IgG4-RD is an immune-mediated fibroinflammatory condition that can affect multiply organ systems with an estimated annual incidence of 0.28–1.08 per 100,000 [2]. HPM is a rare subgroup of this disorder with only 2.4% of patients with CNS IgG4-RD presenting with this condition [6]. In contrast to other autoimmune conditions, IgG4-related HPM generally occurs in men (female: male ratio of 1:5.9) in their fifth to sixth decade [2, 4]. The clinical presentation is protean ranging from diffuse symptoms such as chronic headaches, neck stiffness, cognitive decline, and seizures to focal mechanical symptoms due to nerve compression including optic neuropathy, cranial nerve palsies, and cortico-spinal sensorimotor deficits [3, 7]. As in our second case, spinal HPM occasionally requires neurosurgical decompression due to their diffuse extent of disease within the confined space of the spinal canal [8, 9]. A retrospective review of 33 IgG4-related HPM cases observed that two-thirds of patients experienced headache, a third had cranial nerve palsies, and a fifth had visual disturbances [7]. Systemic involvement was noted in 48% of patients mostly involving the bone (12%) followed by the salivary glands (9%) and lungs (9%) [7].
There are four subclasses of human IgG, the most common type of antibody, and IgG4 is the least abundant subclass constituting < 5% of IgG in healthy individuals [10]. IgG4 is recognized as an anti-inflammatory antibody that is believed to attenuate allergic responses by inhibiting IgE-mediated hypersensitivity reactions [10]. The pathogenesis of IgG4-RD remains to be elucidated, but it is currently understood to be an antigen-driven disease involving IgG4+ B cells and CD4+ cytotoxic T cells [2, 6]. Why B cells are clonally expanded and differentiated to IgG4-producing plasma cells remains unknown, but the prevailing hypothesis seems to involve autoimmunity to an unidentified antigen [2, 3]. This results in the activation of CD4+ cytotoxic T cells and the subsequent induction of inflammation and fibroblast activation [1]. It has also been postulated that since IgG4 is predominantly anti-inflammatory in nature and pivotal in immune tolerance, its elevated expression may not be the primary driver for this disease, but a secondary responding event to attenuate CD4+ T cell activity [1, 7].
Although HPM is rare, our experience indicates that it can mimic conditions commonly encountered in daily neurosurgical practice due to its tumefactive nature [11]. Clinical suspicion should be raised when a patient with a strong history of autoimmune disease, as observed in the present two cases, experience a disproportionately severe subacute headache relative to the minimal mass effect elicited by the dural lesion reflecting the inflammatory nature of the disease. The differential diagnoses include intracranial hypotension, leptomeningeal carcinomatosis, subdural empyema, or other causes of pachymeningitis such as TBM. In most circumstances, with the exception of IgG4-RD, these conditions can be readily excluded clinically. Our second patient was first suspected to have a cervical meningioma due to its suggestive radiological features. But only 15% of spinal meningiomas arise in this region with most based at the anterior thecal sac [12]. Alternatively, a diagnosis of tuberculous granuloma was considered given the patient’s previous history of suspected TBM. However, a review of his initial MRI brain scan showed no evidence of associated characteristic features such as basal cisternal involvement or intraparenchymal granulomas. In IgG4-related HPM, lesions are typically avidly contrast-enhancing and on T2-weighted MRI sequences may exhibit hypointense dural thickening with intralesional hyperintense foci representing areas of inflammation which are more evident on fluid-attenuated inversion recovery (FLAIR) sequences [13].
A definitive diagnosis of IgG4-RD requires the fulfillment of clinical and pathological criteria proposed by an international, multidisciplinary consortium in 2011 [14]. The latter requires the presence of two of three classic morphological histologic features, namely dense lymphoplasmacytic infiltrates, storiform fibrosis, and obliterative phlebitis in conjunction with a positive IgG4 stain [14]. The cutoff IgG4+ plasma cell count required for HPM is 10 per HPF and a IgG4+/IgG+ cell ratio of > 40% [14, 15]. When only one histologic feature is identified, supportive evidence of an elevated serum IgG4 level (> 135 mg/dl), which is present in 70–90% of patients with active disease, and demonstration of multi-organ involvement, by either radiological or pathological examination, will be required [7, 14]. We therefore propose a diagnostic algorithm for clinicians to adopt in confirming IgG4-RD HPM in suspected patients (Fig. 4).
There is no consensus on the treatment of IgG4-related HPM, but initial therapy generally involves a 2- to 4-week course of prednisolone (0.6 mg/kg/day) followed by a 3- to 6-month tapering to a daily maintenance dose of 2.5–5.0 mg for up to 3 years [3, 7]. According to a systematic review of 1 220 IgG4-RD patients, 97% responded to glucocorticoid monotherapy [2]. Therapeutic efficacy with steroid-sparing immunosuppressive agents has also been observed, especially during disease relapse [2]. Agents such as azathioprine, mycophenolate mofetil, and methotrexate have been utilized with treatment response rates of 72–100% [2, 3, 7]. Rituximab, an anti-CD20+ B cell monoclonal antibody, has been discovered to be a promising treatment resulting in rapid clinical, radiological, and serological responses [16]. However, due to its high molecular weight < 1% of systemic rituximab crosses the blood-brain barrier. To address this, Della-Torre et al. reported the successful treatment of IgG4-related HPM by administrating the agent intrathecally with minimal adverse effects [17].
