The modifying role of pregnancy on ophthalmological and neuro-ophthalmological diseases
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Publié-e :
déc. 18, 2017
Mots-clés :
Pregnancy, Ophthalmology, Teratogenicity, Neuro-Ophthalmology
Contenu principal de l'article
Résumé
The female visual system experiences a series of physiological modifications during pregnancy, and these changes have profound implications on many general ophthalmological and neuro-ophthalmological disorders, exacerbating some conditions while alleviating others. Patients with open-angle glaucoma experience improved disease states, with accompanying normal visual fields. Uveitis and MS-induced optic neuritis exhibit decreased rates of occurrence. Non-proliferative diabetic retinopathy initially worsens with gestation, eventually improving in the postpartum state with only 5% of cases progressing into the proliferative stage. As for idiopathic intracranial hypertension, existing symptoms worsen during pregnancy. Therapeutic interventions such as immunosuppressants, anti-neoplastic drugs, and steroids administered prophylactically during fetal development may lead to potential teratogenic outcomes manifesting in devastating birth defects and should be administered with caution.
Résumé
Le système visuel féminin subit une série de modifications physiologiques pendant la grossesse, et ces changements ont des implications profondes sur de nombreux troubles ophtalmologiques et neuro-ophtalmologiques généraux, exacerbant certaines conditions tout en soulageant d’autres. Les patients atteints de glaucome à angle ouvert ont une amélioration des états pathologiques, accompagnés de champs visuels normaux. L’uvéite et la névrite optique induite par la SEP présentent des taux d’occurrence réduits. La rétinopathie diabétique non proliférative s’aggrave au début avec la gestation, s’améliorant finalement dans l’état postpartum avec seulement 5% des cas progressant dans le stade prolifératif. En ce qui concerne l’hypertension intracrânienne idiopathique, les symptômes existants s’aggravent pendant la grossesse. Les interventions thérapeutiques comme les immunosuppresseurs, les médicaments antinéoplasiques et les stéroïdes administrés de façon prophylactique pendant le développement du fœtus peuvent entraîner des effets tératogènes potentiels se manifestant par des malformations congénitales dévastatrices et doivent être administrés avec prudence.
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Rubrique
Review & Clinical Practice
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Références
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2. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?. Immunology today. 1993;14(7):353-6.
3. Sharma S, Wuntakal R, Anand A, Sharma TK, Downey G. Pregnancy and the eye. The Obstetrician & Gynaecologist. 2006;8(3):141-6.
4. Qureshi IA, Xi XR, Wu XD. Intraocular pressure trends in pregnancy and in the third trimester hypertensive patients. Acta obstetricia et gynecologica Scandinavica. 1996;75(9):816-9.
5. Garg P, Aggarwal P. Ocular changes in pregnancy. Nepalese Journal of Ophthalmology. 2012;4(1):150-61.
6. Maris PJ, Mandal AK, Netland PA. Medical therapy of pediatric
glaucoma and glaucoma in pregnancy. Ophthalmology Clinics. 2005;18(3):461-8.
7. Brauner SC, Chen TC, Hutchinson BT, Chang MA, Pasquale LR,
Grosskreutz CL. The course of glaucoma during pregnancy: a retrospective case series. Archives of Ophthalmology. 2006;124(8):1089- 94.
8. Vaideanu D, Fraser S. Glaucoma management in pregnancy: a questionnaire survey. Eye. 2007;21(3):341-3.
9. Salim S. Glaucoma in pregnancy. Current opinion in ophthalmology. 2014;25(2):93-7.
10. Thorne JE, Suhler E, Skup M, Tari S, Macaulay D, Chao J, Ganguli A. Prevalence of noninfectious uveitis in the United States: a claims- based analysis. JAMA ophthalmology. 2016;134(11):1237-45.
11. Rabiah PK, Vitale AT. Noninfectious uveitis and pregnancy. American journal of ophthalmology. 2003;136(1):91-8.
12. Chiam NP, Hall AJ, Stawell RJ, Busija L, Lim LL. The course of uveitis in pregnancy and postpartum. British Journal of Ophthalmology. 2013;97:1284–8.
13. Chiam NP, Lim LL. Uveitis and gender: the course of uveitis in pregnancy. Journal of ophthalmology. 2014;2014.
14. Chan CC, Reed GF, Kim Y, Agrón E, Buggage RR. A correlation of pregnancy term, disease activity, serum female hormones, and cyto- kines in uveitis. British Journal of Ophthalmology. 2004;88(12):1506-9.
15. Koren G. Mycophenolate mofetil. Canadian Family Physician. 2008;54(8):1112-3.
16. Wakefield D, El-Asrar AA, McCluskey P. Treatment of severe inflammatory eye disease in patients of reproductive age and during pregnancy. Ocular immunology and inflammation. 2012;20(4):277-87.
17. Best RM, Chakravarthy U. Diabetic retinopathy in pregnancy. British journal of ophthalmology. 1997;81(3):249-51.
18. Sunness JS. The pregnant woman’s eye. Survey of ophthalmology. 1988;32(4):219-38.
19. Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Diabetes care. 2000;23(8):1084-91.
20. Lopez-Lopez F, Gomez-Ulla F, Rodriguez-Cid MJ, Arias L. Triamcinolone and bevacizumab as adjunctive therapies to panretinal photocoagulation for proliferative diabetic retinopathy. ISRN ophthalmology. 2012; 2012.
21. Kitzmiller JL, Aiello LM, Kaldany A, Younger MD. Diabetic vascular disease complicating pregnancy. Clinical obstetrics and gynecology. 1981;24(1):107-23.
22. Kearns PP, Dhillon BJ. Angle closure glaucoma precipitated by labour. Acta ophthalmologica. 1990;68(2):225-6.
23. Tang RA, Dorotheo EU, Schiffman JS, Bahrani HM. Medical and surgical management of idiopathic intracranial hypertension in pregnancy. Current neurology and neuroscience reports. 2004;4(5):398-409.
24. Durcan PJ, Corbett JJ, Wall M. The incidence of pseudotumor cerebri: population studies in Iowa and Louisiana. Archives of Neurology. 1988;45(8):875-7.
25. Markey KA, Mollan SP, Jensen RH, Sinclair AJ. Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions. The Lancet Neurology. 2016;15(1):78-91.
26. Lueck CJ, McIlwaine GG. Idiopathic intracranial hypertension. Practical neurology. 2002;2(5):262-71.
27. Digre KB, Varner MW, Corbett JJ. Pseudotumor Cerebri and Pregnancy. Obstetrical & Gynecological Survey. 1985;40(9):575-6.
28. Daniels AB, Liu GT, Volpe NJ, Galetta SL, Moster ML, Newman NJ, Biousse V, Lee AG, Wall M, Kardon R, Acierno MD. Profiles of obesity, weight gain, and quality of life in idiopathic intracranial hypertension (pseudotumor cerebri). American journal of ophthalmology.
2007;143(4):635-41.
29. Koontz WL, Herbert WN, Cefalo RC. Pseudotumor cerebri in pregnancy. Obstetrics & Gynecology. 1983;62(3):324-7.
30. Katz VL, Peterson R, Cefalo RC. Pseudotumor cerebri and pregnancy. American journal of perinatology. 1989;6(04):442-5.
31. Huna-Baron R, Kupersmith MJ. Idiopathic intracranial hypertension in pregnancy. Journal of neurology. 2002;249(8):1078-81.
32. Wall M, Hart WM, Burde RM. Visual field defects in idiopathic intracranial hypertension (pseudotumor cerebri). American journal of ophthalmology. 1983;96(5):654-69.
33. Evans RW, Friedman DI. The management of pseudotumor cerebri during pregnancy. Headache: The Journal of Head and Face Pain. 2000;40(6):495-7.
34. Della-Giustina K, Chow G. Medications in pregnancy and lactation.
Emergency medicine clinics of North America. 2003;21(3):585-613.
35. Percy AK, Nobrega FT, Kurland LT. Optic neuritis and multiple sclerosis: an epidemiologic study. Archives of Ophthalmology. 1972;87(2):135-9.
36.Balcer LJ. Optic neuritis. New England Journal of Medicine. 2006;354(12):1273-80.
37. Optic Neuritis Study Group. The clinical profile of optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol.
1991;109:1673-8.
38. Liu GT. Visual loss: optic neuropathies. In: Liu GT, Volpe NJ, Galetta SL, eds. Neuro-ophthalmology: diagnosis and management, Philadephia: WB Saunders; 2001:103-87.
39. Wayman D, Carmody KA. Optic Neuritis Diagnosed by Bedside Emergency Physician− Performed Ultrasound: A Case Report. The Journal of emergency medicine. 2014;47(3):301-5.
40. Rodriguez M, Siva A, Cross SA, O’brien PC, Kurland LT. Optic neuritis A population‐based study in Olrnsted County, Minnesota. Neurology. 1995;45(2):244-50.
41. Rizzo JF, Lessell S. Optic neuritis and ischemic optic neuropathy: overlapping clinical profiles. Archives of Ophthalmology. 1991;109(12):1668-72.
42. Frohman EM, Frohman TC, Zee DS, McColl R, Galetta S. The neuro-ophthalmology of multiple sclerosis. The Lancet Neurology. 2005;4(2):111-21.
43. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. New England Journal of Medicine. 1998;339(5):285-91.
44. Birk K, Ford C, Smeltzer S, Ryan D, Miller R, Rudick RA. The clinical course of multiple sclerosis during pregnancy and the puerperium. Archives of Neurology. 1990;47(7):738-42.
45. Sadovnick AD, Eisen K, Hashimoto SA, Farquhar R, Yee IM, Hooge J, Kastrukoff L, Oger JJ, Paty DW. Pregnancy and multiple sclerosis: a prospective study. Archives of neurology. 1994;51(11):1120-4.
46. Van Walderveen MA, Tas MW, Barkhof F, Polman CH, Frequin ST, Hommes OR, Valk J. Magnetic resonance evaluation of disease activity during pregnancy in multiple sclerosis. Neurology. 1994;44(2):327.
47. Poser S, Poser W. Multiple sclerosis and gestation. Neurology. 1983;33(11):1422-.
48. Lu E, Wang BW, Guimond C, Synnes A, Sadovnick D, Tremlett H. Disease-modifying drugs for multiple sclerosis in pregnancy A systematic review. Neurology. 2012;79(11):1130-5.
49. Geissbühler Y, Butzkueven H, Hernandez-Diaz S, Hellwig K, Koren G, MacDonald T, Tilson H, Starzyk K, Plana E, Cremer M, von Rosen- stiel P. Pregnancy outcomes from fingolimod clinical trials and post- marketing experience and the need for a multinational Gilenya (TM) (fingolimod) Pregnancy Exposure Registry in multiple sclerosis. In Multiple Sclerosis Journal 2012 (Vol. 18, pp. 44-44). 1 Olivers Yard, 55 City Road, London, England: Sage Publications ltd.
50. Haghikia A, Rolfes E, Schneider H, Tenenbaum T, Zimmermann J, Marziniak M, Kuempfel T, Meinl I, Plavina T, Gold R, Hellwig K. Natalizumb in Active MS during Pregnancy: Efficacy, Safety, and the Conse- quences for Foetal Haematopoiesis (P02. 125). Neurology. 2013;80(7 Supplement):P02-125.
51. Coyle, Patricia K. Multiple sclerosis in pregnancy. CONTINUUM: Life-long Learning in Neurology. 2014;20(1):42-59.
52. Chung CY, Kwok AK, Chung KL. Use of ophthalmic medications during pregnancy. Hong Kong Medical Journal. 2004;10(3):191-6.
53. Manufacturer’s Information: Azopt product monograph. Texas: Alcon Ophthalmics, Fort Worth, April 1998.
54. Donoway T, Mandeville J, Gauer R. When a fetus survives methotrexate exposure. J Fam Pract. 2012;61(3):E1-4.
55. Kirshon B, Wasserstrum N, Willis R, Herman GE, McCabe ER. Teratogenic effects of first-trimester cyclophosphamide therapy. Obstetrics & Gynecology. 1988;72(3):462-3.
56. Natekar A, Pupco A, Bozzo P, Koren G. Safety of azathioprine use during pregnancy. Canadian Family Physician. 2011;57(12):1401-2.
57. Drugs.com. [Internet]. 2017 [cited 2017 Jul 10]. Available at: www. drugs.com.
58. Falardeau J, Lobb BM, Golden S, Maxfield SD and Tanne E. The use of acetazolamide during pregnancy in intracranial hypertension patients. Journal of Neuro-Ophthalmology. 2013;33(1):9-12.
59. Friend S, Richman S, Bloomgren G, Cristiano LM, Wenten M. Evaluation of pregnancy outcomes from the Tysabri (natalizumab) pregnancy exposure registry: a global, obersvational, follow-up study. BMC neurology. 2016;16(1):150.
60. Kieseier BC, Benamor M. Pregnancy outcomes following maternal and paternal exposure to teriflunomide during treatment for relapsing-remitting multiple sclerosis. Neurology and therapy. 2014;3(2):133-8.
2. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?. Immunology today. 1993;14(7):353-6.
3. Sharma S, Wuntakal R, Anand A, Sharma TK, Downey G. Pregnancy and the eye. The Obstetrician & Gynaecologist. 2006;8(3):141-6.
4. Qureshi IA, Xi XR, Wu XD. Intraocular pressure trends in pregnancy and in the third trimester hypertensive patients. Acta obstetricia et gynecologica Scandinavica. 1996;75(9):816-9.
5. Garg P, Aggarwal P. Ocular changes in pregnancy. Nepalese Journal of Ophthalmology. 2012;4(1):150-61.
6. Maris PJ, Mandal AK, Netland PA. Medical therapy of pediatric
glaucoma and glaucoma in pregnancy. Ophthalmology Clinics. 2005;18(3):461-8.
7. Brauner SC, Chen TC, Hutchinson BT, Chang MA, Pasquale LR,
Grosskreutz CL. The course of glaucoma during pregnancy: a retrospective case series. Archives of Ophthalmology. 2006;124(8):1089- 94.
8. Vaideanu D, Fraser S. Glaucoma management in pregnancy: a questionnaire survey. Eye. 2007;21(3):341-3.
9. Salim S. Glaucoma in pregnancy. Current opinion in ophthalmology. 2014;25(2):93-7.
10. Thorne JE, Suhler E, Skup M, Tari S, Macaulay D, Chao J, Ganguli A. Prevalence of noninfectious uveitis in the United States: a claims- based analysis. JAMA ophthalmology. 2016;134(11):1237-45.
11. Rabiah PK, Vitale AT. Noninfectious uveitis and pregnancy. American journal of ophthalmology. 2003;136(1):91-8.
12. Chiam NP, Hall AJ, Stawell RJ, Busija L, Lim LL. The course of uveitis in pregnancy and postpartum. British Journal of Ophthalmology. 2013;97:1284–8.
13. Chiam NP, Lim LL. Uveitis and gender: the course of uveitis in pregnancy. Journal of ophthalmology. 2014;2014.
14. Chan CC, Reed GF, Kim Y, Agrón E, Buggage RR. A correlation of pregnancy term, disease activity, serum female hormones, and cyto- kines in uveitis. British Journal of Ophthalmology. 2004;88(12):1506-9.
15. Koren G. Mycophenolate mofetil. Canadian Family Physician. 2008;54(8):1112-3.
16. Wakefield D, El-Asrar AA, McCluskey P. Treatment of severe inflammatory eye disease in patients of reproductive age and during pregnancy. Ocular immunology and inflammation. 2012;20(4):277-87.
17. Best RM, Chakravarthy U. Diabetic retinopathy in pregnancy. British journal of ophthalmology. 1997;81(3):249-51.
18. Sunness JS. The pregnant woman’s eye. Survey of ophthalmology. 1988;32(4):219-38.
19. Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Diabetes care. 2000;23(8):1084-91.
20. Lopez-Lopez F, Gomez-Ulla F, Rodriguez-Cid MJ, Arias L. Triamcinolone and bevacizumab as adjunctive therapies to panretinal photocoagulation for proliferative diabetic retinopathy. ISRN ophthalmology. 2012; 2012.
21. Kitzmiller JL, Aiello LM, Kaldany A, Younger MD. Diabetic vascular disease complicating pregnancy. Clinical obstetrics and gynecology. 1981;24(1):107-23.
22. Kearns PP, Dhillon BJ. Angle closure glaucoma precipitated by labour. Acta ophthalmologica. 1990;68(2):225-6.
23. Tang RA, Dorotheo EU, Schiffman JS, Bahrani HM. Medical and surgical management of idiopathic intracranial hypertension in pregnancy. Current neurology and neuroscience reports. 2004;4(5):398-409.
24. Durcan PJ, Corbett JJ, Wall M. The incidence of pseudotumor cerebri: population studies in Iowa and Louisiana. Archives of Neurology. 1988;45(8):875-7.
25. Markey KA, Mollan SP, Jensen RH, Sinclair AJ. Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions. The Lancet Neurology. 2016;15(1):78-91.
26. Lueck CJ, McIlwaine GG. Idiopathic intracranial hypertension. Practical neurology. 2002;2(5):262-71.
27. Digre KB, Varner MW, Corbett JJ. Pseudotumor Cerebri and Pregnancy. Obstetrical & Gynecological Survey. 1985;40(9):575-6.
28. Daniels AB, Liu GT, Volpe NJ, Galetta SL, Moster ML, Newman NJ, Biousse V, Lee AG, Wall M, Kardon R, Acierno MD. Profiles of obesity, weight gain, and quality of life in idiopathic intracranial hypertension (pseudotumor cerebri). American journal of ophthalmology.
2007;143(4):635-41.
29. Koontz WL, Herbert WN, Cefalo RC. Pseudotumor cerebri in pregnancy. Obstetrics & Gynecology. 1983;62(3):324-7.
30. Katz VL, Peterson R, Cefalo RC. Pseudotumor cerebri and pregnancy. American journal of perinatology. 1989;6(04):442-5.
31. Huna-Baron R, Kupersmith MJ. Idiopathic intracranial hypertension in pregnancy. Journal of neurology. 2002;249(8):1078-81.
32. Wall M, Hart WM, Burde RM. Visual field defects in idiopathic intracranial hypertension (pseudotumor cerebri). American journal of ophthalmology. 1983;96(5):654-69.
33. Evans RW, Friedman DI. The management of pseudotumor cerebri during pregnancy. Headache: The Journal of Head and Face Pain. 2000;40(6):495-7.
34. Della-Giustina K, Chow G. Medications in pregnancy and lactation.
Emergency medicine clinics of North America. 2003;21(3):585-613.
35. Percy AK, Nobrega FT, Kurland LT. Optic neuritis and multiple sclerosis: an epidemiologic study. Archives of Ophthalmology. 1972;87(2):135-9.
36.Balcer LJ. Optic neuritis. New England Journal of Medicine. 2006;354(12):1273-80.
37. Optic Neuritis Study Group. The clinical profile of optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol.
1991;109:1673-8.
38. Liu GT. Visual loss: optic neuropathies. In: Liu GT, Volpe NJ, Galetta SL, eds. Neuro-ophthalmology: diagnosis and management, Philadephia: WB Saunders; 2001:103-87.
39. Wayman D, Carmody KA. Optic Neuritis Diagnosed by Bedside Emergency Physician− Performed Ultrasound: A Case Report. The Journal of emergency medicine. 2014;47(3):301-5.
40. Rodriguez M, Siva A, Cross SA, O’brien PC, Kurland LT. Optic neuritis A population‐based study in Olrnsted County, Minnesota. Neurology. 1995;45(2):244-50.
41. Rizzo JF, Lessell S. Optic neuritis and ischemic optic neuropathy: overlapping clinical profiles. Archives of Ophthalmology. 1991;109(12):1668-72.
42. Frohman EM, Frohman TC, Zee DS, McColl R, Galetta S. The neuro-ophthalmology of multiple sclerosis. The Lancet Neurology. 2005;4(2):111-21.
43. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. New England Journal of Medicine. 1998;339(5):285-91.
44. Birk K, Ford C, Smeltzer S, Ryan D, Miller R, Rudick RA. The clinical course of multiple sclerosis during pregnancy and the puerperium. Archives of Neurology. 1990;47(7):738-42.
45. Sadovnick AD, Eisen K, Hashimoto SA, Farquhar R, Yee IM, Hooge J, Kastrukoff L, Oger JJ, Paty DW. Pregnancy and multiple sclerosis: a prospective study. Archives of neurology. 1994;51(11):1120-4.
46. Van Walderveen MA, Tas MW, Barkhof F, Polman CH, Frequin ST, Hommes OR, Valk J. Magnetic resonance evaluation of disease activity during pregnancy in multiple sclerosis. Neurology. 1994;44(2):327.
47. Poser S, Poser W. Multiple sclerosis and gestation. Neurology. 1983;33(11):1422-.
48. Lu E, Wang BW, Guimond C, Synnes A, Sadovnick D, Tremlett H. Disease-modifying drugs for multiple sclerosis in pregnancy A systematic review. Neurology. 2012;79(11):1130-5.
49. Geissbühler Y, Butzkueven H, Hernandez-Diaz S, Hellwig K, Koren G, MacDonald T, Tilson H, Starzyk K, Plana E, Cremer M, von Rosen- stiel P. Pregnancy outcomes from fingolimod clinical trials and post- marketing experience and the need for a multinational Gilenya (TM) (fingolimod) Pregnancy Exposure Registry in multiple sclerosis. In Multiple Sclerosis Journal 2012 (Vol. 18, pp. 44-44). 1 Olivers Yard, 55 City Road, London, England: Sage Publications ltd.
50. Haghikia A, Rolfes E, Schneider H, Tenenbaum T, Zimmermann J, Marziniak M, Kuempfel T, Meinl I, Plavina T, Gold R, Hellwig K. Natalizumb in Active MS during Pregnancy: Efficacy, Safety, and the Conse- quences for Foetal Haematopoiesis (P02. 125). Neurology. 2013;80(7 Supplement):P02-125.
51. Coyle, Patricia K. Multiple sclerosis in pregnancy. CONTINUUM: Life-long Learning in Neurology. 2014;20(1):42-59.
52. Chung CY, Kwok AK, Chung KL. Use of ophthalmic medications during pregnancy. Hong Kong Medical Journal. 2004;10(3):191-6.
53. Manufacturer’s Information: Azopt product monograph. Texas: Alcon Ophthalmics, Fort Worth, April 1998.
54. Donoway T, Mandeville J, Gauer R. When a fetus survives methotrexate exposure. J Fam Pract. 2012;61(3):E1-4.
55. Kirshon B, Wasserstrum N, Willis R, Herman GE, McCabe ER. Teratogenic effects of first-trimester cyclophosphamide therapy. Obstetrics & Gynecology. 1988;72(3):462-3.
56. Natekar A, Pupco A, Bozzo P, Koren G. Safety of azathioprine use during pregnancy. Canadian Family Physician. 2011;57(12):1401-2.
57. Drugs.com. [Internet]. 2017 [cited 2017 Jul 10]. Available at: www. drugs.com.
58. Falardeau J, Lobb BM, Golden S, Maxfield SD and Tanne E. The use of acetazolamide during pregnancy in intracranial hypertension patients. Journal of Neuro-Ophthalmology. 2013;33(1):9-12.
59. Friend S, Richman S, Bloomgren G, Cristiano LM, Wenten M. Evaluation of pregnancy outcomes from the Tysabri (natalizumab) pregnancy exposure registry: a global, obersvational, follow-up study. BMC neurology. 2016;16(1):150.
60. Kieseier BC, Benamor M. Pregnancy outcomes following maternal and paternal exposure to teriflunomide during treatment for relapsing-remitting multiple sclerosis. Neurology and therapy. 2014;3(2):133-8.