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Rasmussen Syndrome Combined With IgA Deficiency and Membranous Nephropathy
Rasmussen Syndrome Combined With IgA Deficiency and Membranous Nephropathy Kazushi Ichikawa, MD, Saoko Takeshita, MD, Shuichi Ito, PhD, and Atsuo Nezu, PhD A 9-year-old boy diagnosed as having Rasmussen syndrome had congenital IgA deficiency and juvenile alopecia. He developed auditory hallucination and consciousness disturbance with intractable complex partial epileptic status. Anti-glutamate receptor 32 antibodies were detected in his serum and cerebrospinal fluid. He was administered immunomodulatory agents and his seizures were treated with an intravenous anticonvulsant for 2 months. Subsequently, he developed a nephrotic syndrome, which proved to be membranous nephropathy and was treated with cyclophosphamide. Anti-basement membrane antibodies were detected in his serum. The boy died at the age of 14 years, and autopsy revealed diffuse brain atrophy with neuronal loss, infiltration of glial cells in the cerebrum, and loss of Purkinje cells in the cerebellum. A kidney specimen contained many sclerotic glomeruli, indicative of progressive membranous nephropathy. The patient was considered to have multimodal autoimmune disorder producing juvenile alopecia, autoimmune encephalitis, and a membranous nephropathy, based on the congenital IgA deficiency. Ó 2009 by Elsevier Inc. All rights reserved. Ichikawa K, Takeshita S, Ito S, Nezu A. Rasmussen syndrome combined with iga deficiency and membranous nephropathy. Pediatr Neurol 2009;40:468-470.
From the Department of Pediatrics, Yokohama City University Medical Center, Yokohama, Japan.
468 PEDIATRIC NEUROLOGY Vol. 40 No. 6
Introduction Rasmussen syndrome is a chronic progressive hemiencephalitis in young children characterized by intractable partial seizures, focal neurologic signs, dementia, and progressive brain atrophy [1,2]. The etiology of Rasmussen syndrome is unknown, but it is speculated that a viral infection or autoimmune response is related to its pathophysiology. It was recently reported that autoantibodies against glutamate receptor 3 or 32 were found in the serum and cerebrospinal fluid of patients [3,4]. These antibodies were presumed to be associated with the encephalitis. Rasmussen syndrome is treated with antiepileptic medications, immunomodulatory therapies (e.g., steroids, plasmapheresis, immunoglobulins), and hemispherectomy [5]. On the other hand, IgA deficiency is reported to be an immune disorder relate to autoimmune diseases, such as systemic lupus erythematosa, rheumatic arthritis, celiac disease, Crohn disease, and various allergic diseases [6]. There have been no previous reports of Rasmussen syndrome with congenital IgA deficiency or a membranous nephropathy. The present case, of a young boy with Rasmussen syndrome combined with congenital IgA deficiency, juvenile alopecia and membranous nephropathy, can shed light on the relationship between Rasmussen syndrome and autoimmune disorders. Case Report At the age of 9 years, a Japanese boy suffered from vomiting, auditory hallucination, deafness, drowsiness, and myoclonic seizures of the left arm. There was no history of preceding infection, and no family history of neurological disorders. His psychomotor development was normal. The boy had a history of juvenile alopecia and blistering diathesis of the skin from the age of 3 years. The boy was referred to our hospital a few days after the onset. He exhibited drowsiness and intellectual disability due to partial complex status epilepticus, and auditory agnosia without impairment of speech, writing, or reading. No neurologic signs were noted in cranial or peripheral nerves. Both Kernig and Lase`gue signs were negative. He exhibited partial myoclonic convulsions at the left angle of the mouth, myoclonic jerks of the left arm which was developed to epilepsia partialis continua, and secondary generalized tonic convulsions. Hematologic examinations revealed no abnormalities, except IgA of <5 mg/dL. Other immunologic data were IgG, 1400 mg/dL; IgM, 145 mg/dL; C3, 131 mg/dL; C4, 21 mg/dL; and CH50, 47 U/mL. The IgG subclasses were within normal limits. Cerebrospinal fluid test results were as follows: leukocyte count, 4/mL; glucose, 83 mg/dL; protein, 16 mg/dL; and IgG, 1.3 mg/dL. Viral antibodies in the serum were negative for herpes
Communications should be addressed to: Dr. Ichikawa; Yokohama City University Medical Center; 4-57 Urafune-cho; Minami-ku; Yokohama 232-0024, Japan E-mail: [email protected] Received June 30, 2008; accepted December 15, 2008.
Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2008.12.008 0887-8994/09/$—see front matter
improved his condition, and he then entered a vegetative state over several months and required tracheostomy. The magnetic resonance images revealed high intensity of the right parietal cortex 1 month after the hospitalization and then slowly progressive brain atrophy (Fig 1). The seizures were suppressed by valproic acid, carbamazepine, zonisamide, and phenytoin. Subsequently, he had the complication of a nephrotic syndrome that was diagnosed as membranous nephropathy (stage II) on renal needle biopsy with IgG and C3 deposition on the basement membrane of the glomeruli. Steroids and cyclosporine failed to ameliorate the nephrosis, but cyclophosphamide was effective. Anti-basement membrane (BM) antibodies were detected in his serum. At the age of 14 years, he died of sudden intratracheal bleeding from a tracheo-innominate artery fistula due to the tracheostomy tube (Fig 2). The autopsy findings revealed diffuse brain atrophy with enlargement of the lateral ventricle. Cerebral specimens revealed neuronal loss, gliosis, and spongy degeneration in the gray matter, and demyelination, gliosis, and perivascular CD3+ T-cell infiltration in the white matter, which was stained with monoclonal antibody against CD3 (PS1, Nichirei, Tokyo, Japan) (Fig 3). These findings were dominant in the frontal, parietal, and occipital lobes; the temporal lobe and basal ganglia were relatively preserved. Cerebellar specimens revealed loss of the granular layer and Purkinje cells. Kidney specimens revealed thickening and spikes of the basement membrane with global sclerosis of the glomeruli, which indicated stages III-IV of membranous nephropathy. Figure 1. Cranial T2-weighted magnetic resonance image, axial, 5 months after hospitalization in a case of Rasmussen syndrome combined with IgA deficiency and membranous nephropathy, demonstrated slowly progressive change of brain atrophy (TR/TE = 2500/100 ms).
simplex, varicella zoster, cytomegalovirus, Epstein-Barr virus, measles, mumps, adenovirus, coxsackievirus, echovirus, influenza, parainfluenza, and Japanese encephalitis virus. Anti-glutamate receptor 32 antibodies were detected in his serum and cerebrospinal fluid on admission. Cranial magnetic resonance imaging revealed no abnormality on admission. Electroencephalograms indicated slowing in the right hemisphere and epileptic discharges in the right central area. When he developed generalized tonic status epilepticus, he was administered intravenous thiopental and pentobarbital in an intensive care unit with ventilator support for 2 months. In view of Rasmussen syndrome, he was treated with intrathecal immunoglobulin, high-dose methylprednisolone at the dose of 30 mg/kg daily for 3 consecutive days, and intramuscular adrenocorticotropic hormone. However, these therapies never
Discussion Rasmussen syndrome is a chronic form of encephalitis that affects one cerebral hemisphere. The present patient had clinical features of Rasmussen syndrome, and his clinical course exhibited gradual progression for several months, suggestive of subacute or chronic encephalitis. This patient subsequently developed bilateral diffuse brain atrophy, and there have been reports of Rasmussen syndrome with bilateral cerebral involvement [7]. Anti-glutamate receptor 32 antibodies were detected in his serum and in the cerebrospinal fluid sample. It was recently reported that autoantibodies against glutamate receptors 3 and 32 were found in the serum and cerebrospinal fluid of a Rasmussen syndrome patient and these antibodies were presumed to have some relation to the pathophysiology of
Figure 2. Clinical course of the patient. mPSL, methylprednisolone; PSL, prednisolone; ACTH; adrenocorticotropic hormone.
Ichikawa et al: Rasmussen Syndrome With IgA Deficiency 469
that the anti-BM antibodies in his serum had some relation to the membranous nephropathy and his blistering diathesis. The patient was considered to have autoimmune disorders such as juvenile alopecia, autoimmune encephalitis, and membranous nephropathy, based on the dysfunction of the immune system as IgA deficiency. The possibility remained, however, that the membranous nephropathy was induced by some drug, possibly antiepileptic agents. In summary, a schoolboy diagnosed with Rasmussen syndrome had congenital IgA deficiency, juvenile alopecia, and membranous nephropathy. He was presumed to have an underlying autoimmune condition. Rasmussen syndrome may be one of the complications of an abnormal autoimmune condition such as IgA deficiency. Thanks go to Dr. Yukitoshi Takahashi, PhD (Department of Pediatrics, National Epilepsy Center Shizuoka Medical Institute of Neurological Disorders, Shizuoka, Japan), for measurement of the anti-glutamate receptor antibodies in the serum and cerebrospinal fluid samples.
References
Figure 3. Autopsy specimen of the patient’s brain with hematoxylineosin stain (original magnification, 400). Frontal cerebral specimen reveals neuronal loss, degeneration, gliosis, and spongy degeneration.
the encephalitis [3,4]. However, there have been reports that anti-glutamate receptor antibodies are not specific for Rasmussen syndrome, but are detected in epilepsy or other types of encephalitis [8]. The present patient’s brain autopsy findings were consistent with progressive Rasmussen syndrome, particularly the CD3+ T-cell infiltration with activated microglial cells [9]. The patient had a history of juvenile alopecia and blistering diathesis from the early childhood, so he was suspected of having autoimmune disease of the skin. The selected IgA deficiency was also revealed by his laboratory data on admission, and there was no history of medication that could have affected his IgA. The conclusion therefore was that the IgA deficiency was congenital, which is reported to complicate some autoimmune disorders. The patient developed a nephrotic syndrome caused by membranous nephropathy in his clinical course. There has been no report on Rasmussen syndrome with IgA deficiency or membranous nephropathy, and only a few reports on membranous nephropathy with IgA deficiency based on another autoimmune disorder [10,11]. Furthermore, it was suggested
470 PEDIATRIC NEUROLOGY Vol. 40 No. 6
[1] Zupanc ML, Handler EG, Levine RL, et al. Rasmussen encephalitis: epilepsia partialis continua secondary to chronic encephalitis. Pediatr Neurol 1990;6:397-401. [2] Freeman JM. Rasmussen’s syndrome: progressive autoimmune multi-focal encephalopathy. Pediatr Neurol 2005;32:295-9. [3] Kumakura A, Miyajima T, Fujii T, Takahashi Y, Ito M. A patient with epilepsia partialis continua with anti-glutamate receptor 32 antibodies. Pediatr Neurol 2003;29:160-3. [4] Takahashi Y, Mori H, Mishina M, et al. Autoantibodies to NMDA receptor in patients with chronic forms of epilepsia partialis continua. Neurology 2003;61:891-6. [5] Granata T, Fusco L, Gobbi G, et al. Experience with immunomodulatory treatments in Rasmussen’s encephalitis. Neurology 2003;61: 1807-10. [6] Cunningham-Rundles C. Physiology of IgA and IgA deficiency. J Clin Immunol 2001;21:303-9. [7] Andermann F. Early onset Rasmussen’s syndrome: a malignant, often bilateral form of the disorder. Epilepsy Res 2006;70(Suppl 1): S259-62. [8] Mantegazza R, Bernasconi P, Baggi F, et al. Antibodies against GluR3 peptides are not specific for Rasmussen’s encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol 2002;131:179-85. [9] Bien CG, Granata T, Antozzi C, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 2005;128:454-71. [10] Huang JB, Yang WC, Hu CC, Yang AH, Lin CC. IgA deficiency with membranous glomerulonephritis: a case report and review. J Nephrol 2003;16:154-8. [11] Kawasaki Y, Suzuki J, Onishi N, Takahashi A, Isome M, Suzuki H. IgA deficiency and membranous glomerulonephritis presenting as nephrotic syndrome. Pediatr Nephrol 2005;20:662-4.
From the Department of Pediatrics, Yokohama City University Medical Center, Yokohama, Japan.
468 PEDIATRIC NEUROLOGY Vol. 40 No. 6
Introduction Rasmussen syndrome is a chronic progressive hemiencephalitis in young children characterized by intractable partial seizures, focal neurologic signs, dementia, and progressive brain atrophy [1,2]. The etiology of Rasmussen syndrome is unknown, but it is speculated that a viral infection or autoimmune response is related to its pathophysiology. It was recently reported that autoantibodies against glutamate receptor 3 or 32 were found in the serum and cerebrospinal fluid of patients [3,4]. These antibodies were presumed to be associated with the encephalitis. Rasmussen syndrome is treated with antiepileptic medications, immunomodulatory therapies (e.g., steroids, plasmapheresis, immunoglobulins), and hemispherectomy [5]. On the other hand, IgA deficiency is reported to be an immune disorder relate to autoimmune diseases, such as systemic lupus erythematosa, rheumatic arthritis, celiac disease, Crohn disease, and various allergic diseases [6]. There have been no previous reports of Rasmussen syndrome with congenital IgA deficiency or a membranous nephropathy. The present case, of a young boy with Rasmussen syndrome combined with congenital IgA deficiency, juvenile alopecia and membranous nephropathy, can shed light on the relationship between Rasmussen syndrome and autoimmune disorders. Case Report At the age of 9 years, a Japanese boy suffered from vomiting, auditory hallucination, deafness, drowsiness, and myoclonic seizures of the left arm. There was no history of preceding infection, and no family history of neurological disorders. His psychomotor development was normal. The boy had a history of juvenile alopecia and blistering diathesis of the skin from the age of 3 years. The boy was referred to our hospital a few days after the onset. He exhibited drowsiness and intellectual disability due to partial complex status epilepticus, and auditory agnosia without impairment of speech, writing, or reading. No neurologic signs were noted in cranial or peripheral nerves. Both Kernig and Lase`gue signs were negative. He exhibited partial myoclonic convulsions at the left angle of the mouth, myoclonic jerks of the left arm which was developed to epilepsia partialis continua, and secondary generalized tonic convulsions. Hematologic examinations revealed no abnormalities, except IgA of <5 mg/dL. Other immunologic data were IgG, 1400 mg/dL; IgM, 145 mg/dL; C3, 131 mg/dL; C4, 21 mg/dL; and CH50, 47 U/mL. The IgG subclasses were within normal limits. Cerebrospinal fluid test results were as follows: leukocyte count, 4/mL; glucose, 83 mg/dL; protein, 16 mg/dL; and IgG, 1.3 mg/dL. Viral antibodies in the serum were negative for herpes
Communications should be addressed to: Dr. Ichikawa; Yokohama City University Medical Center; 4-57 Urafune-cho; Minami-ku; Yokohama 232-0024, Japan E-mail: [email protected] Received June 30, 2008; accepted December 15, 2008.
Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2008.12.008 0887-8994/09/$—see front matter
improved his condition, and he then entered a vegetative state over several months and required tracheostomy. The magnetic resonance images revealed high intensity of the right parietal cortex 1 month after the hospitalization and then slowly progressive brain atrophy (Fig 1). The seizures were suppressed by valproic acid, carbamazepine, zonisamide, and phenytoin. Subsequently, he had the complication of a nephrotic syndrome that was diagnosed as membranous nephropathy (stage II) on renal needle biopsy with IgG and C3 deposition on the basement membrane of the glomeruli. Steroids and cyclosporine failed to ameliorate the nephrosis, but cyclophosphamide was effective. Anti-basement membrane (BM) antibodies were detected in his serum. At the age of 14 years, he died of sudden intratracheal bleeding from a tracheo-innominate artery fistula due to the tracheostomy tube (Fig 2). The autopsy findings revealed diffuse brain atrophy with enlargement of the lateral ventricle. Cerebral specimens revealed neuronal loss, gliosis, and spongy degeneration in the gray matter, and demyelination, gliosis, and perivascular CD3+ T-cell infiltration in the white matter, which was stained with monoclonal antibody against CD3 (PS1, Nichirei, Tokyo, Japan) (Fig 3). These findings were dominant in the frontal, parietal, and occipital lobes; the temporal lobe and basal ganglia were relatively preserved. Cerebellar specimens revealed loss of the granular layer and Purkinje cells. Kidney specimens revealed thickening and spikes of the basement membrane with global sclerosis of the glomeruli, which indicated stages III-IV of membranous nephropathy. Figure 1. Cranial T2-weighted magnetic resonance image, axial, 5 months after hospitalization in a case of Rasmussen syndrome combined with IgA deficiency and membranous nephropathy, demonstrated slowly progressive change of brain atrophy (TR/TE = 2500/100 ms).
simplex, varicella zoster, cytomegalovirus, Epstein-Barr virus, measles, mumps, adenovirus, coxsackievirus, echovirus, influenza, parainfluenza, and Japanese encephalitis virus. Anti-glutamate receptor 32 antibodies were detected in his serum and cerebrospinal fluid on admission. Cranial magnetic resonance imaging revealed no abnormality on admission. Electroencephalograms indicated slowing in the right hemisphere and epileptic discharges in the right central area. When he developed generalized tonic status epilepticus, he was administered intravenous thiopental and pentobarbital in an intensive care unit with ventilator support for 2 months. In view of Rasmussen syndrome, he was treated with intrathecal immunoglobulin, high-dose methylprednisolone at the dose of 30 mg/kg daily for 3 consecutive days, and intramuscular adrenocorticotropic hormone. However, these therapies never
Discussion Rasmussen syndrome is a chronic form of encephalitis that affects one cerebral hemisphere. The present patient had clinical features of Rasmussen syndrome, and his clinical course exhibited gradual progression for several months, suggestive of subacute or chronic encephalitis. This patient subsequently developed bilateral diffuse brain atrophy, and there have been reports of Rasmussen syndrome with bilateral cerebral involvement [7]. Anti-glutamate receptor 32 antibodies were detected in his serum and in the cerebrospinal fluid sample. It was recently reported that autoantibodies against glutamate receptors 3 and 32 were found in the serum and cerebrospinal fluid of a Rasmussen syndrome patient and these antibodies were presumed to have some relation to the pathophysiology of
Figure 2. Clinical course of the patient. mPSL, methylprednisolone; PSL, prednisolone; ACTH; adrenocorticotropic hormone.
Ichikawa et al: Rasmussen Syndrome With IgA Deficiency 469
that the anti-BM antibodies in his serum had some relation to the membranous nephropathy and his blistering diathesis. The patient was considered to have autoimmune disorders such as juvenile alopecia, autoimmune encephalitis, and membranous nephropathy, based on the dysfunction of the immune system as IgA deficiency. The possibility remained, however, that the membranous nephropathy was induced by some drug, possibly antiepileptic agents. In summary, a schoolboy diagnosed with Rasmussen syndrome had congenital IgA deficiency, juvenile alopecia, and membranous nephropathy. He was presumed to have an underlying autoimmune condition. Rasmussen syndrome may be one of the complications of an abnormal autoimmune condition such as IgA deficiency. Thanks go to Dr. Yukitoshi Takahashi, PhD (Department of Pediatrics, National Epilepsy Center Shizuoka Medical Institute of Neurological Disorders, Shizuoka, Japan), for measurement of the anti-glutamate receptor antibodies in the serum and cerebrospinal fluid samples.
References
Figure 3. Autopsy specimen of the patient’s brain with hematoxylineosin stain (original magnification, 400). Frontal cerebral specimen reveals neuronal loss, degeneration, gliosis, and spongy degeneration.
the encephalitis [3,4]. However, there have been reports that anti-glutamate receptor antibodies are not specific for Rasmussen syndrome, but are detected in epilepsy or other types of encephalitis [8]. The present patient’s brain autopsy findings were consistent with progressive Rasmussen syndrome, particularly the CD3+ T-cell infiltration with activated microglial cells [9]. The patient had a history of juvenile alopecia and blistering diathesis from the early childhood, so he was suspected of having autoimmune disease of the skin. The selected IgA deficiency was also revealed by his laboratory data on admission, and there was no history of medication that could have affected his IgA. The conclusion therefore was that the IgA deficiency was congenital, which is reported to complicate some autoimmune disorders. The patient developed a nephrotic syndrome caused by membranous nephropathy in his clinical course. There has been no report on Rasmussen syndrome with IgA deficiency or membranous nephropathy, and only a few reports on membranous nephropathy with IgA deficiency based on another autoimmune disorder [10,11]. Furthermore, it was suggested
470 PEDIATRIC NEUROLOGY Vol. 40 No. 6
[1] Zupanc ML, Handler EG, Levine RL, et al. Rasmussen encephalitis: epilepsia partialis continua secondary to chronic encephalitis. Pediatr Neurol 1990;6:397-401. [2] Freeman JM. Rasmussen’s syndrome: progressive autoimmune multi-focal encephalopathy. Pediatr Neurol 2005;32:295-9. [3] Kumakura A, Miyajima T, Fujii T, Takahashi Y, Ito M. A patient with epilepsia partialis continua with anti-glutamate receptor 32 antibodies. Pediatr Neurol 2003;29:160-3. [4] Takahashi Y, Mori H, Mishina M, et al. Autoantibodies to NMDA receptor in patients with chronic forms of epilepsia partialis continua. Neurology 2003;61:891-6. [5] Granata T, Fusco L, Gobbi G, et al. Experience with immunomodulatory treatments in Rasmussen’s encephalitis. Neurology 2003;61: 1807-10. [6] Cunningham-Rundles C. Physiology of IgA and IgA deficiency. J Clin Immunol 2001;21:303-9. [7] Andermann F. Early onset Rasmussen’s syndrome: a malignant, often bilateral form of the disorder. Epilepsy Res 2006;70(Suppl 1): S259-62. [8] Mantegazza R, Bernasconi P, Baggi F, et al. Antibodies against GluR3 peptides are not specific for Rasmussen’s encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol 2002;131:179-85. [9] Bien CG, Granata T, Antozzi C, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 2005;128:454-71. [10] Huang JB, Yang WC, Hu CC, Yang AH, Lin CC. IgA deficiency with membranous glomerulonephritis: a case report and review. J Nephrol 2003;16:154-8. [11] Kawasaki Y, Suzuki J, Onishi N, Takahashi A, Isome M, Suzuki H. IgA deficiency and membranous glomerulonephritis presenting as nephrotic syndrome. Pediatr Nephrol 2005;20:662-4.