Medicine:Megavitamin-B6 syndrome

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Short description: Syndrome marked by sensory neuropathy induced by excess vitamin B6


Template:Infobox medical conditions

Megavitamin-B6 syndrome is a collection of symptoms that can result from chronic supplementation, or acute overdose, of vitamin B6.[1][2][3] While it is also known as hypervitaminosis B6, vitamin B6 toxicity and vitamin B6 excess, megavitamin-b6 syndrome is the name used in the ICD-10.[4][5][6][lower-alpha 1]

Signs and symptoms

The predominant symptom is peripheral sensory neuropathy[13][1][2][14] that is experienced as numbness, pins-and-needles and burning sensations (paresthesia) in a patient's limbs on both sides of their body.[15][1][16][17] Patients may experience unsteadiness of gait, incoordination (ataxia),[17][18][1][19] involuntary muscle movements (choreoathetosis)[20] the sensation of an electric zap in their bodies (Lhermitte's sign),[17] a heightened sensitivity to sense stimuli including photosensitivity (hyperesthesia),[1][18] impaired skin sensation (hypoesthesia),[21][15] numbness around the mouth,[21][22] and gastrointestinal symptoms such as nausea and heartburn.[18][23] The ability to sense vibrations and to sense one's position are diminished to a greater degree than pain or temperature.[21][22] Skin lesions have also been reported.[18][19][24][23] Megavitamin-B6 syndrome may also contribute to burning mouth syndrome.[25][26] Potential psychiatric symptoms range from anxiety, depression, agitation, and cognitive deficits to psychosis.[27]

Symptom severity appears to be dose-dependent (higher doses cause more severe symptoms)[18] and the duration of supplementation with vitamin B6 before onset of systems appears to be inversely proportional to the amount taken daily (the smaller the daily dosage, the longer it will take for symptoms to develop).[17][1][20][10][28] It is also possible that some individuals are more susceptible to the toxic effects of vitamin B6 than others.[1] Megavitamin-B6 syndrome has been reported in doses as low as 24 mg/day.[29]

Symptoms may also be dependent on the form of vitamin B6 taken in supplements.[14][30] It has been proposed that vitamin B6 in supplements should be in pyridoxal or pyridoxal phosphate form rather than pyridoxine as these are thought to reduce the likelihood of toxicity.[14][31] A tissue culture study, however, showed that all B6 vitamers that could be converted into active coenzymes (pyridoxal, pyridoxine and pyridoxamine) were neurotoxic at similar concentrations.[8][32] It has been shown, in vivo, that supplementing with pyridoxal or pyridoxal phosphate increases pyridoxine concentrations in humans, meaning there are metabolic pathways from each vitamer of B6 to the all other forms.[33][34] Consuming high amounts of vitamin B6 from food has not been reported to cause adverse effects.[18][24][35]

Early diagnosis and cessation of vitamin B6 supplementation can reduce the morbidity of the syndrome.[18][10]

Cause

While vitamin B6 is water-soluble, it has a half-life of 25–33 days and accumulates in the body, where it is stored in muscle, plasma, the liver, red blood cells and bound to proteins in tissues.[36][35][37]

Potential mechanisms

The common supplemental form of vitamin B6, pyridoxine, is similar to pyridine, which can be neurotoxic. Pyridoxine has limited transport across the blood–brain barrier, explaining why the central nervous system is spared. Cell bodies of motor fibers are located within the spinal cord, which is also restricted by the blood-brain barrier, explaining why motor impairment is rare. The dorsal root ganglia, however, are located outside of the blood-brain barrier making them more susceptible.[21]

Pyridoxine is converted to pyridoxal phosphate via two enzymes, pyridoxal kinase and pyridoxine 5′-phosphate oxidase. High levels of pyridoxine can inhibit these enzymes. As pyridoxal phosphate is the active form of vitamin B6 this saturation of pyridoxine could mimic a deficiency of vitamin B6.[21][14]

Tolerable upper limits

Several government agencies have reviewed the data on vitamin B6 supplementation and produced consumption upper limits with the desired goal to prevent sensory neuropathy from excessive amounts. Each agency developed its own criteria for usable studies in relation to tolerable upper limits, and as such the recommendations vary by agency. Between agencies, current tolerable upper limit guidelines vary from 10 mg per day to 100 mg per day.[35]

Daily vitamin B6 tolerable upper limits for adults as established by the agency
Agency Upper limit Notes Reference
National Health Service (NHS) United Kingdom 10 mg/day [38]
Norwegian Scientific Committee for Food and Environment (VKM) 25 mg/day In 2017 VKM proposed to raise this to 25 mg/day, it was previously 4.2 mg/day. [35]
Netherlands Food and Consumer Product Safety Authority [nl] (NVWA) 25 mg/day Supplements may only contain dosages of 21 mg/day. [39]
European Food Safety Authority 25 mg/day [40]
Ministry of Health, Labour and Welfare (厚生労働省, Kōsei-rōdō-shō) Japan 40–60 mg/day The adult UL was set at 40–45 mg/day for women and 50–60 mg/day for men, with the lower values in those ranges for adults over 70 years of age [41]
National Health and Medical Research Council (NHMRC) Australia 50 mg/day [42]
U.S. Institute of Medicine - Food and Nutrition Board 100 mg/day [18]

Reviews of vitamin B6 related neuropathy cautioned that supplementation at doses greater than 50 mg per day for extended periods of time may be harmful and should be discouraged.[43][44] In 2008, the Australian Complementary Medicines Evaluation Committee recommended warning statements appear on products containing daily doses of 50 mg or more vitamin B6 to avoid toxicity.[45]

The relationship between the amount of vitamin B6 consumed, and the serum levels of those who consume it, varies between individuals.[46] Some people may have high serum concentrations without symptoms of neuropathy.[16][47][48] It is not known if inhalation of vitamin B6 while, for example, working with animal feed containing vitamin B6 is safe.[49]

Exceptions

High parenteral doses of vitamin B6 are used to treat isoniazid overdose with no adverse effects found,[1] although a preservative in parenteral vitamin B6 may cause transient worsening of metabolic acidosis.[1] High doses of vitamin B6 are used to treat gyromitra mushroom (false morel) poisoning, hydrazine exposure and homocystinuria[50][51] Doses of 50 mg to 100 mg per day may also be used to treat pyridoxine deficient seizures and when patients are taking other medications that reduce vitamin B6.[15] Daily doses of 10 mg to 50 mg are recommended for patients undergoing hemodialysis.[15]

Outside of rare medical conditions, placebo-controlled studies have generally failed to show benefits of high doses of vitamin B6.[23] Reviews of supplementing with vitamin B6 have not found it to be effective at reducing swelling, reducing stress, producing energy, preventing neurotoxicity, or treating asthma.[21]

Diagnosis

The clinical hallmark of megavitamin-B6 syndrome is ataxia due to sensory polyneuropathy. Blood tests are performed to rule out other causes and to confirm an elevated level of vitamin B6 with an absence of hypophosphatasia.[15][52][10][53][54] Examination does not typically show signs of a motor deficit, dysfunction of the autonomic nervous system or impairment of the central nervous system,[1][22] although in severe cases motor and autonomic imparement can occur.[15][10][55] When examined, patients typically have diminished reflexes (hyporeflexia), such as a diminished response when performing an ankle jerk reflex test.[15][13][22] Nerve conduction studies typically show normal motor conduction but a decrease in large sensory wave amplitude in the arms and legs.[13][20][15][16][22] Needle electromyography studies generally reveal no signs of denervation.[17]

Classification

Megavitamin-B6 syndrome is characterized mainly by degeneration of dorsal root ganglion axons and cell bodies,[56][8][21][10][20][11] although it also affects the trigeminal ganglia.[21][22] It is classified as a sensory ganglionopathy due to involvement of these ganglia.[57][lower-alpha 2] In electrodiagnostic testing, it has characteristic non-length-dependent abnormalities of sensory action potentials that occur globally, rather than distally decreasing of sensory nerve action potential amplitudes.[53] Megavitamin-B6 syndrome is predominately a large fiber neuropathy characterized by sensory loss of joint position, vibration and ataxia.[8][13] Although it has characteristics of small fiber neuropathy in severe cases where there is impairment of pain, temperature, and autonomic functions.[58][59][15][10][55][60][7]

Treatment

The primary treatment for megavitamin-B6 syndrome is to stop taking supplemental vitamin B6.[15] Physical therapy, including vestibular rehabilitation, has been used in attempts to improve recovery following cessation of vitamin B6 supplementation.[45][52] Medications such as amitriptyline have been used to help with neuropathic pain.[9]

In experimental tests using animal subjects, neurotrophic factors, specifically neurotrophin-3, were shown to potentially reverse the neuropathy caused from the vitamin B6 toxicity.[1][8] With rats and mice, improvement has also been seen with 4-methylcatechol, a specific chicory extract, coffee and trigonelline.[61][62][63]

Prognosis

Other than with extremely high doses of vitamin B6, neurologic dysfunction improves following cessation of vitamin B6 supplementation and usually, but not always, resolves within six months.[22][1] In cases of acute high doses, for example in people receiving daily doses of 2 grams of vitamin B6 per kilogram of body weight, symptoms may be irreversible and may additionally cause pseudoathetosis.[22][17][9][64][2][50]

In the immediate 2–6 weeks following discontinuation of vitamin B6, patients may experience a symptom progression before gradual improvement begins. This is known as coasting and is encountered in other toxic neuropathies.[15][1][17][64] A vitamin B6 substance dependency may exist in daily dosages of 200 mg or more, making a drug withdrawal effect possible when discontinued.[21]

See also


Notes

  1. ↑ While megavitamin-B6 syndrome, hypervitaminosis B6, vitamin B6 toxicity and vitamin B6 excess are officially recognized, terms for this in literate vary. Often vitamin B6 and its most common supplemental vitamer, pyridoxine, are used interchangeably. Some other terms include vitamin B6 overdose,[7] pyridoxine abuse,[8][9] pyridoxine megavitamosis,[10] pyridoxine poisoning,[11] and pyridoxine neuropathy.[12]
  2. ↑ The terms sensory ganglionopathy and sensory neuronopathy are interchangeable.[57]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 Lheureux, P.; Penaloza, A.; Gris, M. (2005). "Pyridoxine in clinical toxicology: A review". European Journal of Emergency Medicine 12 (2): 78–85. doi:10.1097/00063110-200504000-00007. PMID 15756083. 
  2. ↑ 2.0 2.1 2.2 James W. Albers; Stanley Berent (15 August 2005). Neurobehavioral Toxicology: Neurological and Neuropsychological Perspectives, Volume II: Peripheral Nervous System. Taylor & Francis. pp. 2–. ISBN 978-1-135-42106-9. https://books.google.com/books?id=sPB4AgAAQBAJ&pg=PT2. 
  3. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named SilvaDCruz2006
  4. ↑ de Onis, Mercedes; Zeitlhuber, Julia; Martínez-Costa, Cecilia (2016). "Nutritional disorders in the proposed 11th revision of the International Classification of Diseases: feedback from a survey of stakeholders". Public Health Nutrition 19 (17): 3135–3141. doi:10.1017/S1368980016001427. ISSN 1368-9800. PMID 27293047. 
  5. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Bell2019
  6. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named C0238176
  7. ↑ 7.0 7.1 Sène, Damien (2018). "Small fiber neuropathy: Diagnosis, causes, and treatment". Joint Bone Spine 85 (5): 553–559. doi:10.1016/j.jbspin.2017.11.002. ISSN 1297-319X. PMID 29154979. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Hlubocky, Ales; Smith, Benn E. (2014). "Dorsal Root Ganglion Disorders". Neuromuscular Disorders in Clinical Practice. pp. 467–491. doi:10.1007/978-1-4614-6567-6_23. ISBN 978-1-4614-6566-9. 
  9. ↑ 9.0 9.1 9.2 Lacerna, Rhodora A.; Chien, Chloe; Yeh, Shing-Shing (2003). "Paresthesias Developing in an Elderly Patient after Chronic Usage of Nitrofurantoin and Vitamin B6". Journal of the American Geriatrics Society 51 (12): 1822–1823. doi:10.1046/j.1532-5415.2003.51572_8.x. PMID 14687374. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 Cite error: Invalid <ref> tag; no text was provided for refs named Velazquez-Rodriguez2014
  11. ↑ 11.0 11.1 Donofrio, Peter Daniel (2000). "Electrophysiological Evaluations". Neurologic Clinics 18 (3): 601–613. doi:10.1016/S0733-8619(05)70213-9. ISSN 0733-8619. PMID 10873233. https://www.neurologic.theclinics.com/article/S0733-8619(05)70213-9/abstract. 
  12. ↑ Schaeppi, U.; Krinke, G. (1982). "Pyridoxine neuropathy: Correlation of functional tests and neuropathology in beagle dogs treated with large doses of vitamin B6". Agents and Actions 12 (4): 575–582. doi:10.1007/BF01965944. ISSN 0065-4299. PMID 7180742. 
  13. ↑ 13.0 13.1 13.2 13.3 Callizot, Noëlle; Poindron, Philippe (2008). "Pyridoxine-Induced Peripheral Neuropathy". New Animal Models of Human Neurological Diseases. Biovalley Monographs. pp. 66–80. doi:10.1159/000117724. ISBN 978-3-8055-8405-0. ""....a specific large-fibre neuropathy (with severe loss of proprioceptive function) is encountered clinically after vitamin B6 (pyridoxine).... All subjects showed paraesthesia and numbness as well as ataxia. The clinical examination showed a large sensory deficit with Achilles' reflex loss, associated with Romberg's signs (loss of proprioceptive control in which increased unsteadiness occurs when standing with the eyes closed compared with standing with the eyes open). The electromyographic examination showed a large sensory wave amplitude decrease but no change in the motor conduction.... small fibres were also involved as shown by the decreased SNCV and the altered thermosensitivity detected in the hot plate test. The same signs are observed in humans suffering from pyridoxine-induced neuropathy."" 
  14. ↑ 14.0 14.1 14.2 14.3 Wilmshurst, Jo M.; Ouvrier, Robert A.; Ryan, Monique M. (2019). "Peripheral nerve disease secondary to systemic conditions in children". Therapeutic Advances in Neurological Disorders 12: 175628641986636. doi:10.1177/1756286419866367. PMID 31447934. 
  15. ↑ 15.00 15.01 15.02 15.03 15.04 15.05 15.06 15.07 15.08 15.09 15.10 Hammond, N.; Wang, Y.; Dimachkie, M.; Barohn, R. (2013). "Nutritional Neuropathies". Neurologic Clinics 31 (2): 477–489. doi:10.1016/j.ncl.2013.02.002. PMID 23642720. 
  16. ↑ 16.0 16.1 16.2 Scott, K.; Zeris, S.; Kothari, M. J. (2008). "Elevated B6 levels and peripheral neuropathies". Electromyography and Clinical Neurophysiology 48 (5): 219–23. PMID 18754531. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 Bromberg, Mark B. (2000). "Peripheral Neurotoxic Disorders". Neurologic Clinics 18 (3): 681–694. doi:10.1016/S0733-8619(05)70218-8. ISSN 0733-8619. PMID 10873238. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 18.7 "Vitamin B6 — Health Professional Fact Sheet". U.S. Department of Health and Human Services. https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/. 
  19. ↑ 19.0 19.1 Stover, Patrick J; Field, Martha S (2015). "Vitamin B-6". Advances in Nutrition 6 (1): 132–133. doi:10.3945/an.113.005207. ISSN 2161-8313. PMID 25593152. 
  20. ↑ 20.0 20.1 20.2 20.3 Donofrio, Peter D. (2005). "Evaluating the Patient With Peripheral Neuropathy". Numbness, Tingling, Pain, and Weakness: A Basic Course in Electrodiagnostic Medicine. Monterey, California: AANEM 52nd Annual Scientific Meeting. https://www.aanem.org/mxonline/resources/downloads/products/2005CourseA.pdf#page=33. 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 Gangsaas, Ingvild (1995). "Dispelling the Myths of Vitamin B6". Nutrition Bytes 1 (1). ISSN 1548-4327. https://escholarship.org/content/qt51t0k2rj/qt51t0k2rj.pdf. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 Koontz, Daniel W; Maddux, Brian; Katirji, Bashar (2004). "Evaluation of a Patient Presenting With Rapidly Progressive Sensory Ataxia". Journal of Clinical Neuromuscular Disease 6 (1): 40–47. doi:10.1097/01.cnd.0000133065.28161.00. ISSN 1522-0443. PMID 19078751. 
  23. ↑ 23.0 23.1 23.2 Chawla, Jasvinder; Kvarnberg, David (2014). "Hydrosoluble vitamins". Neurologic Aspects of Systemic Disease Part II. Handbook of Clinical Neurology. 120. pp. 891–914. doi:10.1016/B978-0-7020-4087-0.00059-0. ISBN 978-0-7020-4087-0. 
  24. ↑ 24.0 24.1 Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline (1998). "Vitamin B6". Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline.. Washington (DC): National Academies Press (US). https://www.ncbi.nlm.nih.gov/books/NBK114313/#_ch7_s51_. 
  25. ↑ Dieb, Wisam; Boucher, Yves (2017). "Burning Mouth Syndome and Vitamin B6". Pain Medicine 18 (8): 1593–1594. doi:10.1093/pm/pnw345. ISSN 1526-2375. PMID 28371806. 
  26. ↑ Dieb, Wisam; Moreau, Nathan; Rochefort, Juliette; Boucher, Yves (2016). "Role of vitamin B6 in idiopathic burning mouth syndrome: some clinical observations". Médecine Buccale Chirurgie Buccale 23 (2): 77–83. doi:10.1051/mbcb/2016038. ISSN 1273-2761. https://www.jomos.org/articles/mbcb/pdf/2017/02/mbcb160045.pdf. 
  27. ↑ Hani R. Khouzam; Doris Tiu Tan; Tirath S. Gill (9 March 2007). Handbook of Emergency Psychiatry E-Book. Elsevier Health Sciences. pp. 65–. ISBN 978-0-323-07661-6. https://books.google.com/books?id=Izob_Qe-EKwC&pg=PA65. 
  28. ↑ Kennedy, Ashleigh; Schaeffer, Tammi (2016). "Pyridoxine". Critical Care Toxicology. pp. 1–4. doi:10.1007/978-3-319-20790-2_174-1. ISBN 978-3-319-20790-2. 
  29. ↑ De Kruijk, J. R.; Notermans, N. C. (2005). "Sensory disturbances caused by multivitamin preparations". Nederlands Tijdschrift voor Geneeskunde 149 (46): 2541–4. PMID 16320661. 
  30. ↑ Levine, Seymour; Saltzman, Arthur (2004). "Pyridoxine (vitamin B6) neurotoxicity: enhancement by protein-defcient diet". Journal of Applied Toxicology 24 (6): 497–500. doi:10.1002/jat.1007. ISSN 0260-437X. PMID 15558839. 
  31. ↑ Vrolijk, M. F.; Opperhuizen, A.; Jansen EHJM; Hageman, G. J.; Bast, A.; Haenen GRMM (2017). "The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function". Toxicology in Vitro 44: 206–212. doi:10.1016/j.tiv.2017.07.009. PMID 28716455. 
  32. ↑ Windebank, Anthony J. (1985). "Neurotoxicity of pyridoxine analogs is related to coenzyme structure". Neurochemical Pathology 3 (3): 159–167. doi:10.1007/BF02834268. ISSN 0734-600X. PMID 4094726. 
  33. ↑ Hadtstein, Felix; Vrolijk, Misha (2021). "Vitamin B-6-Induced Neuropathy: Exploring the Mechanisms of Pyridoxine Toxicity". Advances in Nutrition 12 (5): 1911–1929. doi:10.1093/advances/nmab033. PMID 33912895. 
  34. ↑ Ramos, Rúben J.; Albersen, Monique; Vringer, Esmee; Bosma, Marjolein; Zwakenberg, Susan; Zwartkruis, Fried; Jans, Judith J.M.; Verhoeven-Duif, Nanda M. (2019). "Discovery of pyridoxal reductase activity as part of human vitamin B6 metabolism". Biochimica et Biophysica Acta (BBA) - General Subjects 1863 (6): 1088–1098. doi:10.1016/j.bbagen.2019.03.019. ISSN 0304-4165. PMID 30928491. 
  35. ↑ 35.0 35.1 35.2 35.3 Assessment of vitamin B6 intake in relation to tolerable upper intake levels. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. Oslo, Norway. ISBN 978-82-8259-260-4. https://vkm.no/download/18.645b840415d03a2fe8f2653d/1499330353450/087ba2170f.pdf. Retrieved 2019-12-07. 
  36. ↑ Reeds, Karen (2019-03-04). "Vitamin B Complexities". H-Nutrition. https://networks.h-net.org/node/2324269/pdf. 
  37. ↑ Institute of Medicine (29 September 2006). Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. National Academies Press. pp. 184–. ISBN 978-0-309-15742-1. https://books.google.com/books?id=dYZZTgjDeccC&pg=PA184. 
  38. ↑ "Vitamins and minerals - B vitamins and folic acid - NHS". 3 March 2017. https://www.nhs.uk/conditions/vitamins-and-minerals/vitamin-b/. 
  39. ↑ "Advies van BuRO over vitamine B6 uit voedingssupplementen" (in nl). 2016-12-16. https://www.nvwa.nl/documenten/consument/eten-drinken-roken/supplementen-en-preparaten/risicobeoordelingen/advies-van-buro-over-vitamine-b6-uit-voedingssupplementen. 
  40. ↑ "Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Vitamin B6". Tolerable upper intake levels for vitamins and minerals. European Food Safety Authority (EFSA). 2006. pp. 29–44. ISBN 978-92-9199-014-6. http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf. 
  41. ↑ "Overview of Dietary Reference Intakes for Japanese". 2015. https://www.mhlw.go.jp/file/06-Seisakujouhou-10900000-Kenkoukyoku/Overview.pdf. 
  42. ↑ "Vitamin B6". National Health and Medication Research Council (NHMRC). 2014-03-17. https://www.nrv.gov.au/nutrients/vitamin-b6. 
  43. ↑ Ghavanini, A. A.; Kimpinski, K. (2014). "Revisiting the evidence for neuropathy caused by pyridoxine deficiency and excess". Journal of Clinical Neuromuscular Disease 16 (1): 25–31. doi:10.1097/CND.0000000000000049. PMID 25137514. 
  44. ↑ Bender, David A. (1997). "Vitamin B6". Nutrition & Food Science 97 (4): 128–133. doi:10.1108/00346659710179642. ISSN 0034-6659. 
  45. ↑ 45.0 45.1 Adverse Drug Reactions Advisory Committee (ADRAC) and the Office of Medicine Safety Monitoring (OMSM) of the TGA. (2008-08-01). "High-dose vitamin B6 may cause peripheral neuropathy". Australian Adverse Drug Reactions Bulletin 27 (4). https://www.tga.gov.au/publication-issue/australian-adverse-drug-reactions-bulletin-vol-27-no-4#a2. 
  46. ↑ Vrolijk, Misha F; Hageman, Geja J; van de Koppel, Sonja; van Hunsel, Florence; Bast, Aalt (2020). "Inter-individual differences in pharmacokinetics of vitamin B6: A possible explanation of different sensitivity to its neuropathic effects". PharmaNutrition 12: 100188. doi:10.1016/j.phanu.2020.100188. ISSN 2213-4344. 
  47. ↑ Van Hunsel, Florence; Van De Koppel, Sonja; Van Puijenbroek, Eugène; Kant, Agnes (2018). "Vitamin B6 in Health Supplements and Neuropathy: Case Series Assessment of Spontaneously Reported Cases". Drug Safety 41 (9): 859–869. doi:10.1007/s40264-018-0664-0. PMID 29737502. https://pure.rug.nl/ws/files/61346019/s40264_018_0664_0_1_.pdf. 
  48. ↑ Critcher, Matt S.; Sobczynska-Malefora, Agata (2015-09-15). Vitamin B6: low and very high concentrations in hospital patients. http://www.viapath.co.uk/sites/default/files/upload/B6%20pp504-505%20BMSsept15.pdf. 
  49. ↑ "Scientific Opinion on the safety and efficacy of vitamin B6(pyridoxine hydrochloride) as a feed additive for all animal species". EFSA Journal 9 (5): 2171. 2011. doi:10.2903/j.efsa.2011.2171. ISSN 1831-4732. 
  50. ↑ 50.0 50.1 London, Zachary; Albers, James W. (2007). "Toxic Neuropathies Associated with Pharmaceutic and Industrial Agents". Neurologic Clinics 25 (1): 257–276. doi:10.1016/j.ncl.2006.10.001. ISSN 0733-8619. PMID 17324727. 
  51. ↑ Echaniz-Laguna, Andoni; Mourot-Cottet, Rachel; Noel, Esther; Chanson, Jean-Baptiste (2018). "Regressive pyridoxine-induced sensory neuronopathy in a patient with homocystinuria". BMJ Case Reports 2018: bcr–2018–225059. doi:10.1136/bcr-2018-225059. ISSN 1757-790X. PMID 29954767. 
  52. ↑ 52.0 52.1 Cite error: Invalid <ref> tag; no text was provided for refs named Moudgal2018
  53. ↑ 53.0 53.1 Gdynia, Hans-Jürgen; Müller, Timo; Sperfeld, Anne-Dorte; Kühnlein, Peter; Otto, Markus; Kassubek, Jan; Ludolph, Albert C. (2008). "Severe sensorimotor neuropathy after intake of highest dosages of vitamin B6". Neuromuscular Disorders 18 (2): 156–158. doi:10.1016/j.nmd.2007.09.009. ISSN 0960-8966. PMID 18060778. 
  54. ↑ Whyte, M P; Mahuren, J D; Vrabel, L A; Coburn, S P (1985). "Markedly increased circulating pyridoxal-5'-phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B6 metabolism.". Journal of Clinical Investigation 76 (2): 752–756. doi:10.1172/JCI112031. ISSN 0021-9738. PMID 4031070. 
  55. ↑ 55.0 55.1 Bacharach, Rae; Lowden, Max; Ahmed, Aiesha (2017). "Pyridoxine Toxicity Small Fiber Neuropathy With Dysautonomia". Journal of Clinical Neuromuscular Disease 19 (1): 43–46. doi:10.1097/CND.0000000000000172. ISSN 1522-0443. PMID 28827489. 
  56. ↑ Bashar Katirji; Henry J. Kaminski; Robert L. Ruff (11 October 2013). Neuromuscular Disorders in Clinical Practice. Springer Science & Business Media. pp. 468–. ISBN 978-1-4614-6567-6. https://books.google.com/books?id=XPq8BAAAQBAJ&pg=PA468. 
  57. ↑ 57.0 57.1 Sheikh, S. I.; Amato, A. A. (2010). "The dorsal root ganglion under attack: the acquired sensory ganglionopathies". Practical Neurology 10 (6): 326–334. doi:10.1136/jnnp.2010.230532. ISSN 1474-7758. PMID 21097829. 
  58. ↑ Perry, Tracy Ann; Weerasuriya, Ananda; Mouton, Peter R.; Holloway, Harold W.; Greig, Nigel H. (2004). "Pyridoxine-induced toxicity in rats: A stereological quantification of the sensory neuropathy". Experimental Neurology 190 (1): 133–. doi:10.1016/j.expneurol.2004.07.013. PMID 15473987. https://zenodo.org/record/1258933. 
  59. ↑ Misra, UshaKant; Kalita, Jayantee; Nair, PradeepP (2008). "Diagnostic approach to peripheral neuropathy". Annals of Indian Academy of Neurology 11 (2): 89–97. doi:10.4103/0972-2327.41875. ISSN 0972-2327. PMID 19893645. 
  60. ↑ Bakkers, Mayienne (2015). Small fibers, big troubles: diagnosis and implications of small fiber neuropathy. Datawyse / Universitaire Pers Maastricht. https://cris.maastrichtuniversity.nl/portal/files/1059689/guid-4fb306d4-cfe3-4377-9d6a-735d64cb9acb-ASSET1.0.pdf. 
  61. ↑ Hasannejad, Farkhonde; Ansar, Malek Moein; Rostampour, Mohammad; Mahdavi Fikijivar, Edris; Khakpour Taleghani, Behrooz (2019). "Improvement of pyridoxine-induced peripheral neuropathy by Cichorium intybus hydroalcoholic extract through GABAergic system". The Journal of Physiological Sciences 69 (3): 465–476. doi:10.1007/s12576-019-00659-8. ISSN 1880-6546. PMID 30712095. 
  62. ↑ Callizot, Noelle; Warter, Jean-Marie; Poindron, Philippe (2001). "Pyridoxine-Induced Neuropathy in Rats: A Sensory Neuropathy That Responds to 4-Methylcatechol". Neurobiology of Disease 8 (4): 626–635. doi:10.1006/nbdi.2001.0408. ISSN 0969-9961. PMID 11493027. 
  63. ↑ Hong, Bin Na; Yi, Tae Hoo; Kim, Sun Yeou; Kang, Tong Ho (2009). "High-Dosage Pyridoxine-Induced Auditory Neuropathy and Protection with Coffee in Mice". Biological & Pharmaceutical Bulletin 32 (4): 597–603. doi:10.1248/bpb.32.597. ISSN 0918-6158. PMID 19336890. 
  64. ↑ 64.0 64.1 Saleh, Firas G.; Seidman, Roberta J. (2003-12-01). "Drug-Induced Myopathy and Neuropathy". Journal of Clinical Neuromuscular Disease 5 (2): 81–91. doi:10.1097/00131402-200312000-00003. PMID 19078725. 

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