Grand Rounds
Eddie Apenbrinck M.D.
University of Louisville School of Medicine
Department of Ophthalmology & Visual Sciences
3/7/2014
Subjective
CC: Left inferotemporal periorbital tenderness and
swelling
HPI: 17 year old white female with a 2 ½ month
history of chronic sinus congestion presents to
Kosair ED with 1 day of tenderness and swelling of
the left inferotemporal orbital rim
Treatment prior to ED

Diagnosed with pansinusitis 2 week prior to ED visit


Started on clindamycin and prednisone PO
Minimal improvement on antibiotics and steroids


CT sinuses: erosion of nasal septum
Nasal Mucosa Biopsy:



Initially
read as likely granulomatosis with polyangiitis (GPA)
Second opinion read biopsy as possible Epstein Bar Virus (EBV)
lymphoma
Treated with pulse steroids and scheduled for pediatric
rheumatology appointment
POH: Myopic
PMHx: saddle nose deformity
FHx: seasonal allergies
ROS: intermittent headaches, epistaxis, myalgia and fatigue (~2½
months)
Allergies: cefprozil (hives)
Meds: none
Exam
OD
OS
VA(sc,n):
20/20 OU
Pupils:
3
2 OU
No RAPD
IOP:
12 OU
EOM:
Full OU
slight inferior periorbital
tenderness on upgaze
Orbits:
No proptosis, No lid retraction, No ecchymosis
Exam
OD
OS
Anterior Segment
L/L:
WNL
slight swelling of left
inferotemporal periorbital area
C/S:
K:
AC:
I/L:
Vitreous:
WNL OU
WNL OU
No cell or flare OU
WNL OU
WNL OU
Dilated Fundus Exam:
WNL OU
MRI
T2 Coronal MRI of orbits shows enhancement of ethmoid sinus with erosion into left medial orbit
MRI
T1 Axial with gadolinium shows enhancement of ethmoid sinus with erosion into left medial orbit
Assessment

Assessment: 17yo white female with chronic sinus
congestion found to have an ethmoid sinus lesion with
extension into the left orbit.

DDx



Granulomatosis with polyangiitis (GPA)
EBV lymphoma
Chronic Sinusitis
Plan

Plan

Admission for further workup and treatment


Repeat biopsy of nasal mucosa


Started on IV ampicillin-sulbactam (Unasyn) 3,000mg q6h
Biopsy of left inferior nasal septum and left inferior
turbinate obtained and sent to pathology
Ophthalmology follow-up as outpatient following
discharge
Hospital Course
Labs
ESR: 65
(0-25)
CRP: 166.7 (1.0-9.0)
Proteinase-3 Auto Antibodies:
positive
c-ANCA: negative
p-ANCA: negative
Myeloperoxidase Auto
antibodies: negative
TSH: wnl
Free T4: wnl
Immunoglobulin Panel: (all WNL)
C3 149
C4 25
IgA 165
IgG 949
IgM 67
CBC, CMP and UA: wnl
Gram Stain:
positive for gram negative bacillus
Nasal Mucosa Culture:
Klebsella Pneumonia
Hospital Course
Imaging

CXR, MRI/MRA brain: WNL
Flow Cytometry

normal percentages and absolute numbers of T-cell, B-cell and
natural killer cell populations. No evidence of B-cell
monoclonality or increased blast population
Anatomic Pathology

Both biopsy samples showed necrotizing granulomatous
inflammation consist with GPA
Pathology
10x magnification
granuloma
eosinophiles
20x magnification
Granuloma with
necrotic center
Multinucleated giant cell
Necrotizing granulomatous inflammation
Hospital Course
 Started on Solumedrol 1g once followed by oral taper as
outpatient
 Started on rituximab (15mg/kg) and cyclophosphamide
(15mg/kg) once
 Patient discharged with plan for readmission in 2 weeks for
second dose of rituximab and cyclophosphamide
Ophthalmology 1 week follow up
OD
VA(cc):
Pupils:
IOP:
EOM
Ant Segment:
DFE:
OS
20/20 OU
4
3 OU; No RAPD
13
14
Full OU without pain
WNL OU
WNL OU
Assessment: Patient with GPA currently asymptomatic
Plan: Observe with follow-up in 6 months
Clinical Course

Second dose of rituximab and cyclophosphamide 2 weeks after
discharge




Patient with increased energy, no epistaxis and improved nasal
congestion
CBC & CMP: WNL
CRP = 15.8 (<10.0)
Patient was started on maintenance therapy of Azathioprine,
Bactrim, and continued prednisone taper
Granulomatosis with Polyangiitis

GPA is a multisystem autoimmune disorder characterized by the
classic triad of necrotizing granulomatous vasculitis of the upper and
lower respiratory tract, focal segmental glomerulonephritis, and
necrotizing vasculitis of small vessels

Incidence: 3 per 100,000 reported in United States

Differential Diagnosis:
 Clinical: Orbital pseudotumor, Sarcoidosis, fungal infections,
Histiocytosis X, IGG4-related disease, , Rosai-Dorfman disease
(sinus histiocytosis with massive lymphadenopathy),

Pathology: polyarteritis nodosa, microscopic polyangiitis, Churg-
Strauss syndrome
Granulomatosis with Polyangiitis

Anti-cytoplasmic Nuclear Antibodies (ANCA): staining
occurs in two patterns



32% to >95% of patients with GPA are positive C-ANCA
depending on disease activity 7


Cytoplasmic staining pattern (C-ANCA), which is specific for Proteinase3 (PR3) also called myeloblastin
Perinuclear staining pattern (P-ANCA), which is specific for
myeloperoxidase
91% sensitivity and 99% specificity in active disease 8
Less than 5% of patient with GPA are positive for P-ANCA
Clinical Features

Patient typically have flu-like symptoms lasting several days or
weeks including fever, polymyalgia, polyarthralgia, headache,
malaise, anorexia, unintended weight loss

90% of patients report ear, nose, or throat problems

75% of patients seek care because of upper and lower respiratory
complaints

Ocular or orbital involvement is seen in 15% of patients at
presentation and up to 50% during the course of the disease.
Clinical Features

Chronic Complications: Orbital socket contracture, enophthalmos, restrictive
ophthalmopathy, chronic orbital pain
Foster CS, Yang J. Wegener’s Granulomatosis. Albert & Jakobiec's Principles and Practice of Ophthalmology. Pages 4447- 4460. 2008.
Treatment

There is no standardized treatment regimen for granulomatosis with
polyangiitis

Treatment is aimed at inducing remission
 General approach includes high-dose steroids and cyclophosphamide
 Rituximab-based regimen plus steroids may be considered as
alternative in patients with relapsing or refractory disease

Remission maintained with cyclophosphamide, methotrexate or
azathioprine

Plasma exchange may be beneficial in patients with severe renal disease
Literature Search
Aug 2013



Randomized double blind clinical trial included 197 patients, compared
rituximab (once a week for 4 weeks) followed by placebo to
cyclophosphamide administered for 3 to 6 months followed by
azathioprine for 12 to 15 months.
Both groups showed comparable rates of remission at 6, 12 and 18
months
Conclusion: a single course of rituximab was as effective as continuous
conventional immunosuppressive therapy for the induction and
maintenance of remission over the course of 18 months.
Literature Search
Ophthalmology. 2014 Feb
Retrospective noninterventional comparative case series including 247 patients with orbital
inflammation, compared GPA with other causes of orbital inflammation to identify the
presenting clinical and radiographic features most likely to predict GPA
Features highly suggestive of GPA: sinonasal symptoms, sinonasal changes, or paranasal bone
erosion on imaging.
22% of patients (8/37) with GPA had evidence of systemic involvement at presentation, and
no patient presenting with only orbital GPA developed later systemic disease over a median
follow-up of 2.7 years.
Thank You
References
1. BCSC: Intraocular Inflammation and Uveitis. Pgs :145-146
2. BCSC: Update on General Medicine. Optic Neuritis. Pgs 177-179
3. Pakrou N, Selva D, Leibovitch I. Wegener;s Granulomatosis: ophthalmic manifestations and
management. Semin Arthritis Rheum. 2006;35(5):284-292
4. Berden A, Göçeroglu A, Jayne D, et al. Diagnosis and management of ANCA associated
vasculitis. BMJ. 2012 Jan 16;344:e26.
5. Schilder AM. Wegener's Granulomatosis vasculitis and granuloma. Autoimmun Rev. 2010
May;9(7):483-7.
6. Tan LT, Davagnanam I, et.al. Clinical and Imaging Features Predictive of
Orbital Granulomatosis with Polyangiitis and the Risk of Systemic Involvement.
Ophthalmology. 2014 Feb 20. pii: S0161-6420(13)01175-5. doi:
10.1016/j.ophtha.2013.12.003. [Epub ahead of print]
7. Foster CS, Yang J. Wegener’s Granulomatosis. Albert & Jakobiec's Principles and Practice of
Ophthalmology. Pages 4447- 4460. 2008.
8. Schonermarck U, Lamprecht P, Csernok E, Gross WL. Prevalence and spectrum of
rheumatic diseases associated with proteinase 3-antineutrophil cytoplasmic antibodies
(ANCA) and myeloperoxidases- ANCA. Rheumatology 2001; 40;
178-84
9. Specks U, Merkel PA, Seo P, Spiera R et al. RAVE-ITN Research Group. Efficacy of
remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013 Aug
1;369(5):417-27.