Immunoglobulin G4-related disease in an elderly patient with treatment-resistant headache: a case report
Article information
Abstract
Immunoglobulin G4 (IgG4)-related disease is an immune-mediated, fibroinflammatory condition that causes multisystemic contrast enhancement and is predominantly observed in elderly male patients. The most prominent features of IgG4-related disease are systemic involvement affecting from two to six systems. In the central nervous system, these contrast enhancements are typically found in the meninges and orbit. This case study describes a 78-year-old female patient with persistent headaches and constant diarrhea who underwent treatment for IgG4-related disease. Despite two months of treatment with non-steroidal and opioid analgesics, the patient remained unresponsive and continued to experience diarrhea for 4 months. Brain magnetic resonance imaging revealed contrast enhancement in the leptomeningeal surfaces, and a biopsy of the gastrointestinal mucosa confirmed the diagnosis of IgG4-related disease, showing widespread plasma cell infiltration and IgG4 expression on plasma cells. The patient was initially treated with 1.0 g/day of pulse therapy for 5 days, followed by a maintenance dose of 1.0 mg/kg oral azathioprine. When azathioprine caused significant pancytopenia, rituximab therapy was initiated. The patient’s headaches resolved completely, and the diarrheal attacks were controlled. This case highlights the importance of considering IgG4-related disease as a potential cause of headache or multiorgan symptoms in elderly patients with new-onset headache unresponsive to conventional analgesics. IgG4-related disease can often be effectively treated with steroids and monoclonal antibodies.
Introduction
Immunoglobulin G4 (IgG4)-related disease is a multisystemic, immune-mediated, and fibroinflammatory illness. Although the exact pathophysiology remains unclear, CD4+ and T-helper cells are believed to play a significant role. Histopathologically, the condition is characterized by dense lymphoplasmacytic infiltration, IgG4-positive plasma cells, fibrosis, obliterative phlebitis, and eosinophilia. The disease can affect single or multiple organs, including the lacrimal and salivary glands, pancreas, bile ducts, kidneys, lungs, and retroperitoneal cavity [1-3]. Central nervous system (CNS) involvement is rare but can occur, often presenting with pituitary and/or meningeal involvement. This condition can manifest as a tumor-like mass or hypertrophy in peripheral tissues or the CNS and can lead to progressive neurological deficits, blindness, headaches, and cerebellar ataxia. Treatment typically includes glucocorticoids; if the patient is unresponsive, azathioprine is the treatment of choice, followed by mycophenolate mofetil and rituximab.
Case Report
A 78-year-old female patient with a history of essential tremor, coronary artery disease, and heart failure presented with bilateral throbbing headaches accompanied by nausea, diarrhea for 3 to 4 months, photophobia, and phonophobia. Her symptoms disrupted her sleep, worsened with movement, and did not respond to analgesics. Neurological examination revealed limited cooperation; she could follow simple commands but struggled with complex ones. She also experienced horizontal gaze impairment in the left eye, bilateral postural tremor, and jaw tremor. Brain magnetic resonance imaging (MRI) showed leptomeningeal thickening and local leptomeningeal contrast enhancement (Figure 1A and B), with no abnormalities detected in the fundus. Cerebrospinal fluid (CSF) pressure was 450 mm H2O, and the CSF protein level was 77.4 mg/dL. No malignant cells were found, and C-reactive protein and complete blood count values were normal. Tests for hepatitis B, hepatitis C, HIV, brucella, borrelia, and syphilis markers were negative. The patient experienced non-parasitic watery diarrhea. Lab results showed elevated IgE (293 IU/mL; normal range, 0–160 IU/mL), elevated IgG4 (1.31 mg/dL; normal range, 0–1.25 mg/dL), and elevated lipase levels (260 U/L; normal range, 0–67 U/L), which were highly suggestive of IgG4-related disease. Thoracic and abdominal tomography results were normal. Endoscopy, colonoscopy, and biopsies were performed to investigate the cause of the diarrhea. No abnormalities were detected in the stomach and intestines, so we performed a blind biopsy. Histopathological examination revealed dense lymphoplasmacytic cell infiltration in the lamina propria but no significant fibrosis. Differential diagnoses included IgG4-related disease and multiple myeloma. Immunohistochemical staining showed widespread staining of CD138 and IgG4 in plasma cells and polyclonal staining of kappa and lambda. These findings supported a diagnosis of IgG4-related disease (Figure 2). Steroid treatment was initiated, starting with 1.0 g/day pulse therapy for 5 days, followed by 1.0 mg/kg oral maintenance therapy. Partial improvement included a decrease in VAS pain score from 10 to 8, and azathioprine was added but later discontinued due to significant pancytopenia. Rituximab therapy was initiated as an alternative, starting with two initial doses of 1,000 mg at 2-week intervals, followed by 500 mg maintenance every 6 months. After this treatment, the patient became headache-free and her diarrhea was controlled. A follow-up brain MRI 6 months after the first rituximab dose showed resolution of the leptomeningeal contrast enhancement (Figure 1C).
Discussion
The incidence of IgG4-related disease, an autoimmune condition characterized by multiorgan involvement, is estimated to be between 0.78 and 1.39 cases per 100,000 person-years [4]. Due to its recent recognition, the diagnosis of IgG4-related disease can be challenging and is characterized by multisystem involvement with a broad clinical presentation. Reliance on histopathological findings for diagnosis is necessary. Diagnostic criteria are not fully defined; the proposed criteria include enlarged or hypertrophic affected organs; elevated serum IgG4 level (≥135 mg/dL); and the pathological hallmarks of dense lymphoplasmacytic infiltrate with IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Additionally, elevated levels of lipase and IgE may be observed [5].
Our patient presented with gastrointestinal symptoms and leptomeningeal involvement. Elevated serum IgE (293 IU/mL), lipase (260 U/L), and IgG4 (1.31 mg/dL) levels were detected. These findings, along with results of stomach and intestinal biopsy samples to investigate the cause of diarrhea, confirmed the preliminary diagnosis of IgG4-related disease. The patient’s headaches were likely related to increased intracranial pressure and leptomeningeal contrast enhancement.
Glucocorticoids are the first-line treatment for IgG4-related disease, particularly during the induction phase [6]. However, relapses and recurrences are common, occurring in approximately 40% of patients. In some cases, glucocorticoid monotherapy is insufficient to maintain remission, necessitating the use of immunosuppressants as part of maintenance therapy. As our patient’s response to glucocorticoids was incomplete, rituximab was introduced, leading to an adequate clinical response.
This case is important because of the insights provided into the rare presentation of IgG4-related disease in an elderly patient with multiorgan involvement. The case underscores the importance of considering secondary causes of headache and highlights that remission in IgG4-related disease can be achieved with treatments such as glucocorticoids, immunosuppressants, and monoclonal antibodies.
Notes
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Conceptualization: All authors; Investigation: KE, NT, GT; Writing–original draft: KE, NT, GT; Writing–review & editing: NT, MÖ