Cryptococcal meningitis with accompanying recurrent cerebellitis in an immunocompetent patient

Abstract

This report describes a 46-year-old individual with normal immune status and a clinical course marked by headache and nausea–vomiting. He was diagnosed as having cryptococcal meningitis (CM) accompanying with cerebellitis. The interesting element was the observation of recurrent cerebellitis, never before reported in the literature for CM. He was successfully treated with antifungal and steroid therapy and discharged on day 330.

1. Introduction

The great majority of cryptococcosis cases are seen in Acquired Immune Deficiency Syndrome (AIDS) patients with advanced immunosuppression [1,2]. It is much rare in immunocompetent individuals. There are also few studies regarding human immunodeficiency virus (HIV) negatives [3].

CM in our case developed in an immunocompetent individual, and is described here since it was accompanied by cerebellitis, previously unreported for these patients in the literature Fig. 1.

Fig. 1.

Cerebellitisat magneticresonance imaging (MRI) of the brain.

2. Case

A 46-year-old male, self-employed and living in Trabzon, Turkey, presented to our hospital at the end of August 2011 with headache and nausea–vomiting persisting for the preceding month but which had worsened over the previous week. He had no significant fever. The patient had no history of major or chronic disease, although his mother had suffered pulmonary tuberculosis years before. On the first day of hospitalization (day 0) he was lucid, oriented and co-operative. No findings of meningeal irritation or significant pathological findings were determined at physical examination. At magnetic resonance imaging (MRI) of the brain, leptomeningeal contrast was observed in the cerebellum and pons and, together with the existing clinical and radiological findings, cerebellitis and leptomeningeal meningitis were suspected (Fig. 1). Lumbar puncture (LP) was performed; a leukocyte value of 160×10, lymphocyte predominance at Wright staining, protein: 90 mg/dL and CSF/serum glucose: 60/107 mg/dL were determined in the cerebrospinal fluid (CSF), and the patient was started on ceftriaxone 2×2 g iv and prednisolone 80 mg/day. CSF acido-resistant bacilli staining (ARBS) and polymerase chain reaction (PCR) test results were negative and adenosine deaminase (ADA) levels were normal. Brucella agglutination test and Borrelia IgM and G antigens in CSF, performed to investigate other causes of chronic meningitis, were negative. PCR performed in CSF for the Herpes simplex virus that can cause cerebellitis as well as meningoancephalitis was also negative. Tuberculin skin test (PPD) was 25 mm (positive). Ocular fundus examination revealed bilateral obscuration in the optic discs.

Cryptococcal meningoancephalitis was identified when the India ink test revealed typical encapsulated yeast cells. Cryptococcus sp. growth was subsequently seen in CSF culture. The identification of Cryptococcus isolate was confirmed by DNA sequencing of the internal transcribed spacer (ITS) 1 and 4 regions of the 28 S rRNA gene. This revealed that the isolate was 99% identical to C.neoformans var. neoformans, and C. gattii infection was therefore also excluded. E-test, investigated for amphotericin-B, revealed a minimum inhibitory concentration (MIC) value of ≤0.002. Broth microdilution was used to determine the MIC value of flucytocine, calculated at 8 μg/ml. Other antimicrobial treatments were therefore stopped. Combination therapy of liposomal amphotericin-B 5 mg/kg iv and 5-flucytosine 100 mg/kg/day PO was started and continued on days 21 to 35. No growth was seen in blood cultures taken, and no growth was observed in fluid collected after bronchoalveolar lavage (BAL) performed due to a frosted glass appearance in bilateral lung fields. Fever and agitation findings decreased at day 30 and ceased entirely at day 42. Maintenance treatment of fluconazole (FZ) 2×400 mg/day iv was started at day 35. Since CM had been identified, detailed tests in terms of a chronic underlying disease were planned. Anti-HIV antibodies tested by Architect HIV Ag/Ab Combo assay (Wiesbagen, Germany) were negative in the serum. Whole body scintigraphy and abdominal and thoracic CT were performed for malignities. Serum CD4, immunoglobulin and complement levels were normal. Autoimmunity markers investigated in terms of autoimmune diseases were negative, and he was not thought to have a previous autoimmune disease. He again exhibited headache and nausea–vomiting at day 49, but no pronounced edema was observed at brain CT. LP was then performed. CSF was cloudy in appearance, pressure was 200 mm H₂O, leukocyte value was 20×10 and, protein 96 mg/dL, CSF/serum glucose ratio was 25/135 and FZ therapy was maintained to day 77. Nausea–vomiting symptoms persisted and increased. Brain MRI was repeated, and herniation was suspected due to cerebellar tonsils observed in sections from the foramen magnum. Steroid therapy, which had been stopped by decreasing doses, was restarted with prednisolone 1 mg/kg and mannitol 4×100 mg/day. With these therapies a significant improvement in clinical symptoms was observed within 3–4 days. MRI performed on the day 56 revealed a significant decrease in cerebellar leptomeningeal contrast in parallel to a clinical improvement. Anti-edema treatments were stopped at day 77 and the patient was discharged in a healthy condition.

The patient represented with the same clinical symptoms at day 84. MRI revealed that cerebellitis findings had increased in comparison to the previous session. A relapse in terms of cryptococcal meningoancephalitis was therefore suspected, and the same antifungals were again administered. However, LP could not be performed again due to an increase in edema findings. Since there was no complete improvement on clinical findings, a meeting was held between the Infectious Diseases, Neurology and Radiology departments, at which pulse dose steroid therapy, intravenous immunoglobulin and antiviral therapy were discussed. Although it was foreseen that pulse dose steroid therapy might have a negative effect in terms of underlying fungal infection, a pulse dose of prednisolone of 1 g/day was added to the antifungal therapy due to the patient exhibiting pronounced clinical and radiological benefit when he received anti-edema therapy and steroid therapy being potentially beneficial for certain autoimmune pathologies that may proceed with a picture of cerebellitis. A rapid clinical response was observed on the next day of this therapy. Pronounced radiological regression, particularly in cerebellitis findings, was observed at control MRI. The 3-day pulse steroid therapy was gradually decreased and stopped in the following days. The existing pathological findings had all disappeared at MRI of the brain. The patient had received 135 days of antifungal therapy was stopped, and he was discharged in a healthy condition.

He was again admitted with similar symptoms at day 330. MRI revealed increased cerebellitis findings compared to the previous session. Biopsy material was obtained from cerebellum. This was cultured and examined histopathologically. Direct and histopathological examination of the biopsy material revealed no significant features. No bacterial or fungal growth were seen. ARBS and polymerase chain reaction results for Mycobacterium tuberculosis were negative. Time line of disease is shown in the Fig. 2.

Fig. 2.

Time line of disease in patient.

3. Discussion

CM, which may be seen in immunocompetent individuals, albeit rarely, may appear in all age groups [3]. It is more frequent among males, and may lead to severe results, particularly in individuals with underlying immunosuppressive disease, despite appropriate treatment [3]. Our patient was a middle-aged male with no underlying immunosuppressive or chronic disease. The case was concluded healthily, despite being accompanied by severe cerebellitis.

Definitive diagnosis in CM is made with the agent being shown and/or growing in CSF culture [4]. Staining CSF fluid with Indian ink is one of the most commonly employed diagnostic techniques, the frequency of encapsulated yeast cells in CSF seen with this technique ranging from 50% to 69% [3]. Commercially developed latex agglutination tests showing cryptococcus antigens in CSF are also available. Since these can identify the agent with high sensitivity, almost 100%, and specificity, 98%, their use in routine diagnosis is recommended [4]. Diagnosis of CM in our case was made with encapsulated yeast cells being seen in CSF stained with Indian ink and the agent growing in culture.

Headache, fever, confusion and nausea–vomiting are the most commonly seen clinical signs in these patients in general and in CM patients. The disease may also, more rarely, progress with findings such as impaired vision, episodes, nuchal rigidity, impaired gait, shortness of breath or coughing [3]. The most important symptoms in our case were headache and nausea–vomiting, and also fever, which is rare in the clinical course.

CSF findings (cell number, protein, glucose) have been reported to be almost always significantly pronounced in CM patients with negative HIV [3]. In our case, CSF findings were increased cell count, with lymphocyte predominance, and protein and decreased glucose values.

Central nervous system radiological findings are normal in the great majority of HIV positive CM patients, while abnormal findings determined at CT/MRI of the brain are seen in the majority of HIV negative CM subjects. However, none of these findings are pathognomonic for CM [3]. Of these findings, hydrocephaly is more frequently seen in HIV negatives compared to HIV positives; this is thought to stem from a more aggressive inflammatory response in the subarachnoid area in these patients [3]. Cerebral infarcts are also more common in HIV negative CM patients compared to positives, though it is difficult to document these lesions thought to develop in direct association with CM [3]. Increased meningeal contrast, vasculitis, edema, single/multiple nodes (cryptococcoma) and cysts are other lesions that can be seen at CT [5,6]. Cerebellar and pons meningeal contrast, edema and hydrocephaly and cerebellar herniation are some of the findings present in our patient.

Acute cerebellitis is an acute onset, rare, inflammatory condition characterized by cerebellar function impairment. It can develop infectiously, post-infection or with a non-infectious etiology, while it may sometimes not be possible to identify the agent [7]. In our case, the infectious agents described in the literature were investigated, but no positive findings for these were encountered. Since non-infectious causes were also excluded, it was evaluated as CM-associated cerebellitis. Clinical findings are not specific, and radiology occupies an important place in the diagnosis of cerebellitis [7]. The most commonly seen findings in cerebellitis are headache, nausea–vomiting, vertigo, myoclonus, truncal ataxia, dysarthria, tremor and altered mental state [7]. Fickweiler et al. reported a case of CM with a picture of cerebellitis accompanied by nausea–vomiting and vertigo [8]. Both clinical and radiological findings were also compatible with cerebellitis in our case.

There are various alternatives in fungal therapy for CM patients. One contemporary approach is a 2–6 weeks induction treatment with amphotericin-B and 5-flucytozine, followed by maintenance treatment with FZ [9]. In our case, 2-week induction treatment with liposomal amphotericin-B and 5-flucytozin was administered, followed by FZ maintenance treatment. However, this was administered in 2 separate courses because of concerns over recurrence. We could not be sure of recurrence because LP was contraindicated. The most striking factor during the second course of treatment was that clinical findings again worsened once anti-edema therapy had been concluded. Retrospective analysis showed that the clinical worsening was closely correlated with the course of the cerebellitis picture, rather than lack of response to antifungal therapy or recurrence.

There is no generally accepted therapeutic approach in acute cerebellitis, and individual treatments predominate [7]. Treatment is generally symptomatic, and antiviral therapies and high-dose pulse steroids can be used [7]. External ventricular drainage, decompression surgery and recombinant-interferon gamma can be applied in cases with hydrocephaly and brain stem compression despite medical treatment [7,10]. In our case, clinical and radiological improvement without sequelae was achieved with antifungal therapy directed toward the agent and pulse dose steroid therapy.

Several factors determine prognosis in these patients. The most important of these are cryptococcus isolation from an area other than CSF, alterations in mental state, opening CSF pressure >200 mmH₂O, CSF glucose <40 mg/dL, CSF cell number <20/mm³, absence of lymphocyte predominance in CSF, high latex agglutination in CSF, positive Indian ink smear and lack of leptomeningeal staining at CT of the brain [3]. The majority of poor prognostic factors were not present in our case. Acute cerebellitis generally follows a benign course, but may sometimes end in herniation and death, and can lead to the development of sequelae in healing cases, such as cerebral atrophy, calcification and gliosis [7]. Edema in one period and cerebellar herniation associated with mass effect was seen at MRI of the brain, but this picture completely resolved with anti-edema therapy, and no subsequent sequelae were observed.

It should be remembered that cryptococcal meningitis can also develop in immunocompetent individuals, and cryptococci should be considered in differential diagnosis in order to avoid late diagnosis and treatment, without considering the immune status of chronic meningitis cases. After diagnosis, in addition to appropriate antifungal therapy, it is exceedingly important in terms of prognosis for patients to be closely monitored and effective intracranial pressure to be established.

Conflict of interest

No conflict of interest is declared.