Figure 14-21 Erythema chronicum migrans, the characteristic skin rash of stage 1 Lyme disease. (Courtesy of Rob ert L.
Lesser, MD.)
Stage 2 follows within days or weeks and represents disseminated infection through the blood or lymphatic system. Stage 2 is associated with symptoms in the skin, nervous system, or musculoskeletal sites. Annular or malar rash, arthralgia, pancarditis, lymphadenopathy, splenomegaly, hepatitis, hematuria, proteinuria, malaise, and fatigue may be present. Neuro-ophthalmic findings at this stage consist of keratitis, panophthalmitis, papilledema (IIH-like syndrome), granulomatous iritis, vitritis, pars planitis, and orbital myositis. Two-thirds of patients have ocular findings at this stage. Cranial neuropathies can occur, most commonly facial nerve palsy, optic neuritis, meningitis with headache and neck stiffness, and radiculopathies.
Stage 3 represents persistent infection. Arthritis and scleroderma-like skin lesions are prominent. Keratitis and neurologic conditions predominate, including chronic encephalomyelitis, spastic paraparesis, ataxic gait, subtle mental disorders, and chronic radiculopathy. The neurologic picture may resemble that of MS, clinically and radiographically.
The diagnosis is made clinically when the patient has been exposed to an endemic area (the patient might not recall a tick bite) and shows the typical rash of erythema chronicum migrans. The presence of an elevated Lyme antibody titer in the serum or CSF is helpful. The enzyme-linked immunosorbent assay (ELISA) is typically used for screening, but a positive result using the Western blot technique confirms the diagnosis.
Treatment should be orchestrated by a specialist in infectious diseases.
Balcer LJ, Winterkorn JM, Galetta SL. Neuro-ophthalmic manifestations of Lyme disease. J Neuroophthalmol. 1997;17(2):108–121.
Fungal Infections
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. Yeasts 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.
Weinstein JM. Fungi and mycotic diseases. In: Miller NR, Newman NJ, eds. Walsh and Hoyt’s Clinical NeuroOphthalmology. Vol 3. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:2775–2852.
Aspergillosis
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. Neuro-ophthalmic findings are rare; they occur secondarily with sphenoid sinus involvement. Signs and symptoms include optic neuropathy, proptosis, diplopia, and headache. 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 neuroophthalmic findings (Fig 14-22). Intracranial aspergillomas act like mass lesions in causing progressive neurologic deficits. Invasive aspergillosis typically occurs in immunocompromised 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. 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 14-22 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, which on fine-needle aspiration biopsy (C) proved to be an aspergilloma.
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 is extremely high (>90%).
Metcalf SC, Dockrell DH. Improved outcomes associated with advances in therapy for invasive fungal infections in immunocompromised hosts. J Infect. 2007;55(4):287–299. Epub 2007 Aug 13.
Mucormycosis
Mucormycosis is caused by several types of Zygomycetes, which 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 mucormycosis producing ophthalmic involvement are rhinocerebral and CNS mucormycosis.
Rhinocerebral mucormycosis 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 14-23). 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. Untreated, rhinocerebral mucormycosis may bring about rapid deterioration, leading to death within days. A few patients 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.
Figure 14-23 A, A patient with rhinocerebral mucormycosis eroding the hard palate. B, Biopsy specimen demonstrated
typical nonseptate hyphae. (Courtesy of Lanning B. Kline, MD.)
Central nervous system mucormycosis is very rare. The fungus usually gains access to 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, cranial nerve involvement, and seizures are common.
The diagnosis of mucormycosis requires a high index of suspicion. CT studies 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
showing 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).
Mucormycosis 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 described to be helpful.
Spellberg B, Edwards J, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev. 2005;18(3):556–569.
Cryptococcosis
Cryptococcus neoformans, the most common fungus causing cryptococcosis, is found in pigeon droppings and contaminated soil. Although it is ubiquitous, it rarely causes infection in otherwise healthy people. However, infection does occur in approximately 10% of patients with AIDS, and it is the most common life-threatening mycosis in these patients.
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 papilledema, retinochoroiditis, and cotton-wool spots. Cranial neuropathies may be observed including unilateral or bilateral sixth nerve 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 demonstrating the C neoformans capsular antigen or by isolating the yeast in the CSF. Most patients with CNS cryptococcosis have disseminated disease, with 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. 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.
Perfect JR, Casadevall A. Cryptococcosis. Infect Dis Clin North Am. 2002;16(4):837–874.
Prion Diseases
Prion diseases, also known as transmissible spongiform encephalopathies, include kuru in New Guinea; sporadic Creutzfeldt-Jakob disease (sCJD), which is found worldwide; and a variant of CJD (vCJD) found mostly in the United Kingdom and France. Variant CJD has been linked to bovine spongiform encephalopathy (“mad cow” disease), which is a prion disease in cattle.
Prions are infectious agents formed by the conversion of a normal cell surface protein (PrPC) to a misfolded cell surface protein called PrPCJD or PrPSC (for the animal prion disease scrapie). Upon association with a normal PrPC molecule, an abnormal PrPCJD induces a conformational change in the normal protein, resulting in propagation of the abnormal form. The resulting accumulation of the abnormal prion protein alters neuronal function, causing the symptoms of CJD. Sporadic CJD may