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[1–8] [PREPRINTER stage]
Int J STD AIDS OnlineFirst, published on February 18, 2015 as doi:10.1177/0956462415574633
Original research article
Neuroimaging of HIV-associated cryptococcal meningitis: comparison of magnetic resonance imaging findings in patients with and without immune reconstitution
International Journal of STD & AIDS 0(0) 1–8 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462415574633 std.sagepub.com
Juri Katchanov1, Gordian Branding2, Laura Jefferys1, Keikawus Araste´h1, Hartmut Stocker1 and Eberhard Siebert3
Abstract Aim: To determine the frequency, imaging characteristics, neuroanatomical distribution and dynamics of magnetic resonance imaging findings in HIV-associated cryptococcal meningitis in immunocompromised patients without antiretroviral therapy compared with patients undergoing immune reconstitution. Design: Retrospective analysis of imaging data and clinical case records. Methods: Neuroimaging and clinical data of 21 consecutive patients presenting to a German HIV centre in a 10-year period between 2005 and 2014 were reviewed. Results: We identified eight patients with magnetic resonance imaging findings related to cryptococcal disease: five patients without antiretroviral therapy and three patients receiving effective antiretroviral therapy resulting in immune reconstitution. The pattern of magnetic resonance imaging manifestations was different in the two groups. In patients not on antiretroviral therapy pseudocysts (n ¼ 3) and lacunar ischaemic lesions (n ¼ 2) were detected. Contrast-enhancing focal leptomeningeal and/or parenchymal lesions were found in all patients under immune reconstitution (n ¼ 3). Conclusions: Magnetic resonance imaging lesions suggestive of leptomeningitis or meningoencephalitis were detected in all patients with a recurrence of cryptococcal meningitis under immune reconstitution, this differs from the classical magnetic resonance imaging findings in patients without antiretroviral therapy. In antiretroviral therapy-treated patients with past medical history of cryptococcal meningitis detection of contrast-enhancing focal meningeal and/or parenchymal lesions should prompt further investigations for a recurrence of cryptococcal meningitis under immune reconstitution.
Keywords Europe, location, AIDS, viral disease Date received: 22 November 2014; accepted: 1 February 2015
In this study, we retrospectively analysed neuroimaging of 21 consecutive patients presenting with
Introduction Cryptococcal meningitis is a devastating disease common in regions with a high HIV prevalence.1,2 The majority of studies on cryptococcal meningitis are conducted in resource-limited settings, where availability of routine neuroimaging is restricted.3 Hence, systematic data on neuroimaging in cryptococcal meningitis is limited.4 Moreover, the majority of studies were conducted in the pre-HAART era5–9 and therefore do not report on patients presenting with cryptococcocal meningitis under immune reconstitution.10,11
1 Department of Infectious Diseases, Vivantes Auguste-Viktoria Klinikum, Berlin, Germany 2 Department of Radiology, Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany 3 Department of Neuroradiology, Campus Charite´ Mitte, Charite´, Berlin, Germany
Corresponding author: Juri Katchanov, Auguste-Viktoria-Klinikum, Rubensstraße 125 12157 Berlin, Germany. Email: [email protected]
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[1–8] [PREPRINTER stage]
2
International Journal of STD & AIDS 0(0)
Table 1. Clinico-microbiological patterns of meningeal cryptococcal disease in our study.
Typical cryptococcal meningitis (n ¼ 18) Microbiological relapse (n ¼ 2) Recurrence under immune reconstitution (n ¼ 3)
History of cryptococcal meningitis
CSF culture
Evidence of active cryptococcal infection
Median CD4 count, /ml
ART
No
Positive
Yes, by positive CSF culture
28 (range: 5–72)
No
Yes
Positive
Yes, by positive CSF culture
78 (range: 11–145)
No
Yes
Negative
Yes, by detection of budding fungi OR by increased CSF CRAG
150 (range: 150–180)
Yes
ART: antiretroviral therapy; CSF: cerebrospinal fluid.
HIV-associated cryptococcal meningitis to a HIV medicine centre in Berlin, Germany. We compared the frequency, nature, timing and distribution of findings on magnetic resonance imaging (MRI) in immunocompromised patients without antiretroviral therapy (ART) and in ART-treated patients undergoing immune reconstitution.
Methods Patients Between March 2005 and February 2014, 21 adult patients were treated in the Department of Infectious Diseases, Vivantes Auguste-Viktoria- Klinikum, Berlin, Germany, with the diagnosis of cryptococcal meningitis. We performed a retrospective review of all electronic and paper records including laboratory and microbiological results as well as treatment charts and neuroimaging data.
Imaging All patients received neuroimaging. MRI was performed in 11 (52%) patients. All of these 11 patients were studied with a 1.5 Tesla system. The protocols comprised T1-weighted spin-echo, T2-weighted turbospin echo, fluid attenuated inversion recovery (FLAIR) sequences, echo-planar diffusion-weighted imaging (DWI-EPI) as well as T1-weighted imaging after intravenous administration of Gadolinium chelate (0.2 ml/kg body weight). CT imaging, including contrast-enhanced CT scanning, was performed in 15 patients (71%). Retrospective review of all neuroimaging studies was conducted independently by two neuroradiologists (G.B. and E.S.). Both neuroradiologists have more than 10 years experience in HIV-related neuroradiology and, with relevance to this study, were aware of the diagnosis of cryptococcal meningitis.
Definition of radiological findings All radiological findings were categorised according to their location (neuroanatomical and, if applicable, vascular territory) as well as imaging characteristics such as lesion size, shape, diffusivity and contrast enhancement. Pseudocysts were defined as foci of elevated T2 signal and reduced T1 signal in the presence of dilated perivascular spaces not showing restricted diffusivity (T2 shine through on DWI images was possible with correspondingly elevated ADC values). Acute lacunar infarcts were defined as subcortical foci of restricted diffusivity (high DWI signal and correspondingly low ADC) in a perforator-type arterysupplied brain area. Focal meningitis was defined as areas of leptomeningeal thickening and pathologically increased enhancement. Focal meningoencephalitis was defined as focal meningitis with signs of parenchymal involvement: T2 signal elevation as a correlate of oedema and/or pathologic parenchymal enhancement. ‘Hazy brain base’ sign signifies a rather uniform and diffuse hazy T2 signal elevation of the basal brain parenchyma in (basal ganglia, thalamus, hypothalamus and midbrain) in the immediate vicinity of the anterior and posterior perforate substances where the perforating arteries of the anterior, middle and posterior cerebral arteries enter the brain.
Results Patients Cerebral imaging data of 21 consecutive adult patients with cryptococcal meningitis on 23 separate admissions were reviewed. The median age was 40 years (range: 24–61). Fifteen patients (71%) were Caucasian from Europe, four patients originated from Sub-Saharan
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(STD)
[1–8] [PREPRINTER stage]
Katchanov et al.
3
Table 2. Characteristics of recurrence under immune reconstitution. Features of IRIS Features of microbiologic relapse
– Effective ART with undetectable viral load or decrease >3 log10- Immune recovery with increased CD4 count- Negative fungal cultures of CSF and brain tissue – Presence of numerous intact, budding yeasts on brain biopsy in one patientIncrease in CSF CRAG in two patients (1:32 and 1:512)
ART: antiretroviral therapy; CRAG: cryptococcal antigen; CSF: cerebrospinal fluid; IRIS: immune reconstitution inflammatory syndrome.
Figure 1. Imaging manifestations in typical cerebral cryptococcosis. (a and b) Basal ganglia pseudocysts. Three weeks after establishing the diagnosis of culture-positive cryptococcal meningitis MRI shows bilateral basal ganglia T2-hyperinse lesions (a) with mild patchy contrast enhancement. (b and c) Hazy brain base sign on a T2-weighted image representing diffuse oedematisation of the basal brain parenchyma abutting the anterior and posterior perforate substances where the perforating arteries of the anterior, middle and posterior arteries penetrate the brain. (d) Cryptoccocus-related cerebral ischaemia. On admission, diffusion weighted imaging (DWI) shows multiple acute periventricular, thalamic and basal ganglia lacunar-type ischaemic lesions in the distribution of the penetrating branches of the middle and posterior cerebral arteries.
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International Journal of STD & AIDS 0(0)
Table 3. Characteristics of the patients with recurrence under immune reconstitution.
Age, gender
CD4 count
CD4 count at base-linea
CRAG titer (CSF CRAG titer)
43, m
180
30
49, m
150
54, m
150
Clinical presentation
MRI findings
1: 4 (0)
Focal epileptic seizures, subacute mild hemiparesis
40
1: 32 (1: 16)
58
1: 512 (1: 16)
Focal epileptic seizures, headache Reduced level of consciousness
multifocal leptomeningeal enhancement over right convexity, cortical enhancement and parenchymal edema in the central parasagittal area multifocal circumscript leptomeningeal enhancement over the convexities mild circumscript multifocal leptomeningeal enhancement mainly along the convexities, two circumscript infarctions (juxtacortical right frontal, callosal)
CSF: cerebrospinal fluid; CRAG: cryptococcal antigen; MRI: magnetic resonance imaging. a Baseline ¼ first episode of cryptococcal meningitis.
Africa (19%) and two patients (10%) from Southeast Asia. All patients were infected with HIV. The median CD4 count at time of diagnosis of CM was 30/ml (range: 5–180). The number of admissions exceeds the number of patients as two patients were admitted twice with two separate episodes of cryptococcal meningitis within 10-year period of the study. We identified three clinical patterns: typical cryptococcal meningitis, microbiological relapse and recurrence under immune reconstitution (Table 1).
Recurrence under immune reconstitution The patient group designated as ‘recurrence under immune reconstitution’ encompasses patients with history of culture-positive cryptococcal meningitis currently on ART who presented with a second episode of culture-negative cryptococcal meningitis. In these patients, CD4 count at current presentation increased as compared to the time point of the first episode of cryptococcal meningitis (150 [range: 150–180] vs 40 [range: 30–58]) and plasma HIV load was undetectable or decreased by >3 log10. Clinical features of their presentation have both features of paradoxical immune reconstitution inflammatory syndrome (IRIS) and microbiological relapse (Table 2). Of note, patients with recurrence under immune reconstitution reported poor adherence to fluconazole during consolidation and maintenance phases of antifungal therapy. The time between the first episode of cryptococcal meningitis and recurrence under immune reconstitution was 99 days, 2727 days and 2900 days. The time
between ART initiation and recurrence under immune reconstitution was 60 days, 1518 days and 2853 days.
Radiological findings in patients with typical cryptococcal meningitis Among eight patients with typical cryptococcal meningitis and performed brain MRI, five patients were identified with lesions on MRI related to cryptococcal disease. Three patients had parenchymal masses, two patients presented with cerebral ischaemia. All parenchymal mass lesions were classified as ‘pseudocysts’ (Figure 1a and b). They were located in the basal ganglia (three patients), in the cerebellum (one patient), in the midbrain (one patient) and corpus callosum (one patient). All patients with pseudocysts had normal initial imaging and developed lesions while on amphotericin B-based antifungal therapy. The ischaemic lesions were present on admission and located in the territories of small penetrating branches of anterior, middle and posterior cerebral arteries in the basal ganglia, thalamus, corpus callosum and the base of the frontal lobe. All infarctions were of the lacunar type (subcortical,
(STD)
[1–8] [PREPRINTER stage]
Int J STD AIDS OnlineFirst, published on February 18, 2015 as doi:10.1177/0956462415574633
Original research article
Neuroimaging of HIV-associated cryptococcal meningitis: comparison of magnetic resonance imaging findings in patients with and without immune reconstitution
International Journal of STD & AIDS 0(0) 1–8 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462415574633 std.sagepub.com
Juri Katchanov1, Gordian Branding2, Laura Jefferys1, Keikawus Araste´h1, Hartmut Stocker1 and Eberhard Siebert3
Abstract Aim: To determine the frequency, imaging characteristics, neuroanatomical distribution and dynamics of magnetic resonance imaging findings in HIV-associated cryptococcal meningitis in immunocompromised patients without antiretroviral therapy compared with patients undergoing immune reconstitution. Design: Retrospective analysis of imaging data and clinical case records. Methods: Neuroimaging and clinical data of 21 consecutive patients presenting to a German HIV centre in a 10-year period between 2005 and 2014 were reviewed. Results: We identified eight patients with magnetic resonance imaging findings related to cryptococcal disease: five patients without antiretroviral therapy and three patients receiving effective antiretroviral therapy resulting in immune reconstitution. The pattern of magnetic resonance imaging manifestations was different in the two groups. In patients not on antiretroviral therapy pseudocysts (n ¼ 3) and lacunar ischaemic lesions (n ¼ 2) were detected. Contrast-enhancing focal leptomeningeal and/or parenchymal lesions were found in all patients under immune reconstitution (n ¼ 3). Conclusions: Magnetic resonance imaging lesions suggestive of leptomeningitis or meningoencephalitis were detected in all patients with a recurrence of cryptococcal meningitis under immune reconstitution, this differs from the classical magnetic resonance imaging findings in patients without antiretroviral therapy. In antiretroviral therapy-treated patients with past medical history of cryptococcal meningitis detection of contrast-enhancing focal meningeal and/or parenchymal lesions should prompt further investigations for a recurrence of cryptococcal meningitis under immune reconstitution.
Keywords Europe, location, AIDS, viral disease Date received: 22 November 2014; accepted: 1 February 2015
In this study, we retrospectively analysed neuroimaging of 21 consecutive patients presenting with
Introduction Cryptococcal meningitis is a devastating disease common in regions with a high HIV prevalence.1,2 The majority of studies on cryptococcal meningitis are conducted in resource-limited settings, where availability of routine neuroimaging is restricted.3 Hence, systematic data on neuroimaging in cryptococcal meningitis is limited.4 Moreover, the majority of studies were conducted in the pre-HAART era5–9 and therefore do not report on patients presenting with cryptococcocal meningitis under immune reconstitution.10,11
1 Department of Infectious Diseases, Vivantes Auguste-Viktoria Klinikum, Berlin, Germany 2 Department of Radiology, Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany 3 Department of Neuroradiology, Campus Charite´ Mitte, Charite´, Berlin, Germany
Corresponding author: Juri Katchanov, Auguste-Viktoria-Klinikum, Rubensstraße 125 12157 Berlin, Germany. Email: [email protected]
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(STD)
[1–8] [PREPRINTER stage]
2
International Journal of STD & AIDS 0(0)
Table 1. Clinico-microbiological patterns of meningeal cryptococcal disease in our study.
Typical cryptococcal meningitis (n ¼ 18) Microbiological relapse (n ¼ 2) Recurrence under immune reconstitution (n ¼ 3)
History of cryptococcal meningitis
CSF culture
Evidence of active cryptococcal infection
Median CD4 count, /ml
ART
No
Positive
Yes, by positive CSF culture
28 (range: 5–72)
No
Yes
Positive
Yes, by positive CSF culture
78 (range: 11–145)
No
Yes
Negative
Yes, by detection of budding fungi OR by increased CSF CRAG
150 (range: 150–180)
Yes
ART: antiretroviral therapy; CSF: cerebrospinal fluid.
HIV-associated cryptococcal meningitis to a HIV medicine centre in Berlin, Germany. We compared the frequency, nature, timing and distribution of findings on magnetic resonance imaging (MRI) in immunocompromised patients without antiretroviral therapy (ART) and in ART-treated patients undergoing immune reconstitution.
Methods Patients Between March 2005 and February 2014, 21 adult patients were treated in the Department of Infectious Diseases, Vivantes Auguste-Viktoria- Klinikum, Berlin, Germany, with the diagnosis of cryptococcal meningitis. We performed a retrospective review of all electronic and paper records including laboratory and microbiological results as well as treatment charts and neuroimaging data.
Imaging All patients received neuroimaging. MRI was performed in 11 (52%) patients. All of these 11 patients were studied with a 1.5 Tesla system. The protocols comprised T1-weighted spin-echo, T2-weighted turbospin echo, fluid attenuated inversion recovery (FLAIR) sequences, echo-planar diffusion-weighted imaging (DWI-EPI) as well as T1-weighted imaging after intravenous administration of Gadolinium chelate (0.2 ml/kg body weight). CT imaging, including contrast-enhanced CT scanning, was performed in 15 patients (71%). Retrospective review of all neuroimaging studies was conducted independently by two neuroradiologists (G.B. and E.S.). Both neuroradiologists have more than 10 years experience in HIV-related neuroradiology and, with relevance to this study, were aware of the diagnosis of cryptococcal meningitis.
Definition of radiological findings All radiological findings were categorised according to their location (neuroanatomical and, if applicable, vascular territory) as well as imaging characteristics such as lesion size, shape, diffusivity and contrast enhancement. Pseudocysts were defined as foci of elevated T2 signal and reduced T1 signal in the presence of dilated perivascular spaces not showing restricted diffusivity (T2 shine through on DWI images was possible with correspondingly elevated ADC values). Acute lacunar infarcts were defined as subcortical foci of restricted diffusivity (high DWI signal and correspondingly low ADC) in a perforator-type arterysupplied brain area. Focal meningitis was defined as areas of leptomeningeal thickening and pathologically increased enhancement. Focal meningoencephalitis was defined as focal meningitis with signs of parenchymal involvement: T2 signal elevation as a correlate of oedema and/or pathologic parenchymal enhancement. ‘Hazy brain base’ sign signifies a rather uniform and diffuse hazy T2 signal elevation of the basal brain parenchyma in (basal ganglia, thalamus, hypothalamus and midbrain) in the immediate vicinity of the anterior and posterior perforate substances where the perforating arteries of the anterior, middle and posterior cerebral arteries enter the brain.
Results Patients Cerebral imaging data of 21 consecutive adult patients with cryptococcal meningitis on 23 separate admissions were reviewed. The median age was 40 years (range: 24–61). Fifteen patients (71%) were Caucasian from Europe, four patients originated from Sub-Saharan
Downloaded from std.sagepub.com at SUNY HEALTH SCIENCE CENTER on April 6, 2015
XML Template (2015) [13.2.2015–12:23pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/STDJ/Vol00000/150018/APPFile/SG-STDJ150018.3d
(STD)
[1–8] [PREPRINTER stage]
Katchanov et al.
3
Table 2. Characteristics of recurrence under immune reconstitution. Features of IRIS Features of microbiologic relapse
– Effective ART with undetectable viral load or decrease >3 log10- Immune recovery with increased CD4 count- Negative fungal cultures of CSF and brain tissue – Presence of numerous intact, budding yeasts on brain biopsy in one patientIncrease in CSF CRAG in two patients (1:32 and 1:512)
ART: antiretroviral therapy; CRAG: cryptococcal antigen; CSF: cerebrospinal fluid; IRIS: immune reconstitution inflammatory syndrome.
Figure 1. Imaging manifestations in typical cerebral cryptococcosis. (a and b) Basal ganglia pseudocysts. Three weeks after establishing the diagnosis of culture-positive cryptococcal meningitis MRI shows bilateral basal ganglia T2-hyperinse lesions (a) with mild patchy contrast enhancement. (b and c) Hazy brain base sign on a T2-weighted image representing diffuse oedematisation of the basal brain parenchyma abutting the anterior and posterior perforate substances where the perforating arteries of the anterior, middle and posterior arteries penetrate the brain. (d) Cryptoccocus-related cerebral ischaemia. On admission, diffusion weighted imaging (DWI) shows multiple acute periventricular, thalamic and basal ganglia lacunar-type ischaemic lesions in the distribution of the penetrating branches of the middle and posterior cerebral arteries.
Downloaded from std.sagepub.com at SUNY HEALTH SCIENCE CENTER on April 6, 2015
XML Template (2015) [13.2.2015–12:23pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/STDJ/Vol00000/150018/APPFile/SG-STDJ150018.3d
(STD)
[1–8] [PREPRINTER stage]
4
International Journal of STD & AIDS 0(0)
Table 3. Characteristics of the patients with recurrence under immune reconstitution.
Age, gender
CD4 count
CD4 count at base-linea
CRAG titer (CSF CRAG titer)
43, m
180
30
49, m
150
54, m
150
Clinical presentation
MRI findings
1: 4 (0)
Focal epileptic seizures, subacute mild hemiparesis
40
1: 32 (1: 16)
58
1: 512 (1: 16)
Focal epileptic seizures, headache Reduced level of consciousness
multifocal leptomeningeal enhancement over right convexity, cortical enhancement and parenchymal edema in the central parasagittal area multifocal circumscript leptomeningeal enhancement over the convexities mild circumscript multifocal leptomeningeal enhancement mainly along the convexities, two circumscript infarctions (juxtacortical right frontal, callosal)
CSF: cerebrospinal fluid; CRAG: cryptococcal antigen; MRI: magnetic resonance imaging. a Baseline ¼ first episode of cryptococcal meningitis.
Africa (19%) and two patients (10%) from Southeast Asia. All patients were infected with HIV. The median CD4 count at time of diagnosis of CM was 30/ml (range: 5–180). The number of admissions exceeds the number of patients as two patients were admitted twice with two separate episodes of cryptococcal meningitis within 10-year period of the study. We identified three clinical patterns: typical cryptococcal meningitis, microbiological relapse and recurrence under immune reconstitution (Table 1).
Recurrence under immune reconstitution The patient group designated as ‘recurrence under immune reconstitution’ encompasses patients with history of culture-positive cryptococcal meningitis currently on ART who presented with a second episode of culture-negative cryptococcal meningitis. In these patients, CD4 count at current presentation increased as compared to the time point of the first episode of cryptococcal meningitis (150 [range: 150–180] vs 40 [range: 30–58]) and plasma HIV load was undetectable or decreased by >3 log10. Clinical features of their presentation have both features of paradoxical immune reconstitution inflammatory syndrome (IRIS) and microbiological relapse (Table 2). Of note, patients with recurrence under immune reconstitution reported poor adherence to fluconazole during consolidation and maintenance phases of antifungal therapy. The time between the first episode of cryptococcal meningitis and recurrence under immune reconstitution was 99 days, 2727 days and 2900 days. The time
between ART initiation and recurrence under immune reconstitution was 60 days, 1518 days and 2853 days.
Radiological findings in patients with typical cryptococcal meningitis Among eight patients with typical cryptococcal meningitis and performed brain MRI, five patients were identified with lesions on MRI related to cryptococcal disease. Three patients had parenchymal masses, two patients presented with cerebral ischaemia. All parenchymal mass lesions were classified as ‘pseudocysts’ (Figure 1a and b). They were located in the basal ganglia (three patients), in the cerebellum (one patient), in the midbrain (one patient) and corpus callosum (one patient). All patients with pseudocysts had normal initial imaging and developed lesions while on amphotericin B-based antifungal therapy. The ischaemic lesions were present on admission and located in the territories of small penetrating branches of anterior, middle and posterior cerebral arteries in the basal ganglia, thalamus, corpus callosum and the base of the frontal lobe. All infarctions were of the lacunar type (subcortical,
