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Progressive multifocal leukoencephalopathy in an adult patient with ICF syndrome
Journal of the Neurological Sciences 217 (2004) 107 – 110 www.elsevier.com/locate/jns
Short communication
Progressive multifocal leukoencephalopathy in an adult patient with ICF syndrome Monica Colucci a, Leonardo Cocito a,*, Elisabetta Capello a, Gian Luigi Mancardi a, Carlo Serrati a, Paola Cinque b, Angelo Schenone a,c a
Dipartimento di Neuroscienze, Oftalmologia e Genetica dell’Universita` di Genova, Via Antonio De Toni 5, I-16132 Genoa, Italy b Division of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy c Center of Excellence for Biomedical Research, University of Genova, Genoa, Italy Received 12 February 2003; received in revised form 29 July 2003; accepted 12 August 2003
Abstract We report on a patient affected by ICF syndrome (immunodeficiency, centromeric instability of chromosomes 1, 9 and 16 and facial dysmorphism), who presented with slowing in mentation, mild right hemiparesis and focal motor seizures. MRI study of the brain suggested a diagnosis of progressive multifocal leukoencephalopathy (PML), which was confirmed by JC virus DNA detection on CSF by polymerase chain reaction (PCR). This is a unique case of adult infective neurological complication described in ICF Syndrome. D 2003 Elsevier B.V. All rights reserved. Keywords: ICF syndrome; Progressive Multifocal Leukoencephalopathy; JC virus
1. Introduction ICF syndrome is a rare autosomal recessive disorder, which recognizes a wide spectrum of phenotypic variability and is characterized by immunodeficiency, centromeric instability and facial anomalies, possibly associated with mental retardation. ICF is linked to mutations in the DNA methyltransferase 3B (DNMT 3B) gene and its diagnostic features are the juxtacentromeric abnormalities involving chromosomes 1, 9 and 16 [1]. To date, only about 20 cases have been reported [2]. The patients usually develop recurrent respiratory and gastrointestinal infections, related to hypogammaglobulinemia, lymphopenia, inverted CD4/CD8 ratio, or a combination of these conditions [2]. However, the natural history of ICF has not yet been fully established because of both the small number of cases and the wide phenotypic variability. In 1993, Gimelli et al. [3] described a new familial case of this syndrome in two sibs, a 29-year-old woman and a 30-
* Corresponding author. Tel.: +39-010-353-7040; fax: +39-010-3538631. E-mail address: [email protected] (L. Cocito). 0022-510X/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2003.08.009
year-old man. The sister showed typical paracentromeric heterochromatin instability and combined deficit of IgM and IgE immunoglobulin classes with recurrent respiratory infections, facial anomalies and mental retardation. Her brother had an apparently normal phenotype, despite the immunoglobulin deficit. We are reporting on the further clinical course of this woman, eventually complicated by progressive multifocal leukoencephalopathy (PML).
2. Case report A 35-year-old woman [3] was admitted to our Department in March 1995 for a first generalized tonic –clonic seizure. She reported episodes of peripheral facial palsy at ages 2, 20 and 35, and recurrent respiratory and gastrointestinal infections since the age of 4. Neurological examination, brain CT and MRI studies, and CSF findings indicated no abnormalities. Antiepileptic treatment with phenytoin was started, with a single seizure recurrence over the next 6 years. In December 2001, phenytoin was replaced by topiramate due to signs of liver toxicity. One month later, she was admitted again to our department
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because of vomiting, slowing in mentation, disorientation in space and time, and progressive mild right side weakness associated with focal motor seizures. Seizures were initially limited to the right hand but later on the whole right side of the body was involved, with gaze deviation to the left. Physical findings indicated hypoacusia, hepatosplenomegaly, facial dysmorphism with hypertelorism, epicanthus, micrognatia, and macroglossia. Neurological examination indicated mental retardation, mild diffuse pyramidal impairment, weakness and dysmetria of the right arm. Laboratory tests showed a moderate increase of serum transaminases, and a marked increase of alkaline phosphatase (1984 U/l; normal values 98 – 279). Neither hyperammonemia nor lactic acidosis was detected. Protein serum electrophoresis revealed marked hypogammaglobulinemia (4%; normal values 10.5 –18.5%), which involved IgG (148 mg/dl; normal values 800 – 1700), IgA (6 mg/dl; normal values 70– 400), and IgM (18 mg/dl; normal values 40 –280). Investigations on the peripheral lymphocyte subset showed a moderate decrease of CD4 T-cell population (319 cells/Al, 28.7%) and a relative increase of NK cells (40%). Serology for HBV, HCV, HIV, and Treponema pallidum was non-reactive. The ECG was normal; the abdominal ultrasound confirmed splenomegaly and was consistent with chronic hepatitis.
CSF findings were normal, including cell count, total protein, glucose, total IgG and IgG index; oligoclonal bands were not detected, and bacteriological and virological studies (including the search for BK and polymerase chain reaction (PCR) for HSV) were also negative. EEG recorded during a seizure showed diffuse paroxysmal abnormalities which were replaced by a low voltage rapid discharge 20 min after intravenous lorazepam administration. Despite the addition of phenobarbital, in the next days the EEG repeatedly showed a nearly continuous sharpwave activity (1 – 3 Hz, 50 – 120 AV) over a wide left hemispheric region. CT scan revealed hypodensities in the white matter of bilateral posterior regions, with no mass effect. MRI study of the brain showed confluent T2-hyperintense lesions in the white matter of both hemispheres, which particularly involved the temporal and parietal regions, the splenium of corpus callosum, and the frontal left centrum semiovalis extending to the cortico-spinal tract (Fig. 1A). The clinical suspicion of PML was confirmed by JC virus DNA detection on CSF, according to a previously described nested PCR method [4] (Fig. 1B). The further clinical course was characterized by a progressive deterioration of general and neurological conditions. She developed severe right hemiparesis and coma, and died 2.5 months after admission due to a fatal oxacillin-resistant Staphylococcus aureus sepsis. Permission for necropsy was refused.
Fig. 1. (A) T2-weighted MRI of the brain, showing confluent hyperintense lesions in the white matter of both hemispheres. (B) Agarose gel electrophoresis of amplified product of polymerase chain reaction for JCV DNA (173 bp). Lane 1: 100-bp DNA ladder marker, lanes 2 and 3: CSF from patient, lane 4: water negative control; lanes 5 and 6: positive controls (1000 and 10,000 copies/reaction, respectively).
M. Colucci et al. / Journal of the Neurological Sciences 217 (2004) 107–110
3. Discussion Described for the first time in 1958 by Astro¨m et al. [5], PML is a subacute and fatal demyelinating encephalitis caused by the reactivation of the polyomavirus JC (JCV) in immunocompromised patients. JCV lytic infection of oligodendrocytes determines peculiar demyelinating lesions, especially in the subcortical white matter. PML most often occurs in patients with acquired immunodeficiency syndrome (AIDS), affecting about 4% of HIV patients with a mean CD4 lymphocytes count < 200/Al. It has also been reported in chronic lympho- and myeloproliferative disorders, systemic lupus erythematosus, immunosuppressive therapy after organ transplantation and, as anecdotal reports, in other diseases characterized by immunodeficiency, such as hyperimmunoglobulin E recurrent infection syndrome (HIES) [6] and idiopathic CD4+ lymphocytopenia [7]. The diagnosis is suggested by the evidence of progressive and focal neurological deficits, developing in immunocompromised patients and associated with typical demyelinating MRI findings. The neurological symptoms include monoparesis, hemiparesis, hemianopia, aphasia, ataxia, dysarthria, deficits in sensitive functions, mental deterioration, and, rarely, epileptic seizures. MRI of the brain shows demyelinating lesions, especially in the posterior regions, without mass effect and contrast enhancement (negative in more than 90% of the cases). An evidence of clinical JC virus infection is conclusively supported by the CSF detection of JC virus DNA by PCR. This assays for JCV have a sensitivity of 74– 92%, and a specificity of 92 – 100% according to different studies [8 – 10]. The predictive value of this non-invasive method is increased by the association of typical clinical and neuroimaging findings [11]. Several authors maintain that brain biopsy is no longer recommended [11,12], but this opinion is not universally held. In fact, brain biopsy is the gold standard and often necessary in patients presenting with neuroimaging findings or clinical course strongly suggestive for PML, but with negative PCR. On the other hand, false positive PCR for JCV may be observed [8,10], so that a comfortable diagnosis with PCR requires a compatible clinical and radiographic picture and the established absence of other diseases that might result in the findings. No effective therapy is available and the outcome of PML is fatal, with death usually occurring within 2.5 –4 months. HIV patients receiving highly active antiretroviral therapy (HAART) may have a more prolonged clinical course (10 months, or even up to some years) [9]. To our knowledge, this is the first report of PML occurring in a patient with ICF syndrome. This patient had a history of recurrent peripheral facial palsy since childhood, probably linked to infections, and developed cryptogenic seizures at age 35. The relevance of epilepsy to the phenotypic spectrum of ICF syndrome at this stage of the disease is uncertain, but this unreported association is
109
worth recording. At the age of 40, she presented with progressive neurological deficits and drug resistant focal seizures. Appropriate investigations ruled out other possible diagnoses such as HSV and cytomegalovirus encephalitis, primary central nervous system lymphoma (PCNSL) associated with Epstein-Barr virus, toxoplasma encephalitis, cryptococcal meningoencephalitis, and vasculitis. The diagnosis of PML was supported by MRI findings and confirmed by the detection of JCV DNA by PCR in CSF. Due to improvement of therapies for infections, ICF patients reach adult age more often than before. So, further infective complications of their immunodeficiency would be expected. Our observation of PML in an adult patient with ICF suggests that search for JCV is included in the diagnostic work up of ICF patients, irrespective of phenotype, presenting with neurological progressive impairment. Finally, an additional feature of our patient was the occurrence of JCV reactivation in the absence of a very severe reduction of CD4 count. Although PML can occur in patients with a CD4 count of over 200/Al [13], this is an uncommon finding, which suggests that in patients with associated T-cell immunodeficiency, the humoral immunosuppression could play a role in JCV reactivation.
Acknowledgements This research was financially supported by FISM 2001R59 (to A.S.), Telethon GUP02169 (to A.S.), FIRB 2001RBAU01 (to A.S.).
References [1] Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, et al. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A 1999;96:14412 – 7. [2] Pezzolo A, Prigione I, Chiesa S, Castellano E, Gimelli G, Pistoia V. A novel case of immunodeficiency, centromeric instability, and facial anomalies (the ICF syndrome): immunologic and cytogenetic studies. Haematologica 2002;87:329 – 31. [3] Gimelli G, Varone P, Pezzolo A, Lerone M, Pistoia V. ICF syndrome with variable expression in sibs. J Med Genet 1993;30:429 – 32. [4] Cinque P, Vago L, Dahl H, Brytting M, Terreni MR, Fornara C, et al. Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIV-infected patients. AIDS 1996;10:951 – 8. [5] Astro¨m KE, Mancall EL, Richardson EP. Progressive multifocal leukoencephalopathy: a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin’s disease. Brain 1958;81:93 – 111. [6] Angelini L, Pietrogrande MC, Delle Piane MR, Zibordi F, Cinque P, Maccagnano C, et al. Progressive multifocal leukoencephalopathy in a child with hyperimmunoglobulin E recurrent infection syndrome and review of the literature. Neuropediatrics 2001;32:250 – 5. [7] Haider S, Nafziger D, Gutierrez JA, Brar I, Mateo N, Fogle J. Progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia: a case report and review of reported cases. Clin Infect Dis 2000;31:E20 – 2. [8] De Luca A, Cingolani A, Linzalone A, Ammassari A, Murri R,
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Giancola, ML, et al. Improved detection of JC virus DNA in cerebrospinal fluid for diagnosis of AIDS-related progressive multifocal leukoencephalopathy. J Clin Microbiol 1996;34:1343 – 6. [9] Goodkin K, Wilkie FL, Concha M, Hinkin CH, Symes S, Baldewicz TT, et al. Aging and neuro-AIDS conditions and the changing spectrum of HIV-1-associated morbidity and mortality. J Clin Epidemiol 2001;54(Suppl. 1):S35 – 43. [10] McGuire D, Barhite S, Hollander H, Miles M. JC virus DNA in cerebrospinal fluid of human immunodeficiency virus-infected patients: predictive value for progressive multifocal leukoencephalopathy. Ann Neurol 1995;37:395 – 9.
[11] Hall CD. JC virus neurologic infection. In: Dolin R, Masur H, Saag MS, editors. AIDS Therapy. Edinburgh: Churchill Livingstone; 1999. p. 565 – 72. [12] Antinori A, Ammassari A, De Luca A, Cingolani A, Murri R, Scoppettuolo G, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology 1997;48:687 – 94. [13] Berger JR, Pall L, Lanska D, Whiteman M. Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirology 1998;4:59 – 68.
Short communication
Progressive multifocal leukoencephalopathy in an adult patient with ICF syndrome Monica Colucci a, Leonardo Cocito a,*, Elisabetta Capello a, Gian Luigi Mancardi a, Carlo Serrati a, Paola Cinque b, Angelo Schenone a,c a
Dipartimento di Neuroscienze, Oftalmologia e Genetica dell’Universita` di Genova, Via Antonio De Toni 5, I-16132 Genoa, Italy b Division of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy c Center of Excellence for Biomedical Research, University of Genova, Genoa, Italy Received 12 February 2003; received in revised form 29 July 2003; accepted 12 August 2003
Abstract We report on a patient affected by ICF syndrome (immunodeficiency, centromeric instability of chromosomes 1, 9 and 16 and facial dysmorphism), who presented with slowing in mentation, mild right hemiparesis and focal motor seizures. MRI study of the brain suggested a diagnosis of progressive multifocal leukoencephalopathy (PML), which was confirmed by JC virus DNA detection on CSF by polymerase chain reaction (PCR). This is a unique case of adult infective neurological complication described in ICF Syndrome. D 2003 Elsevier B.V. All rights reserved. Keywords: ICF syndrome; Progressive Multifocal Leukoencephalopathy; JC virus
1. Introduction ICF syndrome is a rare autosomal recessive disorder, which recognizes a wide spectrum of phenotypic variability and is characterized by immunodeficiency, centromeric instability and facial anomalies, possibly associated with mental retardation. ICF is linked to mutations in the DNA methyltransferase 3B (DNMT 3B) gene and its diagnostic features are the juxtacentromeric abnormalities involving chromosomes 1, 9 and 16 [1]. To date, only about 20 cases have been reported [2]. The patients usually develop recurrent respiratory and gastrointestinal infections, related to hypogammaglobulinemia, lymphopenia, inverted CD4/CD8 ratio, or a combination of these conditions [2]. However, the natural history of ICF has not yet been fully established because of both the small number of cases and the wide phenotypic variability. In 1993, Gimelli et al. [3] described a new familial case of this syndrome in two sibs, a 29-year-old woman and a 30-
* Corresponding author. Tel.: +39-010-353-7040; fax: +39-010-3538631. E-mail address: [email protected] (L. Cocito). 0022-510X/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2003.08.009
year-old man. The sister showed typical paracentromeric heterochromatin instability and combined deficit of IgM and IgE immunoglobulin classes with recurrent respiratory infections, facial anomalies and mental retardation. Her brother had an apparently normal phenotype, despite the immunoglobulin deficit. We are reporting on the further clinical course of this woman, eventually complicated by progressive multifocal leukoencephalopathy (PML).
2. Case report A 35-year-old woman [3] was admitted to our Department in March 1995 for a first generalized tonic –clonic seizure. She reported episodes of peripheral facial palsy at ages 2, 20 and 35, and recurrent respiratory and gastrointestinal infections since the age of 4. Neurological examination, brain CT and MRI studies, and CSF findings indicated no abnormalities. Antiepileptic treatment with phenytoin was started, with a single seizure recurrence over the next 6 years. In December 2001, phenytoin was replaced by topiramate due to signs of liver toxicity. One month later, she was admitted again to our department
108
M. Colucci et al. / Journal of the Neurological Sciences 217 (2004) 107–110
because of vomiting, slowing in mentation, disorientation in space and time, and progressive mild right side weakness associated with focal motor seizures. Seizures were initially limited to the right hand but later on the whole right side of the body was involved, with gaze deviation to the left. Physical findings indicated hypoacusia, hepatosplenomegaly, facial dysmorphism with hypertelorism, epicanthus, micrognatia, and macroglossia. Neurological examination indicated mental retardation, mild diffuse pyramidal impairment, weakness and dysmetria of the right arm. Laboratory tests showed a moderate increase of serum transaminases, and a marked increase of alkaline phosphatase (1984 U/l; normal values 98 – 279). Neither hyperammonemia nor lactic acidosis was detected. Protein serum electrophoresis revealed marked hypogammaglobulinemia (4%; normal values 10.5 –18.5%), which involved IgG (148 mg/dl; normal values 800 – 1700), IgA (6 mg/dl; normal values 70– 400), and IgM (18 mg/dl; normal values 40 –280). Investigations on the peripheral lymphocyte subset showed a moderate decrease of CD4 T-cell population (319 cells/Al, 28.7%) and a relative increase of NK cells (40%). Serology for HBV, HCV, HIV, and Treponema pallidum was non-reactive. The ECG was normal; the abdominal ultrasound confirmed splenomegaly and was consistent with chronic hepatitis.
CSF findings were normal, including cell count, total protein, glucose, total IgG and IgG index; oligoclonal bands were not detected, and bacteriological and virological studies (including the search for BK and polymerase chain reaction (PCR) for HSV) were also negative. EEG recorded during a seizure showed diffuse paroxysmal abnormalities which were replaced by a low voltage rapid discharge 20 min after intravenous lorazepam administration. Despite the addition of phenobarbital, in the next days the EEG repeatedly showed a nearly continuous sharpwave activity (1 – 3 Hz, 50 – 120 AV) over a wide left hemispheric region. CT scan revealed hypodensities in the white matter of bilateral posterior regions, with no mass effect. MRI study of the brain showed confluent T2-hyperintense lesions in the white matter of both hemispheres, which particularly involved the temporal and parietal regions, the splenium of corpus callosum, and the frontal left centrum semiovalis extending to the cortico-spinal tract (Fig. 1A). The clinical suspicion of PML was confirmed by JC virus DNA detection on CSF, according to a previously described nested PCR method [4] (Fig. 1B). The further clinical course was characterized by a progressive deterioration of general and neurological conditions. She developed severe right hemiparesis and coma, and died 2.5 months after admission due to a fatal oxacillin-resistant Staphylococcus aureus sepsis. Permission for necropsy was refused.
Fig. 1. (A) T2-weighted MRI of the brain, showing confluent hyperintense lesions in the white matter of both hemispheres. (B) Agarose gel electrophoresis of amplified product of polymerase chain reaction for JCV DNA (173 bp). Lane 1: 100-bp DNA ladder marker, lanes 2 and 3: CSF from patient, lane 4: water negative control; lanes 5 and 6: positive controls (1000 and 10,000 copies/reaction, respectively).
M. Colucci et al. / Journal of the Neurological Sciences 217 (2004) 107–110
3. Discussion Described for the first time in 1958 by Astro¨m et al. [5], PML is a subacute and fatal demyelinating encephalitis caused by the reactivation of the polyomavirus JC (JCV) in immunocompromised patients. JCV lytic infection of oligodendrocytes determines peculiar demyelinating lesions, especially in the subcortical white matter. PML most often occurs in patients with acquired immunodeficiency syndrome (AIDS), affecting about 4% of HIV patients with a mean CD4 lymphocytes count < 200/Al. It has also been reported in chronic lympho- and myeloproliferative disorders, systemic lupus erythematosus, immunosuppressive therapy after organ transplantation and, as anecdotal reports, in other diseases characterized by immunodeficiency, such as hyperimmunoglobulin E recurrent infection syndrome (HIES) [6] and idiopathic CD4+ lymphocytopenia [7]. The diagnosis is suggested by the evidence of progressive and focal neurological deficits, developing in immunocompromised patients and associated with typical demyelinating MRI findings. The neurological symptoms include monoparesis, hemiparesis, hemianopia, aphasia, ataxia, dysarthria, deficits in sensitive functions, mental deterioration, and, rarely, epileptic seizures. MRI of the brain shows demyelinating lesions, especially in the posterior regions, without mass effect and contrast enhancement (negative in more than 90% of the cases). An evidence of clinical JC virus infection is conclusively supported by the CSF detection of JC virus DNA by PCR. This assays for JCV have a sensitivity of 74– 92%, and a specificity of 92 – 100% according to different studies [8 – 10]. The predictive value of this non-invasive method is increased by the association of typical clinical and neuroimaging findings [11]. Several authors maintain that brain biopsy is no longer recommended [11,12], but this opinion is not universally held. In fact, brain biopsy is the gold standard and often necessary in patients presenting with neuroimaging findings or clinical course strongly suggestive for PML, but with negative PCR. On the other hand, false positive PCR for JCV may be observed [8,10], so that a comfortable diagnosis with PCR requires a compatible clinical and radiographic picture and the established absence of other diseases that might result in the findings. No effective therapy is available and the outcome of PML is fatal, with death usually occurring within 2.5 –4 months. HIV patients receiving highly active antiretroviral therapy (HAART) may have a more prolonged clinical course (10 months, or even up to some years) [9]. To our knowledge, this is the first report of PML occurring in a patient with ICF syndrome. This patient had a history of recurrent peripheral facial palsy since childhood, probably linked to infections, and developed cryptogenic seizures at age 35. The relevance of epilepsy to the phenotypic spectrum of ICF syndrome at this stage of the disease is uncertain, but this unreported association is
109
worth recording. At the age of 40, she presented with progressive neurological deficits and drug resistant focal seizures. Appropriate investigations ruled out other possible diagnoses such as HSV and cytomegalovirus encephalitis, primary central nervous system lymphoma (PCNSL) associated with Epstein-Barr virus, toxoplasma encephalitis, cryptococcal meningoencephalitis, and vasculitis. The diagnosis of PML was supported by MRI findings and confirmed by the detection of JCV DNA by PCR in CSF. Due to improvement of therapies for infections, ICF patients reach adult age more often than before. So, further infective complications of their immunodeficiency would be expected. Our observation of PML in an adult patient with ICF suggests that search for JCV is included in the diagnostic work up of ICF patients, irrespective of phenotype, presenting with neurological progressive impairment. Finally, an additional feature of our patient was the occurrence of JCV reactivation in the absence of a very severe reduction of CD4 count. Although PML can occur in patients with a CD4 count of over 200/Al [13], this is an uncommon finding, which suggests that in patients with associated T-cell immunodeficiency, the humoral immunosuppression could play a role in JCV reactivation.
Acknowledgements This research was financially supported by FISM 2001R59 (to A.S.), Telethon GUP02169 (to A.S.), FIRB 2001RBAU01 (to A.S.).
References [1] Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, et al. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A 1999;96:14412 – 7. [2] Pezzolo A, Prigione I, Chiesa S, Castellano E, Gimelli G, Pistoia V. A novel case of immunodeficiency, centromeric instability, and facial anomalies (the ICF syndrome): immunologic and cytogenetic studies. Haematologica 2002;87:329 – 31. [3] Gimelli G, Varone P, Pezzolo A, Lerone M, Pistoia V. ICF syndrome with variable expression in sibs. J Med Genet 1993;30:429 – 32. [4] Cinque P, Vago L, Dahl H, Brytting M, Terreni MR, Fornara C, et al. Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIV-infected patients. AIDS 1996;10:951 – 8. [5] Astro¨m KE, Mancall EL, Richardson EP. Progressive multifocal leukoencephalopathy: a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin’s disease. Brain 1958;81:93 – 111. [6] Angelini L, Pietrogrande MC, Delle Piane MR, Zibordi F, Cinque P, Maccagnano C, et al. Progressive multifocal leukoencephalopathy in a child with hyperimmunoglobulin E recurrent infection syndrome and review of the literature. Neuropediatrics 2001;32:250 – 5. [7] Haider S, Nafziger D, Gutierrez JA, Brar I, Mateo N, Fogle J. Progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia: a case report and review of reported cases. Clin Infect Dis 2000;31:E20 – 2. [8] De Luca A, Cingolani A, Linzalone A, Ammassari A, Murri R,
110
M. Colucci et al. / Journal of the Neurological Sciences 217 (2004) 107–110
Giancola, ML, et al. Improved detection of JC virus DNA in cerebrospinal fluid for diagnosis of AIDS-related progressive multifocal leukoencephalopathy. J Clin Microbiol 1996;34:1343 – 6. [9] Goodkin K, Wilkie FL, Concha M, Hinkin CH, Symes S, Baldewicz TT, et al. Aging and neuro-AIDS conditions and the changing spectrum of HIV-1-associated morbidity and mortality. J Clin Epidemiol 2001;54(Suppl. 1):S35 – 43. [10] McGuire D, Barhite S, Hollander H, Miles M. JC virus DNA in cerebrospinal fluid of human immunodeficiency virus-infected patients: predictive value for progressive multifocal leukoencephalopathy. Ann Neurol 1995;37:395 – 9.
[11] Hall CD. JC virus neurologic infection. In: Dolin R, Masur H, Saag MS, editors. AIDS Therapy. Edinburgh: Churchill Livingstone; 1999. p. 565 – 72. [12] Antinori A, Ammassari A, De Luca A, Cingolani A, Murri R, Scoppettuolo G, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology 1997;48:687 – 94. [13] Berger JR, Pall L, Lanska D, Whiteman M. Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirology 1998;4:59 – 68.