Neuro-ophthalmic Manifestations of Cryptococcal Meningitis

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Article initiated by:

Andrew Go Lee, MD, Cina Karimaghaei, Peter W. Mortensen, MD, Subahari Raviskanthan, MBBS

All contributors:

Nagham Al-Zubidi, MD, Ayman Okla Suleiman, MD, Subahari Raviskanthan, MBBS

Assigned editor:

Ayman Okla Suleiman, MD

Review:

Assigned status Up to Date

 by Ayman Okla Suleiman, MD on March 28, 2024.

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Introduction

Cryptococcosis is a fungal infection that can have systemic and neuro-ophthalmic manifestations. There are two main pathogens, Cryptococcus neoformans and Cryptococcus gattii. Both pathogens usually become more symptomatic when localized to the central nervous system. Cryptococcosis presents as a subacute meningoencephalitis and generally manifests as an opportunistic infection in immunosuppressed patients (e.g., human immunodeficiency virus (HIV)).

The most common initial complaint is headache, but other symptoms include mental status and visual changes, nausea and vomiting, fever, weakness, and neck pain. A number of ophthalmologic complaints have been reported, which include blurred vision, loss of visual acuity, diplopia, photophobia, retrobulbar pain, amblyopia, nystagmus, ophthalmoplegia, anisocoria, and papilledema. While many symptoms are a manifestation of elevated intracranial pressure (ICP), some ophthalmologic findings are a result of direct extension of infection to the eye, optic nerve, or brain parenchyma.

Pathogenesis

There are many suggested hypotheses for neuro-ophthalmic manifestations in cryptococcal meningitis (CM). One implicated mechanism for injury is increased ICP, which most commonly causes a unilateral or bilateral non-localizing CN VI palsy and/or papilledema. The cryptococcal organism blocks passage of cerebrospinal fluid (CSF) in the subarachnoid space through the arachnoid villi, and can also deposit capsular polysaccharide in the CSF that increases osmolality and fluid retention, thereby increasing ICP and causing cranial nerve compression. Improvement of vision and ocular motility with ICP-lowering therapies supports this proposed mechanism of injury.

Direct infection and inflammation of CN II, III, IV, and VI have also been implicated in loss of visual acuity and diplopia. Histologic evidence following autopsy of patients with CM have found invasion and destruction of the optic nerve by cryptococci as a primary cause of optic nerve atrophy. CN II injury due to direct invasion can be contrasted clinically from injury due to elevated ICP by the absence of papilledema, where optic nerve atrophy secondary to increased ICP is frequently preceded by papilledema, although this cannot be used as an absolute differentiator. In addition to direct invasion of CN III, histologic evidence of cryptococcal vasculitis leading to transient vasospasm and ischemia of the third nerve has been reported to cause intermittent symptoms ranging from complete third nerve palsy to isolated mydriasis and ptosis. Post-inflammatory shrinking of the arachnoid leading to stretching of the trochlear nerve has also been reported as a cause of bilateral fourth nerve palsy.

Epidemiology

CM is a common cause of adult meningitis in immunocompromised patients especially in HIV infected individuals. HIV accounts for up to 79% of CM cases with an incidence up to one million cases per year. Approximately 700,000 deaths occur per year, with up to 500,000 deaths per year occurring in Sub-Saharan Africa alone where there is an increased HIV burden. CM is the cause of 15-17% of AIDS-related mortality. While less common, CM occurs in HIV-negative individuals, with one large series identifying chronic steroids as the cause for 25% of cases; chronic kidney, liver, or lung disease for 24% of cases; malignancy for 16% of cases; and solid-organ transplants for 15% of cases. The mortality rate can be as high as 20-30% in HIV-negative patients with CM. Interestingly, up to 30% of CM cases occur in immunocompetent individuals without evidence of underlying disease, with C. gattii recognized as the most common culprit in these cases.

Neuro-ophthalmologic Manifestations

Patients with CM may develop optic neuropathy (CN II) from direct infiltration or due to chronic papilledema. Diplopia and ophthalmoplegia may occur in CM from involvement of CN III, IV, and VI. Internuclear ophthalmoplegia (INO), conjugate gaze deficits, and nystagmus have all been reported in CM. Cases of both unilateral and bilateral involvement of the medial longitudinal fasciculus (MLF) have been recorded. Proposed mechanisms based on clinical and neuroradiologic data include vascular compression, infiltration, or inflammation and thrombosis of branching vessels of the basilar artery leading to infarction of the MLF. Gross anatomical evidence was reported in a case of a patient with unilateral INO and CM, where autopsy showed endarteritis of the small branches of the basilar artery supplying the brainstem, along with evidence of brainstem infarction. In addition to optic neuropathy, involvement of the optic tract due to invasion of the brain parenchyma has also been noted as a cause of vision loss. Depending on the region of the tract involved, patients have been reported to develop homonymous hemianopias or homonymous quadrantanopias.

Intraocular Manifestations

Direct ocular involvement in the setting of CM occurs due to either hematogenous dissemination to the eye or via extension through the leptomeninges. Reported intraocular manifestations include endophthalmitis, which has been associated with choroiditis, chorioretinitis, vitritis, and anterior uveitis. Symptoms and complications in these patients include vision loss, pain, floaters, photophobia, and retinal detachment. Chorioretinitis and neuroretinitis in the absence of aqueous humor or vitreous cavity infection and inflammation have also been reported. Granulomatous conjunctivitis has also been reported as an ocular manifestation of CM. Finally, cryptococci can also invade the cornea to cause a keratitis, leading to corneal scarring and subsequent loss of visual acuity.

Management

Treatment of CM includes three main steps – induction, consolidation, and maintenance therapy and should be performed in conjunction with an infectious diseases specialist, and with consideration of the side effects of these drugs. Induction therapy, the first phase of treatment, typically involves weight-adjusted dosing of liposomal amphotericin B or amphotericin B deoxycholate daily in combination with flucytosine. The duration of the induction phase may depend on patient immune status. In general, HIV-positive patients may receive 2 weeks of induction, transplant recipients might be longer. Non immunosuppressive patients will typically receive 4-6 weeks induction. Consolidation therapy, the second phase of therapy, includes fluconazole daily and the initiation of antiretroviral therapy at 4 weeks in HIV-positive patients. This phase often lasts for 8 weeks. Maintenance therapy, the final phase of treatment, includes fluconazole 200 mg daily. This phase of treatment is typically continued for at least one year.

The management of CM also involves managing elevated CSF pressure. Daily therapeutic lumbar punctures provide sufficient control in most patients. While the safe maximum volume of CSF drained during one lumbar puncture is unknown, up to 30 mL are generally removed in patients with high CSF pressure. There is conflicting evidence on the use of acetazolamide for elevated ICP secondary to cryptococcal meningitis. In one randomized clinical trial of oral acetazolamide for the treatment of CM in 22 adults in Thailand with elevated opening pressures (> 200 mm of water), the trial had to be terminated prematurely because patients who received acetazolamide developed significantly lower venous bicarbonate levels and higher chloride levels and had more-frequent serious adverse events than placebo controls. However, effective treatment of elevated ICP without significant adverse events using acetazolamide in the setting of CM has been reported in isolated cases – overall the evidence would support avoiding acetazolamide where possible. The role of surgical treatments for elevated ICP in CM has also been described (e.g., Ommaya reservoir, CSF shunting procedures).

Summary

CM is a fungal infection of the central nervous system that predominately occurs in immunocompromised individuals and can present with numerous ocular manifestations. Ocular symptoms are either secondary to increased ICP or a result of direct invasion of the eye, optic nerve, or brain parenchyma by the organism. Treatment with antifungal therapy, therapeutic serial lumbar puncture, and potentially surgical measures to reduce ICP may be helpful but acetazolamide might be harmful.