Pediatric Neurology
Volume 27, Issue 2 , Pages 85-92 , August 2002

Neurologic manifestations of iron deficiency in childhood

  • Jerome Y Yager, MD

      Affiliations

    • Department of Pediatrics; University of Saskatchewan; Saskatoon, Canada
    • Corresponding Author InformationCommunications should be addressed to: Dr. Yager; Room 3717; Royal University Hospital; 103 Hospital Drive; Saskatoon S7N 0W8, Canada.
  • ,
  • Dawn S Hartfield, MD

      Affiliations

    • Department of Pediatrics; University of Saskatchewan; Saskatoon, Canada

Received 16 October 2001 ,Accepted 21 March 2002.

References 

  1. Looker AC, Dallman PR, Carroll MD, Gunter MT, Johnson CL. Prevalence of iron deficiency in the United States. JAMA. 1997;277:973–976
  2. Oski FA. Iron deficiency in infancy and childhood. N Engl J Med. 1993;329:190–193
  3. Oski FA. The nonhematologic manifestations of iron deficiency. Am J Dis Child. 1979;133:315–322
  4. Prasad AN, Prasad C. Iron deficiency; non- hematological manifestations. Prog Food Nutr Sci. 1991;15:255–283
  5. Connor JR, Fine RE. Development of transferrin-positive oligodendrocytes in the rat central nervous system. J Neurosci Res. 1987;17:51–59
  6. Dwork AJ, Lawler G, Zybert PA, et al.  An autoradiographic study of the uptake and distribution of iron by the brain of the young rat. Brain Res. 1990;518:31–39
  7. Beard JL. Iron deficiency and neural development (An update). Arch Latinosam Nutr. 1999;49:34S–39S
  8. Hill JM, Switzer RC. The regional distribution and cellular localization of iron in the rat brain. Neuroscience. 1984;11:595–603
  9. Connor JR, Menzies SL. Relationship of iron to oligodendrocytes and myelination. Glia. 1996;17:83–89
  10. LeVine SM, Macklin WB. Iron-enriched oligodendrocytes (A reexamination of their spatial distribution). J Neurosci Res. 1990;26:508–512
  11. Barkai AI, Durkin M, Dwork AJ, Nelson HD. Autoradiographic study of iron-binding sites in the rat brain (Distribution and relationship to aging). J Neurosci Res. 1991;29:390–395
  12. Connor JR, Fine RE. The distribution of transferrin immunoreactivity in the rat central nervous system. Brain Res. 1986;368:319–328
  13. Connor JR, Phillips TM, Lakshman MR, Barron KD, Fine RE, Csiza CK. Regional variation in the levels of transferrin in the CNS of normal and myelin-deficient rats. J Neurochem. 1987;49:1523–1529
  14. Beard JL, Connor JD, Jones BC. Brain iron (Location and function). Prog Food Nutr Sci. 1993;17:183–221
  15. Swaiman KF. Hallervorden-Spatz syndrome. Pediatr Neurol. 2001;25:102–108
  16. Koeppen AH, Dickson AC. Iron in the Hallervorden-Spatz syndrome. Pediatr Neurol. 2001;25:148–155
  17. Lin HH, Connor JR. The development of the transferrin-transferrin receptor system in relation to astrocytes, MBP and galactocerebroside in normal and myelin-deficient rat optic nerves. Dev Brain Res. 1989;49:281–293
  18. Connor JR, Menzies SL. Altered cellular distribution of iron in the central nervous system of myelin deficient rats. Neuroscience. 1990;34:265–271
  19. Gerber MR, Connor JR. Do oligodendrocytes mediate iron regulation in the human brain?. Neurology. 1989;26:95–98
  20. Erikson KM, Pinero DJ, Connor JR, Beard JL. Regional brain iron, ferritin and transferrin concentrations during iron deficiency and iron repletion in developing rats. J Nutr. 1997;127:2030–2038
  21. Pinero DJ, Li NQ, Connor JR, Beard JL. Variations in dietary iron alter brain iron metabolism in developing rats. J Nutr. 2000;130:254–263
  22. Yu GSM, Steinkirchner TM, Rao GA, Larkin EC. Effect of prenatal iron deficiency on myelination in rat pups. Am J Pathol. 1986;125:620–624
  23. Taneja V, Mishra K, Agarwal KN. Effect of early iron deficiency in rat on the gamma-aminobutyric acid shunt in brain. J Neurochem. 1986;46:1670–1674
  24. Li D. Effects of iron deficiency on iron distribution and gamma-aminobutyric (GABA) metabolism in young rat brain tissues. Hokkaido J Med Sci. 1998;73:215–225
  25. Taneja V, Mishra KP, Agarwal KN. Effect of maternal iron deficiency on GABA shunt pathway of developing rat brain. Ind J Exp Bio. 1990;28:466–469
  26. Shukla A, Agarwal KN, Shukla GS. Latent iron deficiency alters gamma-aminobutyric acid and glutamate metabolism in rat brain. Experientia. 1989;45:343–345
  27. Ben-Schachar D, Ashkenazi R, Youdim MBH. Long-term consequence of early iron-deficiency on dopaminergic neurotransmission in rats. Int J Dev Neurosc. 1986;4:81–88
  28. Youdim MBH, Ben-Schachar D, Yehuda S. Putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behavior. Am J Clin Nutr. 1989;50:607–617
  29. Youdim MBH, Ben-Schachar D. Minimal brain damage induced by early iron deficiency (Modified dopaminergic neurotransmission). Isr J Med Sci. 1987;23:19–25
  30. Youdim MBH, Sills MA, Heydorn WE, Creed GJ, Jacobowitz DM. Iron deficiency alters discrete proteins in rat caudate nucleus and nucleus accumbens. J Neurochem. 1986;47:794–799
  31. Shukla A, Agarwal KN, Chansuria JPN, Taneja V. Effect of latent iron deficiency on 5-hydroxytryptamine metabolism in rat brain. J Neurochem. 1989;52:730–735
  32. Mackler B, Finch C. Iron in central nervous system oxidative metabolism. In:  Pollitt E,  Leibel RL editor. Iron deficiency (Brain biochemistry and behavior). New York: Raven Press; 1982;p. 31–38
  33. Adhami VM, Husain R, Husain R, Seth PK. Influence of iron deficiency and lead treatment on behavior and cerebellar and hippocampal polyamine levels in neonatal rats. Neurochem Res. 1996;21:915–922
  34. Moriarty PM, Picciano MF, Beard JL, Reddy CC. Classical selenium-dependent glutathione peroxidase expression is decreased secondary to iron deficiency in rats. J Nutr. 1995;125:293–301
  35. Rao R, deUngria M, Sullivan D, et al.  Perinatal brain iron deficiency increases the vulnerability of rat hippocampus to hypoxic ischemic insult. J Nutr. 1999;129:199–206
  36. Ruiz S, Walter T, Perez H, Stekel A, Hernandez A, Soto-Moyano R. Effect of early iron deficiency on reactivity of the rat parietal association cortex. Int J Neurosci. 1984;23:161–168
  37. Felt BT, Lozoff B. Brain iron and behavior of rats are not normalized by treatment of iron deficiency anemia during early development. J Nutr. 1996;126:693–701
  38. Yehuda S, Youdim MEH, Mostofsky DI. Brain iron-deficiency causes reduced learning capacity in rats. Pharmacol Biochem Behav. 1986;25:141–144
  39. Kwik-Uribe CL, Golub MS, Keen CL. Behavioral consequences of marginal iron deficiency during development in a murine model. Neurotoxicol Teratol. 1999;21:661–672
  40. Kwik-Uribe CL, Golub MS, Keen CL. Chronic marginal iron intakes during early development in mice alter brain iron concentrations and behavior despite postnatal iron supplementation. J Nutr. 2000;130:2040–2048
  41. Sun AH, Wang ZM, Xiao SZ, Li ZJ, Zheng Z, Li JY. Sudden sensorineural hearing loss induced by experimental iron deficiency in rats. ORL. 1992;54:246–250
  42. Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B. Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo (Delayed maturation of auditory brainstem responses). Am J Clin Nutr. 1998;68:683–690
  43. Lozoff B, Brittenham GM, Wolf AW, et al.  Iron deficiency anemia and iron therapy effects on infant developmental test performance. Pediatrics. 1987;79:981–995
  44. Lozoff B, Wolf AW, Jimenez E. Iron-deficiency anemia and infant development (Effects of extended oral iron therapy). J Pediatr. 1996;129:382–389
  45. Lozoff B, Jimenez E, Wolf AW. Long-term developmental outcome of infants with iron deficiency. N Engl J Med. 1991;325:687–694
  46. Lozoff B, Jimenez E, Hagen J, Mollen E, Wolf AW. Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Pediatrics. 2000;105:1–11
  47. Walter T, De Andraca I, Chadud P, Perales CG. Iron deficiency anemia (Adverse effects on infant psychomotor development). Pediatrics. 1989;84:7–17
  48. Walter T. Effect of iron-deficiency anaemia on cognitive skills in infancy and childhood. Baillieres Clin Haem. 1994;7:815–827
  49. Palti H, Meijer A, Adler B. Learning achievement and behavior at school of anemic and non-anemic infants. Early Hum Dev. 1985;10:217–223
  50. Hurtado EK, Claussen AH, Scott KG. Early childhood anemia and mild or moderate mental retardation. Am J Clin Nutr. 1999;69:115–119
  51. Lozoff B, Brittenham G, Viteri FE, Urrutia JJ. Behavioral abnormalities in infants with iron deficiency anemia. In:  Pollitt E,  Leibel RL editor. Iron deficiency (Brain biochemistry and behavior). New York: Raven Press; 1982;p. 183–194
  52. Lozoff B, Brittenham GM, Viteri FE, Wolf AW, Urrutia JJ. The effects of short-term oral iron therapy on developmental deficits in iron-deficient anemic infants. J Pediatr. 1982;100:351–357
  53. Lozoff B, Klein NK, Nelson EC, McClish DK, Manel M, Chacon ME. Behavior of infants with iron-deficiency anemia. Child Dev. 1998;69:24–36
  54. Deinard AS, List A, Lindgren B, Hunt JV, Chang PN. Cognitive deficits in iron-deficient and iron-deficient anemic children. J Pediatr. 1986;108:681–689
  55. Idjradinata P, Pollitt E. Reversal of developmental delays in iron-deficient anaemic infants treated with iron. Lancet. 1993;341:1–4
  56. Moffatt MEK, Longstaffe S, Besant J, Dureski C. Prevention of iron deficiency and psychomotor decline in high-risk infants through use of iron-fortified infant formula (A randomized clinical trial). J Pediatr. 1994;125:527–534
  57. Oski FA, Honig AS, Helu B, Howanitz P. Effect of iron therapy on behavior performance in nonanemic, iron-deficient infants. Pediatrics. 1983;71:877–880
  58. Deinard A, Gilbert A, Dodds M, Egeland B. Iron deficiency and behavioral deficits. Pediatrics. 1981;68:828–833
  59. Pollitt E, Saco-Pollitt C, Leibel RL, Viteri FE. Iron deficiency and behavioral development in infants and preschool children. Am J Clin Nutr. 1986;43:555–565
  60. Webb TE, Oski FA. Iron deficiency anemia and scholastic achievement in young adolescents. J Pediatr. 1973;82:827–830
  61. Halterman JS, Kaczorowski JM, Aligne CA, Auinger P, Szilagyi PG. Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States. Pediatrics. 2001;107:1381–1386
  62. Lanthier S, Carmant L, David M, Larbrisseau A, de Veber G. Stroke in children the coexistence of multiple risk factors predicts poor outcome. Neurology. 2000;54:371–378
  63. Cottrill CM, Kaplan S. Cerebral vascular accidents in cyanotic congenital heart disease. Am J Dis Child. 1973;125:484–487
  64. Perloff JK, Marelli AJ, Miner PD. Risk of stroke in adults with cyanotic congenital heart disease. Circulation. 1993;87:1954–1959
  65. Hartfield DS, Lowry NJ, Keene DL, Yager JY. Iron deficiency (A cause of stroke in infants and children). Pediatr Neurol. 1997;16:50–53
  66. Belman AL, Roque CT, Ancona R, Anand AK, Davis RP. Cerebral venous thrombosis in a child with iron deficiency anemia and thrombocytosis. Stroke. 1990;21:488–493
  67. Bruggers CS, Ware R, Altman AJ, Rourk MH, Vedanarayanan V, Chaffee S. Reversible focal neurologic deficits in severe iron deficiency anemia. J Pediatr. 1990;117:430–432
  68. Huttenlocher PR, Smith DB. Acute infantile hemiplegia associated with thrombocytosis. Dev Med Child Neurol. 1968;10:621–625
  69. Knizley H, Noyes WD. Iron deficiency anemia, papilledema, thrombocytosis, and transient hemiparesis. Arch Intern Med. 1972;129:483–486
  70. Kokkinos J, Levine SR. Thrombocytosis secondary to iron deficiency and recurrent cerebral ischemia possible improved by plateletpheresis. Cerebrovasc Dis. 1993;3:177–178
  71. Ready WK, Lowry NJ. Anemia causing cerebral infarction in a child. CMAJ. 1989;140:303–304
  72. Siekert RG, Whisnant JP, Millikan CH. Anemia and intermittent focal cerebral arterial insufficiency. Arch Neurol. 1960;3:386–391
  73. Stehle G, Buss J, Heene DL. Noninfectious thrombosis of the superior sagittal sinus in a patient with iron deficiency anemia. Stroke. 1990;21:414
  74. Swann IL, Kendra JR. Severe iron deficiency anaemia and stroke. Clin Lab Haem. 2000;22:221–223
  75. Young RSK, Rannels DE, Hilmo A, Gerson JM, Goodrich D. Severe anemia in childhood presenting as transient ischemic attacks. Stroke. 1983;14:622–623
  76. Karpatkin S, Garg SK, Freedman ML. Role of iron as a regulator of thrombopoiesis. Am J Med. 1974;57:521–525
  77. Colina KF, Abelson HT. Resolution of breath-holding spells with treatment of concomitant anemia. J Pediatr. 1995;126:395–397
  78. Daoud AS, Batieha A, Al-sheyyab M, Abuekteish F, Hijazi S. Effectiveness of iron therapy on breath-holding spells. J Pediatr. 1997;130:547–550
  79. Holowach J, Thurston DL. Breath-holding spells and anemia. N Engl J Med. 1963;268:21–23
  80. Bhatia MS, Singhal PK, Dhar NK, Nigam VR, Malik SC, Mullick DN. Breath holding spells (An analysis of 50 cases). Indian Pediatr. 1990;27:1073–1079
  81. Forster HS. Optic disc edema due to iron deficiency. Conn Med. 1985;49:290–292
  82. Parag KB, Omar MAK. Benign intracranial hypertension associated with iron deficiency anaemia. S Afr Med J. 1983;63:981–982
  83. Pless M, Lipton SA. Iron deficiency in children. N Engl J Med. 1993;329:1741
  84. Stoebner R, Kiser R, Alperin JB. Iron deficiency anemia and papilledema (Rapid resolution with oral iron therapy). Am J Dig Dis. 1970;15:919–922
  85. Trujillo MH, Desenne JJ, Benaim Pinto H. Reversible papilledema in iron deficiency anemia (Two cases with normal spinal fluid pressure). Ann Ophthalmol. 1972;4:378–380
  86. Tugal O, Jacobson R, Berezin S, et al.  Recurrent benign intracranial hypertension due to iron deficiency anemia (Case report and review of the literature). Am J Pediatr Hematol Oncol. 1994;16:266–270

PII: S0887-8994(02)00417-4

Pediatric Neurology
Volume 27, Issue 2 , Pages 85-92 , August 2002