What are the causes of subacute unilateral hemispheric encephalitis in adults?

Causes of Subacute Unilateral Hemispheric Encephalitis in Adults

The primary causes of subacute unilateral hemispheric encephalitis in adults are autoimmune encephalitis (particularly MOG antibody-associated and VGKC-complex antibody-associated), Rasmussen encephalitis (though rare in adults), and varicella-zoster virus (VZV) reactivation. 1, 2, 3

Autoimmune Etiologies (Most Common in Adults)

Autoimmune encephalitis should be the first consideration in adults presenting with subacute unilateral hemispheric involvement, particularly when accompanied by specific clinical features 1:

• MOG antibody-associated encephalitis presents with unilateral cerebral cortical involvement, epileptic seizures, and swollen FLAIR hyperintense lesions on MRI that correspond to hyperperfusion on SPECT 2

• Predominantly affects adult men (median age 37 years) with generalized seizures, abnormal behavior, or consciousness disturbance 2

• May be associated with unilateral benign optic neuritis occurring before or after seizures 2

• VGKC-complex antibody-associated encephalitis (including anti-LGI1 and anti-CASPR2) presents with limbic encephalitis, speech and movement disorders, refractory seizures, and hyponatremia (in approximately 60% of cases) 1

• Brain MRI may show characteristic hippocampal high signal, though 30-40% have normal MRI findings 1

• Anti-NMDAR encephalitis can occasionally present with asymmetric involvement and includes behavioral disturbances, new-onset psychosis, choreoathetosis, seizures, aphasia, and autonomic instability 4

Infectious Etiologies

VZV reactivation is a critical infectious cause of subacute unilateral hemispheric encephalitis in adults 3, 4:

• Onset is typically insidious and may occur without zoster rash, fever, or CSF pleocytosis 4
• More common in elderly and immunocompromised patients 4, 3
• Can cause small-vessel vasculopathy or large-vessel stroke syndrome 4
• May present with brainstem encephalitis associated with Ramsay Hunt syndrome 4
• CSF PCR for VZV has 80-95% sensitivity in immunocompromised patients, though antibody detection in CSF may have greater sensitivity than viral DNA detection 4, 3

HSV encephalitis typically causes bilateral temporal lobe involvement but can occasionally present with asymmetric or predominantly unilateral disease 4:

• More common in elderly adults and should be considered promptly in this population 4
• Presents with fever (91% of cases), disorientation, speech disturbances, behavioral changes, and seizures 4
• CSF PCR has >95% sensitivity between days 2-10 of illness 4

Rasmussen Encephalitis (Rare in Adults)

Rasmussen encephalitis is a chronic progressive unilateral hemispheric encephalitis that, while predominantly pediatric, can occur in adults 5, 6:

• Characterized by refractory focal epilepsy or epilepsia partialis continua, hemiparesis, and progressive cognitive decline 5
• Autoimmune pathogenesis with T-cell involvement 5
• Progressive course distinguishes it from other benign unilateral encephalitides 7

Diagnostic Algorithm

When evaluating subacute unilateral hemispheric encephalitis, proceed systematically 1, 4:

1. Immediate CSF analysis (unless contraindicated by increased intracranial pressure) should include: cell count with differential, protein, glucose, opening pressure, and PCR for HSV-1, HSV-2, VZV, and enteroviruses 4

2. Serum and CSF neuronal autoantibody panels including anti-NMDAR, anti-VGKC, anti-LGI1, anti-CASPR2, and anti-MOG antibodies 1, 2

3. Brain MRI with contrast is essential and may show unilateral hippocampal high signal, cortical swelling with FLAIR hyperintensity, or be normal in 30-40% of autoimmune cases 1, 2

4. EEG to evaluate for non-convulsive status epilepticus and lateralized abnormalities 4

5. Check serum sodium as hyponatremia occurs in approximately 60% of VGKC-complex antibody-associated encephalitis 1

Critical Clinical Clues

Specific features suggesting autoimmune rather than infectious etiology include 4, 1:

• Subacute presentation over weeks to months (rather than days)
• Orofacial dyskinesia, choreoathetosis, or faciobrachial dystonia
• Intractable seizures without fever
• Hyponatremia
• Movement disorders or psychiatric symptoms as prominent features

Features suggesting VZV reactivation include 4, 3:

• Elderly or immunocompromised status
• Insidious onset without fever
• History of recent or concurrent zoster (though absence does not exclude diagnosis)
• Brainstem involvement or cranial neuropathies

Important Pitfalls

• Do not wait for virological confirmation before initiating treatment for suspected VZV or HSV encephalitis; treatment should begin immediately upon clinical suspicion 3
• Normal MRI does not exclude autoimmune encephalitis, as up to 30-40% of cases have normal imaging 1
• HSV CSF PCR can be falsely negative early in disease course; if initial testing is negative and HSE remains suspected, repeat LP within 3-7 days 4
• VZV encephalitis frequently occurs without rash, particularly in reactivation cases 4, 3
• Acellular CSF can occur in VZV, EBV, and CMV encephalitis, especially in immunocompromised patients, and should not exclude viral etiologies 4