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Effective immunoglobulin therapy for brief tonic seizures in methylmalonic acidemia
Brain & Development 19 (1997) 502–505
Case report
Effective immunoglobulin therapy for brief tonic seizures in methylmalonic acidemia Hiroshi Aikoh a, Masayuki Sasaki a ,*, Kenji Sugai a, Hiroshi Yoshida b, Norio Sakuragawa c a Department of Child Neurology, National Center Hospital for Mental, Nervous and Muscular Disorders, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187, Japan b Department of Pediatrics, Shonai Hospital, Yamagata, Japan c Department of Inherited Metabolic Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187, Japan
Received 27 February 1997; revised version received 16 June 1997; accepted 4 August 1997
Abstract We report on a patient with methylmalonic acidemia (MMA). He experienced a metabolic acidosis attack at 3 weeks of age. He immediately received peritoneal dialysis and exchange transfusion, and recovered from the attack. His MMA phenotype was mut0. Dietary therapy (strict protein restriction) was found to be effective in preventing further attacks, and he had mild hypotonia and impaired psychomotor development. At 9 months of age, he developed brief tonic seizures, which showed polyspike bursts under EEG. His psychomotor development continued to deteriorate. However, intravenous administration of immunoglobulin (200 mg/kg/day for 5 consecutive days) had a dramatic effect; his seizures disappeared and his psychomotor development improved. 1997 Elsevier Science B.V. Keywords: Methylmalonic acidemia; Immunoglobulin therapy; Epilepsy; West syndrome; Inborn error
1. Introduction Methylmalonic acidemia (MMA) is a genetic disorder affecting branched-chain amino acid metabolism [1], and can be divided into two major types. One is characterized by methylmalonyl CoA mutase apoenzyme deficiency (mut0 and mut−), and the other by an abnormality in adenosylcobalamin synthesis. The latter responds to pharmacological doses of hydroxycobalamin (B12-responsive MMA). In extreme cases of the first type, methylmalonyl CoA mutase activity is completely absent (mut0), which has a poor prognosis [2]. Sixty percent of cases with this phenotype die and the other 40% are impaired developmentally [2]. There are two forms of therapy, i.e., immediate therapy for metabolic ketoacidosis and hyperammonemia attacks and maintenance therapy during times of no attacks. Maintenance therapy involves strict protein restriction, especially
* Corresponding author. Fax: +81 423 446 745.
0387-7604/97/$17.00 1997 Elsevier Science B.V. All rights reserved PII S0387-7604 (97 )0 0059-4
of precursor amino acids for methylmalonate, and l-carnitine supplementation. In spite of these therapies, various neurological symptoms, including hypotonia, mental retardation, motor delay, dystonia and spastic quadriparesis, have been reported for this disorder [2–4]. Here we provide a report on a patient with MMA (mut0 phenotype) who presented brief tonic seizures despite fairly good maintenance therapy and we found that immunoglobulin was very effective for treating these seizures.
2. Case report The clinical course is shown in Fig. 1. This patient was born to healthy and unrelated parents after a full-term uncomplicated pregnancy, weighing 2.1 kg. He has a healthy brother. He was well until 23 days of age, when he developed poor feeding, tachypnea and loss of consciousness. Blood analysis revealed metabolic acidosis (pH 7.057, base excess 24.8 mmol/l) and hyperammonemia
H. Aikoh et al. / Brain & Development 19 (1997) 502–505
503
high intensity areas in the basal ganglia, which are often seen in MMA [6–8]. The auditory brainstem response was normal. Clonazepam (CZP) was partially effective for decreasing the frequency and duration of the seizures. Then intravenous administration of immunoglobulin (200 mg/kg per day for 5 consecutive days) was started and seizure frequency decreased immediately and stopped completely on the 5th day of this therapy. They never reappeared. Immunoglobulin therapy did not alter the amount of methylmalonic acid excreted. The EEG findings also improved. Polyspike bursts disappeared and sleep spindles were observed (Fig. 2b). The child’s psychomotor development also improved. At 2 years
Fig. 1. Schema of the clinical course.
(more than 400 mg/dl). He received peritoneal dialysis and exchange transfusion, and was given sodium bicarbonate and sodium benzoate. He consequently recovered from this attack. Organic acid analysis of urine measured high levels of methylmalonic acid, leading to a diagnosis of MMA. The standard therapy of orally administered vitamin B12 and l-carnitine, and protein restriction (1.2 g/kg per day) was then started. Vitamin B12 did not change methylmalonic acid excretion. Methylmalonyl CoA mutase activity was found to be completely absent (patient: 0; control: 1066 pmol/mg protein/min) in fibroblasts using the method of Ledley et al. [5], indicating the patient was mut0 subtype. Following this first attack, his psychomotor development was slow, e.g., head control at 7 months, rolling over at 8 months and sitting without support at 9 months of age. His general condition was stable and weight gain was fairly good (8 kg at 9 months). There was good control of blood gases (pH 7.40~7.35, BE 0~−5) and ammonia level (~100 mg/dl). No metabolic acidosis attack was observed thereafter. However, at 9 months of age, he developed brief individual tonic seizures approximately one every 30–60 min every day. Valproic acid (VPA) and nitrazepam (NZP) did not stop these seizures and their frequency increased and psychomotor regression also occurred. He lost the ability to sit without support and to maintain head control. He was admitted to hospital at 12 months, showing hypotonia. Neither spasticity nor involuntary movements were observed. He could not formulate any words and comprehension was also delayed. The tonic seizures did not come in clusters and lasted for a few seconds. They consisted of brief flexions of the extremities and neck, followed by brief extensions of the extremities. The seizures occurred about 20–30 times a day. Interictal EEG during wakefulness revealed diffuse polyspike bursts (Fig. 2a). Ictal EEG also showed diffuse polyspike bursts. Magnetic resonance (MR) imaging at 13 months of age showed mild cerebral atrophy, especially of the cerebral cortex, corpus callosum and pons (Fig. 3). Myelination was slightly delayed and there were no
Fig. 2. (a) Interictal EEG during wakefulness before immunoglobulin therapy frequently showed diffuse polyspike bursts. (b) EEG during sleep following immunoglobulin therapy reveals sleep spindles. Polyspike bursts have disappeared.
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H. Aikoh et al. / Brain & Development 19 (1997) 502–505
Fig. 3. MR imagings at 13 months revealed mild cerebral atrophy, especially of the cerebral cortex, corpus callosum and pons. Myelination was slightly delayed and there were no high intensity areas in the basal ganglia ((a,b) axial T2-weighted images; (c) sagittal T1-weighted images).
of age, he could sit by himself, though he still showed mild hypotonia. He could not crawl. No spasticity was observed. He spoke no meaningful words, just jargon, and understood some words.
3. Discussion Seizures in patients with MMA are not uncommon during a ketoacidosis episode. Hyperammonemia also induces seizure disorders. However, convulsions in the chronic phase have not been commonly described in MMA [2–4]. Our patient showed brief tonic seizures. This seizure type resembled that seen in infantile spasms (West syndrome). However, EEG did not reveal hypsarrhythmia in this patient, it just showed diffuse polyspike bursts. These attacks started at 9 months of age and following the seizures, psychomotor deterioration was observed. It was probably the high methylmalonic acid levels, metabolic acidosis and/or hyperammonemia which induced this brain damage. It is possible that the cause of this type of seizure may be the same as that of West syndrome due to other metabolic disorders such as maple syrup disease or phenylketonurea. Basal ganglia are often involved in MMA, but MR imaging showed this not to be the case. Only mild brain atrophy in the cerebral cortex and pons was observed, indicating that the brain damage was probably not so severe. The effect of immunoglobulin treatment on infantile spasms or other types of epilepsy is occasionally positive in children [9,10]. Ariizumi et al. [9,10] used immunoglobulin on patients with infantile spasms or other intractable epilepsies. They administered immunoglobulin at 100–200 mg/kg of body weight at intervals of 2–3 weeks. We decided to use immunoglobulin at 200 mg/kg for 5 consecutive days in order to produce a rapid therapeutic effect. The seizures ceased on the 5th day of the therapy. The mechanisms by which immunoglobulin is effective in several types of seizures have not yet been completely elucidated. Since immunoglobulin did not alter the amount of
methylmalonic acid excreted, there must be some other factors which reduced the epileptic seizures. To our knowledge, there have been no previous reports that immunoglobulin is an effective treatment of epilepsy as caused by MMA. However, the fact that immunoglobulin was effective in this patient with MMA is important, as this implies that immunoglobulin therapy can be useful for treating some intractable seizures of metabolic origin.
Acknowledgements The authors are very grateful to Dr. Yozo Ichiba (National Okayama Children’s Hospital), Dr. Masato Ogasawara (Tohoku University), and Dr. Masaki Takayanagi (Chiba University) for their great help and suggestions regarding diagnosis and treatment.
References [1] Fenton WA, Rosenberg LE. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill, 1995:1423–1449. [2] Matsui SM, Mahoney MJ, Rosenberg LE. The natural history of the inherited methylmalonic acidemias. N Engl J Med 1983;308:857– 861. [3] Shevel MI, Matiaszuk N, Ledley FD, Rosenblatt DS. Varying neurological phenotypes among mut0 and mut − patients with methylmalonyl CoA mutase deficiency. Am J Med Genet 1993;45:619– 624. [4] van der Meer SB, Poggi F, Spada M, Bonnefont JP, Ogier H, Hubert P. et al. Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia. J Pediatr 1994; 125:903–908. [5] Ledley FD, Crane AM, Lumetta M. Heterogeneous alleles and expression of methylmalonyl CoA mutase in mut methylmalonic acidemia. Am J Hum Genet 1990;46:539–547. [6] Korf B, Wallman JK, Levy HL. Bilateral lucency of the globus pallidus complicating methylmalonic acidemia. Ann Neurol 1986;20:364–366.
H. Aikoh et al. / Brain & Development 19 (1997) 502–505 [7] Andreula CF, DeBlasi R, Carella A. CT and MR studies of methylmalonic acidemia. Am J Neuroradiol 1991;12:410–412. [8] Brismar J, Ozand PT. CT and MR of the brain in the diagnosis of organic acidemias. Experiences from 107 patients. Brain Dev 1994;16 (Suppl.):104–124. [9] Ariizumi M, Baba K, Shiihara H, Ogawa K, Hibio S, Suzuki Y. et al.
505
High dose gammaglobulin for intractable childhood epilepsy. Lancet 1983;8342:162–163. [10] Ariizumi M, Baba K, Hibio S, Shiihara H, Michihiro N, Ogawa K. et al. Immunoglobulin therapy in the West syndrome. Brain Dev 1987;9:422–425.
Case report
Effective immunoglobulin therapy for brief tonic seizures in methylmalonic acidemia Hiroshi Aikoh a, Masayuki Sasaki a ,*, Kenji Sugai a, Hiroshi Yoshida b, Norio Sakuragawa c a Department of Child Neurology, National Center Hospital for Mental, Nervous and Muscular Disorders, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187, Japan b Department of Pediatrics, Shonai Hospital, Yamagata, Japan c Department of Inherited Metabolic Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187, Japan
Received 27 February 1997; revised version received 16 June 1997; accepted 4 August 1997
Abstract We report on a patient with methylmalonic acidemia (MMA). He experienced a metabolic acidosis attack at 3 weeks of age. He immediately received peritoneal dialysis and exchange transfusion, and recovered from the attack. His MMA phenotype was mut0. Dietary therapy (strict protein restriction) was found to be effective in preventing further attacks, and he had mild hypotonia and impaired psychomotor development. At 9 months of age, he developed brief tonic seizures, which showed polyspike bursts under EEG. His psychomotor development continued to deteriorate. However, intravenous administration of immunoglobulin (200 mg/kg/day for 5 consecutive days) had a dramatic effect; his seizures disappeared and his psychomotor development improved. 1997 Elsevier Science B.V. Keywords: Methylmalonic acidemia; Immunoglobulin therapy; Epilepsy; West syndrome; Inborn error
1. Introduction Methylmalonic acidemia (MMA) is a genetic disorder affecting branched-chain amino acid metabolism [1], and can be divided into two major types. One is characterized by methylmalonyl CoA mutase apoenzyme deficiency (mut0 and mut−), and the other by an abnormality in adenosylcobalamin synthesis. The latter responds to pharmacological doses of hydroxycobalamin (B12-responsive MMA). In extreme cases of the first type, methylmalonyl CoA mutase activity is completely absent (mut0), which has a poor prognosis [2]. Sixty percent of cases with this phenotype die and the other 40% are impaired developmentally [2]. There are two forms of therapy, i.e., immediate therapy for metabolic ketoacidosis and hyperammonemia attacks and maintenance therapy during times of no attacks. Maintenance therapy involves strict protein restriction, especially
* Corresponding author. Fax: +81 423 446 745.
0387-7604/97/$17.00 1997 Elsevier Science B.V. All rights reserved PII S0387-7604 (97 )0 0059-4
of precursor amino acids for methylmalonate, and l-carnitine supplementation. In spite of these therapies, various neurological symptoms, including hypotonia, mental retardation, motor delay, dystonia and spastic quadriparesis, have been reported for this disorder [2–4]. Here we provide a report on a patient with MMA (mut0 phenotype) who presented brief tonic seizures despite fairly good maintenance therapy and we found that immunoglobulin was very effective for treating these seizures.
2. Case report The clinical course is shown in Fig. 1. This patient was born to healthy and unrelated parents after a full-term uncomplicated pregnancy, weighing 2.1 kg. He has a healthy brother. He was well until 23 days of age, when he developed poor feeding, tachypnea and loss of consciousness. Blood analysis revealed metabolic acidosis (pH 7.057, base excess 24.8 mmol/l) and hyperammonemia
H. Aikoh et al. / Brain & Development 19 (1997) 502–505
503
high intensity areas in the basal ganglia, which are often seen in MMA [6–8]. The auditory brainstem response was normal. Clonazepam (CZP) was partially effective for decreasing the frequency and duration of the seizures. Then intravenous administration of immunoglobulin (200 mg/kg per day for 5 consecutive days) was started and seizure frequency decreased immediately and stopped completely on the 5th day of this therapy. They never reappeared. Immunoglobulin therapy did not alter the amount of methylmalonic acid excreted. The EEG findings also improved. Polyspike bursts disappeared and sleep spindles were observed (Fig. 2b). The child’s psychomotor development also improved. At 2 years
Fig. 1. Schema of the clinical course.
(more than 400 mg/dl). He received peritoneal dialysis and exchange transfusion, and was given sodium bicarbonate and sodium benzoate. He consequently recovered from this attack. Organic acid analysis of urine measured high levels of methylmalonic acid, leading to a diagnosis of MMA. The standard therapy of orally administered vitamin B12 and l-carnitine, and protein restriction (1.2 g/kg per day) was then started. Vitamin B12 did not change methylmalonic acid excretion. Methylmalonyl CoA mutase activity was found to be completely absent (patient: 0; control: 1066 pmol/mg protein/min) in fibroblasts using the method of Ledley et al. [5], indicating the patient was mut0 subtype. Following this first attack, his psychomotor development was slow, e.g., head control at 7 months, rolling over at 8 months and sitting without support at 9 months of age. His general condition was stable and weight gain was fairly good (8 kg at 9 months). There was good control of blood gases (pH 7.40~7.35, BE 0~−5) and ammonia level (~100 mg/dl). No metabolic acidosis attack was observed thereafter. However, at 9 months of age, he developed brief individual tonic seizures approximately one every 30–60 min every day. Valproic acid (VPA) and nitrazepam (NZP) did not stop these seizures and their frequency increased and psychomotor regression also occurred. He lost the ability to sit without support and to maintain head control. He was admitted to hospital at 12 months, showing hypotonia. Neither spasticity nor involuntary movements were observed. He could not formulate any words and comprehension was also delayed. The tonic seizures did not come in clusters and lasted for a few seconds. They consisted of brief flexions of the extremities and neck, followed by brief extensions of the extremities. The seizures occurred about 20–30 times a day. Interictal EEG during wakefulness revealed diffuse polyspike bursts (Fig. 2a). Ictal EEG also showed diffuse polyspike bursts. Magnetic resonance (MR) imaging at 13 months of age showed mild cerebral atrophy, especially of the cerebral cortex, corpus callosum and pons (Fig. 3). Myelination was slightly delayed and there were no
Fig. 2. (a) Interictal EEG during wakefulness before immunoglobulin therapy frequently showed diffuse polyspike bursts. (b) EEG during sleep following immunoglobulin therapy reveals sleep spindles. Polyspike bursts have disappeared.
504
H. Aikoh et al. / Brain & Development 19 (1997) 502–505
Fig. 3. MR imagings at 13 months revealed mild cerebral atrophy, especially of the cerebral cortex, corpus callosum and pons. Myelination was slightly delayed and there were no high intensity areas in the basal ganglia ((a,b) axial T2-weighted images; (c) sagittal T1-weighted images).
of age, he could sit by himself, though he still showed mild hypotonia. He could not crawl. No spasticity was observed. He spoke no meaningful words, just jargon, and understood some words.
3. Discussion Seizures in patients with MMA are not uncommon during a ketoacidosis episode. Hyperammonemia also induces seizure disorders. However, convulsions in the chronic phase have not been commonly described in MMA [2–4]. Our patient showed brief tonic seizures. This seizure type resembled that seen in infantile spasms (West syndrome). However, EEG did not reveal hypsarrhythmia in this patient, it just showed diffuse polyspike bursts. These attacks started at 9 months of age and following the seizures, psychomotor deterioration was observed. It was probably the high methylmalonic acid levels, metabolic acidosis and/or hyperammonemia which induced this brain damage. It is possible that the cause of this type of seizure may be the same as that of West syndrome due to other metabolic disorders such as maple syrup disease or phenylketonurea. Basal ganglia are often involved in MMA, but MR imaging showed this not to be the case. Only mild brain atrophy in the cerebral cortex and pons was observed, indicating that the brain damage was probably not so severe. The effect of immunoglobulin treatment on infantile spasms or other types of epilepsy is occasionally positive in children [9,10]. Ariizumi et al. [9,10] used immunoglobulin on patients with infantile spasms or other intractable epilepsies. They administered immunoglobulin at 100–200 mg/kg of body weight at intervals of 2–3 weeks. We decided to use immunoglobulin at 200 mg/kg for 5 consecutive days in order to produce a rapid therapeutic effect. The seizures ceased on the 5th day of the therapy. The mechanisms by which immunoglobulin is effective in several types of seizures have not yet been completely elucidated. Since immunoglobulin did not alter the amount of
methylmalonic acid excreted, there must be some other factors which reduced the epileptic seizures. To our knowledge, there have been no previous reports that immunoglobulin is an effective treatment of epilepsy as caused by MMA. However, the fact that immunoglobulin was effective in this patient with MMA is important, as this implies that immunoglobulin therapy can be useful for treating some intractable seizures of metabolic origin.
Acknowledgements The authors are very grateful to Dr. Yozo Ichiba (National Okayama Children’s Hospital), Dr. Masato Ogasawara (Tohoku University), and Dr. Masaki Takayanagi (Chiba University) for their great help and suggestions regarding diagnosis and treatment.
References [1] Fenton WA, Rosenberg LE. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill, 1995:1423–1449. [2] Matsui SM, Mahoney MJ, Rosenberg LE. The natural history of the inherited methylmalonic acidemias. N Engl J Med 1983;308:857– 861. [3] Shevel MI, Matiaszuk N, Ledley FD, Rosenblatt DS. Varying neurological phenotypes among mut0 and mut − patients with methylmalonyl CoA mutase deficiency. Am J Med Genet 1993;45:619– 624. [4] van der Meer SB, Poggi F, Spada M, Bonnefont JP, Ogier H, Hubert P. et al. Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia. J Pediatr 1994; 125:903–908. [5] Ledley FD, Crane AM, Lumetta M. Heterogeneous alleles and expression of methylmalonyl CoA mutase in mut methylmalonic acidemia. Am J Hum Genet 1990;46:539–547. [6] Korf B, Wallman JK, Levy HL. Bilateral lucency of the globus pallidus complicating methylmalonic acidemia. Ann Neurol 1986;20:364–366.
H. Aikoh et al. / Brain & Development 19 (1997) 502–505 [7] Andreula CF, DeBlasi R, Carella A. CT and MR studies of methylmalonic acidemia. Am J Neuroradiol 1991;12:410–412. [8] Brismar J, Ozand PT. CT and MR of the brain in the diagnosis of organic acidemias. Experiences from 107 patients. Brain Dev 1994;16 (Suppl.):104–124. [9] Ariizumi M, Baba K, Shiihara H, Ogawa K, Hibio S, Suzuki Y. et al.
505
High dose gammaglobulin for intractable childhood epilepsy. Lancet 1983;8342:162–163. [10] Ariizumi M, Baba K, Hibio S, Shiihara H, Michihiro N, Ogawa K. et al. Immunoglobulin therapy in the West syndrome. Brain Dev 1987;9:422–425.