Excerpta Extraordinaire IgG4-related Infundibulo-hypophysitis and Hypertrophic Pachymeningitis in a Patient with Panhypopituitarism EE-02 Excerpta Extraordinaire Lopez, Dayibi 61614485 Sana Ali, MD; R Sharma, MD; E G Stein, MD, PhD. contact: sana.ali@gmail.com

Disclosure No potential conflicts to disclose Join us for our oral excerpta extraordinaire (E-10) showcasing a case of idiopathic hypertrophic pachymeningitis of the cervical spine Monday, May 23, 2016: 2:00-2:05 pm

Purpose Outline a case of IgG4-related infundibulo-hypophysitis and hypertrophic pachymeningitis and elucidate radiographic findings Brief overview of IgG4-related disease and its manifestations with a special emphasis on central nervous system (CNS) involvement Review of other entities that can cause hypertrophic pachymeningitis

Case Report 54-year-old female with rheumatoid arthritis, hypertension, Chiari I malformation, diabetes mellitus type II and hypothyroidism was admitted for worsening headaches, diplopia, nausea and vomiting. The headaches were exacerbated during Valsalva-type maneuvers. Patient subsequently also diagnosed with panhypopituitarism.

Imaging Findings Magnetic resonance imaging (MRI) of the brain with intravenous gadolinium contrast. Coronal (a) and sagittal (b) post-contrast T1 images demonstrate an enlarged, thickened and markedly enhancing pituitary gland and stalk (arrows). Findings are most compatible with infundibulo-hypophysitis of infectious or inflammatory origin. (Additionally seen is downward tonsillar herniation consistent with known Chiari I.) a b 4652453 4/8/15

Imaging Findings MRI of the brain with intravenous gadolinium contrast. Axial post-contrast T1 image (a) demonstrates marked thickening and enhancement of the tentorium and posterior falx with effacement of the perimesencephalic cisterns and midbrain compression. Axial post-contrast FLAIR images (b and c) demonstrate pachymeningeal hyperintensity (arrows). Findings are most compatible with pachymeningitis of infectious or inflammatory origin. a b c 4652453 4/8/15

Hospital Course & Assessment Hospital Course: surgical biopsy of dural lesion, high dose steroids and medical management for panhypopituitarism (diabetes insipidus) Serum IgG elevated Pathology: No organisms detected. Dense fibroconnective tissue with mixed inflammatory infiltrate and multinucleated giant cells, focally positive for IgG4 Constellation of findings consistent with IgG4-related infundibulo-hypophysitis and hypertrophic pachymeningitis

Post-Treatment Imaging Findings MRI of the brain with intravenous gadolinium contrast. Axial post-contrast T1 images before (a and c) and after (b and d) treatment with high-dose steroids demonstrate interval decrease in dural thickening and almost complete resolution of pituitary gland and stalk thickening and enlargement (arrows). a b c d Before treatment 10 days after treatment 4652453 4/8/15 4660118 4/18/15

IgG4-related Disease

General Overview of IgG4-related Disease Immunoglobulin G4 (IgG4)-related disease is an immune-mediated systemic condition that includes a group of disorders that were previously thought to be distinct, but with shared pathologic, serologic, and clinical features Recognized as a systemic disease in 2003 Pancreas is the most commonly involved organ Pituitary gland and meninges are the most commonly involved organs in the CNS Marked response to corticosteroid therapy Recognized as a systemic disease in 2003 when extra-pancreatic manifestations were identified in patients with autoimmune pancreatitis.

IgG4-related Disease Spectrum Head & Neck Biliary & Endocrine Hypertrophic pachymeningitis Autoimmune hypophysitis Orbital pseudotumor Mikulicz syndrome (Sjogren type I) Kuttner’s tumor (chronic sclerosing sialoadenitis) Riedel’s thyroiditis Hashimoto’s thyroiditis Autoimmune pancreatitis Sclerosing cholangitis Liver pseudotumor Retroperitoneal fibrosis Sclerosing mesenteritis GU & Vascular Tubulointerstitial nephritis Prostatitis, testicular involvement Cutaneous pseudolymphoma Inflammatory aortic aneurysm Lymphadenopathy Chest Pulmonary pseudotumor Interstitial pneumonia

Diagnostic Criteria Kamisawa, et al. proposed three major diagnostic criteria: Clinical – characteristic diffuse or localized swelling/masses in one or more organs Serologic – elevated IgG4 concentrations (≥135 mg/dl) Histopathologic – marked lymphoplasmacytic infiltration and storiform fibrosis, as well as IgG4-positive plasma cells Diagnosis considered definite if all three criteria are met, probable if first and third are met, and possible if first and second criteria are met. (Umehara, et al.)

IgG4-related Hypophysitis 72-year-old male presenting with general fatigue and weakness. Patient found to have diabetes insipidus and hypopituitarism with an elevated serum IgG4. Sagittal T1 post-contrast MRI prior to steroid therapy (A) shows an enlarged pituitary stalk (arrow) consistent with hypophysitis. Sagittal T1 post-contrast MRI after steroid therapy (B) reveals interval decrease in pituitary stalk size. This patient had biopsy proven IgG4-related disease of additional renal nodules. Harano et al. Clin Med Insights Case Rep. 2015;8:23-6

Hypertrophic Pachymeningitis

Hypertrophic Pachymeningitis: Overview Hypertrophic pachymeningitis (HP) refers to localized or diffuse thickening of the cranial or spinal cord dura mater due to inflammation Often resultant progressive neurological deficits Headache Vision loss Cranial nerve palsies Seizures Hearing loss Clinical management heavily relies on ability to differentiate primary or idiopathic hypertrophic pachymeningitis from secondary causes

Hypertrophic Pachymeningitis: Imaging Findings Low T1 and T2 signal intensity with peripheral contrast enhancement Dural thickening/dural mass Falco-tentorial, medial and basifrontal, frontal/temporal convexities Sinus thrombosis (venous congestion) White matter changes Biopsy is gold standard for definitive diagnosis

Hypertrophic Pachymeningitis: Etiology Causes of Hypertrophic Pachymeningitis Primary or Idiopathic (diagnosis of exclusion) Secondary Infectious – TB, fungal, Lyme disease, syphilis, eosinophilic meningitis due to parasitic disease Systemic autoimmune/vasculitis – Sarcoidosis, granulomatosis with polyangiitis (GPA), Rheumatoid arthritis, Behcet’s disease, Sjogren syndrome, temporal arteritis, mixed connective tissue disorder, orbital pseudotumor, IgG4-related disease, inflammatory bowel disease Others – dural carcinomatosis, meningioma, lymphoma, etc. Adapted from Dash et al Journal of Neurological Sciences. 250 (2015); 51-60.

GPA-associated Pachymeningitis b c d Biopsy proven focal GPA- associated hypertrophic pachymeningitis. Axial non- enhanced CT (a) shows an anterior falcine hyperdense ovoid nodule. Axial FLAIR (b), axial post-contrast T1 (c) and DWI (d) reveal a peripherally enhancing ovoid nodule (arrow) with adjacent leptomeningeal enhancement and FLAIR hyperintensity over the frontal lobes. No associated restricted diffusion. 4593441

Sarcoid Leptomeningitis As with many conditions that can infiltrate or inflame the pachymeninges, Sarcoid can also cause a leptomeningitis as in this patient with pathologically proven sarcoidosis. Axial non-contrast chest CT (a and b) demonstrates bilateral upper lobe parenchymal pulmonary disease. Axial post-contrast T1 images (c and d) demonstrate classic bilateral frontal leptomeningeal enhancement. a b c d NEW

Lymphoma-associated Pachymeningitis Lymphoma-associated pachymeningitis and clival infiltration in a patient with CNS lymphoma. Sagittal and axial post-contrast T1 images at presentation (a and c) and after intrathecal methotrexate (b and d). Interval resolution of patchy irregular enhancement in the clivus (arrowhead) and resolution of diffuse thickened pachymeningeal enhancement (arrows). a b c d At presentation Post-chemotherapy 5/24/2010 6/1/2009 51137894

Infectious Pachymeningitis Diffuse hypertrophic pachymeningitis in a patient with known tuberculosis. Axial post-contrast T1 image (a) demonstrates uniform tentorial enhancement. Axial post-contrast image (b) two years later in the same patient demonstrates interval resolution of previously seen dural enhancement. Dash et al Journal of Neurological Sciences. 250 (2015); 51-60.

Metastatic Pachymeningitis Metastatic pachymeningitis in a patient with prostate cancer. Axial non-contrast head CT image in bone windows (a) demonstrates extensive blastic and lytic osseous lesions. Axial post-contrast (b) head CT demonstrates enhancing nodular soft tissue masses along the dura. Axial T1 post-contrast (c and d) images demonstrate bilateral heterogeneously enhancing lobulated dural-based masses and diffuse dural enhancement. There is additional heterogeneous enhancement of the left temporal calvarium and scalp (arrow) consistent with transcalvarial metastases. 01613839 a b c d

Idiopathic Pachymeningitis Biopsy proven idiopathic intra-cranial and cervical pachymeningitis. MR sagittal T1 (a), T2 (b) and post-contrast T1 (c) images demonstrate mass-like nodular enhancing dural thickening both anteriorly and posteriorly (arrows) extending into the cervical spine. a b c

Summary IgG4-related disease is an immune-mediated systemic condition that includes a group of disorders that were previously thought to be distinct, but with shared pathologic, serologic, and clinical features. Many cases of HP that were originally thought to be idiopathic have been found to be IgG4-related. Clinical management heavily relies on ability to differentiate idiopathic hypertrophic pachymeningitis from secondary causes.

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