orbital igg4-related disease
TRANSCRIPT
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Orbital IgG4-Related Disease
Raed Behbehani , MD FRCSC
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Case• A 36 year old Philippino : acute painful loss of vision and
droopy lid in the right eye.
• H/O right 6th nerve palsy 2 years ago , MRI showed right cavernous sinus and sphenoid sinus lesion.
• He was referred to ENT later by ENT and then was lost to follow up by me.
• Recent contact with ENT : biopsy was “non-specific inflammatory” and was treated with oral steroids only.
• PMH : no TB
• Social history : Smoker for 15 years
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Case• VA : HM recognition OD , 20/20 OS.
• TA : 14 mm/Hg OU.
• Pupils : large right RAPD
• Complete ptosis and severe limitation of eye movement in all gaze direction OD.
• Anterior and posterior segment normal OU.
• Humphrey automated visual field testing was normal OS.
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MRI
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MRI
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Investigations• PPD : negative
• Serum ACE : 20 U/L (range 8-52 U/L)
• C-ANCA : 4 U/ml (normal < 23 U/ml)
• (P-ANCA) : 1 U/ml (normal < 22 U/ml).
• Chest x-ray was normal
• Gallium 67 scan : no uptake in the lacrimal gland, parotid gland or mediastinum.
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Management
• Rx : IV methylprednisolone 1 gram/day for 5 days followed by oral steroids 1 mg/Kg.
• Improvement in his ptosis and ocular motility.
• Visual acuity deteriorated to LP OD
• Neurosurgical consultation to obtain a dural biopsy.
• Dura Histology : “Patchy lymphocytic infiltration” few plasma cells.
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Follow up
• Presented 2 months later with sudden decrease in vision OS !
• VA was light perception OD and hand motion recognition OS !
• Pupils : bilaterally sluggish.
• Normal lids and full ocular motility and intact corneal reflexes and facial sensation.
• Fundoscopy : optic nerve pallor OD , normal optic nerve OS.
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Follow up MRI
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Follow up MRI
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Follow up
• VDRL , TPHA, and HIV serology : negatives.
• Lumbar puncture : normal CSF analysis (cells , glucose , protein) and negative staining for AFB , no fungus and negative bacterial culture growth.
• IV steroids
• Review initial specimen of the paranasal polyp biopsy.
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Pathology
H&E stain x400 Masson’s Trichrome Stain x 100
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Pathology
IgG4 positive plasma cells 80/hpf (x 400).
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Follow Up
• Dx : Orbital and intracranial IgG4-related disease
• He received two infusion of 1000 mg IV Rituximab.
• Two months following Rituximab infusion, his serum IgG 4 was elevated at 1440 mg/L (normal 39.2-864 mg/L).
• 6/12 later (2nd infusion Rituximab) : VA NLP OD VA 20/40 OS.
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Follow up MRI
May 2014 October 2014
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Case
• A 32 with recurrent bilateral painless orbital swelling and puffiness for 3 years.
• Severe asthma for 3 years and with that he noticed resolution of eye swelling with oral steroids.
• Significant peripheral esinophilia and high IgE level necessitating treatment with anti IgE therapy.
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Case
Both lacrimal glands were palpable and firm
No other palpable masses or lymphadenopathy or any skin lesions
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CT
2014
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CT
2010
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Case
• IgG 24.1 g/L (6-16g/L) , IgG4 >1440 mg/L ( 39.2- 864 mg/L).
• ANA, p-ANCA ,c-ANCA - negative
• Bilateral lacrimal gland biopsy performed.
• Biopsy - high IgG4 plasma cell infiltrate.
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Case
Oral steroids (Recurrence)IV Rituximab
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IgG4-RD• An inflammatory condition of unknown etiology.• Autoimmune pancreatitis (AIP) with elevated serum
IgG4 levels and later systemic lesions found (Hamano H et al. NEJM 2001)
• Tumefactive lesions in a number of tissues and organs.
• Diagnosis is established by IgG4-bearing plasma cells in addition to characteristic morphologic features, with or without elevated serum IgG4.
2,
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Mikulicz
Johann von Milulicz-Radecki , 1888
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IgG4-RD
Mickulicz disease, Kuttner tumor (sclerosing sialadenitis)Riedel thyroiditismultifocal fibrosclerosisOrmond disease (idiopathic retroperitoneal fibrosis)Aortitis, periaortitis Retroperitoneal fibrosis, Eosinophilic angiocentric fibrosis (EAF)
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Diagnosis
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Orbital IgG4-RD and AIP
• 50% of patients with Orbital IgG4-RD will have systemic lesions (salivary gland, liver , pituitary , pancreas, retroperitoneeum) .
• 20-45% of patients with AIP will have orbital IgG4-RD.
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Orbital IgG4-RD• Clinically can be confused with idiopathic
orbital inflammatory (IOI) , infectious and neoplastic conditions.
• Many patients with IOI do not undergo biopsy and even if done biopsy is no stained routinely for IgG4.
• Many cases of IOI represent misdiagnosed IgG-RD. (Geyer et al. 2010).
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Patterns or Orbital IgR4-RD
1) IgG-4 Dacryoadenitis (62%-88) (Sogabe et al. Wallace et al. Sato et al. )
2) Enlargement of orbital nerves (V2) associated with orbital
myositis and lacrimal gland disease, +_ with paranasal sinus
disease, eosinophilia, and systemic involvement; and
3) Sclerosing orbital inflammation
4) Optic nerve involvement
5) Ocular adnexal involvement
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IgG4-RD Darcyoadenitis
• The most common maniesfation of orbital Ig4-RD (62%-88) (Sogabe et al. Wallace et al)
• Unilateral , Bilateral • History of allergy with an elevated IgE
levels (50%) .
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Enlargement of the Infra-orbital Nerve
• In 39% of cases (Sogabe et al.) usually with EOM and Sinus involvement.
• In 20 of 68 patients with “Miculikz IgG-4 RD”. (Takano K at al. 2014)
• In 20 of the 28 eyes with either RLH or IgG4-RD. (Hardy et al. Ophthalmology 2014)
• Incidence higher in IgG4-ROD patient group than non-IgG4-ROD (p < 0.0001). (Ohshima et al. 2012)
• No sensory disturbance.
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IgG4-RD vs IOIIgR4-RD
Idiopathic Orbital
InflammationMode of Onset Chronic Acute-Subacute
Pain - + severe
Laterality Bilateral Unialteral
Infra-orbital nerve
enlargement+ pathognomonic -
Associated systemic diseases
Allergic rhinitis, asthma rare
Other organ involvement
AIP, sclerosing cholangitis,
retoperitoneal fibrosis -
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Optic Neuropathy
• Usually compressive (enlarged V2, enlarged EOM, fat, mass)
• Infiltrative or inflammatory.
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Ocular Adnexal IgG4-RD
• Orbital Myositis• Lacrimal Sac• Conjunctiva and sclera
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Orbital IgG4-RD Mimickers
Andrew NH, BJO 2015
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Pathology
lymphocytic infiltrates are usually composed ofreactive lymphoid follicles with germinal centers + plasma cells ( +- Arteritis +_ Eosinophlis)Storiform fibrosis
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Pathology (IgG4 Stain)
• No of IgG4-positive cells is variable (>= 10 cells/hpf).
• In lacrimal glands (100/hpf).
• Depends on fibrosis (sclerosing IOI) , amount of systemic lesions, and serum IgG4.
• IgG4+/IgG+ plasma cell ratio (>40%)
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Orbital IgG4-RD and Lymphoma
• 44 of 448 (9.8%) cases of extranodal marginal B-cell lymphoma of (MALT) type had IgG4+ plasma cell infiltrates. (Japanese Study Group of IgG4-Related Ophthalmic Disease. . Jpn J Ophthalmol. 2013)
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Pathogenesis• Abnormal immune response to food
and environmental agents (microbes or tissue damage) .
• Humoral auto-immunity (B-cells) : response to Rituximab.
• Increased mRNA levels of cytokines IL-4,IL-5, and IL-13, suggestive of Th2 cell response (atopy).
• Low levels of C3,C4.
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Treatment• Steroids have been the mainstay
of treatment.• Relapses common (50%).• Serum IgG4 fall with steroid
therapy.• Steroid-spraing (azathioprine,
methotrexate, and mycophenolate)
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Anti-CD 20 (Rituximab)
• Many series shown dramatic response.
• Relapses occurred when B-cells recovered after 6 months, and responded well to a repeat dose.
• Single-dose Rituximab can be effective sometimes.
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Summary• Orbital IgG4-RD can present with
inflammtion of the orbit and ocular adnexa.• Clinical should keep high-index of suspicion. • Orbital IgG4-RD has distinctive pathologic
features.• Good communication with a pathologist is
essential.• Steroids and anti-CD 20 can be useful in
treatment.