Neuro-Ophthalmic Manifestations of Celiac Disease

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Article initiated by:
Ritu Sampige, Andrew Go Lee, MD, Nagham Al-Zubidi, MD, Osama Al Deyabat, MBBS, Saif Aldeen Alryalat, MD
All contributors:
Ritu Sampige, Andrew Go Lee, MD, Nagham Al-Zubidi, MD, Osama Al Deyabat, MBBS, Saif Aldeen Alryalat, MD, Osama Al Deyabat, MBBS
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Clinicians should be aware of the possible neuro-ophthalmic manifestations of CD including secondary vitamin deficiency related conditions. The treatment of CD is a gluten-free diet, but some patients are refractory to treatment. Patients with chronic CD are at a higher risk for neoplasm including lymphoma and adenocarcinoma.

Disease Entity

General

Celiac disease (CD) is an autoimmune disorder that is characterized by an immune-mediated reaction upon consumption of gluten, a protein that is present in wheat, rye, and barley[1]. The pathogenesis of CD involves sensitivity of the gastrointestinal (GI) tract towards gluten[2] and may affect individuals with a genetic predisposition[3]. Other names for CD include celiac sprue or gluten-sensitive enteropathy[3]. The incidence of CD continues to rise worldwide, including in countries where the disorder was previously uncommon. This rise in incidence of CD may be due to the increasing testing and awareness of CD, increasing autoimmunity, or the spread of Western diets worldwide[1][3][4].

CD results in a wide range of clinical manifestations, including neurologic and ophthalmic manifestations[2], and is a multisystemic rather than strictly GI disorder[1]. In addition, the ocular findings related to CD may be the presenting manifestation of the disease[5][6].

Celiac Disease and Neuro-Ophthalmic Manifestations

Dysfunction of the small intestine in untreated CD can lead to a host of nutritional and vitamin deficiencies, including inadequacies of iron, zinc, magnesium, vitamins B12 (cobalamin), B6 (pyridoxine), B1 (thiamine), B2 (riboflavin), D, folic acid (B9), and fat-soluble vitamins including vitamins A, D, E, and K[7][8][9][10][11]. These resulting nutritional deficiencies may lead to neuro-ophthalmic manifestations.

In patients with celiac disease, vitamin A deficiency can lead to nyctalopia[5]. Furthermore, vitamin A deficiency and excess have both been associated with pseudotumor cerebri[5]. In the context of vitamin A deficiency, arachnoid villi are affected, leading to the lack of adequate cerebrospinal fluid absorption, thus contributing to pseudotumor cerebri and an associated rise in intracranial pressure, papilledema, defects in the visual field, photophobia, and transient vision loss[5]. Other ophthalmic findings associated with vitamin A deficiency include retinopathy, keratomalacia, corneal ulcer, and dry eye[5].

Deficiencies in vitamin D, along with B6, B9, B12, folic acid, and selenium contribute to the increased risk of cataracts among patients with celiac disease[5]. Other neurological symptoms and signs that have been associated with CD include headache, cerebral ataxia, epilepsy, sensorineural hearing loss, and occipital calcification[5][6].

CD, especially in combination with alcohol abuse can lead to vitamin B1 (thiamine) deficiency[12]. Thiamine deficiency in CD can present acutely with ataxia, ophthalmoplegia, mental status change, and nystagmus[12][13]. Vitamin B2 (riboflavin) deficiency is also rarely associated with ophthalmoplegia[12]. Vitamin B9 and B12 deficiency can lead to neuropathy (peripheral and optic neuropathy) in the context of CD[12]. While uncommon in uncomplicated CD, vitamin B12 deficiency can lead to optic nerve dysfunction (loss of central vision, central/cecocentral scotoma, optic atrophy), myelopathy, or dementia[12]. Vitamin B6 deficiency can lead to peripheral neuropathy, and vitamin E deficiency can lead to ophthalmoplegia, ptosis, myopathy, head tremor, sensory neuropathy, and loss of joint-position sense[12][14].

Disease Epidemiology

The global seroprevalence of CD with positive anti–tissue transglutaminase and/or anti-endomysial antibodies results, is 1.4%[15]. The prevalence of biopsy-proven CD has been reported as 0.7% globally[15]. Many population studies report a CD prevalence of 1% but the incidence of CD has been increasing over the past decades[1][16]. While CD has traditionally been described in Europe, North America, and Oceania, emerging population-based data on CD epidemiology in Africa, Asia, and Latin America suggest a more global distribution[16].

With regards to vitamin deficiencies, 7.5-32.5% of patients with CD have vitamin A deficiency, 20-60% of patients have vitamin D deficiency, and 8-41% of patients with untreated CD have vitamin B12 deficiency[5][17]. Patients with CD also have a 20-30% risk of folate deficiency, and 40% of patients with CD have iron deficiency anemia as their only irregularity[18].

About 50% of patients with CD experience extraintestinal symptoms[6]. Furthermore, up to about 40% experience neurological illnesses or gluten neuropathy[19].

Etiology

Genetic predisposition is a salient player in the development of CD. While 1/3 of the general population have the HLA-DQ2 haplotype, up to 90% of people with CD have the HLA-DQ2 haplotype[4]. In addition, 5% of CD have the HLA-DQ8 haplotype, and 5% of CD have at least one gene that encodes for DQ2[4]. However, non-HLA genes involved in inflammation and immune reactions also play a role in increasing genetic predisposition for CD[4]. The onset of CD may also be associated with other immune conditions, such as type 1 diabetes, thyroiditis, Sjögren syndrome, and IgA nephropathy[3].

Risk Factors

CD is often hereditary and runs in families; thus, a risk factor for celiac disease is having a first-degree relative with CD[20]. Variations in HLA-DQA1 and HLA-DQB1, which are genes encoding for HLA-DQ2 and HLA-DQ8 haplotypes, increase an individual’s genetic predisposition for CD[21][22]. Other potential risk factors in CD include iron deficiency anemia, osteopenic disease, type I diabetes, Down syndrome, Turner syndrome, autoimmune thyroid disease, and dermatitis herpetiformis[23].

Pathophysiology

The primary causative component of CD is gliadin, a protein fraction that is found within gluten[3]. When gluten is consumed, it is digested by a variety of hydrolytic enzymes in the small intestine lumen and brush border, leading to the formation of peptides such as α-gliadin that can activate innate and adaptive immune responses[3][24]. More specifically, resulting peptides stimulate the expression of pro-inflammatory cytokines, such as IL-15, leading to the spread of CD8+ intraepithelial T cells that contain a natural killer marker (NKG2D) and associated receptor for MIC-A[3]. When intestinal cells are stimulated to express MIC-A due to stress, such CD8+ intraepithelial T cells with NKG2D attack MIC-A-expressing enterocytes[3]. Damage to enterocytes and the epithelium of the small intestine increases the allowance of gliadin entry into the lamina propria layer of the small intestine epithelium, leading to gliadin deamidation by tissue transglutaminase[3]. Furthermore, the presentation of gliadin by HLA-DQ2 or HLA-DQ8 leads to the CD4+ T cell activation and subsequent production of cytokines and associated inflammatory damage in the small intestine[3].

Classification

CD can be classical, nonclassical, silent, latent, potential, or refractory. Patients with classical CD display symptoms and signs of malabsorption, including diarrhea, steatorrhea, and weight loss. Patients with nonclassical CD tend to present with extraintestinal symptoms, such as anemia, neuropathy, ataxia, osteoporosis, infertility, and liver dysfunction[25][26][27][28].

Subclinical or asymptomatic CD is characterized as having positive serology findings and atrophy of the intestinal villi but not presenting with typical identifiable symptoms and signs of CD[3]. Individuals with latent CD have positive serology findings and normal intestinal biopsy with normal diet, followed by a second timepoint of abnormal biopsy findings, such as future small intestine villi atrophy[29][30]. Prior to the subsequent small intestine villi atrophy, celiac disease is described as “potential,” which is when individuals have positive serology results but negative biopsy findings for CD[29]. Refractory CD presents with continued malabsorption and positive biopsy findings even after adopting a strict gluten-free diet for at least 6-12 months without other causes or signs of malignancy[31].

Histological characteristics seen on biopsy may also be classified through the Marsh–Oberhuber classification system[22]. Infiltration of intraepithelial lymphocytes indicates Marsh I classification[22]. Infiltration with hypertrophy of the crypt indicates Marsh II classification, and the presence of villous atrophy indicates Marsh III classification[22].

Diagnosis

History

CD typically presents with GI symptoms and signs but extraintestinal presentations of CD may also occur. A thorough review of systems should be elicited when inquiring about patients’ GI and non-GI symptoms. Common GI symptoms of CD include chronic diarrhea, abdominal distention, and weight loss[4]. However, complications that may arise from untreated CD include neurologic manifestations due to vitamin deficiency disorders (e.g., optic neuropathy, nystagmus, ophthalmoplegia, cerebellar ataxia, peripheral neuropathy, and dementia)[12][32].

Physical Examination

A full neuro-ophthalmic exam[5][6][12][13][14] should be considered in patients with CD with visual symptoms.

Ocular Findings

Signs & Symptoms

Neuro-ophthalmic signs and symptoms include the following:

  • Vitamin A deficiency can lead to nyctalopia or secondary pseudotumor cerebri[5]. Pseudotumor cerebri is associated with symptoms of increased intracranial pressure (e.g., defects in the visual field, headache, diplopia, and transient visual obscurations) or signs of increased ICP (e.g., papilledema, sixth nerve palsy)[5]. Other ophthalmic findings of CD-related vitamin A deficiency might include retinopathy, keratomalacia, corneal ulcer, and dry eye[5].
  • Vitamin D, B6, B9, B12, folic acid, and selenium deficiencies can lead to increased risk of cataracts[5].
  • Thiamine deficiency can lead to chronic Wernicke-Korsakoff syndrome or an acute Wernicke syndrome (e.g., cerebellar ataxia, ophthalmoplegia, mental status change, and nystagmus)[12][13]. Vitamin B1 (thiamine) deficiency can also be associated with neuropathy, dementia, and optic neuritis[12].
  • Vitamin B9 and B12 deficiency can lead to neuropathy (peripheral and optic neuropathy)[12]. Vitamin B12 deficiency can lead to ophthalmoplegia, optic nerves dysfunction, optic neuritis, cerebellar ataxia, myelopathy, and dementia[12][13].
  • Vitamin B6 deficiency can lead to peripheral neuropathy[12].
  • Vitamin B2 deficiency is associated with ophthalmoplegia[12].
  • Vitamin E deficiency can lead to ophthalmoplegia, ptosis, myopathy, myelopathy, head tremor, sensory neuropathy, loss of joint-position sense, cerebellar ataxia, extrapyramidal disorders, and dementia[12][13][14].

Diagnostic Procedures

Laboratory Testing & Imaging

According to the 2023 American College of Gastroenterology Guideline on the Diagnosis and Management of Celiac Disease, identification of positive test results for tissue transglutaminase in serum is a screening tool for celiac disease while multiple biopsies of the intestine is most often necessary for diagnosis[1]. Serology testing is conducted to identify IgA anti–tissue transglutaminase antibodies, and upper endoscopy is conducted for biopsy confirmation[4].

In terms of biopsy specimens, the second duodenum portion and proximal jejunum are sites utilized for diagnostic purposes in CD, for they are exposed to the greatest amounts of gluten[3]. Histological signs of CD include atrophy of the small intestine villi, greater levels of CD8+ T lymphocytes, hyperplasia and elongation of intestinal crypts, and greater amounts of immune cells such as plasma cells, mast cells, and eosinophils[3]. Both positive histology and serology findings are necessary to confirm the diagnosis[3].

Cranial and orbital magnetic resonance imaging (MRI) with and without contrast may be necessary in the evaluation of neuro-ophthalmic presentations of CD. In addition, the evaluation of CD might overlap with the management of secondary pseudotumor cerebri[33], neuromyelitis optica[34], and orbital myositis[35].

Differential Diagnosis

While neuro-ophthalmic manifestations have been associated with CD, patients who present with such symptoms along with GI symptoms and signs may be experiencing inflammatory bowel disease symptoms as opposed to those of CD[5]. Testing for alternative etiologies (e.g., infectious, ischemic, inflammatory, neoplastic, paraneoplastic, etc.) may be necessary in the evaluation of patients with CD who present with neuro-ophthalmic symptoms and signs.

Management & Outcomes

Prevention

To date, the only available treatment for CD is a lifelong gluten-free diet[3][4][36]. Additionally, long-term monitoring is necessary for individuals with CD[1] for anemia and nutritional deficiencies, and vitamins and supplementation can be administered to ameliorate symptoms of nutritional deficiencies[5][9].

Prognosis

With the correct diagnosis and treatment, the prognosis is favorable for CD after a strict gluten-free diet[37]. However, strict adherence to a gluten-free diet is difficult in light of the widespread nature of gluten, contamination, and labeling inadequacies, leading to variable compliance[38]. Unfortunately, up to 2-5% of patients with CD have refractory CD and a worse prognosis. These individuals are also at higher risk for secondary lymphoma[39] and GI adenocarcinoma compared to the general population[3].

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Rubio-Tapia A, Hill ID, Semrad C, et al. American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease. Official Journal of the American College of Gastroenterology | ACG. 2023;118(1):59-76. doi:10.14309/ajg.0000000000002075
  2. ↑ 2.0 2.1 Rani U, Imdad A, Beg M. Rare Neurological Manifestation of Celiac Disease. Case Reports in Gastroenterology. 2015;9(2):200-205. doi:10.1159/000431170
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. 10 ed. Elsevier; 2021
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Fasano A, Catassi C. Celiac Disease. New England Journal of Medicine. 2012;367(25):2419-2426. doi:10.1056/NEJMcp1113994
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 Fousekis FS, Katsanos A, Katsanos KH, Christodoulou DK. Ocular manifestations in celiac disease: an overview. International Ophthalmology. 2020;40(4):1049-1054. doi:10.1007/s10792-019-01254-x
  6. ↑ 6.0 6.1 6.2 6.3 Martins TG, Costa AL, Oyamada MK, Schor P, Sipahi AM. Ophthalmologic manifestations of celiac disease. Int J Ophthalmol. 2016;9(1):159-62. doi:10.18240/ijo.2016.01.26
  7. ↑ García-Manzanares Á, Lucendo AJ. Nutritional and Dietary Aspects of Celiac Disease. Nutrition in Clinical Practice. 2011;26(2):163-173. doi:10.1177/0884533611399773
  8. ↑ Wierdsma NJ, Van Bokhorst-de van der Schueren MAE, Berkenpas M, Mulder CJJ, Van Bodegraven AA. Vitamin and Mineral Deficiencies Are Highly Prevalent in Newly Diagnosed Celiac Disease Patients. Nutrients. 2013;5(10):3975-3992.
  9. ↑ 9.0 9.1 Caruso R, Pallone F, Stasi E, Romeo S, Monteleone G. Appropriate nutrient supplementation in celiac disease. Annals of Medicine. 2013;45(8):522-531. doi:10.3109/07853890.2013.849383
  10. ↑ Martin J, Geisel T, Maresch C, Krieger K, Stein J. Inadequate Nutrient Intake in Patients with Celiac Disease: Results from a German Dietary Survey. Digestion. 2013;87(4):240-246. doi:10.1159/000348850
  11. ↑ Valente FX, Campos TdN, Moraes LFdS, et al. B vitamins related to homocysteine metabolism in adults celiac disease patients: a cross-sectional study. Nutrition Journal. 2015;14(1):110. doi:10.1186/s12937-015-0099-8
  12. ↑ 12.00 12.01 12.02 12.03 12.04 12.05 12.06 12.07 12.08 12.09 12.10 12.11 12.12 12.13 12.14 Freeman HJ. Neurological Disorders in Adult Celiac Disease. Canadian Journal of Gastroenterology. 2008;22:824631. doi:10.1155/2008/824631
  13. ↑ 13.0 13.1 13.2 13.3 13.4 Dhawan PS, Goodman BP. Chapter 15 - Neurologic Manifestations of Nutritional Disorders. In: Aminoff MJ, Josephson SA, eds. Aminoff's Neurology and General Medicine (Fifth Edition). Academic Press; 2014:273-290.
  14. ↑ 14.0 14.1 14.2 Henri-Bhargava A, Melmed C, Glikstein R, Schipper HM. Neurologic Impairment Due to Vitamin E and Copper Deficiencies in Celiac Disease. Neurology. 2008;71(11):860-861. doi:10.1212/01.wnl.0000325473.13088.18
  15. ↑ 15.0 15.1 Singh P, Arora A, Strand TA, et al. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clinical Gastroenterology and Hepatology. 2018;16(6):823-836.e2. doi:10.1016/j.cgh.2017.06.037
  16. ↑ 16.0 16.1 King JA, Jeong J, Underwood FE, et al. Incidence of Celiac Disease Is Increasing Over Time: A Systematic Review and Meta-analysis. Official Journal of the American College of Gastroenterology | ACG. 2020;115(4):507-525. doi:10.14309/ajg.0000000000000523
  17. ↑ Halfdanarson TR, Litzow MR, Murray JA. Hematologic manifestations of celiac disease. Blood. 2006;109(2):412-421. doi:10.1182/blood-2006-07-031104
  18. ↑ Stefanelli G, Viscido A, Longo S, Magistroni M, Latella G. Persistent Iron Deficiency Anemia in Patients with Celiac Disease Despite a Gluten-Free Diet. Nutrients. 2020;12(8)doi:10.3390/nu12082176
  19. ↑ Osman D, Umar S, Muhammad H, Nikfekr E, Rostami K, Ishaq S. Neurological manifestation of coeliac disease with particular emphasis on gluten ataxia and immunological injury: a review article. Gastroenterol Hepatol Bed Bench. 2021;14(1):1-7.
  20. ↑ Singh P, Arora S, Lal S, Strand TA, Makharia GK. Risk of Celiac Disease in the First- and Second-Degree Relatives of Patients With Celiac Disease: A Systematic Review and Meta-Analysis. Official journal of the American College of Gastroenterology | ACG. 2015;110(11):1539-1548. doi:10.1038/ajg.2015.296
  21. ↑ Brown NK, Guandalini S, Semrad C, Kupfer SS. A Clinician's Guide to Celiac Disease HLA Genetics. Official journal of the American College of Gastroenterology | ACG. 2019;114(10):1587-1592. doi:10.14309/ajg.0000000000000310
  22. ↑ 22.0 22.1 22.2 22.3 Tonutti E, Bizzaro N. Diagnosis and classification of celiac disease and gluten sensitivity. Autoimmunity Reviews. 2014;13(4):472-476. doi:10.1016/j.autrev.2014.01.043
  23. ↑ Freeman HJ. Risk factors in familial forms of celiac disease. World J Gastroenterol. 2010;16(15):1828-31. doi:10.3748/wjg.v16.i15.1828
  24. ↑ Falcigno L, Calvanese L, Conte M, Nanayakkara M, Barone MV, D’Auria G. Structural Perspective of Gliadin Peptides Active in Celiac Disease. International Journal of Molecular Sciences. 2020;21(23):9301.
  25. ↑ Singh P, Makharia GK. Non-classical celiac disease: often missed. International Journal of Celiac Disease. 2014;2(3):76-85.
  26. ↑ Choung RS, Lamba A, Marietta EV, et al. Effect of a Gluten-free Diet on Quality of Life in Patients With Nonclassical Versus Classical Presentations of Celiac Disease. Journal of Clinical Gastroenterology. 2020;54(7):620-625. doi:10.1097/mcg.0000000000001277
  27. ↑ Tarar ZI, Zafar MU, Farooq U, Basar O, Tahan V, Daglilar E. The Progression of Celiac Disease, Diagnostic Modalities, and Treatment Options. Journal of Investigative Medicine High Impact Case Reports. 2021;9. doi:10.1177/23247096211053702
  28. ↑ Sood A, Midha V, Makharia G, et al. A simple phenotypic classification for celiac disease. Intest Res. 2018;16(2):288-292. doi:10.5217/ir.2018.16.2.288
  29. ↑ 29.0 29.1 Holmes GKT. Potential and latent coeliac disease. European Journal of Gastroenterology & Hepatology. 2001;13(9):1057-1060.
  30. ↑ Kaukinen K, Collin P, Mäki M. Latent coeliac disease or coeliac disease beyond villous atrophy? Gut. 2007;56(10):1339-1340. doi:10.1136/gut.2006.113084
  31. ↑ Rubio-Tapia A, Murray JA. Classification and management of refractory coeliac disease. Gut. Apr 2010;59(4):547-57. doi:10.1136/gut.2009.195131
  32. ↑ Bushara KO. Neurologic presentation of celiac disease. Gastroenterology. 2005;128(4, Supplement 1):S92-S97. doi:10.1053/j.gastro.2005.02.018
  33. ↑ Delen F, Peker E, Onay M, Altay ÇM, Tekeli O, Togay Işıkay C. The Significance and Reliability of Imaging Findings in Pseudotumor Cerebri. Neuroophthalmology. 2019;43(2):81-90. doi:10.1080/01658107.2018.1493514
  34. ↑ Kim HJ, Paul F, Lana-Peixoto MA, et al. MRI characteristics of neuromyelitis optica spectrum disorder An international update. Neurology. 2015;84(11):1165-1173. doi:10.1212/wnl.0000000000001367
  35. ↑ Costa RMS, Dumitrascu OM, Gordon LK. Orbital myositis: Diagnosis and management. Current Allergy and Asthma Reports. 2009;9(4):316-323. doi:10.1007/s11882-009-0045-y
  36. ↑ Iversen R, Sollid LM. The Immunobiology and Pathogenesis of Celiac Disease. Annual Review of Pathology: Mechanisms of Disease. 2023;18(1):47-70. doi:10.1146/annurev-pathmechdis-031521-032634
  37. ↑ Posner EB, Haseeb M. Celiac Disease. StatPearls Publishing, Treasure Island (FL); 2022.
  38. ↑ Wieser H, Ruiz-Carnicer Á, Segura V, Comino I, Sousa C. Challenges of Monitoring the Gluten-Free Diet Adherence in the Management and Follow-Up of Patients with Celiac Disease. Nutrients. 2021;13(7):2274.
  39. ↑ Tack GJ, Verbeek WHM, Schreurs MWJ, Mulder CJJ. The spectrum of celiac disease: epidemiology, clinical aspects and treatment. Nature Reviews Gastroenterology & Hepatology. 2010;7(4):204-213. doi:10.1038/nrgastro.2010.23
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