Background: Paraneoplastic syndromes that affect both the optic disc and the brain parenchyma typically harbor antibodies directed toward CV2/collapsin response-mediator protein 5 (anti-CRMP5), amphiphysin, Ma antigen 2 (Ma2/Ta), and Yo. The most common cancers linked to anti-CRMP5 antibodies include small-cell lung carcinoma (SCLC), followed by thymoma, renal cell carcinoma, and thyroid papillary carcinoma. A long-held belief explains papilledema as related to increased pressure within the subarachnoid space or the microvascular capillaries, but intracranial pressures within the normal standard range may exist in a person with a paraneoplastic syndrome and papilledema. The glymphatic system, a central waste-clearance conduit, may play a crucial role in the development of papilledema in paraneoplastic syndromes. Case Report: This case illustrates a patient with extra-pulmonary small cell carcinoma and 24 months of progressive papilledema and recurrent encephalopathy in the setting of hyponatremia and generalized seizures. Two separate lumbar punctures showed lymphocytosis with normal opening pressures. Magnetic resonance imaging sequences demonstrated an empty sella and prominent tubular Virchow-Robin perivascular spaces that fan circumferentially, coined as the “Comb sign,” which may be an indirect indicator of bilateral papilledema. A mass in the right adrenal gland was biopsied, which yielded small-cell carcinoma immunostaining phenotype. The patient’s lumbar puncture demonstrated lymphocytosis with polyclonality, CRMP5-IgG reactivity, but negative immunoblotting. Conclusion: Patients presenting with insidious progressive neuro-ophthalmological symptoms should raise suspicion for paraneoplastic syndrome, in particular, anti-CRMP5 immunoreactivity. Although intracranial pressures by lumbar puncture are within the normal limits in this case, magnetic resonance imaging sequences may elucidate distinct comb-like patterns within the Virchow-Robin spaces, indicative of elevated tone within the interstitium. The implications of negative immunoblotting with positive reactivity are discussed.
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