Vitamin B12 Deficiency and Neuro-Ophthalmic Manifestations

This presentation covers vitamin B12 deficiency, including etiology, signs and symptoms, neurologic and ophthalmic findings, a case presentation and treatment.

Indiana University School of Medicine Vitamin B12 Deficiency and NeuroOphthalmic Manifestations Jourdan Carroll1, Devin D. Mackay, MD1-4 1Indiana University School of Medicine, 2Indiana University Department of Neurology, 3Indiana University Department of Ophthalmology, 4Indiana University Department of Neurosurgery INDIANA UNIVERSITY SCHOOL OF MEDICINE Outline Outline • • Vitamin B12 Biochemical Function Vitamin B12 Deficiency • Etiologies • Signs and Symptoms • Neurologic Findings • Ophthalmologic Findings • Vitamin B12 Deficiency Case Presentation • Treatment of Vitamin B12 Deficiency INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Vitamin B12 • • • Water soluble, derived from animal products “Cobalamin” is the core molecule within vitamin B12 • modified versions of cobalamin include cyanocobalamin, hydroxycobalamin, methylcobalamin, etc.; all are absorbed and metabolized differently Absorbed in the ileum via binding intrinsic factor (IF), a glycoprotein produced by the parietal cells of the stomach Vitamin B12 Chemical Structure Alsosaid1987, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons Ankar A, Kumar A. “Vitamin B12 Deficiency.” StatPearls, StatPearls Publishing, 5 June 2022. Paul C, Brady DM. “Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms.” Integr. Med. (Encinitas) vol. 16,1 (2017): 42-49. INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Biochemical Function • • Vitamin B12 Biochemical Function Vitamin B12 is used as a cofactor in two biochemical pathways • The homocysteine pathway takes place in the cytosol and leads to the production of methionine, an amino acid essential for production of proteins, DNA, neurotransmitters, myelin, etc. • The methylmalonyl CoA pathway takes place in the mitochondria and leads to production of succinyl CoA, an intermediate in the Krebs cycle Lack of vitamin B12 causes an inability to convert homocysteine and methylmalonyl CoA to their final products, resulting in high serum levels of homocysteine and methylmalonic acid (MMA) Myelin, catecholamine, phosphatidylcholine, DNA, RNA, etc. Biochemical mechanism of action of vitamin B12 in homocysteine pathway akane700, Public domain, via Wikimedia Commons Calderón-Ospina CA and Nava-Mesa MO. “B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin.” CNS Neurosci. Ther. vol. 26,1 (2020): 5-13. doi:10.1111/cns.13207 INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Deficiency Vitamin B12 Deficiency - Etiologies Autoimmune • Pernicious anemia: antibodies to IF inhibit ileal absorption of vitamin B12 Malabsorption • Gastric bypass surgery decreases IF production • Damage to the terminal ileum (e.g., Crohn’s disease): loss of site of vitamin B12 absorption Dietary Insufficiency • Prolonged vegan diet, excessive alcohol intake, poor nutritional intake • Vitamin B12 is stored in the liver but storage can be depleted with lack of dietary intake Ankar A, Kumar A. “Vitamin B12 Deficiency.” StatPearls, StatPearls Publishing, 5 June 2022. INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Deficiency Signs and Symptoms • Fatigue, pallor, dizziness, tachycardia, shortness of breath • Peripheral neuropathy, ataxia, loss of proprioception, headaches, neuropsychiatric disturbances • Presenting symptoms are often symmetric and can be a manifestation of subacute combined degeneration of the spinal cord • Diarrhea, gastrointestinal disturbance • Megaloblastic anemia • Glossitis • Jaundice Ankar A, Kumar A. “Vitamin B12 Deficiency.” StatPearls, StatPearls Publishing, 5 June 2022. INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Deficiency Neurological Findings • Spinal cord subacute combined degeneration • Dorsal column: impaired tactile discrimination, proprioception, and vibration sense, Lhermitte’s sign • Lateral corticospinal tract: muscle weakness, hyperreflexia, and spasticity • Can progress to paraplegia and eventual sphincter involvement including bladder or bowel incontinence in a late stage • Spinocerebellar tract: sensory ataxia, Romberg’s sign Qudsiya Z, De Jesus O. “Subacute Combined Degeneration of the Spinal Cord.” StatPearls, StatPearls Publishing, 21 June 2022. Spinal cord axial section Polarlys and Mikael Häggström, CC BY-SA 3.0 <https://creativecommons.org/licenses/bysa/3.0>, via Wikimedia Commons OpenStax, CC BY 4.0 <https://creativecommons.org/licenses/by/4.0>, via Wikimedia Commons INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Deficiency Ophthalmic Findings • Progressive, bilateral, painless, symmetrical vision loss with a central or cecocentral scotoma • Peripheral vision is typically preserved • Most common ophthalmologic manifestation of vitamin B12 deficiency is optic atrophy • Still, reported in less than 1% of vitamin B12 deficient patients • As disease progresses the optic disc becomes pale with preferential loss of papillomacular bundle fibers of the retinal nerve fiber layer • Optic atrophy presents as final stage and treatment is most successful before the development of atrophy Ata F, et al. “Optic neuropathy as a presenting feature of vitamin B-12 deficiency: A systematic review of literature and a case report.” Ann. Med. Surg. (2012) vol. 60 316-322. 5 Nov. 2020, doi:10.1016/j.amsu.2020.11.010 Roda M, et al. “Nutritional Optic Neuropathies: State of the Art and Emerging Evidences.” Nutrients vol. 12,9 2653. 31 Aug. 2020, doi:10.3390/nu12092653 Das Gupta S, Shakeel T, Dhawan A, Kakkar A. Effect of vitamin B12 deficiency anemia on peripapillary retinal nerve fiber layer. Int. J. Ophthalmol. 2021;14(9):1424-1429. INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Deficiency Ophthalmic Findings • Patients with B12 deficiency had reduced visual evoked potential (VEP) amplitudes and prolonged VEP latencies, even without visual symptoms • Suggests optic nerve dysfunction despite lack of ophthalmic symptoms • Emphasizes the importance of early management in asymptomatic patients VEP Parameters Eye Tested Latency P100 (ms) Right Left Amplitude P100 (µm) Right Left Patients (n = 30) mean ± 𝐒𝐒𝐒𝐒 112.7 ± 18 112.6 ± 17 5.1 ± 2.8 5.7 ± 2.9 Controls (n = 15) mean ± 𝐒𝐒𝐒𝐒 106 ± 5.4 106.5 ± 6.2 7.7 ± 2.3 8.8 ± 2.3 p-value 0.239 0.110 0.012 0.003 Gökçe Çokal B, et al. “Visual and somotosensory evoked potentials in asymptomatic patients with vitamin B12 deficiency.” Eur. Rev. Med. Pharmacol. Sci. vol. 20,21 (2016): 4525-4529. INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Deficiency • • Vitamin B12 Deficiency Case - Patient Information 41 year old woman with progressive painless central vision loss • She noticed having to bring items closer to her face to see them and endorsed difficulty driving and reading • Past medical history of alcohol use disorder, cirrhosis, and anemia Eye Exam Left Eye Right Eye Poor nutritional intake (often one 20/200; did not improve with pinhole small meal a day) over the past year Visual acuity 20/400 Amsler grid full full • Visual symptoms worsened equal and reactive with no relative equal and reactive with no relative following hospitalization for liver Pupils afferent pupillary defect afferent pupillary defect 13/14 correct failure and pneumonia requiring Color plates 11/14 correct Anterior normal normal total parenteral nutrition (TPN) segment and ventilator support Fundoscopic temporal pallor of optic disc, no temporal pallor of optic disc, no edema, exam edema, cup-to-disc ratio 0.3 cup-to-disc ratio 0.3 INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Deficiency Lab Findings • Decreased B12, increased homocysteine • Normal MMA value and lack of macrocytic anemia in this patient demonstrate these features may not always part of vitamin B12 deficiency presentation • Neurologic and ophthalmologic symptoms may present prior to changes in lab values Vitamin A (retinol) 0.34 mg/L Vitamin A/retinyl palmitate <0.02 mg/L Vitamin A (retinol)-interpr Normal Vitamin B1 Bld QN 224 nmol/L Folate SerPI QN 17.2 ng/mL Vitamin B12 SerPI QN 104 pg/mL (reference: 200 – 1,000 pg/mL) Methylmalonic Acid (MMA) 0.1 mCmol/L (reference: 0.0 – 0.4 mCmol/L) Homocysteine SerPI QN 14.3 mCmol/L (reference: 4.9 – 11.6 mCmol/L) WBC 4.2 k/cumm RBC 4.08 million/cumm Hgb 12 GM/dL (reference: 12 – 15 GM/dL) Hct 36.7% MVC 90 fL MCH 29.5 pg MCHC 32.9 GM/dL RDW 17.4% Platelet 94 k/cumm MPV 7.8 fL (reference: 81 – 99 fL) (reference: 11.5 – 14.5%) INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Deficiency Visual Field Results • Humphrey visual fields (24-2 SITA Faster program) • Showed high number of fixation losses in both eyes • Deficits in visual field testing can often be subtle Left Eye Right Eye Visual Field Deficit Cecocentral scotoma Central scotoma Foveal Sensitivity 31 dB (low) 32 dB (low) Mean Deviation -1.88 dB -1.11 dB Left eye visual field testing Red circle shows a subtle central scotoma and green circle highlights decreased foveal sensitivity. Right eye visual field testing Red circle shows a subtle central scotoma and green circle highlights decreased foveal sensitivity. INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Deficiency OCT Results • Peripapillary retinal nerve fiber layer shows temporal thinning in both eyes • Ganglion cell analysis showed thinning in both eyes • Macula was otherwise unremarkable Ganglion Cell Analysis Thinning is present in both eyes. ONH and RNFL Analysis Temporal thinning is present in both eyes due to papillomacular bundle atrophy INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Deficiency Treatment of Vitamin B12 Deficiency • Dosing regimen for patients with neurologic symptoms - 1000 mcg parenterally every other day for two weeks, then once every month • Doses of 1000 mcg cyanocobalamin orally once daily maintenance dosing • Clinical improvement for neurologic symptoms may take 3 to 12 months • SCD: 86% showed partial resolution post-treatment, 14% attained complete symptomatic resolution • Ophthalmic symptoms post-treatment: 25% had complete resolution, 33.3% had partial resolution, 29% had no improvement, 4% progressed to complete blindness Qudsiya Z, De Jesus O. “Subacute Combined Degeneration of the Spinal Cord.” StatPearls, StatPearls Publishing, 21 June 2022. Ata F, et al. “Optic neuropathy as a presenting feature of vitamin B-12 deficiency: A systematic review of literature and a case report.” Ann. Med. Surg. (2012) vol. 60 316-322. 5 Nov. 2020, doi:10.1016/j.amsu.2020.11.010 INDIANA UNIVERSITY SCHOOL OF MEDICINE Vitamin B12 Deficiency Summary • Vitamin B12 deficiency can present with relatively subtle subacute central vision loss that can be difficult to detect without a heightened clinical suspicion • Symptoms: painless and progressive loss of central vision • Lab findings: decreased vitamin B12 level, increased homocysteine and methylmalonic acid levels • Visual Field results: central/cecocentral visual field depression • OCT may show peripapillary retinal nerve fiber layer thinning, particularly temporally and ganglion cell loss in both eyes, typically symmetrically INDIANA UNIVERSITY SCHOOL OF MEDICINE