orbital igg4-related disease

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Orbital IgG4-Related DiseaseRaed Behbehani , MD FRCSC

Good morning .. this an interesting condition yet is uncommon but it has gained a lot of interest lately and thought the best way to talk about it is to go over some illustrative cases that I have seen recently that would capture the spectrum of the disease and will depicts the clinical presentation and some of the diagnostic challenges . I do both neuroophthalmology and also oculoplastics and orbit

CaseA 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

CaseVA : HM recognition OD , 20/20 OS.TA : 14 mm/Hg OU.Pupils : large right RAPDComplete 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.

MRI

You can see her the high signal lesion on T1 with contrast right in the posterior orbit/orbital apex area and the Cavernous sinus , which fits his clinical presentation.

MRI

On the coronal you can see the CS lesion and the high signal lesion in the intracranial part of the right ON with nodular enhancement with GdYou can also the medial meninges are also enhancing and in other scans there was more lateral enhancement of the dura of temporal lobe

InvestigationsPPD : negativeSerum 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 normalGallium 67 scan : no uptake in the lacrimal gland, parotid gland or mediastinum.

So although you can see idiopathic orbital inflammation with intracranial extension this is just looked too atypical especially with involvement of the optic nerve . I have to say that I did suspect Igg4 at that time because there has been few cases reported around that time that looked very similar especially the neuro-imaging findings . We did try to get serum IgG4 test was available in eye hospital

ManagementRx : 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.

I have discussed the case with the pathologist and asked him to stain for IgG4. However, surprisingly there was very little useful tissue to look at. It is either the that they missed the lesion or there was some problem in handling the specimen .

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.

So he sort of disappeared for 2 months and he told he was put on oral dexamthasone by his neurosurgeon and then came back to see me because his vision had deteriorated now recently in the left eye (was originally un-involved)

Follow up MRI

Axial MRI shows extension of the high signal lesion across the pre-clinoidal area to the left. Some post-operative changes seen in the right temporal lobe from biopsy.

Follow up MRI

And on the coronal cuts the left intracranial ON is now involved and enhancing and even the chiasm on the right looks thickened.

Follow upVDRL , 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.

So now I am seeing this patient again who is going blind both eyes I admitted to the hospital, did more tests .. and done LP.I contacted the pathologist and asked him to review the old biopsy of the PNS that he did and asked him specifically for IgG4 staining.

Pathology

H&E stain x400Massons Trichrome Stain x 100

On the left : Plasma cell rich inflammatory cell infiltrate and on the right you see Fibrosis

Pathology

IgG4 positive plasma cells 80/hpf (x 400).

The plasma cells were polyclonal. Special IgG4 staining showed IgG4 positive cells with density of 80/per high power field. There was no necrosis or vasculitis. Fungal stains were negative.

Follow UpDx : 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.

So he received IV Rituximab and we did obtain serum IgG4 in another hospital . I have seen his vision improv slowly in the left eye from HM to 2/40 !!

Follow up MRI

May 2014October 2014

This is the MRI before before his IV Rituximab when he was having his 2nd eye involved and 5 months after Rituximab .As you can see there is resolution of the abnormal signal of the intracrinal optic nerves and chiasm and he is doing well as I have seen few months back is able to go back to work.

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.

He has seen several ophthalmologists who and used drops such as topical steroids.

Case

Both lacrimal glands were palpable and firmNo other palpable masses or lymphadenopathy or any skin lesions

CT

2014

This is was a year old CT scan but you clearly see the Bilateral lacrimal gland enlargement with no bony erosions and extensive pansinusitis

CT

2010

He showed a CT scan which was done 5 years ago and it clearly shows the bilateral lacrimal gland enlargement but it went completely unnoticed by the radiologist and the clinician.

Case

IgG 24.1 g/L (6-16g/L) , IgG4 >1440 mg/L ( 39.2- 864 mg/L). ANA, p-ANCA ,c-ANCA - negativeBilateral lacrimal gland biopsy performed.Biopsy - high IgG4 plasma cell infiltrate.

His serum IgG4 was markedly elevated ..I did biopsy both his lacrimal glands and that showed ..Later on I cam to know that he two years ago had sialoadenitis and therefore would be called what used to be known as Mikulicz Syndrome (now known as IgG4-related sialoadenitis)

Case

Oral steroids (Recurrence)IV Rituximab

After the biopsy he received systemic steroids but relapsed with tapering so he was also given Rituximab and improved and is doing really well now and even his Asthma and allergic sinusitis greatly improved.

IgG4-RDAn 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,

So I will start to talk about this entity IgG4-RD and it started out when a japanese group reported a series of patients with AIP , systemic lesions and high IgG4 serology levels.IgG4-RD can produce lesions in a number of tissues and organs The diagnosis is established by IgG4-cell infiltration plus other histopathologic features .

Mikulicz

Johann von Milulicz-Radecki , 1888

In 1888, Johann von Mikulicz-Radecki, a Polish-Austrian surgeon surgeon, described a patient with bilateral, symmetric, andpainless swelling of the lacrimal, parotid, and submandibular

IgG4-RDMickulicz disease, Kuttner tumor (sclerosing sialadenitis)Riedel thyroiditismultifocal fibrosclerosisOrmond disease (idiopathic retroperitoneal fibrosis)Aortitis, periaortitis Retroperitoneal fibrosis, Eosinophilic angiocentric fibrosis (EAF)

Now, all these conditions that were considered to be seperate entities are now grouped under the umbrella of IgG4-RD

Diagnosis

These are the diagnostic criteria and basically you need a clinical lesion, with raised serum IgG4 and the typical IgG4 plasma cell infiltration.

Some of these criteria do not strictly apply to the orbit as for example a much higher number of IgG4 positive cells is required to be seen in the lacrimal glands.However, It is the is the only classification that incorporated clinical and pathological findings

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.

Many of these patients will have systemic manifestations so It is important for ophthalmologist and orbital specialist who diagnose IgG4-RD to work up these patients or at least send them to specialists who can work them up for systemic involvement.On the other hand, we can expect referral from other specialists of patients with systemic IgG4-RD to rule out ophthalmic manifestations.

Orbital IgG4-RDClinically 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).

Depending on your traini

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