Autoimmune Encephalitis: IAP Guidelines

TABLE 2: Categories of autoimmune encephalitis.

Antigen location

Type of antibodies

Comments

Cell surface

þ Anti-NMDAR (most common)

• VGKC
• LGI1
• CASPR2
• Anti-GABA-A receptors
• Anti-GABA-B receptors
• Anti-Glycine
• Anti-D2 receptors
• Anti-AMPA receptors
• Anti-mGlu5
• Anti-neurexin3 alpha
• Anti-glutamate receptors

þ Common in children

• Lower association with malignancy
• Mediated by humoral immune system
• Better response to immunotherapy
• Favorable outcome

Antigen location

Type of antibodies

Comments

Intracellular

þ Anti-Hu

• Anti-Ma2
• Anti-GAD

þ Less relevant in pediatric

• Usually, paraneoplastic
• Mediated by cytotoxic T-cells
• Respond poorly to immunomodulatory therapy
• Poorer outcomes

TABLE 3: Diagnostic tests for autoimmune encephalitis (AE).

Diagnostic tests

Comments

CSF examination

It is suggestive of CNS inflammation. About 80% cases may have abnormal CSF in form of CSF pleocytosis (lymphocytic), normal/mild elevation in proteins, normal glucose, and elevated IgG index, oligoclonal bands, or CSF neopterin.

MRI brain (anti- NMDAR)

• Unilateral or bilateral T2/FLAIR signal hyperintensities involving mesial temporal lobe, hippocampal, cerebellar, and cerebral cortex.
• Hyperintensities may be seen throughout brain.
• Cortical enhancement in absence of restricted diffusion.
• MRI may be normal in 50–60% cases.
• PET scan can highlight involvement of mesial temporal lobes.

Diagnostic tests

Comments

EEG

• EEG is abnormal in most patients. The findings are usually nonspecific including extreme or diffuse slowing, epileptiform discharges, and disorganized activity.
• Extreme delta brushes are seen in 30% of anti-NMDAR cases.

Antibody testing

þ Detection of pathogenic antibody is basis for diagnosis of AE.

• Positive: Definite cases; Negative: Suspected case.
• Methods: Cell-based assays with live or fixed eukaryotic cells or IgG-based assays.
• Testing both serum and CSF is preferred.
• However, in resource limited setup, only CSF can be done as it is more sensitive.
• In anti-NMDAR, CSF testing is more sensitive (100% vs. 86%).
• In protracted disease, delayed diagnosis, and after IVIG/PE, antibodies may be present only in CSF.
• Only 40–50% cases with AE have antibody positivity.
• It has limited utility of follow-up evaluation.

TABLE 4: Differentiation between autoimmune encephalitis (AE) and acute infectious encephalitis.

Salient features

Autoimmune encephalitis

Infectious encephalitis

Clinical manifestations

• Seizures, movement disorders, speech abnormalities, sleep problems, and behavioral issues
• Fever in 50%

þ Autonomic dysfunction

þ Rash is rare

• Fever, seizures, and altered sensorium.
• Most cases have fever.
• Rash may be present in VZV and HSV encephalitis.

CSF

Mild CSF pleocytosis

More CSF pleocytosis

Salient features

Autoimmune encephalitis

Infectious encephalitis

MRI brain

• It is recommended in children with suspected AE during initial evaluation and to rule out alternate causes.
• MRI abnormalities seen in AE are commonly subtle and may be discordant from dramatic clinical features.
• MRI may be normal (50–66%), especially early in the course.

þ Basal ganglia often involved.

• Lateral temporal lobes and insula less commonly involved.
• There can be T2-weighted fluid- attenuated inversion recovery abnormalities throughout the brain and in cortical and subcortical areas, including temporal, frontal, and parietal lobes; hippocampi and amygdalae, cerebellum; thalamus; and basal ganglia.
• There may be contrast enhancement and abnormal diffusion-weighted images.
• Mesial temporal lobe involvement in characteristic (HSV)
• Lateral temporal lobe and insula may be involved
• Basal ganglia spared

Treatment

• Immunotherapy (±surgical removal of tumor)

Antiviral (acyclovir)

TABLE 5: Agents and their recommended dosages.

Agents

Dose and comments

First line

Corticosteroids

• Corticosteroids are the cornerstone of treatment with broad spectrum of anti-inflammatory activity and good penetration across blood–brain barrier.
• Methylprednisolone: 30 mg/kg/day (maximum 1 g/day) for 3–5 days, followed by sustained oral steroids (prednisolone 1–2 mg kg/day) and slow taper over 6–12 months.

IVIG or PE

• It is commonly used as alternatives and occasionally, concomitantly.
• IVIG (2 g/kg given over 5 days) or PE (5–7 exchanges of 50 mL/kg every alternate day).
• Early PE along with corticosteroids have better outcomes than either alone.
• No evidence exists regarding superiority of PE versus IVIG.
• However, considering that cases with AE are often sick, IVIG might be easier.
• Common regimens used: Methylprednisolone ± IVIG or IVIG/PE during acute stage in cases with inadequate response to methylprednisolone.

Second line

Rituximab

• It is chimeric monoclonal antibody against CD20.
• Dose: 375 mg/m2 weekly for 4 weeks or 750 mg/m2 (maximum 1 g) IV twice separated by 2 weeks.
• Resulting in B-cell depletion and reduced proinflammatory CD4+ and CD8+ T cells.
• B-cell count after 2–4 weeks and 3–6 months.
• To consider redosing if symptoms persist or relapse.
• Well tolerated and serious adverse events are rare.
• Infusion reactions 12%.

Cyclophosphamide

• It has broad cellular immune suppression effects.
• Dose: Monthly IV infusions 500–1,000 mg/m2 BSA for 6–9 months.
• Limitations: Risks of infertility and secondary malignancies which depend on cumulative dose received.
• Doses <7.5 g/m2 are justified in sick patients.
• Concomitant rituximab and cyclophosphamide have been tried without any increase in adverse effect profile.

Third line

• When both first- and second-line agents fail
• Bortezomib (protease inhibitor-inhibits proinflammatory signaling cascade)
• Tocilizumab (anti-IL-6)
• Intrathecal steroids and methotrexate