Neurological Complications of Vitamin and Mineral Deficiencies

1. NEUROLOGICAL COMPLICATIONS OF
VITAMIN AND MINERAL DEFICIENCIES
ADE WIJAYA, MD – APRIL 2020

2. INTRODUCTION
 Vitamins and minerals have essential functions in the body
 Nutritional deficiencies and excess of certain vitamins and minerals can have profound effects on the
central and peripheral nervous systems from early development into adulthood
Polavarapu, A., & Hasbani, D. (2017, February). Neurological complications of nutritional disease. In Seminars in pediatric neurology (Vol. 24, No. 1, pp. 70-80). WB Saunders.

3. VITAMIN

4. VITAMIN A
 Acute intoxication presents with symptoms of headache, vomiting, diplopia, papilledema, and idiopathic
intracranial hypertension
 Chronic intoxication results in increased intracranial pressure, diplopia
 Teratogenic effects include hydrocephalus, microcephaly, optic nerve defects, and retinal defects
Swaiman, KF, Swaiman's pediatric neurology principles and practice. 2012, Elsevier Saunders,: Edinburgh. p. 1 online resource (2 volumes (xxiii, 1875, i107 pages)).
Rutkowski, M, Grzegorczyk, K: Adverse effects of antioxidative vitamins. Int J Occup Med Environ Health 25: 105-21; 2012.

5. VITAMIN B1 - THIAMINE
 A co-factor in oxidative decarboxylation and has an important function in the metabolism of
carbohydrates, lipids, and amino acids and in the synthesis of nucleotides, fatty acids, ATP, and
neurotransmitters
 It is also involved in myelin maintenance, neuronal membrane transport, and axonal conduction
 Early symptoms of thiamine deficiency are fatigue, depression, anorexia, abdominal discomfort,
peripheral neuropathy, and mental sluggishness
 The syndrome of nutritional thiamine deficiency is known as Beriberi. This manifests as neuronal
degeneration, peripheral nerve demyelination, and endothelial hyperplasia
 Periventricular gray matter hemorrhages, particularly around the third ventricle, Sylvian aqueduct, and
fourth ventricle and hemorrhage of the mammillary bodies can be seen
Swaiman, KF, Swaiman's pediatric neurology principles and practice. 2012, Elsevier Saunders,: Edinburgh. p. 1 online resource (2 volumes (xxiii, 1875, i107 pages)).
Chisolm-Straker, M, Cherkas, D: Altered and unstable: wet beriberi, a clinical review. J Emerg Med 45: 341-4; 2013.
Gliebus, G, Faerber, EN, Valencia, I, et al.: Ataxia, ophthalmoplegia, and impairment of consciousness in a 19-month-old American boy. Semin Pediatr Neurol 21: 139-43; 2014.

6. VITAMIN B1 - THIAMINE
 Chronic thiamine deficiency leads to Wernicke’s encephalopathy. This triad of confusion, ataxia, and
ophthalmoplegia
 Can evolve into Korsakoff’s syndrome, characterized by psychosis, confabulation, memory impairment,
seizures, and coma
Kopelman, MD, Thomson, AD, Guerrini, I, Marshall, EJ: The Korsakoff syndrome: clinical aspects, psychology and treatment. Alcohol Alcohol 44: 148-54; 2009.

7. VITAMIN B2 - RIBOFLAVIN
 The neurologic consequences of chronic B2 deficiency mostly relate to different patterns of neuropathy
Swaiman, KF, Swaiman's pediatric neurology principles and practice. 2012, Elsevier Saunders,: Edinburgh. p. 1 online resource (2 volumes (xxiii, 1875, i107 pages)).

8. VITAMIN B3 - NIACIN
 Pellagra: classic triad involves dermatitis, diarrhea, and dementia
 Nervous system complications are headache, insomnia, depression, memory issues, delusions,
hallucinations, confusion, and even coma
 Peripheral nerve involvement and childhood learning disabilities are other less common neurologic signs
of niacin deficiency
Swaiman, KF, Swaiman's pediatric neurology principles and practice. 2012, Elsevier Saunders,: Edinburgh. p. 1 online resource (2 volumes (xxiii, 1875, i107 pages)).
Barsell, A, Norton, SA: Pellagra's Three Ds: Dermatology, Death, and Dracula. JAMA Dermatol 151: 951; 2015.

9. VITAMIN B6 - PYRIDOXINE
 Vitamin B6 deficiency can have effects on both the central and peripheral nervous systems
 Infants with dietary B6 deficiency can present with seizures, irritability, and exaggerated startle response
 Isoniazid treatment for tuberculosis can result in peripheral neuropathy secondary to vitamin B6
deficiency
 Interestingly, excess B6 can also cause peripheral neuropathy, characterized by a pure sensory
neuropathy or neuronopathy with sensory ataxia
 Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive disorder caused by mutations in the
ALDH7A1 gene leading to decreased antiquitin protein. Antiquitin is involved in the cerebral lysine
catabolism pathway. Classically, neonates present within the first few hours of life with refractory
seizures.
Polavarapu, A., & Hasbani, D. (2017, February). Neurological complications of nutritional disease. In Seminars in pediatric neurology (Vol. 24, No. 1, pp. 70-80). WB Saunders.

10. VITAMIN B12
 Vitamin B12 is intricately involved in DNA synthesis, production of myelin and neurotransmitters
 Psychiatric symptoms include dementia, memory impairment, and attention deficits.
 In many cases, neurologic complications may be the only manifestation of the deficiency.
 Encephalopathy, myelopathy, and peripheral neuropathy are typical, but cranial neuropathies such as
optic neuropathy can also be seen
 In infants, neurologic symptoms of B12 deficiency can include irritability, failure to thrive, developmental
regression, optic nerve atrophy, hypotonia, movement disorders, and even coma
Swaiman, KF, Swaiman's pediatric neurology principles and practice. 2012, Elsevier Saunders,: Edinburgh. p. 1 online resource (2 volumes (xxiii, 1875, i107 pages)).
MJ, AAaK: Recovery of neurologic dysfunction with early intervention of vitamin B12. - PubMed - NCBI. 2016.
Briani C , ea: Cobalamin deficiency: clinical picture and radiological findings. - PubMed - NCBI. 2016.

11. VITAMIN C
 Neurodevelopmental and neuropsychiatric disorders such as autism
 Severe intracranial and orbital hemorrhages can also occur
Agarwal, A, Shaharyar, A, Kumar, A, et al.: Scurvy in pediatric age group – A disease often forgotten? J Clin Orthop Trauma 6: 101-7; 2015.
Gupta, S, Kanojia, R, Jaiman, A, Sabat, D: Scurvy: An unusual presentation of cerebral palsy. World J Orthop 3: 58-61; 2012.

12. VITAMIN D
 Vitamin D receptors are found in the central nervous system and are expressed as early as day 12 of
gestation in the mesencephalon
 The increasing rates of Multiple Sclerosis (MS)
Eyles, DW, Feron, F, Cui, X, et al.: Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology 34 Suppl 1: S247- 57; 2009.
Harms, LR, Burne, TH, Eyles, DW, McGrath, JJ: Vitamin D and the brain. Best Pract Res Clin Endocrinol Metab 25: 657-69; 2011.

13. VITAMIN E
 Progressive weakness, ataxia, ophthalmoplegia, large fiber sensory loss, visual impairment and retinitis
pigmentosa
 Neurologic symptoms are due to cerebellar atrophy, neuron loss in the third and fourth cranial nerve
nuclei, axonal dystrophy in the spinal cord, and lipofuscin accumulation in peripheral nerves
Swaiman, KF, Swaiman's pediatric neurology principles and practice. 2012, Elsevier Saunders,: Edinburgh. p. 1 online resource (2 volumes (xxiii, 1875, i107 pages)).

14. BIOTIN AND VITAMIN K
 Biotin: Developmental delay, seizures, hearing loss, ataxia, and hypotonia
 Vitamin K: Vitamin K deficiency bleeding (VKDB)  intracranial hemorrhage
Baumgartner, MR: Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E. Handb Clin Neurol 113: 1799-810; 2013
Lauer, B, Spector, N: Vitamins. Pediatr Rev 33: 339-51; quiz 351-2; 2012.

15. FOLIC ACID
 Folic acid plays an essential role in neurotransmitter methylation, and myelin synthesis and degradation
 Neurologic symptoms include mood disorders in adults and dementia that resembles Alzheimer’s
disease
 Folic acid deficiency during pregnancy is a well-known risk factor for neural tube defects in the fetus.
Malouf, M, Grimley, EJ, Areosa, SA: Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev CD004514; 2003.
De-Regil, LM, Peña-Rosas, JP, Fernández-Gaxiola, AC, Rayco-Solon, P: Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Syst Rev CD007950; 2015

16. MINERAL

17. CALCIUM
 Calcium is an essential player in signal transduction along the neuronal membrane and nerve terminal
and in other cellular processes including apoptosis
 The release of calcium from the sarcoplasmic reticulum is required for muscle contraction
 Acute hypocalcemia can lead to neuromuscular hyperexcitability which can manifest as tetany and
Chvostek and Trousseau signs
 Altered mental status and seizures may also occur. Hypocalcemic seizures may be generalized tonic-
clonic, focal, absence, or rarely atonic and status epilepticus has been documented
 Seizures may also result from hypercalcemia, though this is less common than with hypocalcemia. A
rapid increase in calcium levels is thought to cause hypertensive encephalopathy and vasoconstriction,
leading to seizures, weakness, and confusion.
 Hypercalcemia – Fahr Disease
Nardone, R, Brigo, F, Trinka, E: Acute Symptomatic Seizures Caused by Electrolyte Disturbances. J Clin Neurol 12: 21-33; 2016.
Dusek, P, Litwin, T, Czlonkowska, A: Wilson disease and other neurodegenerations with metal accumulations. Neurol Clin 33: 175-204; 2015.

18. MAGNESIUM
 Magnesium is the second most abundant intracellular cation in the body and has wide-ranging
biological roles including cellular energy metabolism, nerve conduction, membrane stability, and
synaptic transmission
 Neurological symptoms of hypomagnesemia are similar to those for hypocalcemia and include tetany,
Trousseau and Chvostek signs, weakness, psychosis, vertigo, ataxia, and depression. Hypomagnesemia is
thought to alter intracellular calcium levels and increase excitability of neurons and muscle
 Hypermagnesemia usually results from iatrogenic administration in the form of intravenous magnesium
or antacids. Clinical symptoms include hypotension, bradycardia, encephalopathy, and respiratory
depression
Weisinger, JR, Bellorín-Font, E: Magnesium and phosphorus. Lancet 352: 391-6; 1998.

19. IODINE
 Iodine is essential in the synthesis of thyroid hormones which are essential for neurogenesis, neuronal
migration, synaptogenesis, and myelination
 Congenital hypothyroidism causes cretinism, characterized by severe cognitive impairment, abnormal
facies, visual impairment, and cerebral palsy
 Mild iodine deficiency can result in delays in fine motor skills and deficits in abstract thinking, problem
solving, and visuomotor planning
 Severe deficiency can result in lowered intelligence quotients
 Chronic hypothyroidism is associated with epilepsy, dementia, and depression
Prado, EL, Dewey, KG: Nutrition and brain development in early life. Nutr Rev 72: 267-84; 2014.
Spencer, PS, Palmer, VS: Interrelationships of undernutrition and neurotoxicity: food for thought and research attention. Neurotoxicology 33: 605-16; 2012.
Eastman, C, Zimmermann, M, The Iodine Deficiency Disorders, L. De Groot, et al., Editors. 2014: South Dartmouth (MA).

20. ZINC
 Zinc is critical for the differentiation of neurons, especially stellate, basket, Purkinje, and cerebellar
granule cells
 Zinc receptors are found in high concentrations in the cerebral cortex, dentate gyrus, hippocampus, and
amygdala
 Neuronal excitation is also regulated by zinc through the increase of AMPA receptors on postsynaptic
membranes
 Zinc deficiency has been shown in animal to result in abnormal neurogenesis and brain maturation
 Dysregulation of zinc homeostasis has been postulated to play a role in diseases such as Attention
Deficit Hyperactivity Disorder, Alzheimer’s Disease, Parkinson’s Disease, and traumatic brain injury,
possibly through its role in excitotoxic cascades.
 Zinc overdose is rare but has been reported to cause lethargy and focal neurologic deficits
Tyszka-Czochara, M, Grzywacz, A, Gdula-Argasińska, J, et al.: The role of zinc in the pathogenesis and treatment of central nervous system (CNS) diseases. Implications of zinc homeostasis for proper CNS function. Acta Pol Pharm 71: 369-77; 2014.
Takeda, A, Tamano, H: Significance of the degree of synaptic Zn2+ signaling in cognition. Biometals 29: 177-185; 2015.

21. COPPER
 Copper deficiency can cause a myelopathy
 Copper deficiency can also cause a peripheral axonal sensorimotor neuropathy and rarely optic
neuropathy
 Copper accumulation: Wilson’s disease
Goodman, BP: Metabolic and toxic causes of myelopathy. Continuum (Minneap Minn) 21: 84-99; 2015.
Bandmann, O, Weiss, KH, Kaler, SG: Wilson's disease and other neurological copper disorders. Lancet Neurol 14: 103-13; 2015.

22. IRON
 Iron plays role in the myelin synthesis and neurotransmitter activity
 Iron deficiency has been associated with other neurologic conditions including stroke, breath holding
spells, idiopathic intracranial hypertension, and restless leg syndrome
Yager, JY, Hartfield, DS: Neurologic manifestations of iron deficiency in childhood. Pediatr Neurol 27: 85-92; 2002.

23. SELENIUM
 Selenium does seem to be important for neuronal function as evidenced by mouse models in which
deficiency of selenoprotein P, which transports selenium to various organs, leads to seizures and
movement disorders
 Mutations in selenoprotein N cause a genetic myopathy known as SEPN1-related myopathy. Symptoms
are hypotonia, mild muscle weakness, spine rigidity, scoliosis, and respiratory insufficiency.
 SEPSECS syndrome, which was previously known as progressive cerebellocerebral atrophy, is an
autosomal recessive genetic disease caused by a mutation of selenocysteine synthase gene, affecting
selenoprotein synthesis. This syndrome manifests with neurodegeneration, microcephaly, spasticity,
profound intellectual disability, and epilepsy
Schweizer, U, Fradejas-Villar, N: Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism. FASEB J 2016.

24. MANGANESE
 Manganism:
Early disease manifests as psychiatric symptoms, with mania, violent behavior, emotional lability, sleep or
eating disturbances, and hallucinations.
Established manganism results in extrapyramidal dysfunction, movement abnormalities, dystonia,
dysarthria, parkinsonism, and a typical high-stepping gait known as “cock walk”.
Pathology is due to accumulation of manganese in the basal ganglia, with the highest levels of
accumulation in the globuspallidus
Bouabid, S, Tinakoua, A, Lakhdar-Ghazal, N, Benazzouz, A: Manganese Neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission. J Neurochem 2015.

25. SUMMARY
 Adequate nutrition is essential for the developing and ongoing function of the nervous system in
children and adults.
 Inadequate intake, systemic diseases, genetic conditions and medical therapies can lead to deficiencies
of specific nutrients.

26. THANK YOU