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Aspergillus meningitis: A rare clinical manifestation of central nervous system aspergillosis. Case report and review of 92 cases

Objectives To describe the pathogenesis, clinical presentation, cerebrospinal fluid findings and outcome of Aspergillus meningitis, meningoencephalitis and arachnoiditis. Methods A case of Aspergillus meningitis is described. A comprehensive review of the English-language literature was conducted to identify all reported cases of Aspergillus meningitis described between January 1973 and December 2011. Results Ninety-three cases (including the one described herein) of Aspergillus meningitis were identified. Fifty-two (55.9%) were in individuals without any predisposing factor or known causes of immunosuppression. Acute and chronic meningitis was diagnosed in 65.6% of patients and meningoencephalitis in 24.7% of them with the remaining presenting with spinal arachnoiditis and ventriculitis. Cerebrospinal fluid cultures for Aspergillus spp. were positive in about 31% of cases and the galactomannan antigen test in 87%. Diagnosis during life was achieved in 52 patients (55.9%) with a case fatality rate of 50%. The overall case fatality rate was 72.1%. Conclusions Aspergillus meningitis may occur in both immunocompetent and immunocompromised patients and run an acute or chronic course. The findings of this systematic review extend the information on this life-threatening infection and could assist physicians in achieving an improved outcome.

Conclusions: Aspergillus meningitis may occur in both immunocompetent and immunocompromised patients and run an acute or chronic course. The findings of this systematic review extend the information on this life-threatening infection and could assist physicians in achieving an improved outcome. ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Central nervous system (CNS) infections are well recognized manifestations of disseminated aspergillosis observed in about 10% of immunocompromised patients and with mortality rates greater than 90%. 1,2 By contrast, Aspergillus meningitis is a more seldomly encountered clinical entity and it is found more frequently in immunocompetent rather than in immunocompromised hosts. 3e8 Information about Aspergillus meningitis is limited and sparse and to our knowledge no review on this topic has been published so far. We present here a case of Aspergillus meningitis, along with a review of published cases since 1973.

Methods
Case reports of Aspergillus meningitis, meningoencephalitis, arachnoiditis and ventriculitis as well as series of CNS aspergillosis were identified through a search of PubMed and Scopus databases of the English literature, and the reference lists were reviewed for additional cases. Research was conducted from the year 1973 through 2011. Used research terms included "Aspergillus meningitis", "cerebral aspergillosis", "central nervous system aspergillosis", "Aspergillus arachnoiditis", "mycotic meningitis". For the purpose of this review a case of meningitis or meningoencephalitis caused by Aspergillus spp. was defined during life as follows: 1) a cerebrospinal culture positive for Aspergillus spp. together with a meningeal or encephalic syndrome; 2) the presence of galactomannan antigen or Aspergillus DNA detected by polymerase chain reaction (PCR) test in the CSF, together with a meningeal syndrome. Post-mortem diagnoses of Aspergillus meningitis were included if the autopsy clearly indicated involvement of the meninges or a picture of meningitis with microscopic identification of Aspergillus hyphae or a positive Aspergillus culture. When inflammation involved the spinal leptomeninges the case was classified as spinal arachnoiditis. Patients were considered immunocompromised if the following conditions were met: 1) HIV/AIDS infection; 2) solid organ transplantation; 3) hematologic diseases with or without bone marrow transplantation; 4) autoimmune diseases treated with steroids or other immunosuppressive drugs; 5) diabetes mellitus; 6) any other condition treated with corticosteroids or immunosuppressive drugs.

Case report
A 34-year-old man was referred to our Infectious Diseases ward on February 9, 2010 from a Neurosurgery Unit where a diagnosis of Aspergillus meningitis had been made (Fig. 1). The clinical history was notable for heroin intravenous drug abuse, high alcohol intake, untreated chronic hepatitis C and methadone maintenance therapy (50 mg/ day). One month before he was admitted to the Internal Medicine ward of another Hospital to investigate the nature of low back pain, headache and low grade fever (37.5 C) that had appeared 1 month earlier. Magnetic resonance imaging (MRI) of the brain was negative for parenchimal and meningeal lesions. On the contrary, MRI of the lumbar spine showed abnormal contrast enhancement into the spinal canal between L4 and S1 suggesting an intradural mass lesion conditioning a traction effect on the roots of the cauda equina. A color-doppler echocardiogram showed only a mild mitral regurgitation. Blood and urine cultures were negative as well as a serologic test for HIV. Cerebrospinal fluid (CSF) analysis performed on February 9 is shown in Fig. 1. Gram and Ziehl-Neelsen stains, as well as bacterial and mycobacterial cultures, were negative as was the search for bacterial and Cryptococcus neoformans antigens. Cerebrospinal culture grew Aspergillus flavus that was susceptible to amphotericin B, voriconazole, posaconazole, itraconazole and caspofungin. Aspergillus galactomannan antigen-GM (Platelia Aspergillus, Sanofi Diagnostics Pasteur, Marne-La Coquette, France) was detected both in the CSF and blood with a higher index value in the former (respectively, 7.4 and 2.5). Upon admission to our ward (February 12), the patient had fever (38.5 C), was alert and complained of frontal headache and photophobia, without neck stiffness. Intravenous treatment with voriconazole was started (6 mg/kg every 12 h (q12h) as loading dose, followed by 4 mg/kg q12h) together with ceftriaxone (2 g q12). Two weeks later, a control brain and spinal MRI showed meningeal enhancement with cysternal distribution especially in the pre-pontine area around the basilar artery, together with endocanalar pathologic enhancement between L4 and S2 (Figs. 2, 3a and b). A concomitant CSF analysis showed a reduction of WBCs (180/mL, 61% PMNs), improvement of glucose levels (24 mg/dL, serum 110 mg/dL) and a striking increase of protein level (3705 mg/dl), whereas, at this time point, CSF culture turned negative. The GM index was 6.36 in the CSF and 0.9 in the peripheral blood. Because of persistent fever, headache and worsening of the radiological picture, caspofungin (70 mg loading dose, 50 mg maintenance dose) was added to the antifungal regimen with discontinuation of the antibiotic therapy. Voriconazole blood and CSF trough concentrations obtained after 2 weeks of therapy were similar (5.85 and 5.86 mg/L, respectively). Therapeutic drug monitoring was arranged 6 and 10 days later and it showed toxic concentrations of the drug that prompted dosage adjustments despite the absence of any clinical or biochemical signs of voriconazole toxicity. Another CSF examination performed on March 18, disclosed an improvement of all parameters (Fig. 1). Repeated MRI of the brain and spine (March,17) showed the reduction of the pial and cysternal contrast enhancement but a progression of the endocanalar inflammation now involving the segments L3 to S2. After a new evaluation by the neurosurgery consultant, who deemed any procedure unfeasible, the patient was discharged after having received 38 days of voriconazole therapy (total cumulative dosage: 21,200 mg) and one month of caspofungin (total cumulative dosage:1520 mg). The patient was left on maintenance therapy with oral voriconazole at a dosage of 150 mg q12 due to raised ALT levels (199 U/L), the appearance of visual disturbances and persistently elevated trough voriconazole concentrations (6.2 mg/L). At the end of April, the patient was readmitted to our hospital ward because of persistent abnormal liver function test results and visual disturbances that required discontinuation of voriconazole and its substitution with intravenous liposomal amphotericin B (L-AMB, 250 mg/day). He complained of persistent low back pain that was irradiated to both the lower extremities with preserved deep tendon and superficial reflexes. Repeated attempts to obtain CSF samples by lumbar puncture were unsuccessful. Nerve conduction and electromyography studies showed mild sensorimotor bilateral demyelinating polyneuropathy. A new MRI of the brain and spine (performed on May, 17) was substantially unchanged. During the 30-day therapy with L-AMB, GM was evaluated weekly and showed values ranging from 0.9 to 1.59. Because of the patient's drug addiction history, it was decided to resume oral voriconazole therapy since the positioning of a permanent intravenous device for L-AMB infusion on an outpatient basis was  judged risky. A dosage of 150 mg every 12 h was started on June 9, showing after a week trough and peak concentrations of 3.4 and 3.6 mg/L, respectively. A new MRI of the brain and spine was performed on August 4, that demonstrated a reduction of pial enhancement along the cervical tract, the conus medullaris and cauda equina with a only a mild volumetric reduction of the endocanalar lumbar abscess. Clinically, the patient was well oriented with a positive bilateral Las egue sign at the neurologic examination. He was discharged and subsequently lost to follow-up.

Results
A detailed, chronologically ordered summary of 93 cases of Aspergillus meningitis, chronic meningitis/pachymeningitis, meningoencephalitis, arachnoiditis and ventriculitis including the one presented herein (case 46) is shown in Table 1. There were 46 women (50%) and 46 men, with a median age of 37 years (range 3e75 years). Diagnosis was made during life in 52 patients (55.9%) and at autopsy in 41 patients. A diagnosis was obtained more frequently during life among immunocompetent patients (69%) in comparison with immunocompromised individuals (39%) ( Table 2).
In almost half of the cases (n Z 44) Aspergillus was identified by histology or culture without speciation; all other infections were caused by A. fumigatus (n Z 34), A. flavus (n Z 8) and A. terreus (n Z 3) while A. oryzae, A. granulosus and A. candidus were identified in one case each. Fortyone patients were considered immunocompromised hosts (5 AIDS patients; 3 with autoimmune diseases treated with steroids; 9 solid organ transplant recipients; 10 hematologic patients undergoing chemotherapy or bone marrow transplantation; 5 subjects under steroid therapy for chronic obstructive pulmonary disease (COPD), and Severe Acute Respiratory Syndrome; 7 patients with diabetes and, finally, 1 each with Cushing's disease and sarcoidosis). In the fiftytwo patients without classic risk factors for invasive aspergillosis, central nervous system involvement was presumed to be the result of: direct extension of Aspergillus from the orbit, ear or paranasal sinuses in 6 patients (11.5%); iatrogenic direct inoculation of Aspergillus through spinal anesthesia (13 patients, 25%), neurosurgery (13 patients, 25%) or epidural steroid injections (1 patient). In six intravenous drug abusers (11.5%) the infection was probably acquired by the hematogenous route. Among the remaining subjects, no predisposing factor could be identified in six patients while one patient each were notable for the presence of the following: pregnancy, alcohol abuse, fungal endocarditis and near drowning. The most common syndrome was acute meningitis which was observed in 46 patients, followed by meningoencephalitis (n Z 23). A chronic course of meningitis was observed in 15 patients; five patients showed a picture of spinal arachnoiditis (in 1 case with associated meningitis), and 4 ventriculitis ( Table 2). An acute course characterized by rapid deterioration of the clinical picture usually ending with death was observed among immunocompromised hosts and in patients who had direct inoculation of the fungus into the cerebrospinal fluid or the subarachnoid space. By contrast, a sub-acute or chronic form of meningitis going unrecognized for several weeks and sometimes displaying a relapsing character was the most frequent presentation among immunocompetent patients, intravenous drug abusers and patients with diabetes. However, the latter clinical picture was also observed among several patients who had undergone neurosurgery.
Cerebrospinal fluid culture was positive for Aspergillus spp. in 31% of cases with a slightly higher prevalence among immunocompetent (36.9%), as opposed to immunocompromised hosts (18.2%) ( Table 2). In nine patients, Aspergillus spp. was cultured from CSF only after repeated attempts (median number of lumbar punctures: 4, range 3e9). Antigen-based assays were employed in fifteen patients: GM antigen by use of the Platelia Elisa in 10 patients, with an unspecified assay in 2 patients, with Pastorex assay in 1 patient and 1,3-b-D-glucan in 2 individuals. GM antigen was detected in CSF specimens of 6 out of 8 immunocompetent patients and in all immunocompromised hosts in whom it was assessed (7/7, 100%) with an overall sensitivity of 86.7%. The median CSF GM index was 6.58 (range 2.2e578).
Serum GM was concomitantly measured in 8 cases and turned positive in 3. In 3 patients, CSF GM was serially determined (3e10, median 7), showing a good correlation         Of those patients who had received at least one dose of antifungal agent, 30 (51.7%) died after an interval of time ranging from few days up to 6 years. All patients with chronic meningitis were initially treated with antibiotics and 6 had also received anti-tubercular therapy. An overall casefatality rate (CFR) of 72.1% was observed, with significant differences between immunocompetent (63.5%) as opposed to immunocompromised patients (82.9%) patients.
Autopsy was available in 49 cases and it was the method by which diagnosis was made for 40 patients (81.6%). In twelve cases basilar meningitis was identified; spinal cord involvement was observed in 5 patients; the presence of a mycotic aneurism involving either the internal carotid artery or the basilar artery was shown in 12 patients with concomitant subarachnoid hemorrhage. Transtentorial, tonsillar or uncal herniation was present in three patients.

Discussion
In a 1969 review of the literature, Mukoyama et al., reported 33 cases of aspergillosis involving the CNS of whom 10 had meningitis and 3 had meningoencephalitis. However, Aspergillus isolation failed in all 10 cultured cerebrospinal fluid specimens. 7 In a clinical-pathological study of central nervous system aspergillosis only 1 patient had signs of meningeal irritation during life while at autopsy the meninges were focally affected in nearly half of the cases. 8 In the present series regarding 93 patients, a picture of pure meningitis was observed in 65.6% of cases, 3,8e22,24e49 while meningoencephalitis was diagnosed in about 25% of patients. 5,6,36,50e68 In patients with a diagnosis of meningitis fever and headache were the most common presenting symptoms (78.8%) followed by neck stiffness in 28.2% (24/85). 3e6,9e76  3,6,10,12,13,15,22,23,25e27,29,32,33,39,44,45,47,52,54,56,58,63,76,78,79 PR as opposed to immunocompromised individuals (39%). 5,9,28,29,34,36,40,42,46,48,55,59,74 This difference might be explained by a more aggressive and acute course of the disease observed in immunosuppressed hosts. A culture-based diagnosis of Aspergillus meningitis is hampered by the lack of sensitivity as shown by the 31% of positive results observed in our review of published cases. 3,9,13,22,23,25,26,29,33,35,37,40,45,52e54,56,70 PR It has been previously suggested that a minimum of 5 mL of cerebrospinal fluid should be cultured when a mycosis is suspected or that repeated culture of large volumes of CSF are critical for successful in vitro isolation. However, such large volumes are not easy to obtain in clinical practice. 80 On the other hand, serial lumbar puncture does indeed seem to have a role since in 9 cases, the fungus could be successfully isolated from cerebrospinal fluid only after several attempts. 3,25,26,29,35,37,40,45 Non-culture based diagnostic methods for the diagnosis of aspergillosis were employed on CSF in fifteen patients and seem to outperform traditional culture, with a overall sensitivity of 87%. 23,25,28,29,34,36,48,49,64,75,76PR Although a cut-off value of the GM index has not yet been formally established for the diagnosis of CNS aspergillosis, it has been proposed that it might be lower than that used for serum samples due to the lower back-ground reactivity of CSF. 25,81 The median CSF GM index in this series was 6.58 which is a value higher than what is usually observed in serum and well above the cut-off of 0.5 when two serial serum determinations are used among immunocompromised patients or the 0.7e1 value when a single determination is employed in non-hematological patients. 82,83 Notably, when both serum and CSF GM were screened concomitantly, negative results were observed in three cases in serum and the index value was always higher in CSF than in serum. 29,34,36,64PR Although serial determinations on CSF were available only in three cases they may provide useful information on the therapeutic response. 25,29PR Finally, it seems that the Platelia GM test works well irrespective of the species of Aspergillus involved as shown by the cases described by Verveij, Moling and ourselves in whom A. fumigatus, A. candidus and A. flavus were respectively cultured from the CSF. 25,29PR Our review shows that Aspergillus meningitis has an ominous prognosis with a global case-fatality rate (CFR) of 72.1% but with a much better outcome among immucompetent patients in whom a CFR of 63.5% was observed versus a 83% CFR registered among immunocompromised patients. Our data are only slightly better than the 88% CFR reported by Lin et al. in a literature-based survey published before 2001. 84 The Infectious Diseases Society of America (IDSA) guidelines recommend voriconazole for the treatment of central nervous system aspergillosis but these recommendations are mainly based upon studies regarding patients with hematological disorders and there is no specific mention as to the treatment of Aspergillus meningitis. 85 In our present review, that encompasses a long period of time before the introduction of voriconazole (i.e., 2002), most patients (64.3%) were treated with amphotericin B dehoxycholate and less than 30% received voriconazole at some time of their disease. 32,33,34,36,48,49,67,73e76 PR In a recent analysis conducted by Schwartz et al. on 120 cases of CNS aspergillosis a 47% response rate and a median survival of 159 days among patients treated with voriconazole was shown. 86 Voriconazole shows excellent penetration into the CNS as demonstrated by studies conducted in healthy guinea pigs in whom high cerebrospinal fluid to plasma ratio (0.68) together with rapid penetration across the blood brain barrier were observed. 87 Including the present report, determination of cerebrospinal fluid concentrations of voriconazole were available in four cases, with reported values ranging from 0.8 to 5.86 mg/L and with a CSF/plasma ratio ranging from 38% to 76 %. 25,59PR Hope recently proposed that in the busy clinical setting, voriconazole therapeutic drug monitoring (TDM) should be obtained at the end of day 2 and subsequently in the first week of therapy. 88 An association between poor outcome and voriconazole concentrations has been initially observed by Pascual and coworkers. 89 In addition Miyakis et al. recently showed an 11-fold increased risk of death among patients with invasive mycoses treated with voriconazole who had an initial trough concentration of less than 0.35 mg/L. 90 By contrast, several studies and expert opinion suggest that the optimal maximum voriconazole concentrations should not exceed 5.5e5.8 mg/L 89,91,92 Another crucial issue not yet addressed so far is the optimal length of antifungal therapy in patients with Aspergillus meningitis, as well as for cerebral aspergillosis. In our patient, antifungal treatment was administered for 7 months, 5 of which employing voriconazole but, just before losing the patient to follow-up we were uncertain how long it would have been necessary to continue the specific treatment. Our analysis of the literature regarding patients with Aspergillus meningitis who were treated with voriconazole shows very different lengths of treatment, ranging from 8e14 weeks to 5e12 months. 25,32e34,67,74,76PR However, it should be pointed out that in most cases the outcome following drug discontinuation is not reported. The long term duration of voriconazole treatment for patients with Aspergillus meningitis or with CNS involvement is a matter not only of efficacy but also of toxicity. In this regard, the risk of phototoxicity and, above all, the risk of inducing squamous cell carcinoma should be mentioned. 93 Caspofungin was employed in 5 patients, (in 4 of whom in combination with voriconazole), but its role, if there is any, as a single agent in the treatment of aspergillus meningitis is hampered by the lack of significant penetration across the bloodebrain barrier of this drug. 94 Except one apparently successful case, flucytosine has been used only in association with AMFB and its role in the treatment of aspergillosis remains anecdotal. 9,95 In conclusion, our review shows that Aspergillus meningitis is a rare clinical entity that is much more frequently observed among immunocompetent patients. It is characterized by CSF neutrophil pleocytosis in 68% of cases and hypoglycorrhachia in 62% of cases. Cultures of CSF are positive only in one third of cases, but the GM antigen test is very useful, with a sensitivity reaching 87%. Although our data show a poor prognosis, we believe that the more widespread use of diagnostic methods with greater sensitivity (i.e., PCR and GM), together with the availability of voriconazole therapy, may allow improved outcomes provided that the diagnosis is achieved earlier. The optimal length of antifungal therapy however remains to be determined.

Funding
No particular funding was received to support this work.