- Email: [email protected]
Successful treatment for West syndrome with severe combined immunodeficiency
Brain & Development 37 (2015) 140–144 www.elsevier.com/locate/braindev
Case report
Successful treatment for West syndrome with severe combined immunodeficiency q Mitsuo Motobayashi a, Yuji Inaba a,⇑, Tetsuhiro Fukuyama b, Takashi Kurata a, Taemi Niimi a, Shoji Saito a, Naoko Shiba a, Takafumi Nishimura a, Tomonari Shigemura a, Yozo Nakazawa a, Norimoto Kobayashi a, Kazuo Sakashita a, Kazunaga Agematsu c, Motoki Ichikawa d, Kenichi Koike a a
Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan b Department of Neuropediatrics, Nagano Children’s Hospital, Azumino, Japan c Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, Japan d Department of Family and Child Nursing, Shinshu University School of Medicine, Matsumoto, Japan Received 1 September 2013; received in revised form 19 January 2014; accepted 22 January 2014
Abstract Several immune mechanisms are suspected in the unknown etiology of West syndrome (WS). We report a male infant who suffered from WS and X-linked T B+NK severe combined immunodeficiency (X-SCID) with a missense mutation of the IL2RG gene (c.202G>A, p.Glu68Lys). He promptly began vitamin B6 and valproic acid treatment, but infantile spasms (IS) and hypsarrhythmia persisted. Administration of intravenous immunoglobulin and the change to topiramate (TPM) at 7 months of age resulted in the rapid resolution of IS. The CD4/8 ratio in his peripheral blood increased from 0.04–0.09 to 0.20–1.95 following unrelated cord blood transplantation (UCBT). In vitro lymphocyte proliferation in response to phytohemagglutinin or concanavalin A and the ability of B lymphocytes to produce antibodies improved as well. Electroencephalogram findings became normal 1 month after UCBT. Thus, we consider that T-cell dysfunction and/or impairments in T–B cell interactions due to X-SCID may have played important roles in the onset of WS. Immune-modulating therapies along with the administration of TPM effectively treated this severe epileptic syndrome in our patient. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: West syndrome; Severe combined immunodeficiency syndrome; CD4/8; Hematopoietic stem cell transplantation; Intravenous injection of immunoglobulin
1. Introduction
q
Research Grant from the Japanese Epilepsy Research Foundation (Y.I.), Research Grant from the Preventive Medical Center of Shinshu University Hospital (Y.I.). ⇑ Corresponding author. Address: Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. Tel.: +81 263 37 2642; fax: +81 263 37 3089. E-mail address: [email protected] (Y. Inaba).
West syndrome (WS) is an intractable epileptic disorder that is characterized by infantile spasms (IS), specific interictal electroencephalogram (EEG) findings of hypsarrhythmia, and arrest or regression of psychomotor development [1]. While the etiology of WS remains unknown, several immune mechanisms are suspected on the basis that immune-modulating therapies, such as adrenocorticotropic hormone (ACTH), glucocorticoids, and intravenous immunoglobulin (IVIG) are effective [2,3],
0387-7604/$ - see front matter Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2014.01.012
M. Motobayashi et al. / Brain & Development 37 (2015) 140–144
and that spontaneous WS remission following acute viral infections has been reported [4–7]. X-linked severe combined immunodeficiency (X-SCID) is a rare primary immunodeficiency syndrome caused by a mutation of the IL2RG gene on the X chromosome. X-SCID patients uniformly have low percentages of T and NK cells and a high percentage of B cells which have no capability to produce antibodies, and typically succumb early in life to severe and recurrent infections unless they receive suitable treatment. Hematopoietic stem cell transplantation (HSCT) is the only known curative option for such patients [8]. We report the clinical and immunological course of an infant with X-SCID complicated by WS who has been treated successfully with immunomodulatory therapies in addition to antiepileptic drugs. 2. Case report The patient was the first boy of a healthy nonconsanguineous 40-year-old mother and 46-year-old
A
father. He had a family history suggestive of X-linked disease; many boys on his maternal side had died from unknown causes in early childhood. He was born spontaneously at term after an uneventful pregnancy. From 2 months after birth, he began to suffer from recurrent airway infections and was treated intermittently with antibiotics. IS (3–11 series/day) appeared at the age of 6 months. Interictal EEG findings revealed hypsarrhythmia (Fig. 1A). Immunological examinations showed hypogammaglobulinemia and decreased percentages of CD4+ cells (2%) and CD56+ cells (3%) (Table 1). Circulating CD8+ cells were detected at 48%, but 78% of these cells had derived from his mother according to X/Y fluorescent in situ hybridization analysis. DNA sequencing showed a missense mutation of the IL2RG gene (c.202G>A, p.Glu68Lys). Based on this evidence, he was diagnosed as having X-SCID (T B+NK SCID) complicated by WS. No pathogenic microbes were detected in specimens taken from blood, respiratory tract secretions, gastric fluid, urine, stools and cerebrospinal fluid (CSF). At the initial visit, his
B
Fp1-A1 Fp2-A2 F3-A1 F4-A2 C3-A1 C4-A2 P3-A1 P4-A2 O1-A1 O2-A2 F7-A1 F8-A2 T3-A1 T4-A2 Fz-A1 Cz-A2 ECG
C
141
Fp1-A1 Fp2-A2 F3-A1 F4-A2 C3-A1 C4-A2 O1-A1 O2-A2 T3-A1 T4-A2 ECG 1 sec
50 μV
1 sec
50 μV
D
Fp1-A1 Fp2-A2 F3-A1 F4-A2 C3-A1 C4-A2 O1-A1 O2-A2 F7-A1 F8-A2 T3-A1 T4-A2 Resp ECG
Fp1-A1 Fp2-A2 F3-A1 F4-A2 C3-A1 C4-A2 O1-A1 O2-A2 F7-A1 F8-A2 T3-A1 T4-A2 Resp 1 sec
50 μV
ECG 1 sec
50 μV
Fig. 1. Interictal EEG findings. (A) An interictal EEG during sleep at the age of 6 months showed high amplitude and irregular waves and spikes in a background of chaotic and disorganized activity (hypsarrhythmia). (B) Before UCBT, moderate EEG abnormalities persisted. (C and D) After UCBT, at the age of 9 months, EEG showed no epileptiform discharges with normal background activity during sleep (C) and wakefulness (D).
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M. Motobayashi et al. / Brain & Development 37 (2015) 140–144
Table 1 Immunological and microbiological findings at the onset of West syndrome. Blood examination WBC Neutrophil Lymphocyte Lymphocyte subsets CD19 CD3 CD4 CD8 CD56 HLA DR Blastogenesis PHA Con A Control CRP IgG IgA IgM CMV antigenemia Candida antigen Aspergillus antigen Cryptococcus antigen b-D-glucan Endotoxin Lactic acid Pyruvic acid Amino-acid analysis Acyl carnitine analysis
CSF examination Cell count Protein IgG NSE MBP CMV PCR Viral isolation PCR examination Blood samples CMV, EBV, HHV-6, HHV-7, HSV-1, HSV-2, VZV, HIV, HBV, HCV, TB, AM, MP Urine sample CMV Stomach fluid samples TB, AM, PC Respiratory tract secretion examination RSV antigen Adenovirus antigen Viral isolation Cytokine profiling Serum samples IL-6 IL-2, IL-4, IL-10, IL-17A, TNF-a, IFN-c CSF samples IL-2, IL- 4, IL-6, IL-10, IL-17A, TNF-a, IFN-c
8.1 103/lL 39.0 (%) 30.0 (%) 41.0 (%) 54.0 (%) 2.0 (%) 48.0 (%) 3.0 (%) 99.0 (%) 2370 cpm 1670 cpm 139 cpm 0.21 mg/dL 25 mg/dL <1 mg/dL 7 mg/dL Negative Negative Negative Negative <2.84 pg/mL Negative 11.0 mg/dL 0.3 mg/dL NP NP
<1/lL 25 mg/dL <1.0 mg/dL 14 ng/mL <31.2 pg/mL Negative Negative
All negative
Negative All negative Negative Negative Negative
3.9 pg/ml ND
ND
Abbreviations: AM, atypical mycobacterium; Con A, concanavalin A; CSF, cerebrospinal fluid; MBP, myelin basic protein; MP, mycoplasma pneumonia; ND, not detectable; NP, not particular; PC, pneumocystis carinii; PCR, polymerase chain reaction; PHA, phytohemagglutinin; TB, tuberculosis bacterium.
VPA Vit B6 IVIG
Tacrolimus + mPSL
UCBT
IS
CD4, CD8 (/µL)
TPM
Respiratory infecon 1400 1200
CD4
IL-6
70 60
1000
CD8
IL-10
50
800
40
600
30
400
20
200
10
0
6
8
Age (months)
10
12
IL-6, IL-10 (pg/mL)
psychomotor development was not delayed. He had a developmental quotient (DQ) of 97 on the Kinder Infant Development Scale (KIDS) [9]. A brain MRI showed no significant abnormalities and a normal myelination pattern. His clinical course is shown in Fig. 2. Vitamin B6 and valproic acid (VPA) treatment was promptly started for his WS, but IS and hypsarrhythmia persisted. We considered ACTH therapy to be unsuitable since he had a severe immunodeficiency. IVIG at a daily dose of 400 mg/kg was administrated at the age of 7 months. VPA was replaced with topiramate (TPM). Then, IS was rapidly resolved. Thereafter, IVIG (250 mg/kg) was given every 2–3 weeks as replacement therapy for X-SCID. At 8 months, he received a 4/6 HLA-matched unrelated cord blood transplantation (UCBT) after conditioning with fludarabine phosphate (180 mg/m2), melphalan (140 mg/m2), and rabbit anti-human thymocyte immunoglobulin (2.5 mg/kg). A dose of 12.6 107 mononuclear cells/kg was infused. Methylprednisolone sodium succinate and tacrolimus were used for acute graft-versus-host-disease prophylaxis. Seventeen days after UCBT, the patient achieved neutrophil engraftment. The EEG abnormalities seen before UCBT (Fig. 1B) were profoundly improved 1 month later
0
Fig. 2. Clinical course. The CD4/8 ratio in peripheral blood was dramatically changed after UCBT. Serum IL-6 and IL-10 levels did not correlate with the course of West syndrome. IS, infantile spasms; IVIG, intravenous immunoglobulin; mPSL, methylprednisolone sodium succinate; TPM, topiramate; UCBT, unrelated cord blood transplantation; VPA, valproic acid.
(Fig. 1C and D). After TPM was discontinued at the age of 10 months, EEG recordings revealed subtle abnormalities, but IS did not relapse. His psychomotor
M. Motobayashi et al. / Brain & Development 37 (2015) 140–144
development was normal at the age of 12 months with a DQ of 92 on the KIDS. As presented in Fig. 2, T-cell subsets changed dramatically during the patient’s therapeutic course. The CD4/8 ratio in his peripheral blood increased from 0.04–0.09 to 0.20–1.95 after UCBT. The CD8+ cells originating from his mother had completely disappeared following UCBT according to a chimerism study. On the other hand, there were no significant correlations between serum concentrations of cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-a, and IFN-c) and the initiation of WS. Serum levels of IL-6 and IL-10 were increased soon after UCBT, but their elevations were considered to have resulted largely from engraftment syndrome. The CSF levels of the 7 types of cytokines described above at the age of 6, 7, and 9 months were all below detectable limits. 3. Discussion Several reports exist on the immunological aspects of the pathophysiology in WS. Montelli et al. demonstrated a significant decrease in the proportion of CD4+ cells and an increase in that of CD8+ cells which resulted in a correspondingly low CD4/8 ratio. They also showed that the impairment of cell-mediated immunity, such as the response to phytohemagglutinin (PHA) in vitro, could be related to the pathophysiology of WS [10]. Meanwhile, Shiihara et al. revealed decreased CD19+ CD25+ levels leading to a possible reduction in B cell apoptosis in this disease [11]. Cytokine profiling of WS has implicated increased levels of serum cytokines (IL-1RA, IL-2, IL-5, IL-6, IL-15, TNF-a, IFN-a, and IP-10) and decreased concentrations of CSF cytokines (IL-6 and IL-1RA) [11]. On the other hand, it has been proposed that a wide variety of infectious diseases may play an important role in WS pathogenesis [4,12]. Spontaneous remission after acute viral infections has also been reported. Though the mechanisms are still unclear, it is supposed that anti-inflammatory cytokines, such as IL-10 or transforming growth factor-b, may suppress immuno-pathological processes in the WS, contributing to the spontaneous remission [6,7]. In our patient, there was no relation between his clinical course of WS and changes in serum and CSF cytokine levels including IL-6 and IL-10. The results of lymphocyte proliferation tests in response to PHA or concanavalin A showed a significant impairment in cell-mediated immunity. The CD4/8 ratio in his peripheral blood was markedly low before UCBT but was increased to normal range afterwards. Furthermore, B lymphocytes acquired the ability to produce immunoglobulins after treatment. In accordance with the UCBT-mediated improvement of these immunological findings, both the patient’s IS and EEG abnormalities completely disappeared. Thus, we considered that T-cell dysfunction and/or impairments in T–B
143
cell interactions due to X-SCID played important roles in the onset of WS in this case. The patient became free of IS episodes after receiving the immunological treatments of IVIG, corticosteroids, tacrolimus, and UCBT. The basis of the anticonvulsant effect of IVIG and corticosteroids is unclear, but several reports have demonstrated their effectiveness [2,3]. Tacrolimus is an immunosuppressive drug that blocks the activation of T lymphocytes and inhibits the formation of IL-2 and other soluble mediators [13]. HSCT, including UCBT, is the most aggressive therapy to reconstitute the immune system. Accordingly, it is considered that these immune-modulating therapies improved our patient’s severe epileptic condition along with the administration of TPM and control of infectious disease. This is the first report of an infant with X-SCID complicated by WS who has been successfully treated with TPM and immune modulation including IVIG, corticosteroids, tacrolimus, and UCBT. Conflict of interest There is no conflict of interest to declare.
Acknowledgements This study was funded in part by Research Grant from the Japanese Epilepsy Research Foundation, and Research Grant from the Preventive Medical Center of Shinshu University Hospital. References [1] Kato M. A new paradigm for West syndrome based on molecular and cell biology. Epilepsy Res 2006;70(Suppl. 1): S87–95. [2] Ariizumi M, Baba K, Hibio S, Shiihara H, Michihiro N, Ogawa K, et al. Immunoglobulin therapy in the West syndrome. Brain Dev 1987;9:422–5. [3] Ariizumi M, Baba K, Shiihara H, Ogawa K, Hibio S, Suzuki Y, et al. High dose gammaglobulin for intractable childhood epilepsy. Lancet 1983;2:162–3. [4] Sugiura C, Maegaki Y, Kure H, Inoue T, Ohno K. Spontaneous remission of infantile spasms and hypsarrhythmia following acute infection with high-grade fever. Epilepsy Res 2007;77: 102–7. [5] Tsuji T, Okumura A, Ozawa H, Ito M, Watanabe K. Current treatment of West syndrome in Japan. J Child Neurol 2007;22: 560–4. [6] Hattori H. Spontaneous remission of spasms in West syndrome – implications of viral infection. Brain Dev 2001;23:705–7. [7] Yamamoto H, Yamano T, Niijima S, Kohyama J, Yamanouchi H. Spontaneous improvement of intractable epileptic seizures following acute viral infections. Brain Dev 2004;26:377–9. [8] Fischer A, Le Deist F, Hacein-Bey-Abina S, Andre-Schmutz I, Basile Gde S, de Villartay JP, et al. Severe combined immunodeficiency. A model disease for molecular immunology and therapy. Immunol Rev 2005;203:98–109.
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[9] Cheng S, Maeda T, Yamagata Z, Tomiwa K, Yamakawa N. Comparison of factors contributing to developmental attainment of children between 9 and 18 months. J Epidemiol 2010;20(Suppl. ):S452–8. [10] Montelli TC, Soares AM, Peracoli MT. Immunologic aspects of West syndrome and evidence of plasma inhibitory effects on T cell function. Arq Neuropsiquiatr 2003;61:731–7. [11] Shiihara T, Miyashita M, Yoshizumi M, Watanabe M, Yamada Y, Kato M. Peripheral lymphocyte subset and serum cytokine
profiles of patients with West syndrome. Brain Dev 2010;32:695–702. [12] Riikonen R. Infantile spasms: infectious disorders. Neuropediatrics 1993;24:274–80. [13] Fay JW, Wingard JR, Antin JH, Collins RH, Pineiro LA, Blazar BR, et al. FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation. Blood 1996;87: 3514–9.
Case report
Successful treatment for West syndrome with severe combined immunodeficiency q Mitsuo Motobayashi a, Yuji Inaba a,⇑, Tetsuhiro Fukuyama b, Takashi Kurata a, Taemi Niimi a, Shoji Saito a, Naoko Shiba a, Takafumi Nishimura a, Tomonari Shigemura a, Yozo Nakazawa a, Norimoto Kobayashi a, Kazuo Sakashita a, Kazunaga Agematsu c, Motoki Ichikawa d, Kenichi Koike a a
Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan b Department of Neuropediatrics, Nagano Children’s Hospital, Azumino, Japan c Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, Japan d Department of Family and Child Nursing, Shinshu University School of Medicine, Matsumoto, Japan Received 1 September 2013; received in revised form 19 January 2014; accepted 22 January 2014
Abstract Several immune mechanisms are suspected in the unknown etiology of West syndrome (WS). We report a male infant who suffered from WS and X-linked T B+NK severe combined immunodeficiency (X-SCID) with a missense mutation of the IL2RG gene (c.202G>A, p.Glu68Lys). He promptly began vitamin B6 and valproic acid treatment, but infantile spasms (IS) and hypsarrhythmia persisted. Administration of intravenous immunoglobulin and the change to topiramate (TPM) at 7 months of age resulted in the rapid resolution of IS. The CD4/8 ratio in his peripheral blood increased from 0.04–0.09 to 0.20–1.95 following unrelated cord blood transplantation (UCBT). In vitro lymphocyte proliferation in response to phytohemagglutinin or concanavalin A and the ability of B lymphocytes to produce antibodies improved as well. Electroencephalogram findings became normal 1 month after UCBT. Thus, we consider that T-cell dysfunction and/or impairments in T–B cell interactions due to X-SCID may have played important roles in the onset of WS. Immune-modulating therapies along with the administration of TPM effectively treated this severe epileptic syndrome in our patient. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: West syndrome; Severe combined immunodeficiency syndrome; CD4/8; Hematopoietic stem cell transplantation; Intravenous injection of immunoglobulin
1. Introduction
q
Research Grant from the Japanese Epilepsy Research Foundation (Y.I.), Research Grant from the Preventive Medical Center of Shinshu University Hospital (Y.I.). ⇑ Corresponding author. Address: Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. Tel.: +81 263 37 2642; fax: +81 263 37 3089. E-mail address: [email protected] (Y. Inaba).
West syndrome (WS) is an intractable epileptic disorder that is characterized by infantile spasms (IS), specific interictal electroencephalogram (EEG) findings of hypsarrhythmia, and arrest or regression of psychomotor development [1]. While the etiology of WS remains unknown, several immune mechanisms are suspected on the basis that immune-modulating therapies, such as adrenocorticotropic hormone (ACTH), glucocorticoids, and intravenous immunoglobulin (IVIG) are effective [2,3],
0387-7604/$ - see front matter Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2014.01.012
M. Motobayashi et al. / Brain & Development 37 (2015) 140–144
and that spontaneous WS remission following acute viral infections has been reported [4–7]. X-linked severe combined immunodeficiency (X-SCID) is a rare primary immunodeficiency syndrome caused by a mutation of the IL2RG gene on the X chromosome. X-SCID patients uniformly have low percentages of T and NK cells and a high percentage of B cells which have no capability to produce antibodies, and typically succumb early in life to severe and recurrent infections unless they receive suitable treatment. Hematopoietic stem cell transplantation (HSCT) is the only known curative option for such patients [8]. We report the clinical and immunological course of an infant with X-SCID complicated by WS who has been treated successfully with immunomodulatory therapies in addition to antiepileptic drugs. 2. Case report The patient was the first boy of a healthy nonconsanguineous 40-year-old mother and 46-year-old
A
father. He had a family history suggestive of X-linked disease; many boys on his maternal side had died from unknown causes in early childhood. He was born spontaneously at term after an uneventful pregnancy. From 2 months after birth, he began to suffer from recurrent airway infections and was treated intermittently with antibiotics. IS (3–11 series/day) appeared at the age of 6 months. Interictal EEG findings revealed hypsarrhythmia (Fig. 1A). Immunological examinations showed hypogammaglobulinemia and decreased percentages of CD4+ cells (2%) and CD56+ cells (3%) (Table 1). Circulating CD8+ cells were detected at 48%, but 78% of these cells had derived from his mother according to X/Y fluorescent in situ hybridization analysis. DNA sequencing showed a missense mutation of the IL2RG gene (c.202G>A, p.Glu68Lys). Based on this evidence, he was diagnosed as having X-SCID (T B+NK SCID) complicated by WS. No pathogenic microbes were detected in specimens taken from blood, respiratory tract secretions, gastric fluid, urine, stools and cerebrospinal fluid (CSF). At the initial visit, his
B
Fp1-A1 Fp2-A2 F3-A1 F4-A2 C3-A1 C4-A2 P3-A1 P4-A2 O1-A1 O2-A2 F7-A1 F8-A2 T3-A1 T4-A2 Fz-A1 Cz-A2 ECG
C
141
Fp1-A1 Fp2-A2 F3-A1 F4-A2 C3-A1 C4-A2 O1-A1 O2-A2 T3-A1 T4-A2 ECG 1 sec
50 μV
1 sec
50 μV
D
Fp1-A1 Fp2-A2 F3-A1 F4-A2 C3-A1 C4-A2 O1-A1 O2-A2 F7-A1 F8-A2 T3-A1 T4-A2 Resp ECG
Fp1-A1 Fp2-A2 F3-A1 F4-A2 C3-A1 C4-A2 O1-A1 O2-A2 F7-A1 F8-A2 T3-A1 T4-A2 Resp 1 sec
50 μV
ECG 1 sec
50 μV
Fig. 1. Interictal EEG findings. (A) An interictal EEG during sleep at the age of 6 months showed high amplitude and irregular waves and spikes in a background of chaotic and disorganized activity (hypsarrhythmia). (B) Before UCBT, moderate EEG abnormalities persisted. (C and D) After UCBT, at the age of 9 months, EEG showed no epileptiform discharges with normal background activity during sleep (C) and wakefulness (D).
142
M. Motobayashi et al. / Brain & Development 37 (2015) 140–144
Table 1 Immunological and microbiological findings at the onset of West syndrome. Blood examination WBC Neutrophil Lymphocyte Lymphocyte subsets CD19 CD3 CD4 CD8 CD56 HLA DR Blastogenesis PHA Con A Control CRP IgG IgA IgM CMV antigenemia Candida antigen Aspergillus antigen Cryptococcus antigen b-D-glucan Endotoxin Lactic acid Pyruvic acid Amino-acid analysis Acyl carnitine analysis
CSF examination Cell count Protein IgG NSE MBP CMV PCR Viral isolation PCR examination Blood samples CMV, EBV, HHV-6, HHV-7, HSV-1, HSV-2, VZV, HIV, HBV, HCV, TB, AM, MP Urine sample CMV Stomach fluid samples TB, AM, PC Respiratory tract secretion examination RSV antigen Adenovirus antigen Viral isolation Cytokine profiling Serum samples IL-6 IL-2, IL-4, IL-10, IL-17A, TNF-a, IFN-c CSF samples IL-2, IL- 4, IL-6, IL-10, IL-17A, TNF-a, IFN-c
8.1 103/lL 39.0 (%) 30.0 (%) 41.0 (%) 54.0 (%) 2.0 (%) 48.0 (%) 3.0 (%) 99.0 (%) 2370 cpm 1670 cpm 139 cpm 0.21 mg/dL 25 mg/dL <1 mg/dL 7 mg/dL Negative Negative Negative Negative <2.84 pg/mL Negative 11.0 mg/dL 0.3 mg/dL NP NP
<1/lL 25 mg/dL <1.0 mg/dL 14 ng/mL <31.2 pg/mL Negative Negative
All negative
Negative All negative Negative Negative Negative
3.9 pg/ml ND
ND
Abbreviations: AM, atypical mycobacterium; Con A, concanavalin A; CSF, cerebrospinal fluid; MBP, myelin basic protein; MP, mycoplasma pneumonia; ND, not detectable; NP, not particular; PC, pneumocystis carinii; PCR, polymerase chain reaction; PHA, phytohemagglutinin; TB, tuberculosis bacterium.
VPA Vit B6 IVIG
Tacrolimus + mPSL
UCBT
IS
CD4, CD8 (/µL)
TPM
Respiratory infecon 1400 1200
CD4
IL-6
70 60
1000
CD8
IL-10
50
800
40
600
30
400
20
200
10
0
6
8
Age (months)
10
12
IL-6, IL-10 (pg/mL)
psychomotor development was not delayed. He had a developmental quotient (DQ) of 97 on the Kinder Infant Development Scale (KIDS) [9]. A brain MRI showed no significant abnormalities and a normal myelination pattern. His clinical course is shown in Fig. 2. Vitamin B6 and valproic acid (VPA) treatment was promptly started for his WS, but IS and hypsarrhythmia persisted. We considered ACTH therapy to be unsuitable since he had a severe immunodeficiency. IVIG at a daily dose of 400 mg/kg was administrated at the age of 7 months. VPA was replaced with topiramate (TPM). Then, IS was rapidly resolved. Thereafter, IVIG (250 mg/kg) was given every 2–3 weeks as replacement therapy for X-SCID. At 8 months, he received a 4/6 HLA-matched unrelated cord blood transplantation (UCBT) after conditioning with fludarabine phosphate (180 mg/m2), melphalan (140 mg/m2), and rabbit anti-human thymocyte immunoglobulin (2.5 mg/kg). A dose of 12.6 107 mononuclear cells/kg was infused. Methylprednisolone sodium succinate and tacrolimus were used for acute graft-versus-host-disease prophylaxis. Seventeen days after UCBT, the patient achieved neutrophil engraftment. The EEG abnormalities seen before UCBT (Fig. 1B) were profoundly improved 1 month later
0
Fig. 2. Clinical course. The CD4/8 ratio in peripheral blood was dramatically changed after UCBT. Serum IL-6 and IL-10 levels did not correlate with the course of West syndrome. IS, infantile spasms; IVIG, intravenous immunoglobulin; mPSL, methylprednisolone sodium succinate; TPM, topiramate; UCBT, unrelated cord blood transplantation; VPA, valproic acid.
(Fig. 1C and D). After TPM was discontinued at the age of 10 months, EEG recordings revealed subtle abnormalities, but IS did not relapse. His psychomotor
M. Motobayashi et al. / Brain & Development 37 (2015) 140–144
development was normal at the age of 12 months with a DQ of 92 on the KIDS. As presented in Fig. 2, T-cell subsets changed dramatically during the patient’s therapeutic course. The CD4/8 ratio in his peripheral blood increased from 0.04–0.09 to 0.20–1.95 after UCBT. The CD8+ cells originating from his mother had completely disappeared following UCBT according to a chimerism study. On the other hand, there were no significant correlations between serum concentrations of cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-a, and IFN-c) and the initiation of WS. Serum levels of IL-6 and IL-10 were increased soon after UCBT, but their elevations were considered to have resulted largely from engraftment syndrome. The CSF levels of the 7 types of cytokines described above at the age of 6, 7, and 9 months were all below detectable limits. 3. Discussion Several reports exist on the immunological aspects of the pathophysiology in WS. Montelli et al. demonstrated a significant decrease in the proportion of CD4+ cells and an increase in that of CD8+ cells which resulted in a correspondingly low CD4/8 ratio. They also showed that the impairment of cell-mediated immunity, such as the response to phytohemagglutinin (PHA) in vitro, could be related to the pathophysiology of WS [10]. Meanwhile, Shiihara et al. revealed decreased CD19+ CD25+ levels leading to a possible reduction in B cell apoptosis in this disease [11]. Cytokine profiling of WS has implicated increased levels of serum cytokines (IL-1RA, IL-2, IL-5, IL-6, IL-15, TNF-a, IFN-a, and IP-10) and decreased concentrations of CSF cytokines (IL-6 and IL-1RA) [11]. On the other hand, it has been proposed that a wide variety of infectious diseases may play an important role in WS pathogenesis [4,12]. Spontaneous remission after acute viral infections has also been reported. Though the mechanisms are still unclear, it is supposed that anti-inflammatory cytokines, such as IL-10 or transforming growth factor-b, may suppress immuno-pathological processes in the WS, contributing to the spontaneous remission [6,7]. In our patient, there was no relation between his clinical course of WS and changes in serum and CSF cytokine levels including IL-6 and IL-10. The results of lymphocyte proliferation tests in response to PHA or concanavalin A showed a significant impairment in cell-mediated immunity. The CD4/8 ratio in his peripheral blood was markedly low before UCBT but was increased to normal range afterwards. Furthermore, B lymphocytes acquired the ability to produce immunoglobulins after treatment. In accordance with the UCBT-mediated improvement of these immunological findings, both the patient’s IS and EEG abnormalities completely disappeared. Thus, we considered that T-cell dysfunction and/or impairments in T–B
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cell interactions due to X-SCID played important roles in the onset of WS in this case. The patient became free of IS episodes after receiving the immunological treatments of IVIG, corticosteroids, tacrolimus, and UCBT. The basis of the anticonvulsant effect of IVIG and corticosteroids is unclear, but several reports have demonstrated their effectiveness [2,3]. Tacrolimus is an immunosuppressive drug that blocks the activation of T lymphocytes and inhibits the formation of IL-2 and other soluble mediators [13]. HSCT, including UCBT, is the most aggressive therapy to reconstitute the immune system. Accordingly, it is considered that these immune-modulating therapies improved our patient’s severe epileptic condition along with the administration of TPM and control of infectious disease. This is the first report of an infant with X-SCID complicated by WS who has been successfully treated with TPM and immune modulation including IVIG, corticosteroids, tacrolimus, and UCBT. Conflict of interest There is no conflict of interest to declare.
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