“Pseudo CNS Sarcoidosis”: Histoplasmosis of Brain Mimicking Steroid Refractory Sarcoidosis

A 65-year-old man without major past medical history presented with an insidious constellation of symptoms, including sensorineural hearing loss, holocephalic headache, diplopia, gait unsteadiness, apathy, cognitive impairment, and heat intolerance over a period of 2 years alongside prominent pericardial calcification on radiographic imaging. The patient was a turkey farmer in Ohio. Magnetic resonance imaging at an outside facility revealed multiple T1 isointense, T2 hypointense, negative diffusion restriction, nodular postgadolinium enhancing lesions of the supra- and infratentorial leptomeninges, and the subependymal surface of the lateral ventricles (Figure 1). Initial lumbar puncture revealed cerebrospinal fluid (CSF) with elevated protein 299 mg/dL, glucose 10 mg/dL, and 56 nucleated cells with 72% neutrophils and 23% lymphocytes. The CSF levels of angiotensin-converting enzyme (ACE) were elevated (6.0) and immunoglobulin G index was 2.11. Serum erythrocyte sedimentation rate and C-reactive protein were normal, and additional imaging with positron emission tomography scan and computed tomography of chest, abdomen, and pelvis were negative. He was treated for diagnosis of presumed neurosarcoidosis, prompting prolonged courses of high-dose corticosteroids without improvement in his symptoms. He presented to our facility for a second opinion. Magnetic resonance imaging spinal neuroaxis was negative, and on physical examination, he demonstrated lack of attention, memory difficulty, a sixth nerve palsy, and right V1 numbness. Later pathology from right frontal endoscopic intraventricular brain biopsy revealed fungal elements compatible with Histoplasma capsulatum (Figure 2), prompting the diagnosis of central nervous system (CNS) histoplasmosis. He was initiated on antifungals. The patient had gradual clinical improvement over subsequent weeks but suffered from persistent behavioral and cognitive issues and a facial palsy.

Figure 1.

A, T1-weighted pregadolinium axial magnetic resonance imaging. B, T1-weighted postgadolinium axial magnetic resonance imaging, revealing periventricular enhancement without clinically significant mass effect. C, T2-fluid attenuated inversion recovery sequencing with subcortical and periventricular microvascular disease and perilesional hyperintense confluence.

Figure 2.

A, Hematoxylin and eosin stain showing numerous little pink dots because the outer portion of organism doesn’t stain. B, Grocott’s methenamine silver stain showing budding yeast and morphologic features consistent with Histoplasma capsulatum.

Histoplasmosis frequently presents with symptoms of pulmonary origin, though may disseminate via the vascular system and lead to an estimated 5% to 10% of cases involving the CNS.^1,2 The CNS histoplasmosis presentation is nonspecific and usually manifests as chronic meningitis, focal brain lesions, stroke syndromes, encephalitis, or hydrocephalus.³ Isolated neurosarcoidosis without systemic involvement is also rare,⁴ and because of its nonspecific clinical and radiologic presentation, its diagnosis remains difficult. Common presentation of isolated neurosarcoidosis is headache, paresthesia, and cranial neuropathies. It has a predisposition for leptomeninges⁵ but can involve any part of the brain, causing a wide range of clinical symptoms. Increased ACE levels in serum or CSF are nonspecific for neurosarcoidosis.⁶

Our patient was treated for a presumed diagnosis of neurosarcoidosis without a biopsy, due to involvement of leptomeninges, CSF findings, and elevated ACE levels, and had no other systemic involvement. Several clinical clues were present to suggest an alternative diagnosis to neurosarcoidosis, including region of residence and presence of pericardial calcification. Our illustrative case highlights the importance of acknowledging cognitive heuristics and anchoring bias,⁷ and we urge clinicians to entertain alternative diagnoses should standard treatment of more commonly encountered processes be refractory.