Clinical course of IgG4-related hypophysitis presenting with focal seizure and relapsing lymphocytic hypophysitis

In September 2013, a 43-year-old Thai man was admitted to the hospital with three consecutive episodes of rhythmic jerky movement of left face and arm, as well as speech arrest. These symptoms spontaneously resolved prior to hospital arrival. He also had a two-year history of malaise, loss of appetite, cold intolerance, 10-kg weight loss, headache, and loss of libido. Upon initial physical examination, there was no residual neurological deficit. His visual acuity and visual fields were normal in both eyes. A brain MRI revealed T1W hypointense and T2W hyperintense lesion at right frontal lobe with gyral enhancement (Fig. 1a, b). There was a homogeneous enhancing sellar-suprasellar mass that was abutted to the optic chiasm with pituitary stalk enlargement (Fig. 2a, b) and loss of posterior bright spot. At this point, a neurologist suspected that he had a subacute cerebral infarction with pituitary incidentaloma. An endocrine assessment at the presentation revealed multiple anterior pituitary hormone deficiencies without diabetes insipidus (Table 1). Due to the unavailability of Growth hormone releasing hormone and glucagon, Growth hormone stimulation test was not performed at that time. Insulin tolerance test was also omitted due to the concern of recurrent seizure. Serum alpha-fetoprotein and beta-human chorionic gonadotropin were within normal limits. Anti-thyroperoxidase and Anti-thyroglobulin were negative. He was initially treated with 15 mg of prednisolone daily, levothyroxine replacement, low dose aspirin, simvastatin and phenytoin. The patient gradually improved and was discharged two weeks later.

Since the diagnosis was subacute cerebral infarction, the pituitary biopsy was postponed until six weeks follow-up. We sent separated pituitary tissue for pathologic examination, one for a local pathologist and other to an external pathology laboratory. The tissue that was sent to the local pathologist revealed segments of pituitary tissue, partly infiltrated by lymphocytes plasma cells and fibrous (Fig. 3a, b). No organism was identified by Grocott’s methenamine silver (GMS) and Acid fast bacillus (AFB) stains. Based on Hematoxylin and Eosin (H&E) staining, the specimen was diagnosed as lymphocytic hypophysitis. IgG4-related hypophysitis was not aware at that time since the clinical manifestation and imaging were compatible with lymphocytic hypophysitis. The patient was treated as lymphocytic hypophysitis. Clinically, his headache resolved, his seizure remained in remission and he appropriately regained weight. Following his clinical improvements, prednisolone was subsequently reduced to 10 mg per day. In February 2014, subsequent pituitary MRI showed the same sellar-suprasellar mass with no change in size or shape; however, the lesion at right frontal lobe disappeared (Fig. 1c, d). The patient also remained seizure free after the initial steroid administration. In May 2014, prednisolone was further reduced to 7.5 mg per day.

Three months later, he developed new onset frontal headache and acute visual loss. Ocular examination demonstrated bitemporal hemianopsia. Pituitary MRI revealed slightly decrease in size and less bulbous appearance of the sellar-suprasellar mass but the lesion still abutted to the optic chiasm with mild compression and mild upward displacement of the optic chiasm. The study also showed more hyperintense T2W change and mild heterogeneous enhancement at the optic chiasm, suggesting an increase in swelling of the optic chiasm (Fig. 2c, d). His serum IgG4 was 0.792 g/L (0.030-2.010). However, the following report from external pathology laboratory indicated that the pituitary tissue carried a large area of lymphoplasmacytic infiltration with quite prominent mature plasma cell population and storiform collagenous fibrosis. IgG4 related hypophysitis was suspicious and immunohistochemical studies were performed. The block of pituitary tissue in September 2013 was recut and stained with CD138, IgG, and IgG4 immunohistochemical stain by immunoperoxidase technique. CD138 revealed 100–200 plasma cells per high power field. IgG and IgG4 showed up to 80 IgG4 positive plasma cells (Fig. 3c) with IgG4/IgG ratio up to 42 %. Computerized tomography scan of neck, chest, whole abdomen, and pelvis were also performed to search for other internal organ involvement of IgG4-related disease. These studies did not detect any abnormality. Prednisolone was promptly increased to 60 mg per day. Two weeks after prednisolone increment, headache disappeared; the visual field became normal in his left eye while temporal hemianopia persisted in his right eye. Prednisolone was gradually decreased to 30 mg per day. Four weeks later, his right visual field became normal. Prednisolone was further declined to 20 mg per day for 4 weeks then maintained at the dose of 10 mg per day. Pituitary MRI at 4 months after established diagnosis showed markedly decrease in size of sellar mass and decrease in swelling of the optic chiasm (Fig. 2e, f) without abnormal brain parenchymal lesion. Two months later, prednisolone was decrease to 7.5 mg per day. Phenytoin was discontinued after one year of seizure-free period. Statin and aspirin were also ceased following the diagnosis of cerebral involvement of IgG4. The seizure, headache, and visual impairment have continued to be asymptomatic up to one year after established diagnosis. The hormonal assessment at 2 years after presentation remained adrenal insufficiency and hypothyroid. Although there was an increase in sex hormone and IGF-1 levels (Table 1).