Autoimmune Encephalitis

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Continuing Education Activity

Autoimmune encephalitis refers to acute to subacute, progressive inflammation of the brain associated with antibodies against neuronal cell surface and synaptic protein, most commonly being anti - NMDA receptor encephalitis. It is frequently associated with underlying malignancy and needs appropriate screening. This condition is usually treatment responsive with immunotherapy and has better outcomes if initiated early in the clinical course. This activity outlines the pathophysiology, clinical presentation, and management of autoimmune encephalitis and reviews the role of the interprofessional team in managing patients with this condition.

Objectives:

  • Describe the epidemiology of autoimmune encephalitis.
  • Explain the pathophysiology of autoimmune encephalitis.
  • Outline the typical presentation of a patient with autoimmune encephalitis.
  • Summarize the management considerations for patients with autoimmune encephalitis.

Introduction

Autoimmune encephalitis (AIE) is an immune-mediated condition that induces brain inflammation and is one of the most common causes of non-infectious encephalitis. In the past decade, AIE has become an emerging addition to the differential diagnosis when a classical infection cannot explain focal neurological symptoms. While the exact mechanism of AIE is unknown, current literature suggests that autoimmune antibodies target synaptic proteins leading to widespread inflammation.[1]

AIE commonly presents as new onset of memory loss, psychosis, altered mental status, or seizures, with the presentation taking place over a few weeks to three months. AIE involves several parts of the nervous system, including the limbic system, the spinal cord, and/or the entire neuraxis. AIE can be confirmed by multiple modalities, including laboratory testing (antibody detection), neuroimaging, and electrophysiological studies (electroencephalogram).

Although classical paraneoplastic encephalitis is commonly associated with cancer, AIE may or may not be related. Therefore, once the diagnosis is established, patients should undergo cancer screening due to a high degree of association with underlying malignancy. Although these tests can be time-consuming, clinicians should consider initiating treatment early in the course if their clinical suspicion is high as they are often treatment responsive and have significantly improved outcomes. The most commonly studied subtype of AIE is Anti-N-methyl-D-aspartate receptor (anti-NMDA) encephalitis, so the management approach is primarily based on that.[2] This review describes the current state of knowledge on various types of autoimmune encephalitis and educates readers with a concise, up-to-date summary.

Etiology

Although the exact mechanism is currently under investigation, autoimmune encephalitis is thought to be an autoimmune process with an exaggerated response to a neuronal self-antigen. Unlike paraneoplastic encephalitis, which is a T-cell mediated response, antibodies in AIE are intrinsically pathogenic. They induce inflammation by targeting specific neuronal proteins. Synaptic proteins, ion channels, and intracellular receptors are the target proteins that have been established so far. When bound to target proteins, these antibodies induce conformational changes that lead to an inflammatory response.

Epidemiology

Epidemiological data on autoimmune encephalitis is under-reported due to its variable presentation and numerous antibodies responsible, as described below in table-1. The incidence of encephalitis reported in adults varies between 0.7 to 12.6 per 100,000 and has been reported in adult and pediatric populations.[3] 

To date, Anti-NMDAR encephalitis has been commonly reported under AIE, and most studies have been on it. In one large multicentric observational study, 80% of patients with anti-NMDAR encephalitis were female with a median age of disease onset of 21 years. Furthermore, 38% of the population in the study were found to have an underlying neoplasm with a predominance of ovarian teratoma.[4]

Pathophysiology

To this date, the exact mechanism of the collapse of immune tolerance in AIE largely remains unknown. Cases with AIE often have an infection as a preceding event, causing inflammation leading to neurological symptoms. There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers immune response causing Anti- NMDAR encephalitis.[5] Also, genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune response, e.g., IgLON 5 antibody encephalitis.[6]

Table-1 shows the commonly reported antibodies that have been described in the literature so far.

NMDAR - N-methyl-D-aspartate receptor, LG1- anti-leucine-rich glioma-inactivated 1 encephalitis, CASPR2 - contactin associated protein-like 2 receptors, GABA- gamma aminobutyric acid; AMPA- alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; DPPX- dipeptidyl-peptidase-like protein-6, CLL - chronic lymphocytic leukemia; MOG- Myelin oligodendrocyte glycoprotein.

Auto-antibody Median age of onset M: F Clinical manifestations Tumor association Response to therapy
NMDAR[7][4]  21 (2 months-85 yrs) 1:4 
  • Prominent neuropsychiatric manifestations
  • Seizures
  • Movement disorders
  • Language disorders
  • Autonomic dysfunction
  • Central apnea
  • Coma
Ovarian teratoma
  • Almost 53% reported improvement within the first 4 weeks from first-line therapy or tumor removal.
  • Almost 80% achieved good outcomes in the first 24 months with mRS 0-2.
  • About 10 % relapse seen within 2 years. Reduced if treated with IT or tumor removal.
  • 5-7% mortality.
LG1[8][9]  61 (31-84)  2:1
  • Limbic encephalitis
  • Focal seizures
  • Hyponatremia
  • Classical fasciobrachial dystonic seizures
Thymoma, lung, renal, and thyroid cancer
  • 80% response to IT.
  • Mild cognitive defect at 2 yrs follow-up.
  • Relapses are common (35%).

CASPR2[10][11]

66 (25-77)  9:1
  • Limbic encephalitis
  • Morvan syndrome
  • Peripheral nerve excitability
Thymoma
  • Almost 48% had full/good recovery with IT or tumor removal.
  • About 44% had partial recovery with IT.
  • About 25% relapses
  • Case fatality rate 10% after 2 yrs
GABA-a[12][13]  40 (2.5months-88yrs) 1:1 
  • Limbic encephalitis
  • Seizures
  • Refractory status epilepticus
Thymoma
  • substantial improvement( 86%), although mortality with status epilepticus  reported
GABA-b[14]  61 (16-77)  1.5:1
  • Limbic encephalitis
  • Seizures
Small cell lung carcinoma
  • Neurological response with immunotherapy and cancer treatment (90%)
AMPA[15]  53.1 (14-92)  1:2
  • Limbic encephalitis
  • Confusion
  • Amnesia
  • Seizures
  • Psychiatric complaints 
Thymus, lung, breast, and ovarian cancers
  • Good response to IT
  • 16% died from complications related to underlying malignancy
DPPX[16]  53 (13-75)  1.6:1
  • Multifocal encephalitis
  • Amnesia
  • Delirium
  • Myoclonus
  • Prominent weight loss and diarrhea
B-cell neoplasm (gastrointestinal lymphoma and CLL)
  •  ~63% responsive to IT
Glycine[17] 50 (1-75)   1:1
  • Stiff person spectrum syndrome
  • PERM (progressive encephalitis with rigidity and myoclonus)
  • Encephalitis
Thymoma, B -cell lymphoma
  • Good response to IT, with median mRS =1 at most recent follow-up.
  • 29% associated with autoimmune disorders (psoriasis, thyroid, diabetes)
MOG[18]  30.5 (15-69)  1:1
  •  optic neuritis
  • Seizures
  • Encephalitis
 
  • Good response to IT
  • Relapses are common.
Neurexin[19]  44 (23–57)  1:2
  • Prodromal fever
  • Weight loss
  • Gastrointestinal symptoms
  • Confusion
  • Seizures
  • Decreased level of consciousness
 
  • Partial response to IT (60%)
IgLON[6][20]  64 (42-81) 1:1 
  • Sleep disorders, bulbar dysfunction
  • Gait abnormalities.
  • HLADRB1*10:01/HLADQB*05:01 alleles in 87%.
 
  • 43% respond better with combination therapy vs. monotherapy (67 vs. 32)
  • Better with second-line compared to first line. (54 vs. 33)

History and Physical

The initial clinical presentation is vague and non-specific. Also, many patients do not present with common symptoms, so diagnostic modality involving imaging, serology, and EEG remains the mainstay for diagnosing this condition. It varies from typical limbic system involvement to syndromes with complex neuropsychiatric manifestations. There have been specific syndromes associated with particular antibodies. Nonetheless, the presentation in most cases is widely variable.

Approximately 70% of patients have prodromal manifestations of headache, fever, and other symptoms resembling viral etiology. Then, it progresses with acute to subacute onset of memory deficits, altered mental status, behavior changes, psychosis, orofacial dyskinesia, hallucinations, agitation, delusions, catatonia, seizures, or abnormal movements. These patients may have a fluctuating clinical course with interval improvement.[21]

Patients might progress to a decreased level of consciousness, central hypoventilation requiring mechanical ventilation. On review of systems, it will be pertinent to ask for fever, weight loss, and night sweats will be essential to look for any B symptoms or paraneoplastic process. Complete neurological examination is vital to look for focal neurological deficit and rule out other possible causes of encephalitis.

Evaluation

Diagnosing autoimmune encephalitis can be difficult as the average onset of symptoms to diagnosis often takes a few weeks to three months. Infectious encephalitis can be fatal and should always be eliminated from one’s differential before considering AIE. Even after eliminating other potential causes, the diagnosis of AIE is not easy. To diagnose autoimmune encephalitis, we need multiple tools to aid in the diagnosis, although clinical judgment is the key to making decisions. They will include a constellation of neuropsychiatric symptoms, lab studies, neuroimaging, and EEG. Therefore, a group of experts came to a consensus to help clinicians identify the disorder to initiate appropriate treatment. 

Following criteria were adopted for evaluation of possible diagnosis of autoimmune encephalitis:[22]

  1. Subacute onset (usually within a few weeks but less than three months) with change in the level of consciousness or personality; limbic system involvement including working memory deficits, lethargy, or psychiatric manifestations
  2. At least one of the following:
  • New focal clinical CNS findings
  • Seizures not explained by a previously diagnosed seizure disorder
  • CSF pleocytosis (>5 WBC per mm3)
  • MRI Brain findings suggestive of encephalitis

      3. Reasonable exclusion of possible alternative causes*

All three criteria must be met.

#MRI brain 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 grey or white matter compatible with demyelination or inflammation. 

Definite diagnosis of autoimmune limbic encephalitis-

  1. Subacute onset of symptoms (<3 months) involving limbic system area (memory deficits, neuropsychiatric symptoms, or seizures)
  2. MRI brain is suggestive of abnormality highly restricted to bilateral medial temporal lobes on T2 weighted FLAIR images
  3. One of the following is present-
  • CSF pleocytosis (>5 WBC per mm^3)
  • EEG is suggestive of slow-wave or epileptic activity corresponding to temporal lobes.

     4. Reasonable exclusion of alternative causes*

If all four criteria** match, the definitive diagnosis can be made.

*Infectious meningoencephalitis, septic encephalopathy, metabolic encephalopathy, toxins, cerebrovascular disease, neoplasms, Creutzfeldt-Jakob disease, epileptic disorders, Hashimoto encephalopathy, autoimmune disorders, mitochondrial/metabolic storage disorders.

**If one of the first three 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. Antibody should be detected both in sera and CSF fluid for diagnosis.

Studies have shown that out of all patients with NMDAR encephalitis with antibodies detected in CSF, 14% of cases were found to have no detectable antibodies in serum. Therefore, collection of both CSF and serum is recommended to detect antibodies.

Antibody titers may correlate with clinical severity in CSF studies and to a lesser extent with serum, but determining the clinical recovery based on titers remains controversial. Moreover, the clinical picture and associated comorbidities are considered relatively reliable for evaluating the clinical course, treatment response, and overall prognosis.[23]

Following diagnosis, screening for the presence of neoplasm is necessary. There is a correlation seen with coexisting neoplasm with a clinical subtype of antibody detection. (Table-1). The best initial step is to undergo a CT scan of the chest, abdomen, and pelvis to look for pulmonary or abdominal, or urogenital malignancies. Females should undergo gynecological exams with breast and ovarian ultrasound /MRI based on sensitivity and clinical judgment. Similarly, males should undergo testicular ultrasound as a part of the urological evaluation. If the above imaging does not yield any findings, a whole-body 18F-Fluorodeoxyglucose (FDG)-PET should be considered.

Treatment / Management

The treatment options for autoimmune encephalitis include immunosuppression and tumor resection if applicable. The treatment regimen is based on principles of autoimmune disease management with the aim of pathogenic antibody depletion. It is important to note that treatment should not be delayed until detection of the antibody, as early initiation is associated with improved outcomes. A multidisciplinary team should be involved in the team involving neurologists, rheumatologists, and oncologists to manage AIE. First-line therapy for AIE includes corticosteroids (1 g IV methylprednisolone for 3 to 5 days), intravenous immunoglobulins (0.4 g/kg/day for five days), and plasmapheresis alone or combined.

Plasmapheresis should be considered in the treatment when patients have severe dysautonomia, refractory seizures, or central hypoventilation syndrome. Second-line immunotherapy should be considered for patients who fail to improve on these regimens. This includes rituximab (375 mg/m^2 for four weeks) and cyclophosphamide (750 mg/m^2 for six months) alone or combined in the adult population. Nonetheless, if underlying malignancy were found, it should undergo removal or chemotherapy as it accelerates improvement and prevents relapses.[4]

Differential Diagnosis

Due to its variable presentation, it could mimic other clinical conditions, and therefore other differentials should be considered. Most patients develop additional syndrome features within days or a few weeks. Due to the initial prodrome of fever and headache, infectious causes of meningoencephalitis must be ruled out. It progresses with behavior changes, so clinicians should consider toxic and metabolic encephalopathy in these scenarios. Patients can present with focal neurological deficits, so cerebrovascular accidents (CVA) should be higher in the differentials. These patients should undergo a thorough physical examination in conjunction with neuroimaging for diagnosis. Intracranial space-occupying lesions are a possible cause of seizure or behavior disturbances.[24]

Some autoimmune encephalitides have early and prominent psychiatric manifestations, leading to admission to an inpatient psychiatric unit. Clinicians should focus on the clinical progression of the disease as these patients develop additional features of the syndrome within days to a few weeks. Careful examination may reveal subtle neurologic deficits that should lead to the consideration of autoimmune encephalitis. Patients may present with the demyelinating disorder (e.g., Multiple sclerosis) or autoimmune (Lupus, Neurosarcoidosis) that have multi-system involvement and should be appropriately evaluated with CSF studies and neuroimaging. Neurodegenerative diseases like Alzheimer dementia usually have chronic onset and should be further evaluated with neuroimaging. Rarely, inherited and metabolic disorders can cause neuropsychiatric manifestations with a positive family history that needs further study.

Prognosis

As mentioned above, usually, autoimmune encephalitis is treatment responsive with immunosuppression and tumor removal, although staging of the cancer is independently associated with adverse outcomes. According to an observational cohort study, 94% received first-line therapy with immunosuppression or tumor removal that resulted in improvement within four weeks (53%), with most of them having good outcomes in the first 24 months. These outcomes continue to improve up to 18 months from symptom onset. Predictors of good outcomes were associated with early treatment and not requiring ICU admission.[4] 

Patients need to be followed closely after recovery to look for relapse. As per the recommendations, surveillance imaging at 4 to 6 months intervals for at least four years is suggested. Overall, cell-surface antibodies have a better prognosis than those associated with intracellular antibodies.

Complications

Although autoimmune encephalitis is often treatment responsive, it can lead to serious complications if left untreated or if there is a delay in treatment. This includes cognitive impairment, sleep disorders, hyperkinesia, autonomic dysfunction, persistent amnesia (anti LG1 encephalitis), coma, status epilepticus. According to a retrospective study by Xu et al., central hypoventilation syndrome is a key risk factor for mechanical ventilation during hospitalization in anti-NMDAR encephalitis patients and therefore needs to be monitored closely.[25]

Deterrence and Patient Education

Patient education is necessary to understand the etiology, acute and chronic clinical progression of the condition, and its strong association with underlying malignancy. They 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 after hospital discharge with their respective neurologist /oncologist due to concerns of relapse and screening for malignancy.

These patients should undergo imaging every six months for at least four years to look for any growth of tumor or metastasis, which might not be evident early and can lead to neurological manifestations. Families should be involved in the process of healthcare decision-making whenever possible as they may notice unusual changes in the patient's behavior or possible seizures. Moreover, patients should be educated about the side effects of chronic therapy with steroids and the role of immunosuppressive treatment, which may put them at risk of infection or systemic side effects.

Enhancing Healthcare Team Outcomes

An eclectic clinical presentation encompasses autoimmune encephalitis with varying disease progression levels that require the expertise of multiple specialists. Healthcare professionals tasked with the management of AIE need to be well informed about the condition to ensure that the patient receives the most appropriate care. The management of autoimmune encephalitis is complex which requires expert opinion under neurologist, rheumatologist, internist, oncologist, oncosurgeon, and pharmacist, all functioning as a cohesive, interprofessional team. [Level 5]

Once the patient has made significant improvement, they should receive appropriate follow-up for complete recovery, potential side effects of immunotherapy, and tumor screening secondary to AIE. With proper management, the patient should be able to make a full recovery and maintain a state of remission.


Article Details

Article Author

Shrey Gole

Article Editor:

Amritpal Anand

Updated:

3/9/2022 5:54:14 PM

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