Last reviewed: 25 Sep 2021
Last updated: 05 Aug 2020



History and exam

Key diagnostic factors

  • presence of risk factors
  • progressive headache
  • severe headache
  • meningismus
  • symptoms of hydrocephalus (impaired cognitive function, confusion, coordination and gait disturbances, and urinary incontinence)
  • behavioural or personality change
  • reduced visual acuity and papilloedema

Other diagnostic factors

  • nausea or vomiting
  • fever
  • reduced conscious level
  • cranial nerve palsies
  • seizures
  • weight loss
  • mouth ulcers
  • focal neurological signs
  • lymphadenopathy, hepatosplenomegaly
  • dyspnoea
  • papular umbilicated skin lesions
  • retinal defects
  • nasal or palatal eschar

Risk factors

  • HIV infection
  • corticosteroid use
  • underlying chronic disease (e.g., malignancy, organ failure, autoimmune disease, organ transplant)
  • residing in or visiting northern Australia, Papua New Guinea, or Vancouver Island, Canada
  • exposure to disturbed soil, chicken guano, or bat caves
  • impaired cell-mediated immunity
  • Filipinos and African Americans
  • neutropenia or impaired phagocytic function
  • neurosurgery
  • infants and neonates
  • central vascular catheters
  • sinonasal disease
  • antibacterial usage
  • prior surgery
  • hyperalimentation
  • intravenous drug use

Diagnostic investigations

1st investigations to order

  • CT and/or MRI head scan
  • fungal blood cultures (3 sets)
  • serum cryptococcal antigen test
  • serum + urine Histoplasma antigen
  • immunodiffusion tests (IgM and IgG) and complement fixation test (IgG) for coccidioidomycosis
  • cerebrospinal fluid opening pressure
  • cerebrospinal fluid (CSF) WBC and differential
  • cerebrospinal fluid (CSF) protein
  • cerebrospinal fluid (CSF) glucose
  • cerebrospinal fluid India ink stain
  • cerebrospinal fluid (CSF) culture
  • cerebrospinal fluid cryptococcal polysaccharide antigen test
  • cerebrospinal fluid Histoplasma antigen
  • cerebrospinal fluid Histoplasma antibodies
  • cerebrospinal fluid coccidioidal IgG antibodies
  • cerebrospinal fluid (CSF) galactomannan antigen test

Investigations to consider

  • histopathology and culture of biopsies: meningeal, brain, extraneural sites of involvement
  • polymerase chain reaction (PCR)

Emerging tests

  • 18F-fluorodeoxyglucose (FDG) PET/CT
  • cerebrospinal fluid (CSF) (1-3)-beta-D-glucan

Treatment algorithm



Abhijit Chaudhuri, DM, MD, PhD, FACP, FRCP (Glasg), FRCP (Lond)

Consultant Neurologist

Clinical Lead of Neuroinflammation

Department of Neurology

Queen's Hospital




AC declares that he has no competing interests.


Dr Abhijit Chaudhuri would like to gratefully acknowledge Dr Thomas S. Harrison and Dr Angela Loyse, previous contributors to this topic.


TSH and AL declare that they have no competing interests.

Peer reviewers

Robert A. Larsen, MD

Associate Professor of Medicine

University of Southern California

Keck School of Medicine

Los Angeles



RAL declares that he has no competing interests.

Use of this content is subject to our disclaimer