Clinical Diagnosis: Neurosarcoidosis (Probable/Definite)

Clinicopathological Correlation

Why Each Feature Points to Neurosarcoidosis

The "Seronegative" Trap

"Neither the tuberculin skin test, urinary calcium levels, nor the blood concentration of angiotensin-converting enzyme definitively establishes the diagnosis, and each has limited sensitivity and specificity."

• Bradley and Daroff's Neurology in Clinical Practice

Mechanism of IC Bleed in Neurosarcoidosis

• Sarcoid granulomas infiltrate the walls of pial and parenchymal vessels
• This causes transmural inflammation, weakening the vessel wall
• Combined with uncontrolled hypertension, this significantly increases hemorrhagic risk

Histopathology of Neurosarcoidosis

Diagnostic Workup to Confirm

1. CSF analysis - elevated protein, lymphocytic pleocytosis; crucially, CSF ACE may be elevated even when serum ACE is normal (as in the 2026 case above); check CSF CD4:CD8 ratio (>5 supports sarcoidosis)
2. MRI brain with gadolinium - look for leptomeningeal enhancement, periventricular white matter lesions, cranial nerve enhancement, Virchow-Robin space infiltration
3. Whole-body FDG-PET or gallium scan - detects subclinical systemic granulomatous involvement that guides biopsy site
4. High-resolution CT chest - hilar lymphadenopathy or pulmonary infiltrates even if CXR is normal
5. Serum calcium, 24-hr urinary calcium - hypercalcemia/hypercalciuria supports sarcoidosis
6. Conjunctival or accessible tissue biopsy - non-caseating granulomas confirm diagnosis even from clinically unaffected tissue
7. MRI vessel wall imaging or DSA - characterize the cerebral vasculitis component

Differential Diagnoses to Exclude

• Multiple sclerosis - intermediate uveitis and left hemi-sensory symptoms can occur; but MS does not cause IC hemorrhage, and steroid response over 2 years fits better with a progressive granulomatous disease than relapsing-remitting MS
• CNS vasculitis (primary PACNS) - no ocular findings, no systemic disease
• CNS lymphoma - check LDH, CSF cytology, no steroid-dependent improvement over 2 years
• Tuberculosis - negative Mantoux and normal ACE not conclusive for TB exclusion either; but TB uveitis with IC bleed is very rare; QuantiFERON-Gold preferred over Mantoux

Management

Key Teaching Points

1. Normal serum ACE does not exclude neurosarcoidosis - sensitivity is ~60%, and isolated NS often has normal levels; check CSF ACE instead
2. Negative Mantoux supports, not refutes, sarcoidosis - it reflects T-cell anergy
3. IC hemorrhage in sarcoidosis is rare but real - caused by granulomatous vasculitis; recent literature (2025-2026) highlights this as an under-recognized manifestation
4. Intermediate uveitis with snowball opacities in the context of a systemic disease = intermediate uveitis (not pars planitis) - the term "pars planitis" is reserved for idiopathic cases only
5. Steroid response over 2 years is a strong clinical anchor for a granulomatous etiology

HRCT Chest in Neurosarcoidosis - Does It Help?

Short answer: Yes, often - but a negative HRCT does not rule out isolated neurosarcoidosis

What HRCT can show

HRCT patterns in sarcoidosis: perilymphatic nodules and the galaxy sign. - Grainger & Allison's Diagnostic Radiology

The critical caveat for this patient

• HRCT positive → confirms systemic sarcoidosis → provides a safe, accessible biopsy site (bronchoscopy + BAL + transbronchial biopsy) → upgrades diagnosis from "possible" to "probable/definite"
• HRCT negative → does NOT exclude sarcoidosis → move to FDG-PET/gallium scan (detects subclinical granulomatous activity in lymph nodes, skin, muscle) and CSF analysis

CSF ACE - Does It Help?

Short answer: Yes - it is more informative than serum ACE in neurosarcoidosis, but still imperfect

Why CSF ACE > serum ACE in NS

Additional CSF findings to look for simultaneously

Practical Algorithm for This Patient

Serum ACE normal + Mantoux negative
         ↓
    Do not stop here
         ↓
HRCT Chest ──► Positive → Bronchoscopy + BAL + biopsy → Histology
         │
         └──► Negative → FDG-PET whole body
                              ↓
                    CSF (protein, cells, ACE, CD4:CD8, cytology)
                              ↓
                    MRI brain + gadolinium (leptomeningeal enhancement?)
                              ↓
                    Vessel wall MRI / DSA (characterize vasculitis)
                              ↓
                    If still negative: conjunctival/accessible tissue biopsy

Bottom line

• HRCT chest: Order it first - if positive, it provides both diagnostic confirmation and the safest biopsy route. A normal result does not exclude disease in this patient.
• CSF ACE: Definitely send it, but as part of a full CSF panel - not in isolation. Its sensitivity is moderate but it captures what serum ACE misses in isolated NS. It is currently the most accessible intrathecal biomarker for NS.