The 2 main types of fungi are molds and yeasts, although some fungi can have characteristics of both. Molds (filamentous fungi) are composed of hyphae, which extend and branch to form a mycelium, enabling the mold to grow. Molds reproduce when a portion of the hyphae breaks off. Aspergillosis and mucormycosis are CNS infections caused by molds. Yeasts are round, with outpouchings called buds or pseudohyphae. They are septated and reproduce by budding: the parent cell divides and one of the daughter nuclei migrates into a bud on the surface of a cell. Coccidioidomycosis, cryptococcosis, and histoplasmosis are caused by yeasts. Candida can grow as a yeast or a mold.
The most frequent mode of transmission of Aspergillus species is inhalation of spores. The 3 main types of infections are allergic aspergillosis, aspergillomas, and invasive aspergillosis. Allergic aspergillosis affects the bronchopulmonary system and the paranasal sinuses. Allergic Aspergillus sinusitis occurs in immunocompetent patients with chronic sinusitis and nasal polyposis. It can invade the orbit, especially with sphenoid sinus involvement, and can result in secondary optic neuropathy, proptosis, diplopia, and retrobulbar pain. Aspergillomas, or fungus balls, may arise in the orbit, paranasal sinuses, or brain. They can occur in either immunocompromised or immunocompetent patients. Orbital aspergillomas produce symptoms of orbital masses, with proptosis, vision loss, diplopia, and pain. Orbital lesions also typically involve the sinuses or brain. Extension to the optic canal, cavernous sinus, optic nerves, and optic chiasm produces neuro-ophthalmic findings (Fig 14-23). Intracranial aspergillomas act like mass lesions, causing progressive neurologic deficits. Invasive aspergillosis typically occurs in immunocompromised patients; however, the disease can also affect immunocompetent patients. Most patients initially have pulmonary involvement, although the skin, orbit, or sinuses may be the nidus of infection. CNS infection occurs secondarily by either direct or hematogenous spread of organisms. Ophthalmic manifestations include acute retrobulbar optic neuropathy, endophthalmitis, orbital apex syndrome, and cavernous sinus syndrome. The presentation of invasive aspergillosis is highly variable and can mimic malignancy, idiopathic orbital inflammatory syndrome, GCA, and bacterial cellulitis. Vascular invasion produces cerebral infarction or hemorrhage. Meningitis, intracranial abscess, epidural and subdural hematoma, mycotic aneurysm formation, and encephalitis are serious sequelae of invasive aspergillosis.
Figure 14-23 This 82-year-old woman presented with a 6-week history of left brow and orbital pain. A, 4 weeks before evaluation, she suddenly lost vision in her left eye, and ptosis and proptosis developed 1 week later. B, CT scan revealed a destructive lesion at the orbital apex. C, Biopsy of the lesion showed septate hyphae consistent with aspergillosis.
(Part C courtesy of Julie Falardeau, MD.)
Treatment includes antifungal agents such voriconazole, itraconazole, or posaconazole. Voriconazole may be associated with transient visual disturbances. Surgical intervention is often necessary to treat aspergillomas and invasive aspergillosis. The mortality rate for invasive aspergillosis varies from 40%–80%, depending on predisposing risk factors.
Thurtell MJ, Chiu AL, Goold LA, et al. Neuro-ophthalmology of invasive fungal sinusitis: 14 consecutive patients and a review of the literature. Clin Experiment Ophthalmol. 2013; 41(6):567–576.
Zygomycetes (genera Mucor or Rhizopus) are ubiquitous organisms that typically have low virulence, except in debilitated hosts. The mold enters the body through the respiratory tract and proliferates, causing hyphal invasion of tissues. It grows rapidly, producing a more acute infection than other fungi. These organisms have a predilection for blood vessels; hemorrhage, thrombosis, and ischemic necrosis are hallmarks of the disease. Aneurysm and pseudoaneurysm formation in the intracranial vasculature can produce devastating consequences when rupture occurs. The 2 types of zygomycosis (also known as mucormycosis or phycomycosis) that result in ophthalmic involvement are rhinocerebral zygomycosis and CNS zygomycosis.
Rhinocerebral zygomycosis usually occurs in patients with diabetes mellitus, patients taking corticosteroids, or neutropenic patients receiving antibiotics. The initial infection spreads from the facial skin, nasal mucosa, paranasal sinuses, or hard palate (Fig 14-24). The fungus spreads to the nearby blood vessels, affecting the orbital vessels, carotid arteries, cavernous sinuses, or jugular veins. Orbital and neurologic signs are produced by infarction, thrombosis, or hemorrhage. If untreated, rhinocerebral zygomycosis may bring about rapid deterioration, leading to death within days. A few patients may have a chronic course with little indication of systemic illness. The most common signs and symptoms include fever, nasal necrosis, periorbital swelling, decreased vision, ophthalmoplegia, sinusitis, and headache. Retinal infarction, ophthalmic artery occlusion, and optic nerve infiltration are mechanisms of blindness. Neurologic signs include hemiparesis, aphasia, seizures, and altered mental status.
CNS zygomycosis is very rare. The fungus usually gains access into the CNS from the nose or paranasal sinus, but there is no nasal, sinus, ocular, or orbital disease when the neurologic manifestations appear. Infection of the orbit, palate, nose, and sinuses typically occurs secondarily. Meningitis, abscesses, CN involvement, and seizures are common.
The diagnosis of zygomycosis requires a high index of suspicion. CT scan may demonstrate bone destruction, soft-tissue alteration in the paranasal sinuses and orbit, air–fluid levels in the sinuses and orbits, or brain abscess formation. MRI, MRA, and arteriography may be helpful for demonstrating vascular thrombosis. The definitive test is a biopsy specimen that demonstrates vascular invasion, tissue necrosis, eschar formation, inflammatory cells, and nonseptate hyphae (by histologic examination).
Figure 14-24 Rhinocerebral zygomycosis. A, A patient with rhinocerebral zygomycosis eroding the hard palate. B, Biopsy specimen demonstrates typical nonseptate hyphae.
(Courtesy of Lanning B. Kline, MD.)
Zygomycosis has a high mortality rate, although prompt diagnosis and aggressive therapy may be life-saving. The underlying systemic disease should be treated and immunosuppressant agents eliminated, if possible. Therapy includes aggressive surgical debridement of necrotic tissue and administration of antifungal agents both locally and systemically. Hyperbaric oxygen has been used as adjuvant therapy.
Gamaletsou MN, Sipsas NV, Roilides E, Walsh TJ. Rhino-orbital-cerebral mucormycosis. Curr Infect Dis Rep. 2012;14(4):423–434.
Trief D, Gray ST, Jakobiec FA, et al. Invasive fungal disease of the sinus and orbit: a comparison between mucormycosis and Aspergillus. Br J Ophthalmol. 2016;100(2): 184–188.
Cryptococcosis is a fungal disease caused mainly by Cryptococcus neoformans and Cryptococcus gattii. Inhalation of these fungi and subsequent pulmonary infection may spread to the CNS, causing meningitis or meningoencephalitis. Although C neoformans, which is found in pigeon droppings and contaminated soil, is ubiquitous, it rarely causes infection in otherwise healthy people. Affected individuals are typically immunocompromised, predominantly patients with HIV infection or AIDS. C gattii typically grows in soil around various kinds of trees; it can produce severe meningoencephalitis as well as pulmonary disease in immunocompromised or immunocompetent individuals.
The most common neuro-ophthalmic abnormality is papilledema from cryptococcal meningitis. Retrobulbar optic neuritis may also be present with gradual loss of vision over hours to days. Other ophthalmic complications include retinochoroiditis and cotton-wool spots. Cranial neuropathies may be observed, including unilateral or bilateral CN VI palsies. Photophobia, blurred vision, retrobulbar pain, homonymous visual field defects, or nystagmus may occur. The onset of symptoms is usually insidious, with a waxing and waning course. Headache, nausea, vomiting, dizziness, and mental status changes are the most common complaints.
The diagnosis is confirmed by isolating the yeast in the CSF or by demonstrating the capsular antigen for C neoformans or C gattii. In most patients with CNS cryptococcosis the disease is disseminated; there is evidence of infection in the blood, lungs, bone marrow, skin, kidneys, and other organs. Serum antigen titers are helpful for this reason.
Antifungal treatment should be initiated urgently, and aggressive management of intracranial hypertension is often needed. Vision loss caused by papilledema may be treated with CSF shunting or optic nerve sheath fenestration. The mortality rate of patients with treated CNS cryptococcosis is 25%–30%. The prognosis is worse in patients with an underlying malignancy or AIDS.
Franco-Paredes C, Womack T, Bohlmeyer T, et al. Management of Cryptococcus gattii meningoencephalitis. Lancet Infect Dis. 2015;15(3):348–355.
Excerpted from BCSC 2020-2021 series: Section 5 - Neuro-Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.