We read with great interest the reviews by Yamamoto et al (1) and Kashii (2) on IgG4-related disease (IgG4-RD). We recently evaluated a patient with this disease who experienced bilateral optic nerve involvement.
A 36-year-old man presented with acute painful loss of vision and a droopy lid of the right eye. He had developed a right sixth nerve palsy 2 years earlier and brain magnetic resonance imaging (MRI) at that time showed abnormalities of the right cavernous sinus and sphenoid sinus. This prompted a biopsy of a “polyp” from the right sphenoid sinus, which showed an “inflammatory lesion.” The patient improved over the next 2 months after treatment with systemic corticosteroids. He had a 15-year history of tobacco use, but his medical history was otherwise unremarkable.
Visual acuity was hand motions, right eye and 20/20, left eye. There was a right relative afferent pupillary defect with complete ptosis and limitation of right eye movement in all gaze directions. Anterior and posterior segment examinations were normal in both eyes. Automated visual field testing was normal in the left eye. Brain MRI revealed a lesion involving the right cavernous sinus and right prechiasmal optic nerve (Fig. 1A).
Patient evaluation included normal results for purified protein derivative skin testing, serum angiotensin-converting enzyme, anti-proteinase 3, C-ANCA, P-ANCA, antimyeloperoxidase, chest x-ray, and whole body gallium 67 scanning.
The patient received intravenous (IV) methylprednisolone 1 g/d for 5 days followed by oral prednisone 1 mg/kg. Over 2 weeks, he showed marked improvement in his ptosis and ocular motility, but visual acuity deteriorated to light perception in the right eye. A dural biopsy was obtained from the right middle cranial fossa, and the neurosurgeon reported that the dura looked “yellow, white, and thickened.” Dural and temporal lobe brain biopsy specimens showed only “patchy lymphocytic infiltration.” The patient received 4-mg dexamethasone with taper over 2 weeks.
Two months later, the patient reported sudden decrease in vision in his left eye. Visual acuity was light perception in the right eye and hand motions in the left eye. Pupillary reflexes were bilaterally sluggish. Lid position and ocular motility were normal with intact corneal reflexes and facial sensation. Ophthalmoscopy showed right optic disc pallor, and the left disc appeared normal. Brain MRI demonstrated a nodular enhancing lesion involving the left intracranial optic nerve and diffuse thickening of the chiasm (Fig. 1B). Venereal disease research laboratory test, treponema pallidum haemaglutination test, and HIV serologies were negative. Cerebrospinal fluid analysis was unremarkable.
The patient was prescribed prednisone 60 mg/d, and the biopsy specimen from the sphenoid sinus was retrospectively reviewed. It had been described as “sphenoidal sinus mass with the stroma being infiltrated by chronic inflammatory cells, mainly plasma cells.” Special IgG4 staining showed a plasma cell rich infiltrate and focal fibrosis with IgG4-positive cells of 80 per high power field (Fig. 2).
Serum amylase, IgG, and IgG4 levels were within normal limits. One month later, the patient received 2 IV infusions of 1000 mg rituximab 2 weeks apart. Two months later, although his serum IgG remained with normal limits, his serum IgG4 was elevated at 1440 mg/L (normal, 39.2–864 mg/L). Three months after IV rituximab, visual acuity had improved to counting fingers, right eye and 20/200, left eye. Spectral domain optical coherence tomography showed severe bilateral reduction in retinal nerve fiber layer thickness. Oral prednisone was tapered over 2 months, and the patient was maintained on azathioprine 50 mg orally twice a day.
Although optic neuropathy has been associated with IgG4-RD (3–6), we could not find previous documentation of intracranial optic nerve involvement. Rather, optic nerve dysfunction has been described with orbital IgG4-RD, including a case with extension into the ipsilateral cavernous sinus and middle cranial fossa (4). In our patient, there was sequential intracranial optic nerve involvement. Features commonly seen in orbital IgG4-RD such as lacrimal gland, extraocular muscle, and infraorbital nerve involvement were absent in our case.
It is not unusual to make the diagnosis of IgG4-RD retrospectively, either because of omission of IgG4 stain or the biopsy site being inaccessible (7,8). In our patient, the first serum IgG4 level was within normal limits, probably because of prolonged steroid treatment. However, subsequent testing did show elevated serum IgG4 titers. Because we could not find other organ involvement and systemic steroids did not resolve all the clinical findings, our patient was classified as “probable IgG4-RD” (9).
Increased IgG4-positive cells may occur in sinonasal or orbital/periorbital biopsies in patients with Wegner granulomatosis (10). In our patient, serum ANCAs were negative, and the biopsy did not show evidence of necrosis, granuloma, or vasculitis.
Systemic steroids are considered the mainstay treatment or IgG4-RD and are usually associated favorable outcome (11). However, efficacy of steroids in cases of optic nerve involvement is uncertain, and in the few cases reported, there was insufficient follow-up data on visual function (4). Our patient had profound loss of vision despite treatment with high-dose systemic steroids. Discontinuation of steroids led to a relapse in the contralateral optic nerve. Rituximab has been used with success in systemic IgG4-RD (12). We could not find previous reports of its use in optic nerve involvement, but it led to visual impairment in our patient.
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