Cryptococcus Neoformans Meningitis
This patient was initially referred for evaluation of memory deficit and a possible myopathy. An initial evaluation by her referring physician was unrevealing.
A common cause of memory deficit and dementia is Alzheimer's disease, which is a neurodegenerative disorder presenting with progressive deterioration of intellectual and social functioning. A diagnosis of probable Alzheimer's disease can be made by a clinical history of the insidious onset of progressive memory impairments, confirmation with neuropsychological testing, and a lack of other explanations of dementia by history and exam. As well as other neurodegenerative diseases, the differential diagnosis includes Korsakoff's psychosis, pseudodementia, pernicious anemia, thyroid disease, AIDS dementia, infections such as neurosyphilis, brain tumors, and multi-infarct dementia. A multi-infarct state is the second most common cause of dementia and is usually seen in the presence of hypertension, diabetes, or other risk factors for vascular disease. Unlike this patient, multi-infarct symptoms usually present in a stepwise manner. However, ischemia has to be considered in this patient in light of her history of transient vertigo and an episode of syncope. Because of the slow progressive nature of her symptoms without any history or physical evidence of stroke, a diagnosis of possible Alzheimer's disease was considered in the differential. Furthermore, the neuropsychological test results were in accord with this diagnosis, and normal routine laboratory investigations excluded other causes of dementia.
In light of her muscle weakness by history and exam, a dual diagnosis of myopathy and dementia was also considered. There are common neuropathological features in Alzheimer's disease and inclusion body myositis, such as the deposition of ß-amyloid peptides. However, the EMG/NCV showed no evidence of a myopathy, and the abnormalities seen on the MRI and in the CSF made the diagnosis of Alzheimer's disease less likely.
The meningeal enhancement around the brainstem and suprasellar cistern seen on the MRI of the brain suggested a chronic leptomeningeal process such as inflammatory, granulomatous, or neoplastic disease. The spinal tap revealed xanthochromic fluid with an elevated protein, decreased glucose, and lymphocytic-predominant pleocytosis. In conjunction with the MRI findings, a diagnosis of sarcoidosis, lymphoma, or chronic infection (such as tuberculosis or histoplasmosis) was entertained. A chest X-Ray was performed which showed dense fibrotic scarring in the perihilar region bilaterally compatible with, but not diagnostic of, chronic granulomatous disease. A CT scan of the chest confirmed these findings but did not show any active disease. Upon further inquiry, the patient revealed that she had been followed by a pulmonologist for many years for possible sarcoidosis, although there was no evidence of active disease and no formal diagnosis or treatment was given. As part of a syncope evaluation, an echocardiogram was performed which showed a moderate-size pericardial effusion, consistent with the differential diagnosis. A diagnostic pericardiocentesis revealed no evidence of infection or sarcoidosis. A PPD was placed with candida, tetanus toxoid, and trichophyton as controls. Only the candida was reactive, thus making TB and sarcoid less likely. (Patients with sarcoid are often anergic).
Lymphoma was considered, although her physical examination, routine blood work, CT scan of the chest, and CSF cytology did not support this diagnosis. A bronchoscopy with lung biopsy was contemplated, but because of the potential risks, we elected to wait for the final CSF culture results. Antibodies for histoplasmosis were positive in the serum (1:64) and in the CSF (1:32), and Crypto antigen was negative in both serum and CSF. However, only Cryptococcus neoformans was cultured from the CSF from two different spinal taps. It is certainly possible that she had pulmonary histoplasmosis in the past, and with alteration in the blood-CSF barrier, the CSF titer was increased. At present, there was no evidence of active histoplasmosis. Alternatively, the titers could reflect cross reactivity and false positive results. False negative cryptococcal antigens have been reported in biopsy-proven immunocompetent patients with chronic low-grade infections or early in the disease. It can be explained by a host response which inhibits the capsule development needed to produce a detectible antigen response.
In light of these results the patient was admitted and treated with IV amphotericin. Sarcoidosis alters the immune system and is a known risk factor for cryptococcal meningitis. Because of her pulmonary history, chest CT findings, and muscle weakness; a concomitant diagnosis of sarcoid was entertained. She was not treated as she had no evidence of active disease, and the serum and CSF ACE levels were normal. However, if necessary, treatment with prednisone can be considered in these patients. Some studies suggest that if daily corticosteroid therapy is stopped or switched to an alternate-day regimen before stopping anti-fungal therapy, there is no increased risk of recurrence of the infection. However, relapses often occur in patients receiving 20 mg or more of prednisone after therapy is finished.
In conclusion, the patient's symptoms can be best explained by chronic cryptococcal meningitis. Cognitive dysfunction is a common symptom, vertigo and other focal neurological deficits are often seen, and the involvement of multiple spinal nerve roots could cause diffuse weakness. Although up to 30% of cases occur in immunocompetent patients, patients must be followed closely for any underlying predisposing condition. Most importantly, this case illustrates the necessity of a complete evaluation including neuroimaging and lumbar puncture to search for any treatable cause of dementia.
The fungus Cryptococcus neoformans is an encapsulated yeast that exists widely throughout the environment. Its ecological niches include soil, eucalyptus trees, and the excreta of pigeons.[9] Humans are infected by inhalation, but the spores in the lung are usually controlled by a cell-mediated immune response.[13] What determines whether or not the inhaled particles will cause an infection is not known, but it is thought to be related to the quantity of particles inhaled, the size of the capsule, and the virulence of the particular strain.[15] Infection occurs when the yeast invades the tissue and forms a large mucoid capsule which protects the fungi from host defenses.[9] Cryptococcosis is often seen in patients with conditions causing a compromised cellular immune system such as AIDS, steroid therapy, immunosuppression induced after organ transplantation, lymphoproliferative disorders, diabetes, tuberculosis, and sarcoidosis.[1] However, up to 30% of cases of cryptococcosis are reported in patients with no known predisposing condition.[6]
The infection may remain localized in the lung, but dissemination is not uncommon. Hematogenous spread is the likely route in these cases.[15] Any organ may be involved, but the fungus has a predilection for the CNS. Meningitis is the most common presentation of cryptococcosis. It has been theorized that this is related to the organism's ability to utilize catecholamines present in the nervous tissue.[12]
The pathologic response to the fungus is extremely variable. In the CNS, involvement may be isolated to intracerebral collections of yeast cells appearing as mucoid cysts. There may be no cellular reaction, or active inflammation ranging from a polymorphonuclear leukocytosis, to a granulomatous and fibrous reaction appearing as a tumor. Subsequently, the perivascular spaces in the CNS may be full of yeast cells with little or no inflammation noted.[15]
Meningeal inflammation usually begins with the breakthrough of one of the organisms into the subarachnoid space. Cryptococcal meningitis typically presents as a subacute meningitis with spontaneous exacerbations and remissions, or as meningoencephalitis.[15] Chronic headache is the most common symptom, along with fever and malaise.[13] Overt meningeal symptoms and signs like nuchal rigidity are less common, occurring in about one third of patients.[9] Forty percent of patients present with nausea and vomiting, and a minority of patients also have symptoms such as lethargy, altered mentation, personality changes, memory loss, and cranial nerve palsies.[13] Focal neurological signs or seizures occur in about 10% of patients.[9] Rarely, the course may be acute with the rapid development of coma.[15] Because the presentation is frequently nonspecific, there is often a delay of several weeks or months before the diagnosis is made.
CSF Indices: The diagnosis is usually made via lumbar puncture. The opening pressure is often elevated, and the indices are usually abnormal. The CSF white blood cell count is moderately elevated, but rarely greater than 800 cells/mm.[3] The differential usually shows mononuclear predominance, and rarely eosinophilia. CSF protein is elevated, often up to 500 mg/dl or more. CSF glucose is usually low (10 to 40 mg/dl), although normal values can be seen early in the disease. The CSF in patients with AIDS can be entirely normal throughout the course; however, the organism-specific studies are almost always abnormal. India ink staining is positive in 50 to 70% of cases[7] and, CSF cultures are positive in almost all cases.[9]
Antigen Titers: Cryptococcal antigen titers are elevated in the serum and CSF in up to 90% of cases. The detection of serum antigen is felt to be more sensitive than CSF antigen and is generally reported positive in 99% of cases.[7] False-negative antigen results are reported in a small number of immunocompetent patients early in the course of the disease, with chronic low grade infections, or after treatment.[3] It has been suggested that the normal host response may produce a polymorphonuclear response capable of preventing capsule development sufficient to mask detectable antigen.[2]
Although the antigen titers correlate directly with the quantity of yeast, the value of following CSF and serum cryptococcal antigen titers has been debated.[7] In patients with AIDS, most data shows antigen levels after treatment are not predictive of relapse, as there is no correlation between a decrease in titer and outcome. Clinical deterioration occurs frequently with acute or suppressive treatment despite a decreasing antigen titer in the CSF. However, during acute treatment, an unchanged or increased titer does correlate with a poor clinical and fungal response in all patients; as well, a rise in CSF antigen following suppression corresponds with relapse. Overall, following acute treatment, it is important to repeat a lumbar puncture to document decreasing opening pressure, cell counts, glucose, and cryptococcal load. However, an argument can be made for repeating lumbar punctures only on symptomatic patients, as reported relapses exclusively occurred in symptomatic patients.[13]
Features associated with high mortality include an abnormal mental status at presentation, and an initial CSF antigen titer of greater than 1:1,024.[13] Likewise, initial CSF parameters including an elevated opening pressure, a positive India ink stain, glucose less than 20 mg/100 ml., and less than 20 WBC/mm[3] indicated a poor prognosis when patients who were cured were compared to patients who died. The only predictor of failure to respond to treatment is CSF glucose remaining low for more than four weeks.[5]
Without treatment, cryptococcal meningitis is almost always fatal. In a 1952 series of untreated patients, 70% died within three months of the diagnosis, and 86% in the first year. A total of 15 patients with untreated disease lived for more than two years and only one patient lived 13 years.[15]
A six week course of amphotericin B along with flucytosine is the treatment of choice unless patients are immunosuppressed. In AIDS, cure is impossible and long-term treatment is necessary. The treatment of choice is the same, but the optimal treatment length is unknown and is dependant upon the patient's clinical status. Most are treated for 6-10 weeks or until 1 gram has been given followed by long-term maintenance therapy with oral fluconazole.[9]
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