Autoimmune Encephalitis

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. Commonly Reported Antibodies. 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-N-methyl-D-aspartate receptor (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 was 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 an immune response, causing anti-NMDAR encephalitis.[5] Also, genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune responses, eg, IgLON 5 antibody encephalitis.[6]

Table. Commonly Reported Antibodies  

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. A complete neurological examination is vital to look for focal neurological deficits 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 3 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 electroencephalogram. Therefore, a group of experts came to a consensus to help clinicians identify the disorder to initiate appropriate treatment. 

The following criteria were adopted for evaluation of possible diagnosis of autoimmune encephalitis:

• Subacute onset (usually within a few weeks but less than 3 months) with 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
  • CSF pleocytosis (>5 white blood cells per mm³)
  • Magnetic resonance imaging (MRI) brain findings suggestive of encephalitis
•       Reasonable exclusion of possible alternative causes* [22]

All 3 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-

• Subacute onset of symptoms (<3 months) involving the limbic system area (memory deficits, neuropsychiatric symptoms, or seizures)
• MRI brain is suggestive of abnormality highly restricted to bilateral medial temporal lobes on T2 weighted FLAIR images
• One of the following is present:
  • CSF pleocytosis (>5 white blood cells per mm³)
  • Electroencephalogram is suggestive of slow-wave or epileptic activity corresponding to temporal lobes
• Reasonable exclusion of alternative causes*

If all 4 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 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 sera and CSF fluid for diagnosis.

Results from 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 between coexisting neoplasm with a clinical subtype of antibody detection. The best initial step is to undergo a CT scan of the chest, abdomen, and pelvis to look for pulmonary, abdominal, or urogenital malignancies. Females should undergo gynecological exams with breast and ovarian ultrasound/magnetic resonance imaging 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 intravenous methylprednisolone for 3 to 5 days), intravenous immunoglobulins (0.4 g/kg/day for 5 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/m² for 4 weeks) and cyclophosphamide (750 mg/m² for 6 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](B2)

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 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 a demyelinating disorder (eg, 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 intensive care unit admission.[4] Patients need to be followed closely after recovery to look for relapse. As per the recommendations, surveillance imaging at 4 to 6-month intervals for at least 4 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-leucine-rich-glioma-inactivated 1 encephalitis), coma, and 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]