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Is the diagnosis at hand?
Case Report
Is the diagnosis at hand? Michael V Holmes, Mitesh Desai, Olamide Dosekun, Paul Holmes, Sebastian B Lucas, Ranjababu Kulasegaram Lancet 2010; 375: 1134 Department of GU/HIV Medicine (M V Holmes MRCP, M Desai MRCP, O Dosekun MRCP, R Kulasegaram FRCP), Department of Neurology (P Holmes FRCP), and Department of Histopathology (Prof S B Lucas FRCPath), Guy’s and St Thomas’ NHS Foundation Trust, London, UK Correspondence to: Dr Michael V Holmes, Department of GU/HIV Medicine Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK [email protected]
In August, 2008, a 49-year-old west African woman presented to us with a 1-month history of blurred vision, dizziness, and falls. A friend had noticed increasing confusion and unusual behaviour, and found her collapsed at home. She was diagnosed with HIV-1 infection in August, 2007, when the patient presented with fungal nail infection. At diagnosis, HIV VL was 1 967 745 copies per mL with a CD4-cell count of 22 per μL (3·8%) and Pneumocystis jirovecii prophylaxis and combination antiretroviral therapy (cART) were started. Within 12 weeks, VL became undetectable (<40 copies per mL) with a CD4-cell count of 585 per μL (14·6%). During initial clinic attendances, she was quiet and slightly withdrawn, which we attributed to her personality. In April, 2008, she developed HIV viraemia attributed to poor cART concordance. Genotypically confirmed drug resistance prompted cART switch. On examination, she was apyrexial and normotensive. She was disoriented in time, person, and place. She showed subcortical slowing, perseveration, and marked working memory impairment without focal neurological deficit. Fundoscopy was normal. Investigations showed: HIV VL 12 062 copies per mL; CD4-cell count 502 per μL (16·1%); normal C-reactive protein concentration, white cell count, and lactate dehydrogenase. Treponema serology and cryptococcal antigen were negative. Brain MRI (figure A) showed extensive, multifocal signal abnormalities. Crowding of the cerebellar tonsils at the foramen magnum precluded lumbar puncture. The differential diagnoses were: viral encephalitis; acute disseminated encephalomyelitis; diffusely infiltrative neoplasia; or immune reconstitution inflammatory syndrome (IRIS) of pre-existing progressive multifocal leucoencephalopathy, toxoplasmosis, or HIV-associated neurocognitive disorder (HAND). She was treated empirically for herpes encephalitis and cerebral toxoplasmosis; montelukast was administered for possible IRIS. cART was continued. To avoid masking of lymphoma, steroids were withheld. On day 10, she was less disoriented, but repeat MRI showed progression of disease. A brain biopsy sample taken on day 24 showed perivascular large CD20-positive B cells (figure B) with 25% proliferation fraction, but Epstein-Barr virus (EBV) encoded RNA negaA
C
B
65 μm
Figure: MRI (axial FLAIR) brain and histopathology of brain biopsy (A) Signal abnormalities bilaterally in the cerebral hemispheres. (B) Perivascular lymphocytic infiltrate (B cells mixed with CD8-positive T cells; haematoxylin and eosin staining). (C) Improvement on day 34, with reduced cerebral oedema.
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tive on in-situ hybridisation.1 There was also marked perivascular and parenchymal T-cell infiltration (predominantly CD8-positive) and microgliosis (CD68-positive). Tissue immunocytochemistry was negative for all viruses including EBV and HIVp24. She continued to improve without steroids, and repeat MRI (day 34) showed improvement (figure C). Given the clinical evolution and histopathology, a diagnosis of an IRIS driving HAND was made instead of B-cell lymphoma. She was discharged attaining full independence. When seen in November, 2009, she was fully interactive and spontaneously initiated appropriate conversation. HAND is a prevalent cause of morbidity in patients with HIV infection.2 Patients present with subcortical impairment manifested by slowed motor speed and decreased attention. Diagnosis is by exclusion and risk factors include low nadir CD4-cell count, apolipoprotein E4 carriage, and age. IRIS occurs in about a third of patients after cART initiation and probably represents immune hyperactivation towards foreign or self antigen. Diagnostic criteria3 include: worsening inflammatory symptoms unexplained by new or previous infection, disease, or drug toxicity; temporal relation with cART; and ≥1 log fall in HIV VL. IRIS is associated with severe immunosuppression. Histopathological studies of brain-IRIS emphasise CD8-positive T-cell lymphocytosis (CD4expressing T cells absent/rare) and CD68-positive microgliosis.4 Despite limited evidence, corticosteroids, non-steroidal anti-inflammatory drugs, and montelukast have been tried. In retrospect, our patient probably had features of HAND at HIV diagnosis. cART triggered IRIS, unmasking HAND and precipitating cART non-concordance. We propose that patients presenting with advanced HIV infection at diagnosis have formal neurocognitive testing (±brain MRI) to assess for subclinical HAND. Contributors Clinical care of the patient: OD, MD, MVH, RK, PH. Histopathology review: SBL. Writing/editing the report: all authors. Written consent to publish was obtained. References 1 Hamilton-Dutoit SJ, Raphael M, Audouin J, et al. In situ demonstration of Epstein-Barr virus small RNAs (EBER 1) in acquired immunodeficiency syndrome-related lymphomas: correlation with tumor morphology and primary site. Blood 1993; 82: 619–24. 2 Heaton R, Franklin D, Clifford D, et al. HIV-associated neurocognitive impairment remains prevalent in the era of combination ART: The CHARTER Study. Proceedings of the 16th Conference on Retroviruses and Opportunistic Infections, 2009. http://www. retroconference.org/2009/Abstracts/35664.htm (accessed February, 2010). 3 Robertson J, Meier M, Wall J, Ying J, Fichtenbaum CJ. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis 2006; 42: 1639–46. 4 Miller RF, Isaacson PG, Hall-Craggs M, et al. Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART. Acta Neuropathol 2004; 108: 17–23.
www.thelancet.com Vol 375 March 27, 2010
Is the diagnosis at hand? Michael V Holmes, Mitesh Desai, Olamide Dosekun, Paul Holmes, Sebastian B Lucas, Ranjababu Kulasegaram Lancet 2010; 375: 1134 Department of GU/HIV Medicine (M V Holmes MRCP, M Desai MRCP, O Dosekun MRCP, R Kulasegaram FRCP), Department of Neurology (P Holmes FRCP), and Department of Histopathology (Prof S B Lucas FRCPath), Guy’s and St Thomas’ NHS Foundation Trust, London, UK Correspondence to: Dr Michael V Holmes, Department of GU/HIV Medicine Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK [email protected]
In August, 2008, a 49-year-old west African woman presented to us with a 1-month history of blurred vision, dizziness, and falls. A friend had noticed increasing confusion and unusual behaviour, and found her collapsed at home. She was diagnosed with HIV-1 infection in August, 2007, when the patient presented with fungal nail infection. At diagnosis, HIV VL was 1 967 745 copies per mL with a CD4-cell count of 22 per μL (3·8%) and Pneumocystis jirovecii prophylaxis and combination antiretroviral therapy (cART) were started. Within 12 weeks, VL became undetectable (<40 copies per mL) with a CD4-cell count of 585 per μL (14·6%). During initial clinic attendances, she was quiet and slightly withdrawn, which we attributed to her personality. In April, 2008, she developed HIV viraemia attributed to poor cART concordance. Genotypically confirmed drug resistance prompted cART switch. On examination, she was apyrexial and normotensive. She was disoriented in time, person, and place. She showed subcortical slowing, perseveration, and marked working memory impairment without focal neurological deficit. Fundoscopy was normal. Investigations showed: HIV VL 12 062 copies per mL; CD4-cell count 502 per μL (16·1%); normal C-reactive protein concentration, white cell count, and lactate dehydrogenase. Treponema serology and cryptococcal antigen were negative. Brain MRI (figure A) showed extensive, multifocal signal abnormalities. Crowding of the cerebellar tonsils at the foramen magnum precluded lumbar puncture. The differential diagnoses were: viral encephalitis; acute disseminated encephalomyelitis; diffusely infiltrative neoplasia; or immune reconstitution inflammatory syndrome (IRIS) of pre-existing progressive multifocal leucoencephalopathy, toxoplasmosis, or HIV-associated neurocognitive disorder (HAND). She was treated empirically for herpes encephalitis and cerebral toxoplasmosis; montelukast was administered for possible IRIS. cART was continued. To avoid masking of lymphoma, steroids were withheld. On day 10, she was less disoriented, but repeat MRI showed progression of disease. A brain biopsy sample taken on day 24 showed perivascular large CD20-positive B cells (figure B) with 25% proliferation fraction, but Epstein-Barr virus (EBV) encoded RNA negaA
C
B
65 μm
Figure: MRI (axial FLAIR) brain and histopathology of brain biopsy (A) Signal abnormalities bilaterally in the cerebral hemispheres. (B) Perivascular lymphocytic infiltrate (B cells mixed with CD8-positive T cells; haematoxylin and eosin staining). (C) Improvement on day 34, with reduced cerebral oedema.
1134
tive on in-situ hybridisation.1 There was also marked perivascular and parenchymal T-cell infiltration (predominantly CD8-positive) and microgliosis (CD68-positive). Tissue immunocytochemistry was negative for all viruses including EBV and HIVp24. She continued to improve without steroids, and repeat MRI (day 34) showed improvement (figure C). Given the clinical evolution and histopathology, a diagnosis of an IRIS driving HAND was made instead of B-cell lymphoma. She was discharged attaining full independence. When seen in November, 2009, she was fully interactive and spontaneously initiated appropriate conversation. HAND is a prevalent cause of morbidity in patients with HIV infection.2 Patients present with subcortical impairment manifested by slowed motor speed and decreased attention. Diagnosis is by exclusion and risk factors include low nadir CD4-cell count, apolipoprotein E4 carriage, and age. IRIS occurs in about a third of patients after cART initiation and probably represents immune hyperactivation towards foreign or self antigen. Diagnostic criteria3 include: worsening inflammatory symptoms unexplained by new or previous infection, disease, or drug toxicity; temporal relation with cART; and ≥1 log fall in HIV VL. IRIS is associated with severe immunosuppression. Histopathological studies of brain-IRIS emphasise CD8-positive T-cell lymphocytosis (CD4expressing T cells absent/rare) and CD68-positive microgliosis.4 Despite limited evidence, corticosteroids, non-steroidal anti-inflammatory drugs, and montelukast have been tried. In retrospect, our patient probably had features of HAND at HIV diagnosis. cART triggered IRIS, unmasking HAND and precipitating cART non-concordance. We propose that patients presenting with advanced HIV infection at diagnosis have formal neurocognitive testing (±brain MRI) to assess for subclinical HAND. Contributors Clinical care of the patient: OD, MD, MVH, RK, PH. Histopathology review: SBL. Writing/editing the report: all authors. Written consent to publish was obtained. References 1 Hamilton-Dutoit SJ, Raphael M, Audouin J, et al. In situ demonstration of Epstein-Barr virus small RNAs (EBER 1) in acquired immunodeficiency syndrome-related lymphomas: correlation with tumor morphology and primary site. Blood 1993; 82: 619–24. 2 Heaton R, Franklin D, Clifford D, et al. HIV-associated neurocognitive impairment remains prevalent in the era of combination ART: The CHARTER Study. Proceedings of the 16th Conference on Retroviruses and Opportunistic Infections, 2009. http://www. retroconference.org/2009/Abstracts/35664.htm (accessed February, 2010). 3 Robertson J, Meier M, Wall J, Ying J, Fichtenbaum CJ. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis 2006; 42: 1639–46. 4 Miller RF, Isaacson PG, Hall-Craggs M, et al. Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART. Acta Neuropathol 2004; 108: 17–23.
www.thelancet.com Vol 375 March 27, 2010