What is the recommended management for a patient with positive CASPR2 (Contactin‑Associated Protein‑Like 2) antibodies and MRI showing normal ventricles and cortical sulci with scattered small T2‑weighted fluid‑attenuated inversion recovery (T2/FLAIR) hyperintensities in the subcortical and periventricular white matter?

Management of Positive CASPR2 Antibodies with Non-Specific MRI Findings

Initiate immunotherapy immediately despite the non-specific MRI findings, as CASPR2 is classified as a surface antibody with high clinical relevance that warrants treatment, and proceed with comprehensive workup including lumbar puncture, EEG, and malignancy screening. 1

Clinical Context and Antibody Significance

CASPR2 antibodies are surface antigens with high clinical relevance according to current autoimmune encephalitis guidelines 1. The scattered T2/FLAIR hyperintensities you describe in subcortical and periventricular white matter are not typical for CASPR2-associated autoimmune encephalitis, which more commonly shows medial temporal lobe or hippocampal involvement 2, 3. However, atypical imaging patterns have been documented:

• White matter involvement can occur, particularly when concurrent antibodies are present 4
• Cortical and subcortical white matter involvement mimicking other pathology has been reported 5
• MRI is abnormal in only 53% of CASPR2 cases 3, meaning normal or non-specific imaging does not exclude the diagnosis

Immediate Diagnostic Workup

Step 1: Confirm Inflammatory Etiology

• Lumbar puncture with CSF analysis: Test for CASPR2 antibodies in CSF (positive in ~50% of cases), inflammatory markers (IgG index, oligoclonal bands), cell count, protein, and rule out infectious etiologies 1, 3
• EEG: Essential even with non-specific MRI to detect focal/multifocal abnormalities or subclinical seizures 1
• Brain PET scan: Consider if diagnosis remains uncertain, as FDG-PET is abnormal in 85.7% of CASPR2 cases (commonly showing temporomesial hypometabolism) 3

Step 2: Malignancy Screening

CASPR2 has a 21.8% association with thymoma and 10.6% with other malignancies 3. Proceed systematically:

• CT chest, abdomen, pelvis (initial screen)
• Thymic imaging (dedicated chest CT or MRI given thymoma association)
• Mammogram/breast MRI or testicular ultrasound (sex-appropriate)
• Body PET if initial screening negative 1

Immunotherapy Initiation

Do not delay immunotherapy while awaiting complete workup results. The evidence strongly supports early treatment:

• Recent case reports demonstrate that early immunotherapy initiation correlates with better outcomes (mRS 0 vs. mRS 5 based on treatment timing) 6
• CASPR2-associated conditions are immunotherapy-responsive with good prognosis when treated promptly 2, 7, 3

First-Line Treatment Protocol

• High-dose intravenous methylprednisolone (1g daily for 3-5 days)
• Intravenous immunoglobulin (IVIG) (2g/kg divided over 2-5 days)
• Consider plasma exchange for severe or refractory cases 7, 6

Second-Line and Maintenance

• Rituximab for refractory cases or severe presentations 6
• Mycophenolate mofetil for long-term immune maintenance therapy 7
• Oral corticosteroid taper following acute treatment

Clinical Syndrome Recognition

CASPR2 presents with a broad clinical spectrum 2, 3:

Most Common Presentations

• Limbic encephalitis (38.7%): Memory loss, behavioral changes, seizures
• Autoimmune encephalitis (51.5%): Broader cognitive and psychiatric symptoms
• Peripheral nerve hyperexcitability (37.7%): Neuromyotonia, fasciculations
• Morvan syndrome (22.7%): Encephalopathy + neuromyotonia + dysautonomia + insomnia

Key Clinical Features to Assess

• Cognitive impairment and memory deficits
• Seizure semiology (including faciobrachial dystonic seizures, though more common with LGI1)
• Psychiatric symptoms (anxiety, psychosis, behavioral changes)
• Peripheral nerve symptoms (muscle twitching, cramps, hyperhidrosis)
• Autonomic dysfunction
• Sleep disturbances

Critical Pitfalls to Avoid

1. Do not dismiss the diagnosis based on non-specific MRI: Only ~50% have typical temporal lobe findings 3
2. Do not wait for CSF antibody confirmation: Serum positivity is sufficient to initiate treatment, as CSF is positive in only 50% 3
3. Do not attribute symptoms to microvascular disease alone: The scattered white matter changes described are non-specific and may be incidental
4. Do not delay malignancy screening: Thymoma association is significant and requires thorough evaluation 3
5. Do not undertake isolated antiseizure treatment: Immunotherapy is the primary treatment, not just seizure management 8

Monitoring and Follow-up

• Clinical response typically occurs within weeks of immunotherapy 2, 7
• Repeat MRI to assess for evolution of findings
• Monitor for relapse (though less common than with some other antibodies)
• Continue malignancy surveillance if initial screening negative
• Assess for concurrent antibodies (LGI1, GFAPα) if atypical features present 4, 9