Unusual presentations of nervous system infection by Cryptococcus neoformans

Clinical Neurology and Neurosurgery 111 (2009) 638–642

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Case series

Unusual presentations of nervous system infection by Cryptococcus neoformans D. Eric Searls a,∗ , Jason J. Sico b , S. Bulent Omay c , Serguei Bannykh d , Victoria Kuohung e , Joachim Baehring b,c a

Department of Neurology, Harvard University School of Medicine, Palmer 127, 330 Brookline Avenue, Boston, MA 02215, United States Department of Neurology, Yale University School of Medicine, United States Department of Neurosurgery, Yale University School of Medicine, United States d Department of Pathology, Cedars-Sinai Medical Center, United States e Department of Medicine, Harvard University School of Medicine, United States b c

a r t i c l e

i n f o

Article history: Received 23 July 2008 Received in revised form 3 March 2009 Accepted 14 May 2009 Available online 21 June 2009 Keywords: Cryptococcus Cryptococcosis CNS lymphoma EBV AIDS Abscess Meningitis

a b s t r a c t Nervous system infections by Cryptococcus neoformans may occur not only in congenital or acquired immunodeficiency syndromes, but also in immunocompetent hosts. Neurological manifestations of C. neoformans infection include meningitis and, less commonly, parenchymal CNS granulomatous disease. This paper provides detailed clinical descriptions of highly unusual neurological manifestations of cryptococcal nervous system infections. Medical records and diagnostic data including magnetic resonance imaging, histopathology, serology, and CSF analysis were reviewed. A conus medullaris abscess was found in a patient infected with the human immunodeficiency virus (HIV). A patient with Hodgkin’s disease was diagnosed with cryptococcal meningitis and dermatitis mimicking ophthalmic zoster. An immunocompetent patient presented with recurrent cerebral infarctions in the setting of cryptococcal meningitis. Cryptococcal infections of the nervous system can cause severe neurological disability when diagnosis is delayed. Sensitive and specific tests are readily available and should be considered when an unusual clinical presentation is encountered. © 2009 Elsevier B.V. All rights reserved.

1. Introduction Cryptococcus neoformans is an encapsulated yeast found worldwide and is associated with soil contaminated with avian excreta. Immunocompromised hosts, including those with acquired immunodeficiency syndrome (AIDS) and lymphoproliferative disorders, are vulnerable to disseminated infection within the CNS and skin [1]. While neurological manifestations include meningitis and CNS granulomas, spinal cord involvement is exceedingly rare. Dermatologic manifestations are manifold and may include papules, nodules, ulcers, or vesicular rashes mimicking molluscum contagiosum. Immunocompetent hosts rarely develop cryptococcosis [1]. In the pre-AIDS era, a study of patient records in Northern California from 1971 to 1980 found an incidence of 0.8 cases of cryptococcosis per million persons per year [2]. Of HIV-negative patients with cryptococcosis, possibly 10–40% have no known immune disorder [3]. Immunocompetent patients with cryptococcal meningitis may not present with classic symptoms of headache and neck pain, but

∗ Corresponding author. Fax: +1 617 632 8920. E-mail address: [email protected] (D. Eric Searls). 0303-8467/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2009.05.007

rather with altered mental status, seizure, and strokes in multiple vascular territories. This paper will discuss three unusual presentations of cryptococcal disease: a conus medullaris abscess in a patient infected with HIV, cryptococcal meningitis and dermatitis mimicking ophthalmic zoster in a patient with Hodgkin’s disease, and cryptococcal meningitis presenting as recurrent cerebral infarctions in an immunocompetent patient with atrial fibrillation on coumadin. 2. Case reports 2.1. Case 1 A 48-year-old man with a 15-year history of HIV infection (viral load of 5270 copies/␮l, CD4 count of 160 ␮l−1 ) presented with right foot parasthesias and dorsiflexion weakness. Magnetic resonance imaging (MRI) of the spine revealed a rim-enhancing mass lesion within the conus medullaris measuring 2 cm in diameter (Fig. 1A and B). MRI of the brain showed no other lesions. CSF examination revealed an opening pressure of 140 mm of H2 O, 59 erythrocytes, 25 leukocytes (80% lymphocytes and 20% monocytes), glucose 66 mg/dL, and protein 65 mg/dL. CSF analysis yielded a negative latex agglutination test for cryptococcal antigen and neg-

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Fig. 1. (A) Sagittal MRI (T2-weighted image) of the lower thoracic and upper lumbar spine shows an ovoid shaped intramedullary mass lesion surrounded by vasogenic edema. (B) This mass lesion displays rim-enhancement after gadolinium administration (T1-weighted image, fat suppressed). (C) Hematoxylin and eosin-stained section of the removed material shows a sclerosing inflammatory lesion with plasma cells, lymphocytes, histiocytes, neutrophils, and basophilic structures 5–7 ␮m in diameter surrounded by clear halos (black asterisk). The morphology typifies cryptococcosis. Bar: 25 ␮m.

ative serology for Toxoplasma gondii. He failed dexamethasone and empiric treatment for toxoplasma myelitis. Polymerase chain reaction (PCR) for Epstein-Barr virus DNA was positive in the CSF. Given MRI findings and EBV genome detection in CSF, empiric therapy for Non-Hodgkin’s lymphoma was initiated with external beam radiation. However, his syndrome progressed with increasing pain in his lower legs, inability to heel-walk, bilateral ankle clonus and neurogenic bladder dysfunction. A laminectomy and midline myelotomy were performed. Examination of encapsulated purulent material identified C. neoformans as the causative agent (Fig. 1C). Fluconazole treatment completely resolved the patient’s neurological syndrome. 2.2. Case 2 A 38-year-old man with recurrent Hodgkin’s disease treated with radiation, chemotherapy, and autologous bone marrow transplantation, presented with five days of bilateral frontal headache and neck stiffness associated with photophobia, nausea, and vomiting. The patient complained of a left forehead rash without dysesthesias. He was admitted for suspected disseminated herpes zoster. On examination he was afebrile and exhibited a dozen flesh-colored papules throughout the left ophthalmic dermatome. These papules were not associated with clustering, vesicles, or an inflammatory base. He had a positive Brudzinski’s sign, but otherwise his neurological exam was intact. CT and MRI of the brain were remarkable for an osteolytic lesion in the left frontal area (Fig. 2A and B). CSF analysis revealed an opening pressure of greater than 500 mm H2 O, 2 erythrocytes, 21 leukocytes (92% lymphocytes, 8% monocytes), glucose 45 mg/dL, and protein 30 mg/dL. CSF India ink was positive and CSF cryptococcal antigen immunoassay titer was positive at a dilution of 1:8192. PCR for varicella zoster virus was negative. Skin biopsy showed yeast with a thick, clear halo consistent with cutaneous cryptococcal infection (Fig. 2C–E). Following amphotericin B treatment, his meningeal symptoms and skin lesions resolved. 2.3. Case 3 A 77-year-old man with hypertension and atrial fibrillation (on coumadin) presented with transient word finding difficulties. He appeared disoriented, producing neologisms and paraphasic errors. The patient was not taking any immunosuppressive medications. Laboratory testing revealed an international normalized ratio of 1.43. CT of the brain showed periventricular white matter changes. His symptoms resolved, and he returned home after

warfarin dose adjustment. He was hospitalized three additional times for transient neurologic deficits (disorientation, expressive and receptive aphasia, and left-sided motor deficits) despite the addition of aspirin and clopidogrel and an INR ranging from 2.25 to 4.87. He was afebrile on each admission. Clinically and radiographically he developed small infarctions within the right thalamus, putamen, caudate nucleus, centrum semiovale, left basal ganglia, midbrain, and subinsula (Fig. 3A–C). MRA of the brain showed no evidence of major vessel occlusion or vasculitis. Carotid ultrasound revealed no significant stenosis of the carotid arteries. Transthoracic echocardiogram showed no embolic source. Despite his MRA of the brain, concern for vasculitis was raised because he had failed maximum antithrombotic therapy and had developed elevated inflammatory markers with ESR 100 mm/H and CRP 76.6 mg/L. ANA was negative at less than 1:40 dilution. AntiDS DNA was within normal limits at 28 IU/mL. Anti-PR3 antibody and anti-myeloperoxidase antibody were negative at less than 6 detected. Hepatitis C panel and cryoglobulin testing were all negative. CSF examination revealed an opening pressure of 220 mm H2 O, 910 erythrocytes, 70 leukocytes (45% granulocytes, 52% lymphocytes, and 3% monocytes), glucose 40 mg/dL (corresponding blood glucose of 128 mg/dL), and protein 128 mg/dL. Cryptococcal CSF antigen titer was positive at 1:8 dilution and sub-typing revealed C. neoformans var neoformans. Additional CSF testing also included negative HSV PCR, VZV PCR, EBV PCR, JCV PCR, and acid-fast bacillus culture. VDRL and FTA-ABS were non-reactive. Cryptococcal serum antigen titer was positive at 1:8 dilution. Enzyme-linked immunosorbent assay for HIV was negative, and the purified protein derivative test was non-reactive. His CD4+ count was 400 cells/mm3 , representing 31.2% of his total lymphocyte population. His CD4:CD8 ratio was 2.72. CSF flow cytometry reported that no immunophenotypic abnormalities were detected, and no unusual T-cell phenotypes were identified. Serum flow cytometry reported normal lymphoid phenotype for age without surface marker evidence of immunodeficiency disorder. TNF-␣ level was 2.0 pg/mL (range: 1.2–15.3 pg/mL), and interleukin-12 level was less than 14.9 pg/mL (range: less than 35 pg/mL). Treatment with amphotericin B and flucytosine was initiated after the diagnosis was obtained via CSF sampling. His regimen was changed to fluconazole after acute renal failure ensued. Patient had substantial improvement while being treated. He was later discharged on daily fluconazole for suppressive therapy. One year later, he had only a residual left lower facial droop. Follow-up imaging with MRI of the brain showed no evidence of acute ischemic infarction.

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Fig. 2. (A) Axial CT of the brain through the vertex demonstrates an osteolytic lesion in the left frontal area. (B) Coronal fluid attenuated inversion recovery (FLAIR) MRI of the brain reveals a hyperintense lesion within the skull diploe consistent with osteomyelitis. The overlying skin was affected by a papular rash which proved to be cryptococcal dermatitis. (C) Papular skin lesion contained subepidermal collections of fungal organisms (*), eliciting limited inflammatory response, predominantly of histiocytes. (D and E) The organisms (arrows) were positive with Gomori-methenamine stain showing tear-drop budding. Bars: 1 mm (C), 100 ␮m (D and E).

Fig. 3. Axial diffusion-weighted MRI of the brain obtained at two separate presentations over the course of one month. (A) The patient presented with disorientation and receptive aphasia. The head of the caudate nucleus demonstrates restricted proton diffusion consistent with acute infarction in a lenticulostriate artery distribution. (B and C) Twenty days later, the patient presented with elements of receptive and expressive aphasia. A right cerebellar peduncle infarct (B) and a left subinsular infarct (C) were apparent.

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3. Discussion Patients with impaired T-cell immunity have an increased risk of cryptococcosis compared with immunocompetent patients. While the meninges are commonly involved, cryptococcus may affect any part of the central nervous system. The unusual features of each case led to delayed diagnosis and treatment. Case 1 had a conus medullaris abscess. The correct diagnosis was obscured by the negative CSF latex antigen cryptococcal agglutination test. This test has a high sensitivity of 92% in CSF and 97% in serum [4,5]. Potential reasons for false negative results include: low titers, prozone phenomenon of high titers, blocking antibodies, early infection, poorly encapsulated cryptococcal strains, and varying sensitivities of commercially available latex antigen cryptococcal agglutination kits [1,5]. Patients with cryptococcomas may have negative CSF and serum antigen results, and negative CSF cultures [4]. Cryptococcomas may require diagnosis by brain biopsy and culture of the biopsy specimen [4]. Cryptococcal involvement of the spinal cord is typically restricted to the leptomeninges [6]. Only eight intramedullary cryptococcal spinal cord abscesses have been reported, including only one biopsy-proven case in an AIDS patient [6–15]. In a retrospective series of fifty-five AIDS patients with infectious or neoplastic diseases of the spine, ten intramedullary lesions (18%) were found [16]. Toxoplasma myelitis was the most frequent etiology followed by vacuolar myelopathy, HIV myelitis, herpes simplex myelitis, and lymphoma [16]. MRI of the spine in our first case revealed a rimenhancing lesion resembling toxoplasmosis or CNS lymphoma. The latter diagnosis was supported by EBV genome detection in CSF. EBV PCR has sensitivity and specificity up to 80–100% for diagnosing CNS lymphoma in AIDS patients with focal brain lesions [17,18]. Thallium-201 brain SPECT is effective in differentiating toxoplasmosis and lymphoma with sensitivity approaching 100% and specificity of 54–90% [19,20]. Since this patient did not have an intracerebral lesion, thallium-201 brain SPECT was not an option. Brain and spinal cord biopsy in the immunocompromised host is associated with increased morbidity and does not yield a specific diagnosis in up to 50% of cases [21]. This has led to the preferred use of imaging studies, minimally invasive diagnostic tests and empiric treatment. However, when empiric treatment fails, a tissue diagnosis is indispensable. Since this was an intramedullary lesion and did not cause complete obliteration of the subarachnoid space, a lumbar puncture could be safely performed below the level of the lesion. If the subarachnoid space had been obliterated or if an epidural abscess had been present in the lumbar region, then the alternative would have been a lateral cervical puncture or a sub-occipital puncture [22,23]. In case 2, the combination of papular lesions in the left ophthalmic dermatome and meningeal signs in an immunocompromised host led to the clinical diagnosis of disseminated herpes zoster. However, CSF cryptococcal antigen titer and skin biopsy showed that the patient actually had disseminated cryptococcosis with meningitis and cryptococcal cutaneous lesions. While 10% of immunocompromised patients with disseminated cryptococcus have cryptococcal skin lesions, only 5% of patients with cryptococcal meningitis have such lesions [24,25]. In the pre-AIDS era, one review described the following skin manifestations (in order of most frequent first): granulomas, ulcers, subcutaneous nodules, and palpable purpura [26]. Other manifestations included acneiform lesions, cellulitis, papules, and sinus tract lesions [27,28]. AIDS patients most frequently have white to skin-colored papules which may have a crusted or umbilicated appearance similar to molluscum contagiosum [29,30]. In addition, AIDS patients may have lesions mimicking Karposi’s sarcoma, herpetiform lesions, nodules, or acneiform lesions [31–34]. Cutaneous lesions most fre-

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quently affect the head and neck, and may be single or multiple [28,30]. Cutaneous cryptococcal lesions almost always indicate that the patient has disseminated cryptococcosis [35]. Patients with disseminated cryptococcosis affecting organs other than the CNS and lungs have a markedly higher mortality rate [3]. A broad diagnostic panel and retrieval of material from more than one affected site are necessary without delay. Recurrent strokes in an immunocompetent host as described in case 3 are another highly unusual manifestation of cryptococcal meningitis. Immunocompetent hosts are at risk for cryptococcosis when a latent infection is reactivated. Reactivation occurs in 10–40% of HIV-negative patients [3]. Defective transformation of lymphocytes upon exposure to cryptococcal antigens may be responsible for transient deficits in cellular immunity [36]. Up to 4% of cryptococcal meningitis patients manifest secondary cerebral infarction. Areas typically involved include the basal ganglia, thalamus, and internal capsule; large vessels tend to be spared. Infarctions may result from the development of vasculitis, inflammation, or thrombosis of cerebral vasculature [37]. Since our patient had additional infarcts while on an appropriate antithrombotic regimen, other causes of cerebral infarction were considered. These included autoimmune and infectious diseases causing a vasculitis or vasculopathy. His immune status was investigated with HIV testing and a quantitative lymphocyte count with subtype analysis to assess for Idiopathic CD4+ lymphocytopenia. Opportunistic infections such as cryptococcal meningitis have been reported in patients who are HIV negative, without other known cause of immunodeficiency, and with a CD4+ count of <300 cells/mm3 and a CD4+ count <20% of total T-cell count on more than one occasion [38]. Our patient had repeat T-cell testing more than a year later, showing similar values to those found on index admission. Despite not finding an explanation for this patient’s susceptibility to cryptococcal infection, once CSF analysis yielded a positive cryptococcal antigen and antifungal treatment was initiated, his condition improved dramatically. Infectious diseases such as cryptococcal meningitis are a potentially treatable cause of stroke and should be considered when recurrent ischemic events occur in unusual vascular territories in patients already on appropriate antithrombotic treatment. If a patient is not responding to appropriate empiric therapy and cryptococcal disease is suspected, a serum cryptococcal antigen titer should be checked. None of the patients in this case series were evaluated with serum cryptococcal antigen titers. This test has 97% sensitivity and 93–100% specificity [5]. Serum cryptococcal antigen testing is rarely negative in patients with disseminated cryptococcosis, but is occasionally negative in cases of primary cryptococcosis, cryptococcomas, or immunocompetent patients with meningitis [4,39–41]. Since the patient in case 1 had a negative CSF cryptococcal antigen titer and no signs or symptoms of disseminated cryptococcosis, the serum cryptococcal antigen titer would likely have been negative. Given that the patient’s symptoms progressed, abscess drainage would have been necessary in any case. In case 2 evaluating a serum cryptococcal antigen titer would not have appreciably accelerated making the correct diagnosis. The patient in case 3 had no systemic symptoms or signs of cryptococcal disease to suggest the need for a serum cryptococcal antigen titer. If a positive serum cryptococcal antigen titer had been obtained, he would have been started on amphotericin B and flucytosine earlier. 4. Conclusion Without prompt diagnosis, cryptococcal infections of the nervous system can cause severe neurological disability and death. If the patient has a lesion in a high-risk area, minimally invasive and indirect diagnostic methods should be employed first. Sensi-

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tive and specific tests are readily available and should be used in the appropriate setting even if suspicion is low. In the immunocompromised host, reliance upon serological diagnosis may be insufficient. Empiric therapy for conditions mimicking cryptococcosis requires close surveillance. If these patients develop progressive symptoms, then tissue diagnosis should be strongly considered. References

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