Sino-Orbital IgG4 Related Disease- An Uncommon Entity

Abstract

IgG4 related disease (IgG4-RD) is an auto immune fibro-inflammatory condition, characterised by presence of IgG4 positive lymphoplasmacytic infiltrates and extensive fibrosis of the involved organ. It commonly affects pancreas, biliary tract and salivary glands. Sino-orbital involvement is a relatively rare presentation. There is extensive fibrosis of the involved organ. Biopsy is often diagnostic and it shows extensive necrosis and lymphoplasmocytic infiltrates. They show dramatic response to steroid therapy. Here we present three cases of IgG4-RD disease involving orbit and para nasal sinuses who were evaluated and treated in a tertiary care teaching hospital over a period of 2 years.

Introduction

IgG4 related disease (IgG-RD) is an auto-immune disease characterised by the presence of extensive fibrosis and infiltration of IgG4 plasma cell in the involved tissue. It commonly affects pancreas, retro-peritoneal tissue, salivary glands, thyroid gland and biliary tract. In the Head & Neck, it commonly affects salivary glands, thyroid gland, pituitary and lacrimal gland. Sino-orbital involvement is a very rare presentation. Here we present three cases of sino-orbital IgG4 related disease.

Case Details

We submit the three patients case briefs of sino-orbital IgG4 related disease who were evaluated and treated in our tertiary care institute (Table 1).

Table 1.

Case details

Case	Clinical features	MRI / investigations	Outcome after steroid therapy
1	RE- Vision loss, diplopia, proptosis. Vision-only perception of light, restricted EOM with afferent pupillary defect. DNE- Normal	Hypointense lesion (T2WI) with post contrast enhancement in orbital apex, cavernous sinus.KOH negative for fungus, biopsy showed extensive fibrosis with lymphoplasmacytic infiltrates.	Partial recovery of vision, complete resolution of EOM and proptosis
2	LE-Vision loss, diplopia, proptosis, conjunctival chemosis. Left Eye examination showed vision loss, complete ophthalmoplegia, conjunctivalchemosis with elevated intra ocular pressure. DNE- Normal	MRI- mixed density lesion with heterogenous enhancement involving entire orbit, encasing optic nerve with involvement of orbital fissure and infra temporal fossa. KOH- positive and culture negative for fungus. Biopsy showed extensive fibrosis and inflammatory cell infiltrates	Drastic reduction in intra ocular pressure, improvement in vision with complete recovery of ophthalmoplegia
3	RE-Vision loss, head ache, proptosis. Vision- perception of light is present, afferent pupillary defect, proptosis. DNE- Normal	MRI-Hypo intense lesion in orbital apex, orbital fissure and cavernous sinus. Fungal KOH, culture negative. Biopsy shows extensive fibrosis with lymphoplasmacytic infiltrates	Complete recovery of vision after steroid therapy.

Case 1

60 year old Ex-service man, presented with symptoms of acute onset diplopia, progressive vision loss in right eye and head ache for the past 3 weeks. He had history of recent onset diabetes mellitus. He was initially evaluated in an ophthalmology clinic. Ophthalmic evaluation revealed mild proptosis with restricted eye movements in right eye (except abduction). Right eye vision was severely affected and there was only perception of light on right eye. Pupillary reflexes in right eye showed afferent defect. There was reduced corneal sensation on right eye, and fundus examination showed thinning of neuro-retinal rim in temporal aspect. Left eye examination was unremarkable. A clinical diagnosis of orbital apex syndrome with II, III, IV, V cranial nerve palsy was made and MRI of brain and orbit was done.

MRI showed Hypointense lesion (T2WI) with heterogenous enhancement involving posterior ethmoids, bilateral orbital apex and cavernous sinus. Imaging and clinical finding was discussed between ENT surgeon and Ophthalmologist. A clinical diagnosis of orbital apex syndrome (Fungal/Inflammatory etiology) was made and it was decided to perform endoscopic biopsy of the lesion to arrive at diagnosis. Endoscopic transnasal biopsy of the lesion was done. Fungal KOH and culture did not reveal any fungal growth and he was started on intravenous steroids.Histopathology of the lesion showed extensive fibrosis with lymphoplasmocytic infiltration (Fig. 1). Histopathology was discussed with pathologist and rheumatologist. Final diagnosis of IgG4 related disease was made and his steroid therapy was tapered gradually over a period of 1 month. He showed recovery of vision in right eye. Currently it has been two years since surgery and he is symptoms free now.

Fig. 1.

HPE of orbital biopsy showing inflammatory cell infiltrates

Case 2

42 year male patient, presented with symptoms of decreased vision in left eye and diplopia for the past four months. He was initially evaluated by Neurosurgeon. Eye examination revealed proptosis, conjunctival chemosis and complete ophthalmoplegia. Fundus examination showed significant papilledema and there was increased intra ocular pressure. MRI of orbit and para nasal sinuses showed heterogeneously enhancing mixed density lesion involving orbit with intra conal involvement and it was encasing optic nerve with extension into intra temporal fossa, pterygo palatine fossa and inferior/superior orbital fissure (Fig. 2). He was diagnosed to have orbital pseudo tumour/invasive fungal sinusitis and referred to ENT for endoscopic biopsy. Endoscopic biopsy of the lesion was done under general anaesthesia. Intra-operatively there was presence of extensive fibrosis in the orbit with loss of orbital fat pad. Biopsy of the lesion was done along with optic nerve decompression. Fungal KOH of the tissue showed fungal elements but culture did not yield fungal growth. Histopathology showed extensive fibrosis with presence of inflammatory cells. He was started on systemic anti-fungal therapy and there was no improvement in vision and diplopia. Case was further discussed with pathologist, microbiologist, ophthalmologist and radiologist. Since there was no response with anti-fungal therapy, he was stated on low dose steroid therapy and he showed dramatic improvement in his eye symptoms. He regained his left eye vision and there was complete resolution of eye symptoms after steroid treatment. Intra ocular pressure became normal and papilledema resolved completely. Repeat imaging did not show any disease progression and there was some disease resolution. Rheumatologist suggested steroid tapering and regular follow up of the patient to look for recurrence.

Fig. 2.

MRI of case no- 2 showing pan orbital involvement (left side) with extension into infra temporal fossa (arrows)

Case 3

42 year old female patient presented with symptoms of head ache and vision loss in right eye for the past few months. She consulted an Ophthalmologist initially. Her ophthalmic examination showed significant vision loss in right eye with mild proptosis and afferent pupillary defect (only Perception of light is present in right eye). Rest of the eye examination was normal. She was diagnosed as a case of optic neuritis and imaging was done. MRI of brain and orbit showed hypointense (T2WI) lesion in posterior ethmoids, orbital apex, superior orbital fissure and cavernous sinus. This case was referred from ophthalmologist for endoscopic biopsy of the lesion.

Endoscopic examination of nose showed normal paranasal sinuses with no evidence of sinusitis or any other pathology. She was taken up for endoscopic biopsy of the lesion under general anaesthesia. Intra-operatively there was presence of extensive fibrosis in orbital apex and around the optic nerve in optic canal. Biopsy of the lesion was done along with optic nerve decompression under anaesthesia. Biopsy was negative for fungal growth and histopathology of the lesion showed hyalinised fibro-collagenous tissue and mononuclear inflammatory cell infiltration. She was started on high dose steroids and she showed dramatic recovery in vision loss.

Discussion

IgG4 RD is a relatively newer disease and is being reported for the past 10 years. It is characterised by the presence of extensive tissue fibrosis with lympho-plasmacytic infiltration. IgG4-RD is a fibro-inflammatory condition, characterized by a tendency to form tumefactive lesions; a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells; storiform fibrosis; frequent but not invariable elevations of serum IgG4; and a swift initial response to glucocorticoids, provided that tissue fibrosis has not supervened [1].

IgG4-RD is now recognized to be an important cause of “idiopathic” orbital inflammation and a major component of the differential diagnosis includes lymphoma, granulomatosis with polyangiitis, Graves’ orbitopathy, and other conditions [2]. In all our cases biopsy was not suggestive of lymphoma or any other malignancy. None of the patients had any systemic features suggestive of Wegener or Graves` disease.

Ophthalmic symptoms of IgG4-RD can have varied manifestations depending upon the subsite involvement. Lacrimal gland involvement is called IgG4 related Dacryoadenitis, extra ocular muscle involvement is called IgG4 related myositis and pan orbital involvement is called IgG4 related pan orbital inflammation [1]. In our series, case no 2 had pan orbital involvement and extension into infra temporal fossa. Case number 1 had involvement of orbital apex, para nasal sinuses and adjacent meninges.

Serum IgG4 level is found to be elevated in patients with igG4-RD. However 20–40% of biopsy proven cases can have normal serum IgG4 levels [3]. Hence the role of isolated serum IgG4 levels in diagnosing IgG4-RD is of doubtful value. However ratio of IgG4 cells to total IgG cells (> 10%) can be of diagnostic value [4]. Diagnosis of igG4-RD must be based on characteristic clinical and histopathologic features. Clinically there is tumour like enlargement of involved organ with extensive fibrosis. In all our cases extensive fibrosis was encountered during endoscopic biopsy. The fibrosed tissue was very hard and it was very difficult to take a biopsy endoscopically, especially near optic nerve.

Because of the systemic nature of the disease, imaging workup of IgG4-related disease should always include whole-body examinations to detect multiorgan involvement. MRI is the best modality and CT also adds value. In Sino-orbital IgG4 -RD, imaging of paranasal sinuses, orbit and brain plays an important role in diagnosis and treatment planning. CT scan shows enlargement of involved structures with decreased attenuation [5]. In orbital lesions, radiologically there will be presence of inflammation in lacrimal gland, ocular muscles, peri-orbital soft tissue, and trigeminal nerve branches [6]. In MRI, these lesions appear hypo intense on T2 weighted images due to increased cellularity and show heterogeneous contrast enhancement [6]. Common radiological differential for IgG4-RD is chronic invasive fungal sinusitis which can also appear hypo intense on T2 weighted MRI images. Extension into adjacent brain and meninges in present in both fungal disease and IgG4 RD. In view of these diagnostic challenges, biopsy of the lesion is very essential to arrive at diagnosis.

Histopathologic examination of the involved tissue is the gold standard for diagnosing IgG4-RD. Characteristic histopathologic findings include lymphoplasmacytic infiltration with storiform fibrosis (irregular cartwheel like appearance) and obliterative phlebitis. Presence two of the three hallmark findings in pathology and presence of IgG4 + plasma cells in IHC is necessary for pathological diagnosis [7].

Management is mainly medical and surgical intervention is required mainly for tissue biopsy and optic nerve decompression. All the three cases in our series had undergone endoscopic biopsy. Intra-operatively there was extensive fibrosis in all the 3 cases and optic nerve decompression was done in 2 cases. Glucocorticoids remain the first-line induction treatment for the multi-organ manifestations of IgG4-RD. Alternative immunosuppressive agents for maintaining remission are warranted in order to avoid long-term steroid toxicity, and to offer a more mechanistic and personalized therapeutic strategy. Targeting B and T-lymphocyte activation represents the most promising approach, but randomized controlled trials are eagerly awaited [8, 9].

In 2 cases intravenous methylprednisolone was started soon after biopsy after ruling out fungal infection (KOH smear of biopsy was negative for fungal elements). Both the patients showed dramatic recovery of vision and resolution of diplopia after intravenous steroids. Steroid tapering was done over a period of 3–4 weeks in consultation with rheumatologist. In case no 2, steroid was started after 3 months as biopsy tissue revealed fungal elements initially. During the follow up, all the 3 cases were under remission with no further disease progression. Case no 3 developed spontaneous CSF leak 3 months after surgery. MRI imaging of brain and PNS showed features of benign intra cranial hypertension and there was complete resolution of disease in orbit.

The management of our patients involved the ophthalmologists, rheumatologists and ENT surgeons and multidisciplinary approach would add to achieve better outcomes.

Newer Therapeutic approach to IgG4 RD includes biologicals (Rituximab) and immunosupressants (Azathioprime, methotrexate, cyclophosphamide, mycophenolate mofetil). They have been found to be useful in cases showing relapse after steroid tapering [10, 11]. According to Sanne E. Detiger et all in their systematic review, the success of conventional DMARDs varies between 36% and 75% in patients with IgG4-ROD, while rituximab is successful in the majority (93%) of the patients. Based on this systematic review, rituximab is the most effective DMARD in IgG4-ROD, while the efficacy of conventional DMARDs is limited [10]. As per Huahun Zhu and colleagues presented in ACR 2023 [12], the first line of the induction therapy for IgG4-related disease is glucocorticoid, but most patients need the maintenance treatment and experience relapse. It is recently reported that biologic agents, including rituximab and abatacept, are effective for the relapse of IgG4-related disease. It is clear that the tapering effect of glucocorticoid is better than conventional oral immunosuppressants. Long term follow-up of cases is required to look for relapse.

Key messages

• IgG4 related disease (IgG-RD) is an auto-immune disease characterised by the presence of extensive fibrosis and infiltration of IgG4 plasma cell in the involved tissue.

• IgG4-RD is a fibro-inflammatory condition, characterized by a tendency to form.

  • tumefactive lesions;
  • a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells;
  • storiform fibrosis;
  • frequent but not invariable elevations of serum IgG4;
  • Swift initial response to glucocorticoids, provided that tissue fibrosis has not supervened.

• IgG4-RD is now recognized to be an important cause of “idiopathic” orbital inflammation.

• Systemic steroid therapy shows dramatic recovery of symptoms in IgG4 related disease.

Funding

No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Declarations

Conflict of Interest

The authors declare no conflicts of interest.