IgG4-related disease (IgG4-RD) is a multi-organ chronic inflammatory process caused by infiltration of IgG4-positive plasma cells in one or more organs. Intracranial involvement has only recently become better recognized. Our case series adds to the growing literature on the varying presentations of intracranial IgG4 by describing the clinical and imaging findings of three patients who presented to our institution with intracranial involvement. Our first patient presented with a mass-forming IgG4 pachymeningitis mimicking a sphenoid wing meningioma, which is to our knowledge the largest mass-forming pachymeningitis published in the literature. Our second case depicts another presentation of extensive IgG4 pachymeningitis involving both cavernous sinuses and surrounding Meckel's caves. The third case describes a patient with presumed lymphocytic hypophysitis, which was later determined to be IgG4-related hypophysitis with concomitant pachymeningitis and perineural spread along the optic nerves. The delayed diagnoses in our cases illustrates the diagnostic challenge that clinicians face in differentiating intracranial IgG4-RD from other infiltrative diseases such as sarcoidosis, granulomatous disease, tuberculosis and lymphoma. Earlier consideration of IgG4-related hypophysitis and hypertrophic pachymeningitis in the differential diagnosis can prevent significant morbidity including unnecessary surgical intervention and organ failure secondary to extensive fibrosis.

https://journals.sagepub.com/doi/pdf/10.1177/1971400918806323

IgG4-related intracranial disease

Hypertrophic pachymeningitis (HP) is characterized by cranial and/or spinal thickening of the dura mater with or without associated inflammation. Neuroimaging studies reveal dura mater thickening and focal or diffuse contrast enhancement. It is described in association with trauma, infections, tumors, autoimmune/inflammatory diseases, and cerebrospinal fluid hypotension syndrome, with some cases remaining idiopathic. A retrospective study was conducted with patients’ identification through a key terms search within MRI reports in the period of July 2008 to September 2015. Clinical files, MRI, laboratory, and pathology data were reviewed. Fifty-three patients were identified and 20 were excluded because they did not meet the inclusion criteria. Of the 33 included, 19 were female, with a mean age at symptoms onset of 51.2 ± 17.6 years. The most common presenting symptoms were headache and cranial nerves palsy, followed by seizures, delirium, lumbar pain, cognitive decline, motor deficit, and language impairment. In 17 patients, a neoplastic etiology was identified; in eight, inflammatory/autoimmune; in six, infectious; and two were classified as idiopathic. Of the eight patients with inflammatory/autoimmune etiology, four had possible IgG4-related disease (IgG4-RD) and the remaining had granulomatosis with polyangiitis, sarcoidosis, rheumatoid arthritis, and Tolosa-Hunt syndrome. Treatment was directed according to the underlying etiology. In the described series, a female predominance was identified, with symptoms’ onset in the 5th decade. Although headache was the most common symptom, clinical presentation was varied, emphasizing the role of MRI in HP diagnosis. The underlying etiologies were diverse, with only a few cases remaining idiopathic, also reflecting the contribution of the recently described IgG4-RD.

Clinical features of hypertrophic pachymeningitis in a center survey.

Cavernous sinus lesions.

The authors report a case of immunoglobulin G4-related disease (IgG4-RD) presenting as a paraspinal, epidural mass. This disease encompasses a host of autoimmune conditions that were previously thought to be separate entities. It is characterized by fibrosis, mediated by the aberrant proliferation and tissue invasion of IgG4-positive plasma cells, which can occur in any organ. As with other autoimmune conditions, it tends to be responsive to steroids and other immunosuppressants. It can rarely present as a tumefactive lesion of the central nervous system, creating the potential for misdiagnosis (given its similar radiological appearance to malignancy) and mistreatment. In 2015, a panel of experts convened to set forth guidelines for the diagnosis and treatment of IgG4-RD. In the case presented here, the patient initially presented with pain and weakness in the left upper extremity. Initial neuroimages revealed a contrast-enhancing mass extending from C-4 to T-1, invading the epidural spinal canal, encasing the exiting nerve roots, infiltrating the paraspinal musculature, and surrounding the left vertebral artery. A PET scan confirmed the mass was hypermetabolic, but results of fine-needle aspiration and CT-guided biopsy were inconclusive. Open biopsy yielded fibrotic tissue that met the pathological criteria for IgG4-RD: lymphoplasmacytic infiltrate, fibrosis in a storiform pattern, and obliterative phlebitis. The patient was treated with 2 doses of 4 mg of dexamethasone (Decadron) and then 50 mg of prednisone per day. Within 2 weeks, the mass was radiologically shown to have drastically decreased in size. The prednisone dose was decreased to 40 mg per day, and 100 mg of azathioprine per day was added. The patient continued to improve and the mass continued to decrease over the next 6 months. Currently, she has been weaned from all steroids and will be maintained on a daily dose of 100 mg of azathioprine.

/pdf/immunoglobulin-g4-related-disease-mimicking-an-epidural-3urvcp78xx.pdf

Immunoglobulin G4–related disease mimicking an epidural spinal cord tumor: case report

After initial investigation of patients presenting with symptoms suggestive of neuropathy, a clinical decision is made for a minority of patients to undergo further assessment with nerve biopsy. Many nerve biopsies do not demonstrate a definitive pathological diagnosis and there is considerable cost and morbidity associated with the procedure. This highlights the need for appropriate selection of patients, nerves and neuropathology techniques. Additionally, concomitant muscle and skin biopsies may improve the diagnostic yield in some cases. Several advances have been made in diagnostics in recent years, particularly in genomics. The indications for nerve biopsy have consequently changed over time. This review explores the current indications for nerve biopsies and some of the issues surrounding its use. Also included are comments on alternative diagnostic modalities that may help to supplant or reduce the use of nerve biopsy as a diagnostic test. These primarily include extraneural biopsy and neuroimaging techniques such as magnetic resonance neurography and nerve ultrasound. Finally, we propose an algorithm to assist in deciding when to perform nerve biopsies.

Nerve biopsy: Current indications and decision tools.

IgG4-related disease (IgG4-RD) is a multisystem inflammatory disorder. Early recognition of IgG4-RD is important to avoid permanent organ dysfunction and disability. Neurological involvement by IgG4-RD is relatively uncommon, but well recognised-hypertrophic pachymeningitis and hypophysitis are the most frequent manifestations. Although the nervous system may be involved in isolation, this more frequently occurs in conjunction with involvement of other systems. Elevated circulating levels of IgG4 are suggestive of the condition, but these are not pathognomonic and exclusion of other inflammatory disorders including vasculitis is required. Wherever possible, a tissue diagnosis should be established. The characteristic histopathological changes include a lymphoplasmacytoid infiltrate, storiform fibrosis and obliterative phlebitis. IgG4-RD typically responds well to treatment with glucocorticoids, although relapse is relatively common and treatment with a steroid-sparing agent or rituximab may be required. Improved understanding of the pathogenesis of IgG4-RD is likely to lead to the development of more specific disease treatments in the future.

/pdf/neurological-manifestations-of-igg4-related-disease-3qh6lpur0c.pdf

Bernardo Baptista

Papers

Neurological Manifestations of IgG4-Related Disease.