disease with different target and pathogenic mechanism than prototypical autoimmune encephalitides. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Treatment and prognosis".)

•Anakinra – A few case reports describe clinical improvement with the interleukin-1 (IL-1) receptor blocker anakinra in patients with treatment-refractory central nervous system inflammatory disorders [51,52]. Responsive cases were mostly demyelinating in nature (acute disseminated encephalomyelitis [ADEM], primary progressive multiple sclerosis) and had pathologic confirmation of microglial predominant infiltrates. Several cases of seronegative autoimmune encephalitis/meningoencephalitis did not show a response [51].

•Daratumumab – A few case reports suggest that the anti-CD38 monoclonal antibody daratumumab may be of value in treatment-refractory autoimmune encephalitis [53,54]. CD38 is present on the surface of plasma cells, natural killer cells, and some T cell populations.

Relapsed disease — Autoimmune encephalitis can follow a monophasic or relapsing course. In general, the risk of relapse is highest in patients with clinically relevant neuronal cell-surface antibodies (eg, anti-LGI1, anti-contactin-associated protein-like 2 [CASPR2]) and lowest in postviral (eg, anti-NMDA receptor encephalitis occurring after herpes simplex virus 1 [HSV1] encephalitis) and iatrogenic (eg, immune checkpoint inhibitor [ICI]-associated) cases [17,55,56]. Most relapses occur at relatively short intervals from the index illness while immunomodulatory therapies are being tapered.

●Risk of relapse – Accurate estimates of relapse risk are difficult due to multiple factors, including the rarity of individual subtypes; earlier use of therapies such as rituximab, which may lower the risk of relapse; and challenges in defining true relapse. In retrospective cohort studies, recurrence rates in autoimmune encephalitis associated with neuronal cell-surface antibodies range from approximately 10 to 40 percent [13,57-60]. In some subtypes, such as anti-LGI1 encephalitis, relapses tend to be phenotypically identical to the initial episode [61,62], while in others, like anti-NMDA receptor encephalitis, relapses are generally similar but milder in severity [13]. Most relapses in anti-CASPR2 encephalitis are a milder form of the initial presentation, with exceptions [63].

●Evaluation – Patients with a suspected relapse should be examined carefully for secondary causes of worsening. Fluctuations in cognition, symptomatic seizures, and transient worsening of residual sequelae are common during recovery and may not indicate recurrent encephalitis. The likelihood of a relapse should be considered in the context of the encephalitis subtype, clinical symptoms, and supporting evidence including magnetic resonance imaging (MRI), EEG, and/or CSF studies. Patients should also be evaluated for occult or recurrent neoplasm when appropriate.

●Treatment – Confirmed relapses should be treated initially with glucocorticoids, IVIG, and/or TPE, with a goal of rapidly reinducing clinical remission. Selection is individualized based on treatment history, pathogenic mechanism, and clinical severity.

In addition, most patients require initiation of longer-term immunosuppression to prevent further relapses. Azathioprine and mycophenolate mofetil have traditionally been used in this setting, overlapping with oral glucocorticoids for at least three to six months. Maintenance IVIG has also been used. However, increasing evidence and expert consensus support use of rituximab as an alternative in patients with anti-NMDA receptor encephalitis as well as other subtypes [64]. Supporting data in patients with anti-NMDA receptor encephalitis suggest that rituximab has a long-term immunosuppressive effect that lowers relapse risk when used as upfront therapy as well as in those with subsequent relapses [13,16,60]. Mycophenolate or azathioprine may still be preferred in subtypes in which there is stronger evidence for T cell-mediated immunity.

Rituximab takes effect more quickly than either azathioprine or mycophenolate and might be less carcinogenic than other agents [59,65]. It is generally not necessary to give repeated or maintenance doses of rituximab after an initial course in patients with autoimmune encephalitis. Further considerations on dosing and monitoring of rituximab for chronic immunomodulatory therapy are reviewed separately. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

The optimal duration of maintenance therapy in patients with relapsed disease is unknown and should be individualized. Factors to consider include the antibody type, type and severity of prior attacks, reversibility of symptoms, tolerability of the immunosuppressive therapy, and patient comorbidities and cancer risk. Expert opinion supports an initial treatment period of three years, followed by re-evaluation and attempt to withdraw maintenance immunosuppression [55,59,61,64,65]. Patients who have more than one relapse while on immunosuppression or while being weaned should be considered for extended or escalated immunosuppression [65].

SUPPORTIVE CARE

Intensive care management — Patients with severe autoimmune encephalitis often require high doses of sedation, antiseizure medications, and other symptomatic therapies during the acute phase of illness [66]. Specific complications include the following:

●Status epilepticus – Status epilepticus should be treated with a standard protocol, including a fast-acting intravenous benzodiazepine followed by intravenous loading of appropriate antiseizure medications (algorithm 2 and algorithm 3). (See "Convulsive status epilepticus in adults: Management" and "Management of convulsive status epilepticus in children".)

A subset of patients with autoimmune encephalitis present with new-onset refractory status epilepticus (NORSE), which may require iatrogenic-induced coma in an intensive care unit setting with midazolam, propofol, or pentobarbital [67]. Such presentations are best described in patients with anti-N-methyl-D-aspartate (NMDA), anti-gamma-aminobutyric acid A (GABA-A), and anti-gamma-aminobutyric acid B (GABA-B) receptor antibodies [68-71]. In super-refractory status epilepticus, effective seizure control may not be realized until adequate immunosuppression is achieved. (See "Refractory status epilepticus in adults", section on 'Immunomodulatory therapy'.)

Other aspects of seizure management are reviewed below. (See 'Seizures' below.)

●Respiratory failure – Respiratory dysfunction in patients with autoimmune encephalitis may be caused by brainstem involvement, associated neuromuscular symptoms, or iatrogenic hypoventilation due to medications administered for seizures. Central hypoventilation requiring artificial ventilation is mostly seen in anti-NMDA receptor encephalitis.

●Dysautonomia – Severe dysautonomia is a well-recognized feature of anti-NMDA receptor encephalitis but is also seen in brainstem encephalitis and progressive encephalomyelitis with rigidity and myoclonus (PERM) mediated by anti-glycine receptor (GlyR) antibodies. Manifestations may include heart rate and blood pressure instability, gastric dysmotility, and urinary retention.

Careful monitoring and management of heart rate fluctuations and blood pressure are essential in patients with severe dysautonomia. Evidence for symptomatic therapies in patients with autoimmune encephalitis is sparse; when sympathetic overactivity is severe, treatment with nonselective beta blockers, alpha-2 agonists, and/or acetylcholinesterase inhibitors may be required. A pacemaker may be temporarily necessary in patients with severe dysrhythmia (or even asystole) until dysautonomia improves [72].

Patients with serious symptomatic postural hypotension can be treated with midodrine, fludrocortisone, or droxidopa, in addition to sufficient hydration and compressive stockings. (See "Treatment of orthostatic and postprandial hypotension", section on 'Pharmacotherapy'.)

Rare patients with severe gastrointestinal dysmotility refractory to standard symptomatic therapies may require temporary total parenteral nutrition. (See "Treatment of gastroparesis", section on 'Refractory symptoms'.)

Those with urinary retention often require an indwelling catheter during the acute phase of illness. Generally, supportive measures are able to be weaned once the patient is recovering.

●Fevers – High fevers can be a manifestation of autoimmune encephalitis due to hypothalamic involvement or severe dysautonomia. Incidence and risk factors are not well studied, however, and central fever should be considered a diagnosis of exclusion after careful investigation of infectious sources.

●Hyponatremia – Hyponatremia is common in patients who are acutely ill with autoimmune encephalitis, especially those with antibodies against leucine-rich glioma inactivated 1 (LGI1) protein. In most cases, this is due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and fluid restriction is often sufficient. In rare cases, controlled slow correction of sodium levels is required to prevent central pontine myelinolysis. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)

Psychosis and mood disturbances — Agitation and psychosis are prominent symptoms in many patients [73]. To ensure safety and prevention of self-harm, nonpharmacologic measures including padding and soft restraints should be utilized when appropriate.

Despite these measures, antipsychotic medications and benzodiazepines are commonly required, sometimes at high doses to adequately ensure sedation. Specific considerations in patients with autoimmune encephalitis include the following:

●Patients with anti-NMDA receptor encephalitis are particularly sensitive to extrapyramidal side effects of antipsychotic agents [74]. Patients may experience worsening of catatonia or involuntary movements. Cases of neuroleptic malignant syndrome have been described in these patients, although symptoms may overlap with the disease itself and establishing causality can be difficult [75]. (See "Neuroleptic malignant syndrome".)

Clinicians should maintain a high index of suspicion for toxicities when using antipsychotic agents. Offending drugs should be stopped and substituted with an alternative therapy less likely to exacerbate movements, such as benzodiazepines.

●Certain agents may have clinically important effects on seizure threshold (eg, clozapine and olanzapine). Some experts advocate avoiding these medications in patients with autoimmune encephalitis who have clinical or subclinical seizures or lateralized periodic discharges on EEG [76,77].

●Agents with risk of QT interval prolongation (eg, ziprasidone, intravenous haloperidol) should be used very carefully or avoided in patients with dysautonomic symptoms such as severe bradycardia or heart block [78].

Manic symptoms may be a presenting symptom in some patients and are well described in anti-NMDA receptor encephalitis [79]. Mood stabilizers such as valproic acid and carbamazepine are preferred over other agents, especially in patients with comorbid seizures [73]. Elimination or dose reductions of relevant medications may also improve behavior in some patients (eg, steroids, benzodiazepines).

Psychosis and mood disturbances may improve rapidly with successful immunomodulatory therapy, and the need for medications should be reassessed at regular intervals. Clinicians should strive for monotherapy or at least dose reductions as much as possible. Many patients can be fully tapered off of symptomatic medications after clinical status has improved.

Seizures — Immunomodulatory therapy has important antiseizure effects in autoimmune encephalitis caused by antibodies against neuronal cell-surface antigens such as NMDA receptor, LGI1, and GABA-B receptor. Such therapy is felt to be far more effective than antiseizure medications, emphasizing the importance of early treatment [1,28,80-83].

Early in the course, many patients also require antiseizure medications to treat focal seizures effectively [84]. Severe seizures, including status epilepticus, warrant acute treatment with benzodiazepines and intravenous antiseizure medications. (See 'Intensive care management' above.).

Based on observational data, sodium channel blockers (eg, carbamazepine, oxcarbazepine, phenytoin, lacosamide, lamotrigine) may be preferred over other agents for patients with anti-LGI1 encephalitis and possibly other antibody-mediated syndromes [80,81]. Levetiracetam should be used with caution based on several reports of serious behavioral dysfunction (including suicidality) after initiation of levetiracetam in patients with anti-LGI1 encephalitis not yet controlled with immunomodulatory therapy [81].

The natural history of seizures in patients with autoimmune encephalitis appears to be favorable, although risk may vary depending on etiology and the presence of permanent structural deficits. In a nationwide cohort study that included 153 patients with anti-NMDA receptor, anti-LGI1, or anti-GABA-B receptor encephalitis, 72 percent of patients had one or more seizures and 89 percent reached seizure freedom over a median follow-up of 27 months [81]. Median time to seizure freedom was approximately two months. Almost all surviving patients, including those presenting with status epilepticus, were able to be weaned off antiseizure medications after immunomodulatory therapy and resolution of encephalitis. Other data suggest that risk of chronic epilepsy may be increased in patients presenting with NORSE [85].

Decisions about tapering medications should be individualized. Factors to consider in assessing risk of recurrent seizures include the type of antibody, the level of recovery, MRI and EEG findings, and tolerability of the antiseizure medication regimen. It is often reasonable to consider reducing to monotherapy or tapering off antiseizure medication after one year, at least in patients with antibodies against neuronal cell-surface antigens who have been seizure-free since the acute phase of illness.

Movement disorders — Mild movement disorders do not require symptomatic therapy and usually improve with immunomodulatory therapy alone. Severe, dangerous, or disabling movement disorders require directed treatment [86].

Patients with dystonia are typically treated with anticholinergics (eg, trihexyphenidyl) or muscle relaxants (eg, baclofen). Benzodiazepines are more commonly used for myoclonus, PERM, and stiff-person syndrome [64]. (See "Treatment of dystonia in children and adults" and "Treatment of myoclonus".)

Catatonia is typically treated with intravenous lorazepam [73,86]. For severe cases of catatonia, there are reports of electroconvulsive therapy being used effectively, although the risks for long-term cognitive adverse effects should be considered. (See "Catatonia: Treatment and prognosis".)

Severe chorea, athetosis, and ballism can be treated with antipsychotic agents (eg, risperidone) or dopamine depleting agents (eg, tetrabenazine). Patients require careful monitoring to avoid paradoxical worsening of other involuntary movements. (See "Overview of chorea", section on 'Management of chorea'.)

A trial of carbidopa-levodopa or a dopamine agonist is reasonable in patients with acquired parkinsonism or severe akinetic-rigid syndrome [86].

Sleep disorders — Sleep disorders are common and underrecognized in patients with autoimmune encephalitis [87]. Improving sleep quality may facilitate control of neuropsychiatric symptoms including agitation, psychosis, and seizures. Efforts should focus on achieving and maintaining a healthy sleep cycle through behavioral modifications (environmental conditioning and sleep hygiene), appropriate medication scheduling (eg, dosing glucocorticoids in the morning instead of twice per day or evening), and appropriate use of pharmacotherapy for insomnia [74,87]. (See "Poor sleep and insomnia in hospitalized adults", section on 'Pharmacotherapy'.)

PROGNOSIS AND RECOVERY — Autoimmune encephalitis is a heterogeneous disorder, and prognosis varies across different subtypes and etiologies. In general, antibody-mediated disorders with antibodies against neuronal cell-surface antigens tend to be the most responsive to immunomodulatory therapy, but residual neurocognitive dysfunction may last for months to years. Patients with paraneoplastic encephalitis associated with classic onconeuronal antibodies more often have a progressive course and competing risks due to their underlying malignancy.

The natural history of specific disorders is reviewed separately. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

Multidisciplinary care needs — Patients recovering from autoimmune encephalitis require multidisciplinary care, the extent of which depends on the severity of the initial disease, response to treatment, and the number and magnitude of residual deficits [88].

Many patients require longitudinal psychiatric care as well as subspecialty neurology care for management of epilepsy, movement disorders, ataxia, and sleep disorders. Patients with paraneoplastic autoimmune encephalitis require close collaboration between neurology and oncology for optimal treatment and monitoring. Occasionally, patients with gastrointestinal dysmotility may require care with gastroenterology and autonomic specialists.

Patients who require maintenance immunomodulatory therapy and those with coexisting autoimmune disorders may benefit from comanagement with rheumatology to streamline immunomodulatory therapy and laboratory monitoring [89].

Neurocognitive rehabilitation — Cognitive impairment is the most common residual symptom after autoimmune encephalitis [89]. Patients may have deficits in episodic verbal memory, attention and executive function, and visuospatial function. In cohort studies of patients with anti-N-methyl-D-aspartate (NMDA) receptor, anti-leucine-rich glioma inactivated 1 (LGI1), and mixed-subtype encephalitis, nearly all patients have cognitive deficits across multiple domains at early timepoints in the postacute setting [61,89-92]. Cognitive recovery occurs in most patients by two to four years, often most rapidly in the first six months, with residual cognitive deficits present in approximately one-third of patients [89,91].

Residual psychiatric symptoms are also highly prevalent but improve over time. A residual mood disorder was present in 30 percent of survivors of mixed-subtype encephalitis at a mean of 18 months' follow-up [89].

We encourage patients to engage in occupational, speech, and cognitive therapy during recovery. Formal neuropsychologic testing can be obtained to guide treatment and serve as a basis for comparison at follow-up time points. Although interventions have not been systematically evaluated, several case reports suggest positive outcomes after neuropsychologic rehabilitation [93-95].

SUMMARY AND RECOMMENDATIONS

●Avoid treatment delay – In patients meeting criteria for definite autoimmune limbic encephalitis (table 5), probable anti-N-methyl-D-aspartate (NMDA) receptor encephalitis (table 2), or probable anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis, immunomodulatory therapy should be started as soon as infectious encephalitis is ruled out by cerebrospinal fluid (CSF) results. Delayed treatment is associated with poor outcomes. (See 'Timing' above.)

●Treat triggers – All potential triggers of autoimmunity should be promptly addressed, including treatment of the tumor in paraneoplastic cases, treatment of active infections, and removal of iatrogenic triggers such as immune checkpoint inhibitor (ICI) therapy. (See 'Triggers (tumor, infection, drugs)' above and 'Antitumor therapy' above.)

●Initial immunomodulatory therapy – There is broad agreement that high-dose glucocorticoids, intravenous immunoglobulin (IVIG), and therapeutic plasma exchange (TPE) are reasonable first-line therapies, but high-quality evidence on superiority of one agent or combination of agents over another is lacking. We base initial decisions primarily on suspected pathogenic mechanism (table 1) and disease severity (algorithm 1). (See 'Pathogenic mechanism' above.)

•Antibody-mediated or unknown mechanism – For such patients with severe disease (eg, respiratory failure, severe dysautonomia, refractory status epilepticus) and those with probable or definite anti-NMDA receptor encephalitis, we suggest high-dose glucocorticoids plus either IVIG or TPE rather than glucocorticoids alone (Grade 2C). In most other patients, we start with high-dose glucocorticoids and then add IVIG or TPE if there is no improvement by 14 days from the start of the steroid course. (See 'Antibody-mediated mechanism' above and 'Administration of specific therapies' above.)

For patients who do not respond adequately to two first-line therapies, we suggest adding rituximab (Grade 2C). If there is no improvement following rituximab (eg, four weeks after first dose), we begin cyclophosphamide. In severe cases, cyclophosphamide may be started at the same time as rituximab. (See 'Rituximab' above and 'Cyclophosphamide' above.)

•T cell-mediated mechanism – For patients with a classic onconeuronal antibody or high-risk cancer with a consistent neurologic phenotype, we suggest initial treatment with high-dose glucocorticoids (Grade 2C). For patients who do not respond adequately to steroids and have a confirmed onconeuronal antibody, we suggest cyclophosphamide rather than rituximab or other therapies (Grade 2C). IVIG or TPE is a reasonable second-line therapy before starting cyclophosphamide in patients with severe disease and pending antibodies. (See 'T cell-mediated mechanism' above and 'Glucocorticoids' above and 'Cyclophosphamide' above.)

●Treatment duration and taper – Once patients have achieved a maximal clinical response, a tapering strategy is advised to avoid early recurrence. We choose between an oral prednisone taper, monthly intravenous methylprednisolone (IVMP), and monthly IVIG for an average of two to six months. Rituximab is another option. (See 'Subsequent immunomodulatory therapy' above.)

●Relapsed disease – Approximately 10 to 50 percent of patients with antibody-mediated disorders experience relapse during or after taper of immunomodulatory therapy. Most such patients require a more extended period of immunomodulatory therapy, depending on the drug administered. (See 'Relapsed disease' above.)

●Prognosis and recovery – Autoimmune encephalitis is a heterogeneous disorder, and prognosis varies across different subtypes and etiologies. Many patients have prolonged cognitive and psychiatric morbidity and require multidisciplinary care and rehabilitation. (See 'Prognosis and recovery' above.)