Brief Communication
Isolated Cerebellar Involvement in Vitamin B12 Deficiency: A Case Report
Journal of Child Neurology 2014, Vol. 29(11) NP161-NP163 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813513498 jcn.sagepub.com
Biswaroop Chakrabarty, DM1, Rachana Dubey, MD1, Sheffali Gulati, MD1, Sangeetha Yoganathan, DM1, Ajay Kumar, MD1, and Atin Kumar, MD2
Abstract Deficiency of vitamin B12 causes megaloblastic anemia and nervous system demyelination. Structures affected in the nervous system include spinal cord, cranial and peripheral nerves, and brain white matter. A 9-year-old boy presented with knuckle hyperpigmentation and oral ulcers for 3 years, pallor and easy fatigability for 6 months, gait abnormalities for 3 months, and abnormal speech and behavioral abnormalities for 3 days. On examination, he had physical signs of megaloblastic anemia, mood swings with intermittent hallucinations, and features of cerebellar impairment. Blood investigations revealed megaloblastic anemia, and pernicious anemia was ruled out. Brain magnetic resonance imaging (MRI) revealed bilateral cerebellar signal changes. He received treatment for vitamin B12 deficiency and appropriate nutritional counseling. Three months later, he showed significant clinical and radiologic resolution. To our knowledge, isolated cerebellar involvement as the sole neurologic manifestation of vitamin B12 deficiency has not been described previously in children. Keywords vitamin B12 deficiency, nervous system demyelination, cerebellum, magnetic resonance imaging (MRI) brain Received September 20, 2013. Received revised October 10, 2013. Accepted for publication October 28, 2013.
Vitamin B12 deficiency has primarily 2 manifestations, megaloblastic anemia and nervous system demyelination. The common causes of deficiency in childhood include nutritional, pernicious anemia, malabsorption syndromes, and gastrointestinal surgeries.1 The common sites affected in the nervous system are the cervicothoracic dorsolateral columns of the spinal cord, the cranial and peripheral nerves, and brain white matter.2 Rarely cerebellar involvement with or without brain imaging corroboration has been described in adults with this condition.3-5 This case report describes a child aged 9 years with predominant cerebellar signs and imaging correlate in a case of vitamin B12 deficiency. To our knowledge, this finding in children has not been reported previously.
in chewing or swallowing, deviation of the angle of mouth, jerky eye movements, involuntary movements on action or at rest, recurrent infections, malabsorption, or any surgical procedure undergone in the past. At 2.5 years of age, he was diagnosed to have megaloblastic anemia; however, treatment compliance was poor. He also had significant food faddism and ate only bread, potato, and biscuits. He was breastfed until 3.5 years of age. Although the mother consumed nonvegetarian diet, her intake was low. She would rarely have red meat and fish (once in 2-3 months) and eggs (once a month). She never consumed milk. Salient features on general physical examination were a pale underweight boy with thin, sparse, hypopigmented, lusterless, and easily pluckable hair, hyperpigmented hands, feet, knuckles, and circumoral region, glossitis, petechial spots on the trunk region, gingival bleeds, and left retinal hemorrhage.
Case Summary A 9-year-old boy, first-born to nonconsanguineous parents, presented with progressive pigmentation of knuckles and recurrent oral ulcers for 3 years, progressive pallor, and easy fatigability for 6 months with 3 episodes of blood transfusion, unsteady gait for last 3 months, excessive lethargy, and slurred speech with intermittent mood swings and hallucinations for the last 3 days. There was no associated history of cognitive impairment, seizures, impaired vision or hearing, restricted eye movement, difficulty
1
Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India 2 Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India Corresponding Author: Sheffali Gulati, MD, Division of Pediatric Neurology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029 India. Email: [email protected]
Downloaded from jcn.sagepub.com at East Tennessee State University on June 6, 2015
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Journal of Child Neurology 29(11)
Figure 1. Brain magnetic resonance imaging (MRI): axial fluidattenuated inversion recovery images show hyperintense signal changes in bilateral cerebellar hemispheres.
Central nervous system examination revealed an irritable child with preserved cognition, mood swings and intermittent hallucinations, scanning dysarthria, normal cranial nerves, hypotonia, no apparent muscle weakness, hyporeflexia, intention tremor without dysmetria, negative Romberg sign, and broad-based gait. It was a limited examination as he would cooperate only occasionally because of his behavioral issues. Rest of the systemic examination was normal. On investigation, he was found to have macrocytic anemia, thrombocytopenia, low serum B12 level (50 mmol/L and 900 nmol/L, respectively), normal serum folate, no antibody to intrinsic factor type I and type II, nonreactive HIV serology, normal nerve conduction studies, mild atrophy with bilateral patchy hyperintensities in the cerebellum on T2-weighted and fluid-attenuated inversion recovery brain magnetic resonance imaging (MRI) images (Figure 1) with normal MRI of the spine and vitreal hemorrhage in the ultrasound B scan of the right eye. A final diagnosis of nutritional megaloblastic anemia was made. He was treated with daily doses of intramuscular 1000 mg vitamin B12 daily for 2 weeks, followed by weekly for 4 weeks and then monthly. A nutritionist and a psychologist counseled the child and parents and stressed on the dietary modifications that he has to follow in future. A week after initiation of treatment, his irritability subsided and visual hallucinations resolved. On follow-up after 3 months, his bleeding manifestations became passive, his hair and skin changes dramatically improved, and he had no behavioral issues, cerebellar or sensory symptoms, and signs. MRI of the brain revealed complete resolution of cerebellar signal changes (Figure 2). His repeat serum vitamin B12 levels were 758 pg/mL.
Discussion Neurologic manifestations of vitamin B12 deficiency usually manifest beyond the fourth decade of life. Two reasons can be cited for this; severity of neurologic symptoms show
Figure 2. Follow-up brain magnetic resonance imaging (MRI) after 3 months: axial fluid-attenuated inversion recovery images show complete resolution of the signal changes in the cerebellar hemispheres.
positive correlation with disease duration and the commonest cause of vitamin B12 deficiency worldwide, pernicious anemia, usually manifests later in life.1,6 The current case showed severe neurologic manifestations very early in life. Dietary deficiency, noncompliance, and unawareness were the primary issues made evident by the facts like prolonged breast feeding with inadequate intake of vitamin B12 by the mother, food faddism, and improper treatment compliance even when the condition was picked up early in life. A very wide spectrum of neurologic manifestations with vitamin B12 deficiency is described in childhood. These include developmental delay, cognitive decline, seizures, encephalopathy, psychiatric manifestations, spastic paraparesis, extrapyramidal features, and neuropathy.6,7 The current case was unique, as only psychiatric manifestations was present among the abovementioned features. Predominant cerebellar manifestations as seen in this case, to our knowledge, has not been previously described in a child with vitamin B12 deficiency. There are rare case reports of cerebellar involvement in vitamin B12 deficiency in patients beyond the fourth decade of life. Two of them had associated classical features of myelopathy and neuropathy. One patient, a 60-year-old woman, had prominent cerebellar features secondary to diffuse dysmyelination in middle cerebellar peduncles bilaterally, without any cord involvement.3-5 Classical radiologic features described with vitamin B12 deficiency are spinal cord (subacute combined degeneration) and brain (predominantly periventricular white matter) demyelination.3,5 Subacute combined degeneration primarily affects the dorsal and lateral columns of the spinal cord; however, rarely spinocerebellar and pyramidal tracts and cerebellum are also involved.3 The current case had isolated cerebellar involvement without any cord or cortical involvement. Studies have shown that isolated cerebellar pathology can manifest as neuropsychiatric symptoms when cerebellar afferents involving the cerebrocerebellar limbic pathway are affected, particularly in vermian lesions.8 The underlying mechanism for the neurologic manifestations of vitamin B12 deficiency are impaired DNA synthesis
Downloaded from jcn.sagepub.com at East Tennessee State University on June 6, 2015
Chakrabarty et al
NP163
and transcription, impaired genomic methylation and epigenetics, and homocysteine-mediated DNA damage.6 It has been reported that the cerebellum requires lower amounts of vitamin B12 as there is minimal protein carboxymethylation activity, implying that it has low stores of vitamin B12. Thus, the cerebellum may be more vulnerable to longstanding vitamin B12 deficiency.5 Various animal models related to the effects of vitamin B12 have been created. One of them have shown that N-methyl-D-aspartate (NMDA) and glutamate-mediated excitotoxic damage to the cerebellar granule neurons is ameliorated by vitamin B12.9 Recently, B12 has been shown to promote cerebellar granule cell neurite outgrowth by activating mammalian target of rapamycin pathway.10 This case describes reversible cerebellar involvement as the sole neurologic manifestation of vitamin B12 deficiency in a child. There were additional clinical clues like anemia, bleeding manifestations, and skin and hair changes. However, neurologic and hematologic manifestations can come in isolation in vitamin B12 deficiency.1,6 Thus, in a case of isolated cerebellar involvement, in relevant clinical and epidemiological settings, vitamin B12 deficiency state should always be considered as it is a treatable condition. Author Contributions BC and SY prepared the manuscript and provided clinical care to the patient. RD and AjK provided clinical care to the patient. AtK provided the radiologic inputs. The final manuscript was approved by all the authors. SG supervised the patient’s workup.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
References 1. Stabler SP. Vitamin B12 deficiency. N Engl J Med. 2013;368: 149-160. 2. Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Medicine. 1991;70: 229-245. 3. Katsaros VK, Glocker FX, Hemmer B, Schumacher M. MRI of spinal cord and brain lesions in subacute combined degeneration. Neuroradiology. 1998;40:716-719. 4. Ahn TB, Cho JW, Jeon BS. Unusual neurological presentations of vitamin B12 deficiency. Eur J Neurol. 2004;11:339-341. 5. Morita S, Miwa H, Kihira T, et al. Cerebellar ataxia and leukoencephalopathy associated with cobalamin deficiency. J Neurol Sci. 2003;216:183-184. 6. Reynolds E. Vitamin B12, folic acid and the nervous system. Lancet Neurol. 2006;5:949-960. 7. Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J. Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr. 1998;157:S77-S83. 8. Stoodley CJ, Schmahamman JD. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex. 2010;46:831-844. 9. Lin Y, Desbois A, Jiang S, Hou ST. Group B vitamins protect murine cerebellar granule cells from glutamate/NMDA toxicity. NeuroReport. 2004;15:2241-2244. 10. Okada K, Tanaka H, Temporin K, et al. Akt/mammalian target of rapamycin signaling pathway regulates neurite outgrowth in cerebellar granule neurons stimulated by methylcobalamin. Neurosci Lett. 2011;495:201-204.
Downloaded from jcn.sagepub.com at East Tennessee State University on June 6, 2015
Isolated Cerebellar Involvement in Vitamin B12 Deficiency: A Case Report
Journal of Child Neurology 2014, Vol. 29(11) NP161-NP163 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813513498 jcn.sagepub.com
Biswaroop Chakrabarty, DM1, Rachana Dubey, MD1, Sheffali Gulati, MD1, Sangeetha Yoganathan, DM1, Ajay Kumar, MD1, and Atin Kumar, MD2
Abstract Deficiency of vitamin B12 causes megaloblastic anemia and nervous system demyelination. Structures affected in the nervous system include spinal cord, cranial and peripheral nerves, and brain white matter. A 9-year-old boy presented with knuckle hyperpigmentation and oral ulcers for 3 years, pallor and easy fatigability for 6 months, gait abnormalities for 3 months, and abnormal speech and behavioral abnormalities for 3 days. On examination, he had physical signs of megaloblastic anemia, mood swings with intermittent hallucinations, and features of cerebellar impairment. Blood investigations revealed megaloblastic anemia, and pernicious anemia was ruled out. Brain magnetic resonance imaging (MRI) revealed bilateral cerebellar signal changes. He received treatment for vitamin B12 deficiency and appropriate nutritional counseling. Three months later, he showed significant clinical and radiologic resolution. To our knowledge, isolated cerebellar involvement as the sole neurologic manifestation of vitamin B12 deficiency has not been described previously in children. Keywords vitamin B12 deficiency, nervous system demyelination, cerebellum, magnetic resonance imaging (MRI) brain Received September 20, 2013. Received revised October 10, 2013. Accepted for publication October 28, 2013.
Vitamin B12 deficiency has primarily 2 manifestations, megaloblastic anemia and nervous system demyelination. The common causes of deficiency in childhood include nutritional, pernicious anemia, malabsorption syndromes, and gastrointestinal surgeries.1 The common sites affected in the nervous system are the cervicothoracic dorsolateral columns of the spinal cord, the cranial and peripheral nerves, and brain white matter.2 Rarely cerebellar involvement with or without brain imaging corroboration has been described in adults with this condition.3-5 This case report describes a child aged 9 years with predominant cerebellar signs and imaging correlate in a case of vitamin B12 deficiency. To our knowledge, this finding in children has not been reported previously.
in chewing or swallowing, deviation of the angle of mouth, jerky eye movements, involuntary movements on action or at rest, recurrent infections, malabsorption, or any surgical procedure undergone in the past. At 2.5 years of age, he was diagnosed to have megaloblastic anemia; however, treatment compliance was poor. He also had significant food faddism and ate only bread, potato, and biscuits. He was breastfed until 3.5 years of age. Although the mother consumed nonvegetarian diet, her intake was low. She would rarely have red meat and fish (once in 2-3 months) and eggs (once a month). She never consumed milk. Salient features on general physical examination were a pale underweight boy with thin, sparse, hypopigmented, lusterless, and easily pluckable hair, hyperpigmented hands, feet, knuckles, and circumoral region, glossitis, petechial spots on the trunk region, gingival bleeds, and left retinal hemorrhage.
Case Summary A 9-year-old boy, first-born to nonconsanguineous parents, presented with progressive pigmentation of knuckles and recurrent oral ulcers for 3 years, progressive pallor, and easy fatigability for 6 months with 3 episodes of blood transfusion, unsteady gait for last 3 months, excessive lethargy, and slurred speech with intermittent mood swings and hallucinations for the last 3 days. There was no associated history of cognitive impairment, seizures, impaired vision or hearing, restricted eye movement, difficulty
1
Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India 2 Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India Corresponding Author: Sheffali Gulati, MD, Division of Pediatric Neurology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029 India. Email: [email protected]
Downloaded from jcn.sagepub.com at East Tennessee State University on June 6, 2015
NP162
Journal of Child Neurology 29(11)
Figure 1. Brain magnetic resonance imaging (MRI): axial fluidattenuated inversion recovery images show hyperintense signal changes in bilateral cerebellar hemispheres.
Central nervous system examination revealed an irritable child with preserved cognition, mood swings and intermittent hallucinations, scanning dysarthria, normal cranial nerves, hypotonia, no apparent muscle weakness, hyporeflexia, intention tremor without dysmetria, negative Romberg sign, and broad-based gait. It was a limited examination as he would cooperate only occasionally because of his behavioral issues. Rest of the systemic examination was normal. On investigation, he was found to have macrocytic anemia, thrombocytopenia, low serum B12 level (50 mmol/L and 900 nmol/L, respectively), normal serum folate, no antibody to intrinsic factor type I and type II, nonreactive HIV serology, normal nerve conduction studies, mild atrophy with bilateral patchy hyperintensities in the cerebellum on T2-weighted and fluid-attenuated inversion recovery brain magnetic resonance imaging (MRI) images (Figure 1) with normal MRI of the spine and vitreal hemorrhage in the ultrasound B scan of the right eye. A final diagnosis of nutritional megaloblastic anemia was made. He was treated with daily doses of intramuscular 1000 mg vitamin B12 daily for 2 weeks, followed by weekly for 4 weeks and then monthly. A nutritionist and a psychologist counseled the child and parents and stressed on the dietary modifications that he has to follow in future. A week after initiation of treatment, his irritability subsided and visual hallucinations resolved. On follow-up after 3 months, his bleeding manifestations became passive, his hair and skin changes dramatically improved, and he had no behavioral issues, cerebellar or sensory symptoms, and signs. MRI of the brain revealed complete resolution of cerebellar signal changes (Figure 2). His repeat serum vitamin B12 levels were 758 pg/mL.
Discussion Neurologic manifestations of vitamin B12 deficiency usually manifest beyond the fourth decade of life. Two reasons can be cited for this; severity of neurologic symptoms show
Figure 2. Follow-up brain magnetic resonance imaging (MRI) after 3 months: axial fluid-attenuated inversion recovery images show complete resolution of the signal changes in the cerebellar hemispheres.
positive correlation with disease duration and the commonest cause of vitamin B12 deficiency worldwide, pernicious anemia, usually manifests later in life.1,6 The current case showed severe neurologic manifestations very early in life. Dietary deficiency, noncompliance, and unawareness were the primary issues made evident by the facts like prolonged breast feeding with inadequate intake of vitamin B12 by the mother, food faddism, and improper treatment compliance even when the condition was picked up early in life. A very wide spectrum of neurologic manifestations with vitamin B12 deficiency is described in childhood. These include developmental delay, cognitive decline, seizures, encephalopathy, psychiatric manifestations, spastic paraparesis, extrapyramidal features, and neuropathy.6,7 The current case was unique, as only psychiatric manifestations was present among the abovementioned features. Predominant cerebellar manifestations as seen in this case, to our knowledge, has not been previously described in a child with vitamin B12 deficiency. There are rare case reports of cerebellar involvement in vitamin B12 deficiency in patients beyond the fourth decade of life. Two of them had associated classical features of myelopathy and neuropathy. One patient, a 60-year-old woman, had prominent cerebellar features secondary to diffuse dysmyelination in middle cerebellar peduncles bilaterally, without any cord involvement.3-5 Classical radiologic features described with vitamin B12 deficiency are spinal cord (subacute combined degeneration) and brain (predominantly periventricular white matter) demyelination.3,5 Subacute combined degeneration primarily affects the dorsal and lateral columns of the spinal cord; however, rarely spinocerebellar and pyramidal tracts and cerebellum are also involved.3 The current case had isolated cerebellar involvement without any cord or cortical involvement. Studies have shown that isolated cerebellar pathology can manifest as neuropsychiatric symptoms when cerebellar afferents involving the cerebrocerebellar limbic pathway are affected, particularly in vermian lesions.8 The underlying mechanism for the neurologic manifestations of vitamin B12 deficiency are impaired DNA synthesis
Downloaded from jcn.sagepub.com at East Tennessee State University on June 6, 2015
Chakrabarty et al
NP163
and transcription, impaired genomic methylation and epigenetics, and homocysteine-mediated DNA damage.6 It has been reported that the cerebellum requires lower amounts of vitamin B12 as there is minimal protein carboxymethylation activity, implying that it has low stores of vitamin B12. Thus, the cerebellum may be more vulnerable to longstanding vitamin B12 deficiency.5 Various animal models related to the effects of vitamin B12 have been created. One of them have shown that N-methyl-D-aspartate (NMDA) and glutamate-mediated excitotoxic damage to the cerebellar granule neurons is ameliorated by vitamin B12.9 Recently, B12 has been shown to promote cerebellar granule cell neurite outgrowth by activating mammalian target of rapamycin pathway.10 This case describes reversible cerebellar involvement as the sole neurologic manifestation of vitamin B12 deficiency in a child. There were additional clinical clues like anemia, bleeding manifestations, and skin and hair changes. However, neurologic and hematologic manifestations can come in isolation in vitamin B12 deficiency.1,6 Thus, in a case of isolated cerebellar involvement, in relevant clinical and epidemiological settings, vitamin B12 deficiency state should always be considered as it is a treatable condition. Author Contributions BC and SY prepared the manuscript and provided clinical care to the patient. RD and AjK provided clinical care to the patient. AtK provided the radiologic inputs. The final manuscript was approved by all the authors. SG supervised the patient’s workup.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
References 1. Stabler SP. Vitamin B12 deficiency. N Engl J Med. 2013;368: 149-160. 2. Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Medicine. 1991;70: 229-245. 3. Katsaros VK, Glocker FX, Hemmer B, Schumacher M. MRI of spinal cord and brain lesions in subacute combined degeneration. Neuroradiology. 1998;40:716-719. 4. Ahn TB, Cho JW, Jeon BS. Unusual neurological presentations of vitamin B12 deficiency. Eur J Neurol. 2004;11:339-341. 5. Morita S, Miwa H, Kihira T, et al. Cerebellar ataxia and leukoencephalopathy associated with cobalamin deficiency. J Neurol Sci. 2003;216:183-184. 6. Reynolds E. Vitamin B12, folic acid and the nervous system. Lancet Neurol. 2006;5:949-960. 7. Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J. Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr. 1998;157:S77-S83. 8. Stoodley CJ, Schmahamman JD. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex. 2010;46:831-844. 9. Lin Y, Desbois A, Jiang S, Hou ST. Group B vitamins protect murine cerebellar granule cells from glutamate/NMDA toxicity. NeuroReport. 2004;15:2241-2244. 10. Okada K, Tanaka H, Temporin K, et al. Akt/mammalian target of rapamycin signaling pathway regulates neurite outgrowth in cerebellar granule neurons stimulated by methylcobalamin. Neurosci Lett. 2011;495:201-204.
Downloaded from jcn.sagepub.com at East Tennessee State University on June 6, 2015
