Invasive aspergillosis (IA) is relatively common in allogeneic stem cell transplant (SCT) recipients. Although lungs are the most common site, central nervous system (CNS) involvement is also observed in this setting. We have retrospectively studied 14 cases of CNS aspergillosis found in a cohort of 455 allogeneic SCT recipients (incidence 3%). All patients, except one, had experienced acute graft-versus-host disease treated with high-dose methylprednisolone, and eight patients (57%) had also received ATG. The median time to the diagnosis of CNS aspergillosis was 124 days (range 49–347 days) from SCT. Pulmonary aspergillosis had been diagnosed earlier in four patients (29%). The most common initial symptoms of CNS aspergillosis were convulsions, hemiparesis, and mental alteration. Neuroradiological studies revealed single (two patients) or multiple (seven patients) focal lesions of 0.2–9 cm in diameter. Despite clinical suspicion in many patients, a confirmed diagnosis of CNS aspergillosis was made during life in only one patient. A total of 12 patients (86%) received amphotericin B. Despite therapy, all patients died 0–27 days (median seven days) after the initial CNS symptoms. CNS aspergillosis is not uncommon in allogeneic SCT recipients. Clinical manifestations are usually dramatic and progress quickly. Earlier and more effective treatment of IA is needed to prevent dissemination of infection into the CNS.
Invasive aspergillosis (IA) is a frequent clinical problem in allogeneic stem cell transplant (SCT) recipients with an incidence of 4–10%.1,2,3,4 The prognosis of IA is very poor.5,6 Lungs are the most common site of aspergillosis and are affected in about 90% of patients.7 Central nervous system (CNS) involvement is also common in allogeneic SCT recipients. Previous studies have indicated that CNS aspergillosis may be found in 40–50% of patients with IA.2,8 Although several reports on CNS aspergillosis have been published,9,10,11,12,13 most of them include few allogeneic SCT recipients.14,15,16,17 We have therefore retrospectively analysed the incidence as well as clinical, radiological, and neuropathological findings of CNS aspergillosis among 455 consecutive allogeneic SCT recipients transplanted during a period of 12 years.
Patients and data collection
A total of 455 adult patients received allogeneic SCT at the Department of Medicine, Helsinki University Central Hospital during 1989–2000. All patient records were retrospectively evaluated to find cases of possible CNS aspergillosis. Autopsy records were also reviewed.
In addition to the demographics of patients with CNS aspergillosis, the time from SCT to diagnosis of CNS aspergillosis was also recorded. The occurrence and treatment of graft-versus-host disease (GVHD) were considered in all patients. Further, symptoms suggesting a CNS infection were sought from the patient records. Laboratory data collected included studies on the cerebrospinal fluid (CSF). All neuroradiological studies including computerized tomography (CT) and magnetic resonance imaging (MRI) were reviewed by two radiologists (one of them a neuroradiologist). Neuropathological autopsy records were available for all patients.
Of the 455 allogeneic SCT recipients, 14 had CNS aspergillosis (incidence 3%). Patient characteristics are summarized in Table 1. Median time to the diagnosis was 124 days (range 49–347 days) from SCT. In four patients (29%), the diagnosis of definite or probable invasive pulmonary aspergillosis had been made 9–91 days earlier.
Initially, all patients engrafted, but 11 (79%) were neutropenic at the time of diagnosis. All patients, except one, had experienced acute GVHD prior to the diagnosis of CNS aspergillosis. In all, 13 patients (93%) had been treated with high-dose methylprednisolone (MP), and eight (57%) had also received ATG. The median dose of MP at the time of diagnosis was 1 mg/kg/day (0.2–2.5 mg/kg/day).
Clinical and laboratory findings
Nine patients (64%) were febrile. The most common initial neurological symptoms were convulsions, hemiparesis, and mental alteration (Table 2). Neurological symptoms usually progressed quickly. Median time from the initial CNS symptoms to the diagnosis or to death was 7 days (0–27 days).
CSF was examined in five patients. The most common finding was a moderate increase in the protein concentration. In one patient Candida albicans grew from CSF, and in another patient a minute amount of mould was seen on microscopy of the CSF. No antigen or PCR tests were performed on CSF in any of these patients.
Neuroradiological studies (CT, MRI) had been performed because of neurological symptoms in nine patients (64%) within a month prior to the diagnosis of CNS aspergillosis. In eight patients at least one CT examination was done. Three of the studies were nonenhanced and five were performed with a contrast medium. All MRI examinations included gadolinium-enhanced images.
On the first study, two out of nine patients had only one lesion; all the others had multiple CNS lesions (Figure 1). The maximum diameter of the lesions ranged from 0.2 to 9 cm. No enhancement was observed in five patients who underwent CT examination with contrast medium. A faint ring-like gadolinium-enhancement was observed around most lesions in MRI (Figure 2). One patient had a large haemorrhagic lesion (Figure 3); in four other patients smaller haemorrhagic areas could be seen in some lesions. The findings are summarized in Table 3.
Treatment and outcome
Nine patients (64%) received systemic amphotericin B at the time of the first neurological symptoms or the presumptive diagnosis of CNS aspergillosis. Altogether, 12 patients (86%) received amphotericin B therapy for proven or suspected aspergillosis. No treatment responses were observed, and the neurological symptoms usually progressed within a few days. The median survival was only 7 days (range 0–27 days) from the onset of the neurological symptoms or signs.
All patients underwent autopsy, which confirmed the diagnosis of CNS aspergillosis in each patient including the patient in whom neurosurgical biopsy had shown aspergillosis in the temporal lobe 10 days prior to death. The most common macroscopic findings were focal necrotic lesions. In two patients, a major cerebral haemorrhage was observed in association with aspergillosis. In one patient, Candida infection was observed in the meninges (diagnosed by culture of the CSF 11 days earlier), in addition to focal necrotic lesions caused by Aspergillus in both hemispheres.
In addition to necrosis and haemorrhage, microscopy revealed fungal invasion and thrombus formation in vessels nourishing the areas of focal lesions (Figure 4). Fungal septate hyphae, typical for moulds, were observed in all cases. The Aspergillus species could be cultured in eight patients (Aspergillus fumigatus in all).
Isolated CNS aspergillosis was not observed in this material. Besides CNS, aspergillosis was observed in the lungs (12 patients, 86%), kidneys (four patients, 29%), liver (three patients, 21%), heart (three patients 21%), and gut (two patients, 14%). The involvement of the spleen, the thyroid gland and the adrenal gland was found in one patient (7%) each.
CNS aspergillosis as a cause of death
Altogether, 168 out of 455 SCT recipients (37%) died within a year after SCT. Therefore, the minimum figure for deaths because of CNS aspergillosis was 8% in this material.
The present retrospective study is one of the largest series of allogeneic SCT recipients with CNS aspergillosis. A strong association with GVHD, dramatic clinical presentation, and relentless progression despite therapy were the major observations. They differ, at least in part, from the features seen in less immunocompromised patients with CNS aspergillosis. CNS aspergillosis has been considered a rare disease. This is certainly the case in patients who have undergone autologous SCT or who have received chemotherapy for leukaemia or other cancers. A retrospective Italian study showed that CNS involvement was observed in only 14% of patients with acute leukaemia and IA.12 However, a previous report of Saugier-Veber et al,2 suggested CNS involvement in up to 40% of allogeneic SCT recipients with IA. We observed CNS involvement in about half of our patients with IA (14/33) during the study period, but this is likely to be an underestimation, as not all patients who were diagnosed with IA during life and subsequently died were autopsied.
The present study yielded an incidence of 3% of CNS aspergillosis in a cohort of allogenic SCT recipients during a 12-year period. A similar incidence has recently been reported by de Medeiros et al18. Coley et al15 observed an incidence of 1.2%. In an autopsy series, an incidence of 5% was reported; >90% of the patients were allogeneic transplant recipients.19 By contrast, Graus et al20 and Maschke et al16 found no CNS aspergillosis in autologous SCT recipients.
Clinical features were usually dramatic, consisting of mental alteration, convulsions, and hemiparesis. The clinical features observed were similar to those in the series by Hagensee et al,21 where altered mental status was observed in 52% of the patients and hemiplegia and seizures in 33 and 30% of the patients, respectively. Although these clinical signs, as such, are non-specific, in high-risk patients they are suggestive of an intracranial process and an indication for neuroradiological studies.
The diagnosis of invasive aspergillosis is difficult, and this is certainly also the case with CNS aspergillosis. Examination of CSF usually gives a low diagnostic yield, which was also observed in some of the present patients. However, CSF examination is useful for differential diagnosis of other pathogens or CNS involvement with malignant cells. Recently, detection of Aspergillus antigen or DNA in CSF has been suggested to be useful in the diagnosis of CNS aspergillosis.22
A definitive diagnosis of CNS aspergillosis requires histopathological samples, that can be obtained only by neurosurgery. These procedures are often not practical in this setting and may unnecessarily delay the start of therapy. In allogeneic SCT recipients, CNS aspergillosis is almost always associated with pulmonary disease,21 which was also confirmed in this study. Thus, patients with previously suspected pulmonary aspergillosis who develop neurological symptoms or signs should initially be treated as having CNS aspergillosis.
Neuroradiological studies are helpful in the diagnosis of CNS infections in transplant recipients. Both CT and MRI are useful, but MRI may be more accurate and reveal more lesions than CT.14 MRI and CT appearances of CNS aspergillosis have been studied in detail by several investigators.11,13,14,17,23 Neuroradiological findings may be of use in the differential diagnosis of CNS infections.15,16 Of other pathogens, Candida or other fungi, Toxoplasma gondii and also bacteria should be taken into consideration.16,18,21,24
The treatment of invasive aspergillosis has proved disappointing in allogeneic SCT recipients.5,6,25,26 Although the response rate in patients with pulmonary disease has been only 10–30%, the prognosis is even worse in patients with CNS involvement. In our series the median survival was only 7 days after the first symptoms, which is comparable to other reports.14,21 However, some promising case reports have been published suggesting that the therapy may be effective in some patients with acute leukaemia27,28 or even in allogeneic SCT recipients.29,30
Amphotericin B, the standard therapy for aspergillosis, as well as itraconazole both have poor penetrance into the CNS.31,32,33 Voriconazole has better penetrance28 and may thus become the therapy of choice in patients with CNS aspergillosis. Recently, voriconazole has been found superior to amphotericin B in the primary treatment of invasive aspergillosis.34 Another study suggested a partial response or stable disease in 42% of the patients with CNS aspergillosis treated with voriconazole,35 but only a minority of the patients were allogeneic SCT recipients. Given the currently poor prognosis of CNS aspergillosis, combination chemotherapy might also be worth trying. In vitro studies as well as animal models have suggested additive or synergistic effects of caspofungin and voriconazole against Aspergillus sp.36,37 However, the diagnosis of CNS aspergillosis is often delayed, the clinical situation is usually complex with severe immunosuppression and efficacy of current therapies is suboptimal. Therefore, treatment results are hard to improve in this patient population. Owing to the often multifocal nature of the CNS infection, surgery is not usually useful in this setting.
To conclude, CNS aspergillosis is fairly common in allogeneic SCT recipients and is usually associated with pulmonary aspergillosis. The clinical presentation is often dramatic and the prognosis is dismal. More effective modes of treatment for IA are needed to prevent dissemination of the infection into the CNS.
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This study was financially supported by Blood Disease Research Foundation of Finland.
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Jantunen, E., Volin, L., Salonen, O. et al. Central nervous system aspergillosis in allogeneic stem cell transplant recipients. Bone Marrow Transplant 31, 191–196 (2003). https://doi.org/10.1038/sj.bmt.1703812
- central nervous system
- allogeneic stem cell transplantation
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