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A case of acquired Brown syndrome treated with adalimumab
Journal Pre-proof A case of acquired Brown syndrome treated with adalimumab Kristi L. Michels, Sudhi P. Kurup, MD, Megan L. Curran, MD, Risa Alperin, MD, Erika De Leon, CO, Rebecca Mets-Halgrimson, MD, MPH PII:
S1091-8531(20)30031-8
DOI:
https://doi.org/10.1016/j.jaapos.2020.01.003
Reference:
YMPA 3147
To appear in:
Journal of AAPOS
Received Date: 25 August 2019 Revised Date:
10 January 2020
Accepted Date: 11 January 2020
Please cite this article as: Michels KL, Kurup SP, Curran ML, Alperin R, De Leon E, Mets-Halgrimson R, A case of acquired Brown syndrome treated with adalimumab, Journal of AAPOS (2020), doi: https:// doi.org/10.1016/j.jaapos.2020.01.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020, American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.
A case of acquired Brown syndrome treated with adalimumab Kristi L. Michels,a Sudhi P. Kurup, MD,b,c Megan L. Curran, MD,d Risa Alperin, MD,e Erika De Leon, CO,b and Rebecca Mets-Halgrimson, MD, MPHb,c Author affiliations: aNorthwestern University Feinberg School of Medicine, Chicago, Illinois; b Division of Ophthalmology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; cDepartment of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; dDepartment of Pediatric Rheumatology, University of Colorado, Aurora, Colorado; ePediatric Rheumatology Division, Children’s Hospital at NYU Langone Medical Center, New York, New York Submitted August 25, 2019. Revision accepted January 11, 2020. Correspondence: Name: Rebecca Mets-Halgrimson, MD, MPH, 225 E. Chicago Avenue, Box 70, Chicago, IL 60611 (email: [email protected]). Word count: 1,128
We present the case of a 4-year-old boy with acquired Brown syndrome of inflammatory origin. Without evidence of systemic inflammation, the disease typically resolves with oral steroids or nonsteroidal anti-inflammatory drugs. Refractory cases can be treated with local steroid injections or surgery. The present case of inflammatory Brown syndrome did not respond to conservative therapy, and parental concerns and wishes precluded more invasive treatments. Adalimumab was initiated and led to complete resolution of the disease. Brown syndrome is a vertical strabismus characterized by restriction of the superior oblique tendon–trochlear complex that causes a characteristic deficit of elevation in adduction.1 Brown syndrome can be unilateral or bilateral, constant or intermittent, and congenital or acquired.1,2 Congenital abnormalities of the superior oblique muscle, tendon, or trochlea as well as abnormal development and innervation of the trochlear nerve may develop, and cases of inheritance as an autosomal dominant trait have been reported.1,3 Acquired causes include trauma, mass lesions, systemic inflammatory disease (eg, juvenile idiopathic arthritis), local inflammation, sinusitis, thyroid ophthalmopathy, neuromuscular junction disease, myopathies, and iatrogenic surgical complications.2 All etiologies cause passive and active restriction of normal movement of the superior oblique tendon through the trochlear pulley. Case Report A previously healthy 4-year-old boy presented at the Ann & Robert H. Lurie Children’s Hospital of Chicago with abnormal eye movements that began a few weeks earlier. His mother noticed that he was unable to elevate his left eye and intermittently adopted chin-up posturing. The patient was able to describe occasional episodes of vertical diplopia. Of note, the mother brought the patient to clinic when he was 2 years of age for an episode of abnormal eye movements; at
that time, his examination was completely normal. On examination, his distance visual acuity was 20/30 in the right eye and 20/25 in the left eye and near visual acuity was 20/20 in both eyes. He appreciated 60 arcsec on the Randot Preschool Stereotest (Stereo Optical Company Inc, Chicago, Il). There were no abnormalities on pupillary, anterior segment, or posterior segment examinations. At a fixation distance of 6 m, the patient had a left hypotropia of 16∆ in primary gaze, 30∆ in upgaze, and only a flick of movement in downgaze. At a fixation of 33 cm, there was a left hypotropia of 18∆ in primary gaze. At distance and near fixation in primary gaze, the patient also had an exotropia of 6∆. Ductions were full in the right eye. The left eye showed restriction in upgaze, greatest in adduction but notable to a lesser degree in direct supraduction and while in abduction (eSupplement 1, available at jaapos.org). The patient also displayed a chin-up head posture and tended to tilt his head leftward. Magnetic resonance imaging (MRI) revealed thickening and enhancement of the anterior portion of the left superior oblique muscle as well as of the superior oblique tendon–trochlear complex, suggesting an inflammatory process (Figure 1). Laboratory tests for systemic inflammatory processes (rheumatoid factor, anti-nuclear antibody, erythrocyte sedimentation rate, and C-reactive protein), myasthenia gravis (acetylcholine receptor antibody and antimuscle-specific kinase antibody), and thyroid eye disease (thyroid stimulating hormone and free T4) were all negative or within normal limits. The patient was started on prednisolone 1 mg/kg daily orally for 5 days without improvement. He was then given naproxen 10 mg/kg/day orally, with minimal improvement. At this point, further management with steroid injections or surgery was offered, but the patient’s family opted not to pursue procedurally invasive treatment options and wished to avoid
anesthesia. Rheumatology was consulted for further systemic investigation and management recommendations. The rheumatologist confirmed that the patient had no signs of systemic inflammatory arthritis or myositis and recommended a trial of a stronger and longer steroid taper (2mg/kg/day ×7 days, 1mg/kg/day ×7 days, 0.5mg/kg/day ×7 days), with repeat MRI at the 2week mark after discussing that, if effective, the patient might then need a steroid-sparing agent. The family deferred a follow-up MRI, but the patient experienced noticeable improvement in symptoms, alignment, and motility with the longer steroid taper, although symptoms returned shortly after the taper was completed (eSupplement 1.) These results supported the indication for a steroid-sparing agent. Disease-modifying antirheumatic drugs (DMARDs) were discussed with the family as a nontraditional approach to Brown syndrome; we noted, in particular, that adalimumab has been used in orbital myositis and tenosynovitis with excellent results.4,5 Adalimumab was initiated after a negative PPD result. The patient showed gradual improvement in symptoms and measurements over the next few months, and his Brown syndrome had resolved entirely after 10 months. He was asymptomatic, with completely normal alignment and motility measurements on examination. Adalimumab was discontinued almost 9 months after initiation. At the most recent follow-up, 19 months since discontinuation of adalimumab, sensorimotor examination was normal, without clinical recurrence of disease (eSupplement 1). The patient retained 20/20 visual acuity, stereoacuity of 40 arcsec, and the ability to fuse on Worth 4 Dot testing at distance and near. Discussion To our knowledge, this is the first reported use of a steroid-sparing immunosuppressant, adalimumab, in the treatment of acquired Brown syndrome of local, inflammatory origin. First-
line treatment for similar cases includes oral steroid or nonsteroidal anti-inflammatory drug (NSAID) therapy.1,6,7 Local steroid injections may be used in refractory cases. Finally, surgery is an option if more conservative management is unsuccessful.1,6,8,9 Because the present case was refractory to steroids and NSAIDs and steroid injections and surgery were not pursued, novel treatment options were explored. The patient’s significant yet short-term response to stronger steroid therapy along with superior oblique myositis on MRI suggested a role for an immunosuppressive agent. Typically, when starting DMARDs in pediatrics, if there is swift resolution of symptoms, a taper of the medication is attempted around 6 months. Clinical findings and imaging are used to help determine when to wean and whether the wean is successful. In this case, parents and providers agreed on the importance of controlling the inflammation to prevent permanent damage to the superior oblique muscle and tendon. Adalimumab was chosen in light of prior success in its use for orbital myositis, which was a component of the child’s disease process along with tenosynovitis and trochleitis. Clinical resolution was achieved gradually over 10 months, and the medication was discontinued after 9 months. No repeat MRI was performed because the child was clinically stable. Although the natural history of the disease in this case or the response to steroid injections or surgical correction cannot be known, adalimumab treatment was successful in preventing permanent muscle and tendon damage from Brown syndrome and led to full resolution of strabismus, with no lingering abnormalities or recurrence at final follow-up. Literature Search PubMed was last searched in July 2019 without date restriction using the terms Brown syndrome, Brown syndrome treatment, Brown syndrome AND adalimumab, and orbital myositis treatment.
References 1.
Anglade E, McKeown CA. Robb RM. Brown’s syndrome. Int Ophthalmnol Clin 1992;32:63-70.
2.
Lang M, Faraji N, Coffey M, Badve C. MRI of acquired Brown syndrome: a report of two cases. Radiol Case Rep 2017;13:92-5.
3.
Kenawy N, Pilz DT, Watts P. Familial unilateral Brown syndrome. Indian J Ophthalmol 2008;56:430-34.
4.
Verma S, Kroeker KI, Fedorak RN. Adalimumab for orbital myositis in a patient with Crohn’s disease who discontinued infliximab: a case report and review of the literature. BMC Gastroenterol 2013;4;13:59.
5.
Adams AB, Kazim M, Lehman TJ. Treatment of orbital myositis with adalimumab (Humira). J Rheumatol 2005;32:1374-5.
6.
Lee J. Management of Brown syndrome. Semin Ophthalmol 2008;23:291-3.
7.
Chhablani PP, Chandrasekharan A. Resolution of acquired Brown syndrome with oral steroid therapy. Oman J Ophthalmol 2017;10:128-30.
8.
Hermann JS. Acquired Brown’s syndrome of inflammatory origin: response to locally injected steroids. Arch Ophthalmol 1978;96:1228-32.
9.
Cho YA, Kim S, Graef MH. Surgical outcomes in correction of Brown syndrome. Korean J Ophthalmol 2006;20:33-40.
Legends FIG 1. T1-weighted fat-saturated coronal (A) and T1-weighted fat-saturated axial (B) magnetic resonance images revealing abnormal enhancement surrounding the left trochlear sling involving the superior oblique tendon and the anterior aspect of the muscle belly. Thickening and enhancement of the left superior oblique as well as the tendon/trochlear sling was suggestive of an inflammatory process.
S1091-8531(20)30031-8
DOI:
https://doi.org/10.1016/j.jaapos.2020.01.003
Reference:
YMPA 3147
To appear in:
Journal of AAPOS
Received Date: 25 August 2019 Revised Date:
10 January 2020
Accepted Date: 11 January 2020
Please cite this article as: Michels KL, Kurup SP, Curran ML, Alperin R, De Leon E, Mets-Halgrimson R, A case of acquired Brown syndrome treated with adalimumab, Journal of AAPOS (2020), doi: https:// doi.org/10.1016/j.jaapos.2020.01.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020, American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.
A case of acquired Brown syndrome treated with adalimumab Kristi L. Michels,a Sudhi P. Kurup, MD,b,c Megan L. Curran, MD,d Risa Alperin, MD,e Erika De Leon, CO,b and Rebecca Mets-Halgrimson, MD, MPHb,c Author affiliations: aNorthwestern University Feinberg School of Medicine, Chicago, Illinois; b Division of Ophthalmology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; cDepartment of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; dDepartment of Pediatric Rheumatology, University of Colorado, Aurora, Colorado; ePediatric Rheumatology Division, Children’s Hospital at NYU Langone Medical Center, New York, New York Submitted August 25, 2019. Revision accepted January 11, 2020. Correspondence: Name: Rebecca Mets-Halgrimson, MD, MPH, 225 E. Chicago Avenue, Box 70, Chicago, IL 60611 (email: [email protected]). Word count: 1,128
We present the case of a 4-year-old boy with acquired Brown syndrome of inflammatory origin. Without evidence of systemic inflammation, the disease typically resolves with oral steroids or nonsteroidal anti-inflammatory drugs. Refractory cases can be treated with local steroid injections or surgery. The present case of inflammatory Brown syndrome did not respond to conservative therapy, and parental concerns and wishes precluded more invasive treatments. Adalimumab was initiated and led to complete resolution of the disease. Brown syndrome is a vertical strabismus characterized by restriction of the superior oblique tendon–trochlear complex that causes a characteristic deficit of elevation in adduction.1 Brown syndrome can be unilateral or bilateral, constant or intermittent, and congenital or acquired.1,2 Congenital abnormalities of the superior oblique muscle, tendon, or trochlea as well as abnormal development and innervation of the trochlear nerve may develop, and cases of inheritance as an autosomal dominant trait have been reported.1,3 Acquired causes include trauma, mass lesions, systemic inflammatory disease (eg, juvenile idiopathic arthritis), local inflammation, sinusitis, thyroid ophthalmopathy, neuromuscular junction disease, myopathies, and iatrogenic surgical complications.2 All etiologies cause passive and active restriction of normal movement of the superior oblique tendon through the trochlear pulley. Case Report A previously healthy 4-year-old boy presented at the Ann & Robert H. Lurie Children’s Hospital of Chicago with abnormal eye movements that began a few weeks earlier. His mother noticed that he was unable to elevate his left eye and intermittently adopted chin-up posturing. The patient was able to describe occasional episodes of vertical diplopia. Of note, the mother brought the patient to clinic when he was 2 years of age for an episode of abnormal eye movements; at
that time, his examination was completely normal. On examination, his distance visual acuity was 20/30 in the right eye and 20/25 in the left eye and near visual acuity was 20/20 in both eyes. He appreciated 60 arcsec on the Randot Preschool Stereotest (Stereo Optical Company Inc, Chicago, Il). There were no abnormalities on pupillary, anterior segment, or posterior segment examinations. At a fixation distance of 6 m, the patient had a left hypotropia of 16∆ in primary gaze, 30∆ in upgaze, and only a flick of movement in downgaze. At a fixation of 33 cm, there was a left hypotropia of 18∆ in primary gaze. At distance and near fixation in primary gaze, the patient also had an exotropia of 6∆. Ductions were full in the right eye. The left eye showed restriction in upgaze, greatest in adduction but notable to a lesser degree in direct supraduction and while in abduction (eSupplement 1, available at jaapos.org). The patient also displayed a chin-up head posture and tended to tilt his head leftward. Magnetic resonance imaging (MRI) revealed thickening and enhancement of the anterior portion of the left superior oblique muscle as well as of the superior oblique tendon–trochlear complex, suggesting an inflammatory process (Figure 1). Laboratory tests for systemic inflammatory processes (rheumatoid factor, anti-nuclear antibody, erythrocyte sedimentation rate, and C-reactive protein), myasthenia gravis (acetylcholine receptor antibody and antimuscle-specific kinase antibody), and thyroid eye disease (thyroid stimulating hormone and free T4) were all negative or within normal limits. The patient was started on prednisolone 1 mg/kg daily orally for 5 days without improvement. He was then given naproxen 10 mg/kg/day orally, with minimal improvement. At this point, further management with steroid injections or surgery was offered, but the patient’s family opted not to pursue procedurally invasive treatment options and wished to avoid
anesthesia. Rheumatology was consulted for further systemic investigation and management recommendations. The rheumatologist confirmed that the patient had no signs of systemic inflammatory arthritis or myositis and recommended a trial of a stronger and longer steroid taper (2mg/kg/day ×7 days, 1mg/kg/day ×7 days, 0.5mg/kg/day ×7 days), with repeat MRI at the 2week mark after discussing that, if effective, the patient might then need a steroid-sparing agent. The family deferred a follow-up MRI, but the patient experienced noticeable improvement in symptoms, alignment, and motility with the longer steroid taper, although symptoms returned shortly after the taper was completed (eSupplement 1.) These results supported the indication for a steroid-sparing agent. Disease-modifying antirheumatic drugs (DMARDs) were discussed with the family as a nontraditional approach to Brown syndrome; we noted, in particular, that adalimumab has been used in orbital myositis and tenosynovitis with excellent results.4,5 Adalimumab was initiated after a negative PPD result. The patient showed gradual improvement in symptoms and measurements over the next few months, and his Brown syndrome had resolved entirely after 10 months. He was asymptomatic, with completely normal alignment and motility measurements on examination. Adalimumab was discontinued almost 9 months after initiation. At the most recent follow-up, 19 months since discontinuation of adalimumab, sensorimotor examination was normal, without clinical recurrence of disease (eSupplement 1). The patient retained 20/20 visual acuity, stereoacuity of 40 arcsec, and the ability to fuse on Worth 4 Dot testing at distance and near. Discussion To our knowledge, this is the first reported use of a steroid-sparing immunosuppressant, adalimumab, in the treatment of acquired Brown syndrome of local, inflammatory origin. First-
line treatment for similar cases includes oral steroid or nonsteroidal anti-inflammatory drug (NSAID) therapy.1,6,7 Local steroid injections may be used in refractory cases. Finally, surgery is an option if more conservative management is unsuccessful.1,6,8,9 Because the present case was refractory to steroids and NSAIDs and steroid injections and surgery were not pursued, novel treatment options were explored. The patient’s significant yet short-term response to stronger steroid therapy along with superior oblique myositis on MRI suggested a role for an immunosuppressive agent. Typically, when starting DMARDs in pediatrics, if there is swift resolution of symptoms, a taper of the medication is attempted around 6 months. Clinical findings and imaging are used to help determine when to wean and whether the wean is successful. In this case, parents and providers agreed on the importance of controlling the inflammation to prevent permanent damage to the superior oblique muscle and tendon. Adalimumab was chosen in light of prior success in its use for orbital myositis, which was a component of the child’s disease process along with tenosynovitis and trochleitis. Clinical resolution was achieved gradually over 10 months, and the medication was discontinued after 9 months. No repeat MRI was performed because the child was clinically stable. Although the natural history of the disease in this case or the response to steroid injections or surgical correction cannot be known, adalimumab treatment was successful in preventing permanent muscle and tendon damage from Brown syndrome and led to full resolution of strabismus, with no lingering abnormalities or recurrence at final follow-up. Literature Search PubMed was last searched in July 2019 without date restriction using the terms Brown syndrome, Brown syndrome treatment, Brown syndrome AND adalimumab, and orbital myositis treatment.
References 1.
Anglade E, McKeown CA. Robb RM. Brown’s syndrome. Int Ophthalmnol Clin 1992;32:63-70.
2.
Lang M, Faraji N, Coffey M, Badve C. MRI of acquired Brown syndrome: a report of two cases. Radiol Case Rep 2017;13:92-5.
3.
Kenawy N, Pilz DT, Watts P. Familial unilateral Brown syndrome. Indian J Ophthalmol 2008;56:430-34.
4.
Verma S, Kroeker KI, Fedorak RN. Adalimumab for orbital myositis in a patient with Crohn’s disease who discontinued infliximab: a case report and review of the literature. BMC Gastroenterol 2013;4;13:59.
5.
Adams AB, Kazim M, Lehman TJ. Treatment of orbital myositis with adalimumab (Humira). J Rheumatol 2005;32:1374-5.
6.
Lee J. Management of Brown syndrome. Semin Ophthalmol 2008;23:291-3.
7.
Chhablani PP, Chandrasekharan A. Resolution of acquired Brown syndrome with oral steroid therapy. Oman J Ophthalmol 2017;10:128-30.
8.
Hermann JS. Acquired Brown’s syndrome of inflammatory origin: response to locally injected steroids. Arch Ophthalmol 1978;96:1228-32.
9.
Cho YA, Kim S, Graef MH. Surgical outcomes in correction of Brown syndrome. Korean J Ophthalmol 2006;20:33-40.
Legends FIG 1. T1-weighted fat-saturated coronal (A) and T1-weighted fat-saturated axial (B) magnetic resonance images revealing abnormal enhancement surrounding the left trochlear sling involving the superior oblique tendon and the anterior aspect of the muscle belly. Thickening and enhancement of the left superior oblique as well as the tendon/trochlear sling was suggestive of an inflammatory process.