Pediatric Neurology xxx (2014) 1e3
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Two Infants With Infantile Spasms Associated With Vitamin B12 Deficiency Baris Malbora MD a, *, Deniz Yuksel MD b, Ayse Aksoy MD b, Mehpare Ozkan MD b a Department of Pediatric Hematology, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases, Ankara, Turkey b Department of Pediatric Neurology, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases, Ankara, Turkey
abstract BACKGROUND: In developing countries, nutritional vitamin B12 deficiency in infants because of maternal deficiency
often causes hematological and neurological disorders. However, epilepsy is a rare manifestation of vitamin B12 deficiency. The biological basis for the observed neurological symptoms of infantile vitamin B12 deficiency remains uncertain. There are only a few reports in the English literature regarding the relationship between infantile spasms and vitamin B12 deficiency. PATIENTS: We report two unrelated infants having infantile spasms associated with vitamin B12 deficiency related to maternal nutritional deficiency. RESULTS: On the first month of adrenocorticotropic hormone (ACTH), phenobarbital, and vitamin B12 treatments, both infants’ abnormalities resolved. After 3 months, electroencephaography was completely normal. ACTH and phenobarbital treatments were ended. Patients are disease-free for 9 months after the treatment. CONCLUSIONS: We suggest that, vitamin B12 deficiency should be considered in the differential diagnosis of infantile spasms as a treatable cause, especially with a history of maternal nutritional deficiency. Keywords: vitamin B12 deficiency, infantile spasms, seizure, treatment
Pediatr Neurol 2014; -: 1-3 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
In developing countries, nutritional vitamin B12 deficiency in infants because of maternal diet without adequate protein of animal origin has characteristic clinical features. It often causes hematological and neurological deficits including macrocytic anemia, neurodevelopmental delay or regression, irritability, weakness, hypotonia, ataxia, apathy, tremor, and seizure.1 Epilepsy is not a common manifestation of vitamin B12 deficiency in older children and adults, who develop more typical peripheral neuropathy, posterior column degeneration, cognitive impairment, psychotic disorder, and hypertension.2,3 There are only a
Article History: Received February 5, 2014; Accepted in final form March 2, 2014 * Communications should be addressed to: Dr. Baris Malbora; Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases; Babur Caddesi No: 44 (06080); Ankara, Turkey. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.03.001
few reports in English literature relating infantile spasms and vitamin B12 deficiency.4,5 We report two infants with infantile spasms because of vitamin B12 deficiency related to maternal nutritional deficiency. Patient descriptions A girl (Patient 1) and a boy baby (Patient 2) ages 7 and 8 months, respectively, were administered to the hospital, both of their abnormalities starting to occur at the age of 6 months, with a series of sudden flexions of the head, trunk, arms, and legs. Patient 1 is the seventh child of healthy parents and was born after an uncomplicated pregnancy with an uneventful delivery. Her parents are first-degree cousins. Patient 2 is the third child of healthy parents and was born after an uncomplicated pregnancy and an uneventful delivery. Family medical histories of both infants were unremarkable. The two families are unrelated. Both of the patients’ families’ income levels were quite low, and they consumed almost no animal originated food. Infants were exclusively breast-fed and received no vitamin supplementation. Motor skills and cognitive development of infants were delayed. Head circumferences of both infants were 25 to 50 percentiles. There were no organomegaly and dysmorphic features. Neurological examination of
2
B. Malbora et al. / Pediatric Neurology xxx (2014) 1e3
FIGURE. Electroencephaographies (EEGs) of patients. EEG at presentation revealed hypsarrhythmia: high voltages, disorganization, and frequent multifocal and generalized spikes (A, Patient 1 and B, Patient 2). Their EEGs became completely normal approximate 3 months after the treatment (C, Patient 1 and D, Patient 2). (The color version of this figure is available in the online edition.)
both infants revealed apathy and profound hypotonia with brisk deep tendon reflexes. They had head control; however, axial and peripheral tonus had slightly weakened. Laboratory findings of the Patient 1 were as follows: hemoglobin (Hb) level, 10.9 g/dL; mean corpuscular volume (MCV), 97 fL; leukocyte count, 10.2 109cells/L; platelet count, 412 109cells/L; vitamin B12 level, 113 pg/mL (normal range, 200-400); and serum homocystein level, 38.2 UM/ L (4.6-8.1). Her mother’s serum vitamin B12 level was 113 pg/mL. Laboratory analyses of the Patient 2 revealed Hb level, 8.4 g/dL; MCV, 101 fL; leukocyte count, 10.8 109cells/L; platelet count, 180 109cells/ L; vitamin B12 level, 56 pg/mL; and serum homocystein level, 189 UM/L. His mother’s serum vitamin B12 level was 54 pg/mL. Serum folic acid levels of both infants were normal. Electroencephalography (EEG) of babies indicated hypsarrhythmia (FigA,B), and they were diagnosed with infantile spasms. Blood chemistry values of both infants, including levels of serum lactate, pyruvate, ammonia, very long chain fatty acids, biotinidase activity, urine organic acids, and urine, blood, and cerebrospinal fluid aminoacids were within the reference range. Tandem mass spectrometry of the patients’ serum revealed no abnormalities of amino acids or acylcarnitine. Brain magnetic resonance imaging results of the patients were normal. Chromosome analyses of babies were normal. The patients were treated with intramuscular cyanocobalamin; 100 mg everyday for 1 week, then 100 mg every week for 4 weeks, and then 100 mg every month for 3 months. In addition, phenobarbital (6 mg/kg/day, twice a day, orally) and synthetic adrenocorticotropic hormone (ACTH; 40 IU/day) were administered intramuscular twice a
week (total of 16 doses). The mothers of patients were also treated with intramuscular cyanocobalamin. On the first month of treatment, patient’s serum vitamin B12 levels and hematologic parameters normalized. Patients did not have seizures. Their EEGs became completely normal approximate 3 months after the treatment (FigC,D), and neuromotor functions of the infants improved. After 3 months, ACTH and phenobarbital treatments were ended. Patients are disease-free for 9 months after the treatment.
Discussion
Infants need adequate vitamin B12 in breast milk to maintain vitamin B12 levels. In infancy, the most common cause of vitamin B12 deficiency is maternal dietary deficiency. It is generally observed in breast-fed infants whose mothers are strict vegetarians or who belong to a low socioeconomic status.1,6 Both of our patients’ families’ income levels were quite low, and they consumed little animal originated food. Both infants and their mothers had nutritional vitamin B12 deficiency. The neurological manifestations of vitamin B12 deficiency in infancy are well characterized through case studies. However, the biological basis for the observed signs
B. Malbora et al. / Pediatric Neurology xxx (2014) 1e3
of infantile vitamin B12 deficiency remains in question. Several mechanisms have been proposed, including delayed myelinization or demyelinization of nerves, alteration in the S-adenosyl methionine:S-adenosyl homocysteine ratio, imbalance of neurotrophic and neurotoxic cytokines, and accumulation of lactate in brain cells.7,8 Infantile spasms represent an age-dependent epilepsy that most frequently presents in the first year of life with ictal episodes consisting of spasms that usually occur in clusters. There is a characteristic chaotic and high-voltage interictal EEG pattern, which, when typical, is called hypsarrhythmia. Subgroups of the proven etiology group can be identified by classification into prenatal, perinatal, postnatal, and other. Hypoxic-ischemic encephalopathy, tuberous sclerosis complex, chromosomal disorders (Down syndrome, XXY, etc), cerebral malformations, infections (meningitis and encephalitis), metabolic disorders (phenylketonuria, organic acidurias, amino acidurias, and mitochondrial disorders), intracranial nontraumatic hemorrhage, and stroke.9,10 A relationship between vitamin B12 deficiency and infantile spasms is suggested by a few reports.4,5 Roschitz et al.5 described hypsarrhytmia in an infant with nutritional vitamin B12 deficiency and focal seizures; however, they did not characterize this patient as having infantile spasms. Similar to the patient in the report by Erol et al.,4 with ACTH, antiepileptic drug, and vitamin B12 treatment, our patients’ seizures had diminished and EEG findings had normalized. Following treatment with vitamin B12, the psychomotor developments are markedly improved, the seizures vanished and EEG findings became normal in both of the patients. In conclusion, vitamin B12 deficiency should be considered in the differential diagnosis of infantile spasms in the setting of severe maternal nutritional deficiency.
3
All authors planned and performed experiments and collaboratively wrote the manuscript. There is no potential conflict of interest to disclose.
References 1. Honzik T, Adamovicova M, Smolka V, Magner M, Hruba E, Zeman J. Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional vitamin B12 deficiencyewhat have we learned? Eur J Paediatr Neurol. 2010;14:488-495. 2. Roach ES, McLean WT. Neurologic disorders of vitamin b12 deficiency. Am Fam Physician. 1982;25:111-115. 3. Dogan M, Ariyuca S, Peker E, et al. Psychotic disorder, hypertension and seizures associated with vitamin B12 deficiency: a case report. Hum Exp Toxicol. 2012;31:410-413. 4. Erol I, Alehan F, Gümüs A. West syndrome in an infant with vitamin B12 deficiency in the absence of macrocytic anaemia. Dev Med Child Neurol. 2007;49:774-776. 5. Roschitz B, Plecko B, Huemer M, Biebl A, Foerster H, Sperl W. Nutritional infantile vitamin B12 deficiency: pathobiochemical considerations in seven patients. Arch Dis Child Fetal Neonatal Ed. 2005;90:281-282. 6. Zengin E, Sarper N, Caki Kilic S. Clinical manifestations of infants with nutritional vitamin B12 deficiency due to maternal dietary deficiency. Acta Paediatr. 2009;98:98-102. 7. Dror DK, Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev. 2008;66:250-255. 8. Nyaradi A, Li J, Hickling S, Foster J, Oddy WH. The role of nutrition in children’s neurocognitive development, from pregnancy through childhood. Front Hum Neurosci. 2013;26:97. 9. Osborne JP, Lux AL, Edwards SW, et al. The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification. Epilepsia. 2010;51:2168-2174. 10. Pavone P, Striano P, Falsaperla R, Pavone L, Ruggieri M. Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013. Brain Dev; 2013:S0387-S7604 (13) 00298-2.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Two Infants With Infantile Spasms Associated With Vitamin B12 Deficiency Baris Malbora MD a, *, Deniz Yuksel MD b, Ayse Aksoy MD b, Mehpare Ozkan MD b a Department of Pediatric Hematology, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases, Ankara, Turkey b Department of Pediatric Neurology, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases, Ankara, Turkey
abstract BACKGROUND: In developing countries, nutritional vitamin B12 deficiency in infants because of maternal deficiency
often causes hematological and neurological disorders. However, epilepsy is a rare manifestation of vitamin B12 deficiency. The biological basis for the observed neurological symptoms of infantile vitamin B12 deficiency remains uncertain. There are only a few reports in the English literature regarding the relationship between infantile spasms and vitamin B12 deficiency. PATIENTS: We report two unrelated infants having infantile spasms associated with vitamin B12 deficiency related to maternal nutritional deficiency. RESULTS: On the first month of adrenocorticotropic hormone (ACTH), phenobarbital, and vitamin B12 treatments, both infants’ abnormalities resolved. After 3 months, electroencephaography was completely normal. ACTH and phenobarbital treatments were ended. Patients are disease-free for 9 months after the treatment. CONCLUSIONS: We suggest that, vitamin B12 deficiency should be considered in the differential diagnosis of infantile spasms as a treatable cause, especially with a history of maternal nutritional deficiency. Keywords: vitamin B12 deficiency, infantile spasms, seizure, treatment
Pediatr Neurol 2014; -: 1-3 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
In developing countries, nutritional vitamin B12 deficiency in infants because of maternal diet without adequate protein of animal origin has characteristic clinical features. It often causes hematological and neurological deficits including macrocytic anemia, neurodevelopmental delay or regression, irritability, weakness, hypotonia, ataxia, apathy, tremor, and seizure.1 Epilepsy is not a common manifestation of vitamin B12 deficiency in older children and adults, who develop more typical peripheral neuropathy, posterior column degeneration, cognitive impairment, psychotic disorder, and hypertension.2,3 There are only a
Article History: Received February 5, 2014; Accepted in final form March 2, 2014 * Communications should be addressed to: Dr. Baris Malbora; Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases; Babur Caddesi No: 44 (06080); Ankara, Turkey. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.03.001
few reports in English literature relating infantile spasms and vitamin B12 deficiency.4,5 We report two infants with infantile spasms because of vitamin B12 deficiency related to maternal nutritional deficiency. Patient descriptions A girl (Patient 1) and a boy baby (Patient 2) ages 7 and 8 months, respectively, were administered to the hospital, both of their abnormalities starting to occur at the age of 6 months, with a series of sudden flexions of the head, trunk, arms, and legs. Patient 1 is the seventh child of healthy parents and was born after an uncomplicated pregnancy with an uneventful delivery. Her parents are first-degree cousins. Patient 2 is the third child of healthy parents and was born after an uncomplicated pregnancy and an uneventful delivery. Family medical histories of both infants were unremarkable. The two families are unrelated. Both of the patients’ families’ income levels were quite low, and they consumed almost no animal originated food. Infants were exclusively breast-fed and received no vitamin supplementation. Motor skills and cognitive development of infants were delayed. Head circumferences of both infants were 25 to 50 percentiles. There were no organomegaly and dysmorphic features. Neurological examination of
2
B. Malbora et al. / Pediatric Neurology xxx (2014) 1e3
FIGURE. Electroencephaographies (EEGs) of patients. EEG at presentation revealed hypsarrhythmia: high voltages, disorganization, and frequent multifocal and generalized spikes (A, Patient 1 and B, Patient 2). Their EEGs became completely normal approximate 3 months after the treatment (C, Patient 1 and D, Patient 2). (The color version of this figure is available in the online edition.)
both infants revealed apathy and profound hypotonia with brisk deep tendon reflexes. They had head control; however, axial and peripheral tonus had slightly weakened. Laboratory findings of the Patient 1 were as follows: hemoglobin (Hb) level, 10.9 g/dL; mean corpuscular volume (MCV), 97 fL; leukocyte count, 10.2 109cells/L; platelet count, 412 109cells/L; vitamin B12 level, 113 pg/mL (normal range, 200-400); and serum homocystein level, 38.2 UM/ L (4.6-8.1). Her mother’s serum vitamin B12 level was 113 pg/mL. Laboratory analyses of the Patient 2 revealed Hb level, 8.4 g/dL; MCV, 101 fL; leukocyte count, 10.8 109cells/L; platelet count, 180 109cells/ L; vitamin B12 level, 56 pg/mL; and serum homocystein level, 189 UM/L. His mother’s serum vitamin B12 level was 54 pg/mL. Serum folic acid levels of both infants were normal. Electroencephalography (EEG) of babies indicated hypsarrhythmia (FigA,B), and they were diagnosed with infantile spasms. Blood chemistry values of both infants, including levels of serum lactate, pyruvate, ammonia, very long chain fatty acids, biotinidase activity, urine organic acids, and urine, blood, and cerebrospinal fluid aminoacids were within the reference range. Tandem mass spectrometry of the patients’ serum revealed no abnormalities of amino acids or acylcarnitine. Brain magnetic resonance imaging results of the patients were normal. Chromosome analyses of babies were normal. The patients were treated with intramuscular cyanocobalamin; 100 mg everyday for 1 week, then 100 mg every week for 4 weeks, and then 100 mg every month for 3 months. In addition, phenobarbital (6 mg/kg/day, twice a day, orally) and synthetic adrenocorticotropic hormone (ACTH; 40 IU/day) were administered intramuscular twice a
week (total of 16 doses). The mothers of patients were also treated with intramuscular cyanocobalamin. On the first month of treatment, patient’s serum vitamin B12 levels and hematologic parameters normalized. Patients did not have seizures. Their EEGs became completely normal approximate 3 months after the treatment (FigC,D), and neuromotor functions of the infants improved. After 3 months, ACTH and phenobarbital treatments were ended. Patients are disease-free for 9 months after the treatment.
Discussion
Infants need adequate vitamin B12 in breast milk to maintain vitamin B12 levels. In infancy, the most common cause of vitamin B12 deficiency is maternal dietary deficiency. It is generally observed in breast-fed infants whose mothers are strict vegetarians or who belong to a low socioeconomic status.1,6 Both of our patients’ families’ income levels were quite low, and they consumed little animal originated food. Both infants and their mothers had nutritional vitamin B12 deficiency. The neurological manifestations of vitamin B12 deficiency in infancy are well characterized through case studies. However, the biological basis for the observed signs
B. Malbora et al. / Pediatric Neurology xxx (2014) 1e3
of infantile vitamin B12 deficiency remains in question. Several mechanisms have been proposed, including delayed myelinization or demyelinization of nerves, alteration in the S-adenosyl methionine:S-adenosyl homocysteine ratio, imbalance of neurotrophic and neurotoxic cytokines, and accumulation of lactate in brain cells.7,8 Infantile spasms represent an age-dependent epilepsy that most frequently presents in the first year of life with ictal episodes consisting of spasms that usually occur in clusters. There is a characteristic chaotic and high-voltage interictal EEG pattern, which, when typical, is called hypsarrhythmia. Subgroups of the proven etiology group can be identified by classification into prenatal, perinatal, postnatal, and other. Hypoxic-ischemic encephalopathy, tuberous sclerosis complex, chromosomal disorders (Down syndrome, XXY, etc), cerebral malformations, infections (meningitis and encephalitis), metabolic disorders (phenylketonuria, organic acidurias, amino acidurias, and mitochondrial disorders), intracranial nontraumatic hemorrhage, and stroke.9,10 A relationship between vitamin B12 deficiency and infantile spasms is suggested by a few reports.4,5 Roschitz et al.5 described hypsarrhytmia in an infant with nutritional vitamin B12 deficiency and focal seizures; however, they did not characterize this patient as having infantile spasms. Similar to the patient in the report by Erol et al.,4 with ACTH, antiepileptic drug, and vitamin B12 treatment, our patients’ seizures had diminished and EEG findings had normalized. Following treatment with vitamin B12, the psychomotor developments are markedly improved, the seizures vanished and EEG findings became normal in both of the patients. In conclusion, vitamin B12 deficiency should be considered in the differential diagnosis of infantile spasms in the setting of severe maternal nutritional deficiency.
3
All authors planned and performed experiments and collaboratively wrote the manuscript. There is no potential conflict of interest to disclose.
References 1. Honzik T, Adamovicova M, Smolka V, Magner M, Hruba E, Zeman J. Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional vitamin B12 deficiencyewhat have we learned? Eur J Paediatr Neurol. 2010;14:488-495. 2. Roach ES, McLean WT. Neurologic disorders of vitamin b12 deficiency. Am Fam Physician. 1982;25:111-115. 3. Dogan M, Ariyuca S, Peker E, et al. Psychotic disorder, hypertension and seizures associated with vitamin B12 deficiency: a case report. Hum Exp Toxicol. 2012;31:410-413. 4. Erol I, Alehan F, Gümüs A. West syndrome in an infant with vitamin B12 deficiency in the absence of macrocytic anaemia. Dev Med Child Neurol. 2007;49:774-776. 5. Roschitz B, Plecko B, Huemer M, Biebl A, Foerster H, Sperl W. Nutritional infantile vitamin B12 deficiency: pathobiochemical considerations in seven patients. Arch Dis Child Fetal Neonatal Ed. 2005;90:281-282. 6. Zengin E, Sarper N, Caki Kilic S. Clinical manifestations of infants with nutritional vitamin B12 deficiency due to maternal dietary deficiency. Acta Paediatr. 2009;98:98-102. 7. Dror DK, Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev. 2008;66:250-255. 8. Nyaradi A, Li J, Hickling S, Foster J, Oddy WH. The role of nutrition in children’s neurocognitive development, from pregnancy through childhood. Front Hum Neurosci. 2013;26:97. 9. Osborne JP, Lux AL, Edwards SW, et al. The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification. Epilepsia. 2010;51:2168-2174. 10. Pavone P, Striano P, Falsaperla R, Pavone L, Ruggieri M. Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013. Brain Dev; 2013:S0387-S7604 (13) 00298-2.
