ADEM

1. Introduction and Definition

• Definition: A diverse group of inflammatory disorders of the central nervous system mediated by autoantibodies targeting neuronal cell surface proteins, ion channels, or receptors.
• Clinical Importance: It represents a treatable cause of encephalopathy that is often misdiagnosed as psychiatric illness or viral encephalitis.
• Pediatric Relevance: Anti-NMDAR encephalitis is the most common cause, surpassing viral etiologies in some cohorts of adolescents.

2. Classification and Pathophysiology

AIE is classified based on the location of the target antigen, which determines the mechanism of injury and response to treatment.

3. Clinical Features

The presentation is typically subacute (< 3 months) and progresses through characteristic phases, particularly in Anti-NMDAR Encephalitis (the prototype).

A. Anti-NMDAR Encephalitis (Classic Progression)

1. Prodromal Phase: Viral-like illness (fever, headache, URI symptoms) 1–2 weeks prior.
2. Psychiatric/Behavioral Phase:
   • Children: Temper tantrums, hyperactivity, irritability, mute/withdrawal.
   • Adolescents: Acute psychosis, hallucinations, mania, insomnia, paranoia.
3. Neurologic Phase (The "Storm"):
   • Movement Disorders: Orofacial dyskinesias (chewing, lip-smacking), choreoathetosis, dystonia, oculogyric crisis.
   • Seizures: Focal or generalized; often resistant to standard anti-epileptics.
   • Autonomic Instability: Tachycardia, hypertension, hyperthermia (central fever).
   • Hypoventilation: Central respiratory failure requiring ventilation.
   • Language: Mutism, echolalia.

B. Other Specific Syndromes

• Anti-LGI1 Encephalitis: Older children/adults. Hallmark is Faciobrachial Dystonic Seizures (FBDS)—brief (<3 sec) dystonic posturing of the face and arm. Associated with hyponatremia (SIADH).
• Anti-GABA-B Encephalitis: Prominent seizures and limbic symptoms.
• Hashimoto Encephalopathy: Associated with anti-TPO antibodies; presents with steroid-responsive tremor, myoclonus, and confusion.

4. Diagnostic Criteria (Graus Criteria 2016)

Diagnosis should not rely solely on antibody testing (which takes weeks). Empiric treatment is based on "Possible AE" criteria.

Criteria for Possible Autoimmune Encephalitis (Requires all 3):

1. Subacute onset (rapid progression < 3 months) of working memory deficits, altered mental status, or psychiatric symptoms.
2. At least one of the following:
   • New focal CNS findings.
   • Seizures not explained by a known seizure disorder.
   • CSF pleocytosis (>5 WBC/mm³).
   • MRI suggestive of encephalitis.
3. Reasonable exclusion of alternative causes (HSV, Metabolic, Toxic).

5. Investigations

A. Neuroimaging (MRI Brain)

• NMDAR: Often Normal (50%) or nonspecific T2/FLAIR hyperintensities.
• Limbic Encephalitis (LGI1/GABA): T2/FLAIR hyperintensity in the medial temporal lobes (amygdala/hippocampus).

B. Electroencephalogram (EEG)

[Image of Extreme Delta Brush EEG]

• General: Diffuse slowing or epileptiform discharges.
• Specific: "Extreme Delta Brush"—rhythmic beta activity superimposed on diffuse delta waves. Highly specific for NMDAR encephalitis.

C. Cerebrospinal Fluid (CSF) & Antibody Testing

• Routine: Mild lymphocytic pleocytosis, normal/mildly elevated protein, Oligoclonal Bands (OCBs) positive in 60%.
• Antibody Panel:
  • NMDAR: CSF is more sensitive than Serum. (False negative serum is common).
  • LGI1/CASPR2: Serum testing may be more sensitive.

D. Tumor Screening

• Females: MRI Pelvis / Ultrasound to rule out Ovarian Teratoma (contains neural tissue driving the immune response).
• General: CT Chest/Abdomen/Pelvis for other malignancies (Neuroblastoma, Thymoma).

6. Differential Diagnosis

• Infectious: HSV Encephalitis (Acute fever, temporal lobe necrosis), Tuberculosis, JE, Enterovirus.
• Metabolic: Wilson disease, Glutaric Aciduria Type 1 (dystonia), Porphyria.
• Psychiatric: Primary Schizophrenia (unlikely if seizures/movement disorders are present).

7. Management

"Time is Brain": Early immunotherapy improves long-term cognitive outcomes.

A. First-Line Immunotherapy (Start Empirically)

1. Corticosteroids: IV Methylprednisolone (Pulse: 30 mg/kg/day for 3–5 days).
2. IV Immunoglobulin (IVIG): 2 g/kg over 2–5 days.
3. Plasmapheresis (PLEX): 5–7 cycles (if severe or no response to steroids/IVIG).

B. Second-Line Immunotherapy (If no improvement in 10–14 days)

1. Rituximab: Anti-CD20 monoclonal antibody (375 mg/m² weekly x 4). Standard of care for NMDAR encephalitis.
2. Cyclophosphamide: Alkylating agent (reserved for severe/refractory cases).

C. Tumor Management

• Immediate surgical resection of the tumor (e.g., teratoma) is curative and prevents relapse.

D. Chronic Maintenance

• Mycophenolate Mofetil (MMF) or Azathioprine may be needed for 1–2 years to prevent relapse.

8. Prognosis

• Recovery: Slow (months to years). Occurs in reverse order of symptom onset (Autonomic $\to$ Movement $\to$ Psychiatric).
• Relapse: Occurs in 12–25% of patients (higher risk if non-paraneoplastic or if immunotherapy is stopped early).
• Mortality: ~5–10% (due to autonomic failure or ICU complications).