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Extremely elevated cerebrospinal fluid protein levels in a child with neurologic symptoms: Beware of haemophagocytic lymphohistiocytosis
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 2 7 e4 2 9
Official Journal of the European Paediatric Neurology Society
Case study
Extremely elevated cerebrospinal fluid protein levels in a child with neurologic symptoms: Beware of haemophagocytic lymphohistiocytosis Michiel Voeten a, Philip Maes b, Marek Wojciechowski a, Luc Vandenbossche c, Isabelle Meyts d, Berten Ceulemans e,* a
University of Antwerp, Antwerp University Hospital, Department of Paediatrics, Belgium University of Antwerp, Antwerp University Hospital, Department of Paediatric Haematology and Oncology, Belgium c Maria Hospital Overpelt, Department of Paediatrics, Belgium d Catholic University of Leuven, University Hospitals Leuven, Department of Microbiology and Immunology, Department of Paediatrics, Belgium e University of Antwerp, Antwerp University Hospital, Department of Paediatric Neurology, Belgium b
article info
abstract
Article history:
Neurologic symptoms can be the initial manifestation of haemophagocytic lymphohis-
Received 29 July 2013
tiocytosis (HLH). In this case study, we present a 3-year old boy with a clinical picture of
Received in revised form
encephalitis, a cerebrospinal fluid (CSF) protein level up to 1165 mg/dl and diffuse cerebral
19 November 2013
MRI abnormalities. The diagnosis of HLH was established only 6 weeks after initial pre-
Accepted 24 November 2013
sentation. The boy recovered after HLH therapy with persisting mild cognitive defects. Genetic investigation demonstrated X-linked lymphoproliferative disease (XLP) as the
Keywords:
underlying cause of HLH. The extremely elevated protein level in CSF in this case has not
Haemophagocytic lymphohistiocy-
yet been reported in patients with HLH.
tosis X-linked lymphoproliferative dis-
ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
ease Cerebrospinal fluid protein Acute disseminated encephalomyelitis Central nervous system Encephalitis
* Corresponding author. Antwerp University Hospital, Department of Neurology e Paediatric Neurology, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel.: þ32 3 821 3810; fax: þ32 3 821 1194. E-mail address: [email protected] (B. Ceulemans). 1090-3798/$ e see front matter ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejpn.2013.11.012
428
1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 2 7 e4 2 9
Introduction
Haemophagocytic lymphohistiocytosis (HLH) is a rare but aggressive and potentially life-threatening disease that predominantly affects young children. The disease is characterised by fever, splenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia and elevated serum transaminases. It is caused by a cytokine dysfunction resulting in uncontrolled accumulation of activated T-lymphocytes and macrophages in many tissues, such as spleen, lymph nodes, bone marrow, liver and also in cerebrospinal fluid. Patients with HLH can have various neurologic symptoms, including abnormalities in cerebrospinal fluid (CSF) analysis and in cranial imaging. We present a case of a 3-year old boy with a clinical picture of encephalitis and an extremely elevated CSF protein level, both caused by HLH.
2.
Case report
A 3-year old boy was referred to our hospital with a decreased consciousness and focal motor epileptic seizures. In the preceding months, there had been a regression in cognitive functioning, dyspraxia, ataxia, disturbed orientation and word finding difficulties. His further medical history reported frequently recurring upper airway infections. Blood analysis showed a normal full blood exam, normal liver enzyme testing and a slightly elevated C-reactive protein (15 mg/l, normal value <5 mg/l). The ferritin level was not tested. A cerebral computed tomography (CT scan) failed to demonstrate any abnormalities. A lumbar puncture was performed showing CSF with a prominent yellow colour. Analysis revealed a markedly elevated protein level of 744 mg/dl (normal range 15e40 mg/dl) with a normal white blood cell count (4/mm3), red blood cell count (5/mm3) and glucose level. Bacterial cultures and polymerase chain reaction (PCR) for herpes simplex virus, enteroviruses and Mycoplasma pneumoniae were all negative. Cerebral magnetic resonance imaging (MRI) demonstrated multiple high intensity lesions in T2 images in large cortical and subcortical areas of both hemispheres and also in the right thalamus (Fig. 1). Suspecting an acute disseminated encephalomyelitis (ADEM), the boy was treated with high-dose methylprednisolon for three days. In the weeks thereafter he received no further steroid treatment. The neurologic symptoms improved only minimally and temporarily. Follow-up of CSF protein level demonstrated an increase up to 1165 mg/dl on day 26 (also a nontraumatic tap). The MRI abnormalities remained unchanged. During the following weeks, several new symptoms developed, namely high fever, splenomegaly, neutropenia, thrombocytopenia, hepatitis, hypertriglyceridemia and a strongly elevated serum ferritin level (4207 mg/l, normal range 7e140 mg/l). The diagnosis of HLH was established only 6 weeks after initial presentation using the revised criteria of the Histiocyte Society (treatment protocol of the second international HLH study 2004, www.histiocytesociety.org). Haemophagocytosis could only be confirmed on a repeated
Fig. 1 e MRI findings at initial presentation: high signal intensity lesions in T2 (left) and FLAIR images (right) in cortical and subcortical areas and right thalamus.
bone marrow biopsy. Serologic studies for different viral and bacterial agents failed to show acute infection. EpsteineBarr virus (EBV) IgG was positive, but IgM was negative. Functional testing showed normal perforin expression in the CD8þ Tcells and natural killer cells. Genetic testing for UNC13D and STXBP2 mutations was negative. Treatment conform the HLH 2004 protocol was initiated with chemotherapy and immunotherapy (dexamethasone, etoposide and cyclosporin), 8 weeks of induction therapy and 32 weeks of continuation therapy. According to the treatment protocol, because of his neurologic disease, he also received intrathecal administration of methotrexate and prednisolon in weeks 3, 4, 5 and 6. Intravenous immunoglobulins (IVIG) were given monthly as supportive therapy. There was an excellent recovery of the clinical symptoms and complete remission was established after induction therapy. The CSF protein level declined quickly and MRI abnormalities almost disappeared, only mild atrophy of the brain was observed. After completion of the continuation therapy during 32 weeks the patient did well and follow-up until present shows only mild cognitive deficits. Several months after discontinuation of the HLH therapy a hypogammaglobulinemia was identified. An underlying immunologic disorder was suspected. Genetic investigation demonstrated a pathogenic mutation in the SH2D1A gene (c.164G>A, R55Q) which confirmed the diagnosis of X-linked lymphoproliferative disease (XLP), a rare hereditary immunodeficiency disorder which is a known underlying cause of HLH. In the majority of cases, the disease is provoked by exposure to EBV infection. Post-hoc PCR analysis for EBV in a blood sample a week before diagnosis of HLH was positive. Unfortunately, in our case no more CSF is available to test EBV PCR. Retrospectively, the frequently recurring upper airway infections of the boy could have been an early presentation of XLP. His IgG level was not checked before the neurologic presentation. Remarkably, during IVIG therapy, infections occurred rarely. Recently the boy underwent a haematopoietic stem cell transplantation. Currently he is doing well.
3.
Discussion
Although the typical clinical presentation of HLH is not neurologic, a puzzling neurologic onset may be observed.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 2 7 e4 2 9
Reported symptoms in order of frequency are seizures, irritability, impaired consciousness, meningismus, microcephaly, psychomotor retardation, hypotonia, motor deficit, cranial nerve palsy and ataxia.1e3 Clinical neurologic symptoms are present at diagnosis in 13e63% of HLH patients and can occur in absence of general HLH symptoms.1e3 An isolated neurologic manifestation of HLH is reported in 7% of the cases according to Deiva et al.2 Moreover, these neurologic symptoms may mimic other more common inflammatory diseases of the brain, such as meningitis, encephalitis and ADEM. When ADEM is suspected and treated with high-dose steroids as in our case, the anti-inflammatory effect can possibly cause a delay in appearance of the other HLH symptoms. Abnormalities in CSF, defined as a protein level of >40e50 mg/dl and/or white blood cell count of 5e10/ml (both depending on the study definition) can be seen in 16e52% of patients at diagnosis of HLH.1e3 In the study of Yang the abnormal protein level ranged from 48 to 387 mg/dl and the WBC count from 6e240/ml.1 The extremely elevated protein level of 1165 mg/dl in our patient has not been reported previously in patients with HLH. In addition to HLH, extremely elevated CSF protein levels of >1000 mg/dl can be seen in bacterial meningitis, brain tumours, cerebral haemorrhage and neurosyphilis.4 Abnormal MRI findings in the diagnosis of HLH are reported in 33e53%.1e3 The most frequent lesions are high signal intensity on T2-weighted images and atrophy. When MRI lesions in HLH are compared to those in ADEM, HLHlesions are more frequently symmetric, periventricular and present in large areas. Lesions in ADEM are more focal and well-defined and can also be observed in basal ganglia and brainstem. Our patient had high intensity abnormalities in T2 images in large cortical and subcortical areas compatible to HLH, however also a lesion in the thalamus was observed. Henter and Nennesmo investigated the neuropathologic post-mortem findings of 23 children with primary HLH.5 The microscopic picture was variable ranging from normal (stage 0), infiltration of the meninges by lymphocytes (stage 1) to
429
advanced changes with infiltration of parenchyma (stage 3) and cerebral tissue necrosis (stage 4). Haemophagocytosis was observed in most of the brains in all stages. The most advanced neuropathologic findings were present in patients with a clinically pronounced neurologic disease. A protein level of >250 mg/dl, was associated with stage III abnormalities. Therefore, we were surprised by the remarkable recovery of our patient. This phenomenon may be explained by the fact that aetiology of HLH is very heterogenic. An early diagnosis and start of therapy is essential for a favourable prognosis in HLH. It is important that paediatricians, neuropaediatricians and neuroradiologists are aware of the possible neurologic onset of HLH. This awareness may induce the clinician to look for clinical, laboratory, radiological and anatomic pathological signs of HLH that may lead to an early diagnosis. This case has shown that neurologic symptoms of encephalitis in combination with an extremely elevated protein level in CSF may be the first signs of HLH.
references
1. Yang S, Zhang L, Jia C, et al. Frequency and development of CNS involvement in Chinese children with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2010 Mar;54(3):408e15. 2. Deiva K, Mahlaoui N, Beaudonnet F, et al. CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis. Neurology 2012 Apr 10;78(15):1150e6. Epub 2012 Mar 14. 3. Horne A, Trottestam H, Aricoo` M, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol 2008 Feb;140(3):327e35. Epub 2007 Dec 10. 4. Seehusen DA, Reeves MM, Fomin DA. Cerebrospinal fluid analysis. Am Fam Physician 2003 Sep 15;68(6):1103e8. 5. Henter JI, Nennesmo I. Neuropathologic findings and neurologic symptoms in twenty-three children with hemophagocytic lymphohistiocytosis. J Pediatr 1997 Mar;130(3):358e65.
Official Journal of the European Paediatric Neurology Society
Case study
Extremely elevated cerebrospinal fluid protein levels in a child with neurologic symptoms: Beware of haemophagocytic lymphohistiocytosis Michiel Voeten a, Philip Maes b, Marek Wojciechowski a, Luc Vandenbossche c, Isabelle Meyts d, Berten Ceulemans e,* a
University of Antwerp, Antwerp University Hospital, Department of Paediatrics, Belgium University of Antwerp, Antwerp University Hospital, Department of Paediatric Haematology and Oncology, Belgium c Maria Hospital Overpelt, Department of Paediatrics, Belgium d Catholic University of Leuven, University Hospitals Leuven, Department of Microbiology and Immunology, Department of Paediatrics, Belgium e University of Antwerp, Antwerp University Hospital, Department of Paediatric Neurology, Belgium b
article info
abstract
Article history:
Neurologic symptoms can be the initial manifestation of haemophagocytic lymphohis-
Received 29 July 2013
tiocytosis (HLH). In this case study, we present a 3-year old boy with a clinical picture of
Received in revised form
encephalitis, a cerebrospinal fluid (CSF) protein level up to 1165 mg/dl and diffuse cerebral
19 November 2013
MRI abnormalities. The diagnosis of HLH was established only 6 weeks after initial pre-
Accepted 24 November 2013
sentation. The boy recovered after HLH therapy with persisting mild cognitive defects. Genetic investigation demonstrated X-linked lymphoproliferative disease (XLP) as the
Keywords:
underlying cause of HLH. The extremely elevated protein level in CSF in this case has not
Haemophagocytic lymphohistiocy-
yet been reported in patients with HLH.
tosis X-linked lymphoproliferative dis-
ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
ease Cerebrospinal fluid protein Acute disseminated encephalomyelitis Central nervous system Encephalitis
* Corresponding author. Antwerp University Hospital, Department of Neurology e Paediatric Neurology, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel.: þ32 3 821 3810; fax: þ32 3 821 1194. E-mail address: [email protected] (B. Ceulemans). 1090-3798/$ e see front matter ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejpn.2013.11.012
428
1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 2 7 e4 2 9
Introduction
Haemophagocytic lymphohistiocytosis (HLH) is a rare but aggressive and potentially life-threatening disease that predominantly affects young children. The disease is characterised by fever, splenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia and elevated serum transaminases. It is caused by a cytokine dysfunction resulting in uncontrolled accumulation of activated T-lymphocytes and macrophages in many tissues, such as spleen, lymph nodes, bone marrow, liver and also in cerebrospinal fluid. Patients with HLH can have various neurologic symptoms, including abnormalities in cerebrospinal fluid (CSF) analysis and in cranial imaging. We present a case of a 3-year old boy with a clinical picture of encephalitis and an extremely elevated CSF protein level, both caused by HLH.
2.
Case report
A 3-year old boy was referred to our hospital with a decreased consciousness and focal motor epileptic seizures. In the preceding months, there had been a regression in cognitive functioning, dyspraxia, ataxia, disturbed orientation and word finding difficulties. His further medical history reported frequently recurring upper airway infections. Blood analysis showed a normal full blood exam, normal liver enzyme testing and a slightly elevated C-reactive protein (15 mg/l, normal value <5 mg/l). The ferritin level was not tested. A cerebral computed tomography (CT scan) failed to demonstrate any abnormalities. A lumbar puncture was performed showing CSF with a prominent yellow colour. Analysis revealed a markedly elevated protein level of 744 mg/dl (normal range 15e40 mg/dl) with a normal white blood cell count (4/mm3), red blood cell count (5/mm3) and glucose level. Bacterial cultures and polymerase chain reaction (PCR) for herpes simplex virus, enteroviruses and Mycoplasma pneumoniae were all negative. Cerebral magnetic resonance imaging (MRI) demonstrated multiple high intensity lesions in T2 images in large cortical and subcortical areas of both hemispheres and also in the right thalamus (Fig. 1). Suspecting an acute disseminated encephalomyelitis (ADEM), the boy was treated with high-dose methylprednisolon for three days. In the weeks thereafter he received no further steroid treatment. The neurologic symptoms improved only minimally and temporarily. Follow-up of CSF protein level demonstrated an increase up to 1165 mg/dl on day 26 (also a nontraumatic tap). The MRI abnormalities remained unchanged. During the following weeks, several new symptoms developed, namely high fever, splenomegaly, neutropenia, thrombocytopenia, hepatitis, hypertriglyceridemia and a strongly elevated serum ferritin level (4207 mg/l, normal range 7e140 mg/l). The diagnosis of HLH was established only 6 weeks after initial presentation using the revised criteria of the Histiocyte Society (treatment protocol of the second international HLH study 2004, www.histiocytesociety.org). Haemophagocytosis could only be confirmed on a repeated
Fig. 1 e MRI findings at initial presentation: high signal intensity lesions in T2 (left) and FLAIR images (right) in cortical and subcortical areas and right thalamus.
bone marrow biopsy. Serologic studies for different viral and bacterial agents failed to show acute infection. EpsteineBarr virus (EBV) IgG was positive, but IgM was negative. Functional testing showed normal perforin expression in the CD8þ Tcells and natural killer cells. Genetic testing for UNC13D and STXBP2 mutations was negative. Treatment conform the HLH 2004 protocol was initiated with chemotherapy and immunotherapy (dexamethasone, etoposide and cyclosporin), 8 weeks of induction therapy and 32 weeks of continuation therapy. According to the treatment protocol, because of his neurologic disease, he also received intrathecal administration of methotrexate and prednisolon in weeks 3, 4, 5 and 6. Intravenous immunoglobulins (IVIG) were given monthly as supportive therapy. There was an excellent recovery of the clinical symptoms and complete remission was established after induction therapy. The CSF protein level declined quickly and MRI abnormalities almost disappeared, only mild atrophy of the brain was observed. After completion of the continuation therapy during 32 weeks the patient did well and follow-up until present shows only mild cognitive deficits. Several months after discontinuation of the HLH therapy a hypogammaglobulinemia was identified. An underlying immunologic disorder was suspected. Genetic investigation demonstrated a pathogenic mutation in the SH2D1A gene (c.164G>A, R55Q) which confirmed the diagnosis of X-linked lymphoproliferative disease (XLP), a rare hereditary immunodeficiency disorder which is a known underlying cause of HLH. In the majority of cases, the disease is provoked by exposure to EBV infection. Post-hoc PCR analysis for EBV in a blood sample a week before diagnosis of HLH was positive. Unfortunately, in our case no more CSF is available to test EBV PCR. Retrospectively, the frequently recurring upper airway infections of the boy could have been an early presentation of XLP. His IgG level was not checked before the neurologic presentation. Remarkably, during IVIG therapy, infections occurred rarely. Recently the boy underwent a haematopoietic stem cell transplantation. Currently he is doing well.
3.
Discussion
Although the typical clinical presentation of HLH is not neurologic, a puzzling neurologic onset may be observed.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 2 7 e4 2 9
Reported symptoms in order of frequency are seizures, irritability, impaired consciousness, meningismus, microcephaly, psychomotor retardation, hypotonia, motor deficit, cranial nerve palsy and ataxia.1e3 Clinical neurologic symptoms are present at diagnosis in 13e63% of HLH patients and can occur in absence of general HLH symptoms.1e3 An isolated neurologic manifestation of HLH is reported in 7% of the cases according to Deiva et al.2 Moreover, these neurologic symptoms may mimic other more common inflammatory diseases of the brain, such as meningitis, encephalitis and ADEM. When ADEM is suspected and treated with high-dose steroids as in our case, the anti-inflammatory effect can possibly cause a delay in appearance of the other HLH symptoms. Abnormalities in CSF, defined as a protein level of >40e50 mg/dl and/or white blood cell count of 5e10/ml (both depending on the study definition) can be seen in 16e52% of patients at diagnosis of HLH.1e3 In the study of Yang the abnormal protein level ranged from 48 to 387 mg/dl and the WBC count from 6e240/ml.1 The extremely elevated protein level of 1165 mg/dl in our patient has not been reported previously in patients with HLH. In addition to HLH, extremely elevated CSF protein levels of >1000 mg/dl can be seen in bacterial meningitis, brain tumours, cerebral haemorrhage and neurosyphilis.4 Abnormal MRI findings in the diagnosis of HLH are reported in 33e53%.1e3 The most frequent lesions are high signal intensity on T2-weighted images and atrophy. When MRI lesions in HLH are compared to those in ADEM, HLHlesions are more frequently symmetric, periventricular and present in large areas. Lesions in ADEM are more focal and well-defined and can also be observed in basal ganglia and brainstem. Our patient had high intensity abnormalities in T2 images in large cortical and subcortical areas compatible to HLH, however also a lesion in the thalamus was observed. Henter and Nennesmo investigated the neuropathologic post-mortem findings of 23 children with primary HLH.5 The microscopic picture was variable ranging from normal (stage 0), infiltration of the meninges by lymphocytes (stage 1) to
429
advanced changes with infiltration of parenchyma (stage 3) and cerebral tissue necrosis (stage 4). Haemophagocytosis was observed in most of the brains in all stages. The most advanced neuropathologic findings were present in patients with a clinically pronounced neurologic disease. A protein level of >250 mg/dl, was associated with stage III abnormalities. Therefore, we were surprised by the remarkable recovery of our patient. This phenomenon may be explained by the fact that aetiology of HLH is very heterogenic. An early diagnosis and start of therapy is essential for a favourable prognosis in HLH. It is important that paediatricians, neuropaediatricians and neuroradiologists are aware of the possible neurologic onset of HLH. This awareness may induce the clinician to look for clinical, laboratory, radiological and anatomic pathological signs of HLH that may lead to an early diagnosis. This case has shown that neurologic symptoms of encephalitis in combination with an extremely elevated protein level in CSF may be the first signs of HLH.
references
1. Yang S, Zhang L, Jia C, et al. Frequency and development of CNS involvement in Chinese children with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2010 Mar;54(3):408e15. 2. Deiva K, Mahlaoui N, Beaudonnet F, et al. CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis. Neurology 2012 Apr 10;78(15):1150e6. Epub 2012 Mar 14. 3. Horne A, Trottestam H, Aricoo` M, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol 2008 Feb;140(3):327e35. Epub 2007 Dec 10. 4. Seehusen DA, Reeves MM, Fomin DA. Cerebrospinal fluid analysis. Am Fam Physician 2003 Sep 15;68(6):1103e8. 5. Henter JI, Nennesmo I. Neuropathologic findings and neurologic symptoms in twenty-three children with hemophagocytic lymphohistiocytosis. J Pediatr 1997 Mar;130(3):358e65.