|CASE BASED REVIEW
|Year : 2021 | Volume
| Issue : 2 | Page : 221-226
IgG4 Licks base of skull, wastes tongue: An unusual presentation
Shekhar Dorle1, Arun Hegde2, Gunjan Dwivedi3, Uday Bhanu Kovilapu4, PS Mishra5, Anurag Jain6, Faiz Ahmed7
1 Department of Internal Medicine, Command Hospital (Southern Command), Pune, Maharashtra, India
2 Department of Rheumatology, Command Hospital (Southern Command), Pune, Maharashtra, India
3 ENT, Command Hospital (Southern Command), Pune, Maharashtra, India
4 Radiology, AFMC, Pune, Maharashtra, India
5 Pathology, Neurology Command Hospital (Southern Command), Pune, Maharashtra, India
6 Nuclear Medicine, Neurology Command Hospital (Southern Command), Pune, Maharashtra, India
7 Neurology Command Hospital (Southern Command), Pune, Maharashtra, India
|Date of Submission||20-Jul-2020|
|Date of Acceptance||25-Nov-2020|
|Date of Web Publication||25-Jun-2021|
Dr. Arun Hegde
CH (SC), Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
IgG4 Related disease (IgG4 RD) is a rapidly evolving clinical entity, involving multiple organs, manifesting clinically as tumefactive lesions, histopathologically characterized by an IgG4 predominant, dense lymphoplasmacytic tissue infiltrate. It might mimic malignancy, infection as well as various other inflammatory disorders. First described in literature in 2003, in the pancreas, it has been subsequently seen to involve a wide range of organs like salivary glands, paranasal sinuses, thyroid gland, retroperitoneum, lung and kidney. Rarely, it may present as a skull base osteomyelitis (SBO). Diagnosing IgG4 RD in such patients is a herculean challenge in view of absence of systemic symptoms, difficulty in obtaining adequate tissue specimens in view of densely fibrotic cranial base lesions, as well as the close proximity of the lesions to critical neurovascular structures. The standard of care, in such cases is medical, and comprises of steroids and rituximab. Herein, we discuss one such case of IgG4 RD, who presented as multiple lower cranial nerve palsies and headache, with imaging evidence of SBO, which was diagnosed as a case of IgG4RD on histopathology, and who despite receiving the standard of care, had a poor outcome. The purpose of presenting this case is to stress upon a high index of suspicion and an aggressive management approach while treating such cases.
Keywords: Immunoglobulin G4-related disease, plasma cells, rituximab, skull base osteomyelitis, steroids
|How to cite this article:|
Dorle S, Hegde A, Dwivedi G, Kovilapu UB, Mishra P S, Jain A, Ahmed F. IgG4 Licks base of skull, wastes tongue: An unusual presentation. Indian J Rheumatol 2021;16:221-6
| Introduction|| |
Immunoglobulin G4-related disease (IgG4 RD) is a systemic, immune mediated, multiorgan, fibro-inflammatory condition. characteristically presenting as tumefactive lesions, histopathologically distinguished by a lymphoplasmacytic infiltrate with obliterative phlebitis and storiform fibrosis, and often associated with a eosinophilic predominance and raised serum IgG4 levels on serology. It may resemble malignancy, infection, autoimmune conditions or inflammatory disorders. It was first described in Japan in 2003.
IgG4-RD can involve the head and neck region in form of submandibular and parotid gland enlargement, apart from involvement of the orbit, paranasal sinuses, middle ear, and pituitary hypophysitis. Approximately one in ten patients also demonstrate involvement of the cranial base. Pseudotumour involving skull base is a common mimic in these clinical settings. IgG4 related skull base osteomyelitis (SBO) has been reported rarely in literature, with the first case having been described only in 2012, that too of temporal bone involvement, and to the best of our knowledge there are no reports from our country, Moreover, it constitutes an orphan presentation in the rheumatology clinic. The purpose of this case report is to highlight this hitherto rare and emerging disease manifestation.
[TAG:2]Case Report [/TAG:2]
Our patient was a 52 years old female, a diagnosed case of type 2 diabetes mellitus (on insulin and oral hypoglycemic agents), and primary hypertension (on anti-hypertensives), who initially presented in October 2019 to the otorhinolaryngologist, with right sided headache and giddiness of 1-month duration associated with a nasal intonation of voice. On clinical examination, the patient had a swelling of the right half of the face along with right sided Xth and XIIth cranial nerve palsy. Initial evaluation by a non-contrast computerized tomography (NCCT) brain, revealed mild right maxillary sinusitis and NCCT paranasal sinus revealed hypodense opacities in right maxillary and ethmoid sinuses, with erosion of sphenoid sinus and petrous bone on right side [Figure 1]. Magnetic resonance imaging (MRI) of brain showed diffuse bone marrow edema involving the clivus and right petrous apex associated with significant soft-tissue edema and thickening along the base of skull. She underwent biopsy of these lesions which revealed necroinflammatory tissue, areas of fibrosis and scattered mixed inflammatory infiltrate comprising of neutrophils, lymphocytes and plasma cells [Figure 2]a and [Figure 2]b, while, no granuloma/giant cell/fungal hyphae or evidence of malignancy was noted. Immunohistochemistry (IHC) of majority of plasma cells was IgG/IgG4 positive [Figure 2]c and [Figure 2]d. She was initially managed by the otorhinolaryngologist, with empirical antibiotics and antifungals as a case of SBO for 6 weeks, and then referred to the rheumatologist in view of poor response to management in January 2020.
|Figure 1: NCCT base of skull axial view in bone window shows erosion and rarefaction of the right petrous and sphenoid bone. NCCT: Non contrast computerized tomography|
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|Figure 2: Slide a and b (H and E, ×10 and × 40) photomicrographs show dense infiltrate of mixed chronic inflammatory cells predominated by mature plasma cells (plasma cells are shown by black arrows; red arrow shows lymphocytes); Slide c and d (immunohistochemistry, ×10 and × 40) photomicrographs show numerous IgG staining plasma cells, many of which are also stained for ? IgG4 with an IgG4: IgG ratio >0.5. Ig: Immunoglobulin|
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On examination by the rheumatologist, the patient had atrophy of tongue on the right side, palatal and vocal cord palsy, suggestive of right IXth, Xth, and XIIth cranial nerve palsy [Figure 3]a, [Figure 3]b, [Figure 3]c. A repeat MRI brain revealed heterogeneously hyper intense signal involving right side of skull base, posteriorly extending up to the right hypoglossal canal [Figure 4]a and [Figure 4]b, with post contrast diffuse enhancement of the right side of skull base suggestive of SBO [Figure 4]c. An 18 fluorodeoxyglucose whole body positron emission tomography (18F-FDGPET) scan of brain and whole body showed soft tissue lesion in the base of skull – right nasopharyngeal region, eroding underlying basiocciput on right side. Salient investigations revealed elevated acute phase reactants (C reactive protein – 21.16 mg/L [<5]). Other investigations revealed a negative anti-nuclear antibody and anti-neutrophil cytoplasmic antibody by immunofluorescence and a HbA1c of 7.1%. Serum angiotensin converting enzyme levels were also normal. Ig profile revealed raised serum IgG levels - 1696 mg/dl (700–1600), with normal IgM and IgA. IgG subclass 4 levels were > 350 mg/dl (3–201). Serum IgE was also high - 649 kUA/L (<64). A relook at the biopsy by the pathologist revealed a ratio of IgG4: IgG >50% on biopsy sample. Based upon this, along with the earlier histopathologic evidence, she was managed as a case of SBO-IgG4 RD; with oral prednisolone 1 mg/kg for 4 weeks.
|Figure 3: (a) Photograph of patient with protruded tongue showing atrophy of tongue on right side. (b) Photograph of patient demonstrating the absent gag reflex. (c) Photograph of pharynx showing right-sided soft palatal palsy|
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|Figure 4: (a) FLAIR axial MRI figure of skull base shows heterogeneously hyper intense signal involving right side of skull base posteriorly extending up to the right hypoglossal canal. (b) T2 axial MRI image of skull base shows heterogeneously hypo intense signal involving right side of skull base. (c) Postcontrast T1W1 MRI image of skull base shows diffuse moderate to intense enhancement of the right side of skull base. MRI: Magnetic resonance imaging, FLAIR: Fluid attenuated inversion recovery|
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On follow-up after 4 weeks, she reported minimal improvement in symptoms, however persistent headache continued. Repeat MRI also showed minimal improvement, as compared to previous scan. However, in view of expected chronicity of disease, she was initiated on B cell depletion with injection rituximab, with first two doses of 500 mg each, given on weekly basis. She showed improvement in clinical status in form of resolution of headache, and was discharged on oral steroids and cotrimoxazole prophylaxis. However, when she reported for the third dose of rituximab, she offered fresh complaints in form of facial deviation toward left side, difficulty in closing right eyelid of 3 days duration along with a hearing loss in right ear. On examination, she was found to have lower motor neuron right sided VIIth cranial nerve palsy and deviation of soft palate toward left. In view of suspicion of progression of disease process, the patient received 3rd dose of Rituximab of 500 mg, on time. A repeat 18F-FDGPET scan in March 2020 [Figure 5]a, [Figure 5]b, [Figure 5]c, [Figure 5]d, revealed ill-defined metabolically active soft-tissue thickening in the posterior wall and roof of nasopharynx with involvement of bone of middle and posterior cranial fossa (right side). In April 2020, while still admitted in hospital, the patient developed fresh left XIIth nerve palsy and worsening of right VIIth, VIIIth, and XIIth cranial nerve palsy. NCCT temporal bone done revealed erosion of anterior wall of carotid canal and eustachian canal. Erosion was also noted in petrous apex and clivus, causing widening of petro-occipital fissure on the right side. Soft-tissue attenuation contents were seen in the adjoining cerebellopontine angle cistern, reaching up to the region of the right internal auditory membrane (IAM). Repeat serum IgG4 assay showed reduced levels (125 mg/dl). A repeat MRI brain showed further disease progression in form of increase in associated soft tissue component, right vertebral artery thrombosis, along with right internal carotid artery complete/near occlusion. Right sigmoid and jugular bulb thrombosis was present, with possible abscess/granulation tissue in right tympanic cavity and petrous temporal bone. The patient was continued on steroids and broad-spectrum antibiotics. Glycemic control was maintained using injection glargine and lispro. She was offered grommet insertion in right ear, but refused consent. She had spontaneous rupture of right IAM, and fungal culture grew candida. Antifungals were added to her regime. However, she continued to worsen, with requirement of mechanical ventilation in view of bilateral vocal cord palsy and antecedent aspiration risk, along with inotropic support, and finally succumbed to her illness on April 9, 2020.
|Figure 5: (a) FDG PET CT axial section of base of skull axial view in soft tissue window shows erosion and rarefaction of the right petrous and sphenoid bone with heterogeneous metabolic activity. (b and c) FDG PET CT axial and coronal section of head in bone window shows ill defined metabolically active lesion involving bones of middle and posterior cranial fossa on right side (body and wings of sphenoid, petrous temporal, clivus and basilar part of occipital bone). (d) FDG PET CT sagittal section of head shows ill defined hypermetabolic soft tissue thickening involving posterior wall of nasopharynx. FDG PET CT: Fluorodeoxyglucose positron emission tomography computed tomography|
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| Discussion|| |
IgG4 RD is an emerging clinical diagnosis worldwide with very few cases being reported from our country. In 2001, Humano et al. first described, high serum levels of IgG4 in patients of pancreatitis, with extensive IgG4-positive plasmacytoid cells being detected on immune histochemistry of pancreatic cells. IgG4 RD can affect nearly every organ in the human body, but in particular, the meninges, orbits (extraocular muscles and retrobulbar masses), lacrimal glands, salivary glands, mastoid bone, thyroid gland, pancreas, bile ducts, lungs, kidneys, aorta, and retroperitoneum, are usually involved. It is typically a slow, progressive disease that is often present for months or even years, before a clinical diagnosis is established.
IgG4 disease-related SBO is a rare and life-threatening disorder, and is often diagnosed late owing to poorly localizing and non-specific symptoms such as headache, giddiness, and otalgia, and a considerable progression of disease before onset of symptoms. Old age, comorbid conditions such as diabetes or immunodeficiency are important factors in susceptibility and course of disease. Inflammatory pseudotumor in sinusoidal cavity can mimic IgG4 RD, in which case serum IgG4 level is the clue to the diagnosis., Our patient too, had a co-morbidity in the form of diabetes mellitus, had poorly localizing symptoms, and presented to the rheumatologist a little late in the course of her illness.
For diagnosis of IgG4 RD the comprehensive diagnostic criteria proposed by Umehara et al., have been applied commonly. As per these criteria, the definitive diagnosis of IgG4 RD is made when patients have at least two or all three amongst the following:
- Organ enlargement, mass or nodular lesions, or organ dysfunction
- Serum IgG4 concentration (135 mg/dl)
- Histopathological findings of >10 IgG4 cells/HPF and an IgG4+/IgG + cell ratio >40%.
In case, all these three criteria are fulfilled, the diagnosis is “definite,” if criteria (1) and (2) are fulfilled, then the diagnosis is termed “possible,” however, it is “probable” if criteria (1) and (3) are fulfilled [Figure 6]. Histopathological findings include storiform or swirling fibrosis and obliterative phlebitis; Eosinophilic infiltration often occurs, along with the infiltration of IgG4+ve cells. A newer criteria have also been proposed in December 2019 by the American College of Rheumatology/European League Against Rheumatism consensus committee. These criteria propose a three-step approach to diagnosis. Initially, the patient is screened for entry criteria comprising of typical organ involvement with characteristic findings clinically or radiologically, and then there are exclusion criteria, which include fever and clinical response to steroids, certain serological, radiological, and pathological findings. Further the patient is given points as per the histological findings, serum IgG4 levels and different organ involved. The disease is classified as IgG4 RD if this score is >20. It is pertinent to note here that, these criteria are intended for research purpose and not for clinical diagnosis, and management should not be deferred if these criteria are not met. Moreover, the experts did not include head and neck related lesions at the time of formulation of these criteria. Our patient had organ involvement in the form of SBO, along with raised serum IgG4 levels, and a ratio of IgG4:IgG >50% on biopsy, on the basis of which she was diagnosed as a definite case of IgG4 RD, as per the comprehensive diagnostic criteria. Hao et al., in their comprehensive systematic review and meta-analysis of nine published studies concluded that serum IgG4 is a modestly effective marker for the disease and doubling the cut-off value for IgG4 could improve the specificity, but inevitably would result in a significant sacrifice in sensitivity. Our patient too had serum IgG4 levels around twice the upper limit of normal and reduced on treatment with steroids (>350 → 125 mg/dl).
|Figure 6: Algorithm of comprehensive diagnostic criteria for immunoglobulin G4 related disease|
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Patients with SBO often present with headache and cranial nerve palsies without evidence of systemic disease. Our case too, presented with headache along with multiple lower cranial nerve palsies. Unlike IgG4 RD, which tends to have a male predilection, the patients with SBO do not have any gender predilection. Our patient too was of female gender. Marinelli et al., in a large case series of 11 patients with IgG4 related SBO, observed that all patients had a lymphoplasmacytic infiltrate, but were conspicuous by an absence of storiform fibrosis and obliterative phlebitis. They also observed an IgG4/IgG ratio of >40%, or >30% IgG4 positive plasma cells on the biopsy specimens. All the biopsies had been obtained by an open craniotomy or a transsphenoidal approach. Our case too had an IgG4 positive lymphoplasmacytic infiltrate on HPE, along with absence of storiform fibrosis and obliterative phlebitis, which is in consonance with findings of Marinelli et al. A comparative table of cases with IgG4 related SBO along with our case is enclosed a [Table 1]. IgG4 RD is also 18F FDGPET avid, as was the finding in our case. Similar findings were brought out in the studies by Marinelli et al., and Thompson and Whyte.
|Table 1: Comparison of various cases of IgG4-related disease with skull base disease|
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Glucocorticoids are the cornerstone of treatment for most patients with IgG4 RD, and patients typically respond well to this intervention. As per the proposed regime, prednisolone is initiated at a dose of 0.6 mg/kg/day for 2–4 weeks followed by gradual tapering every 2 weeks to a maintenance dose of 2.5–5 mg/day, for up to 3 years. However, most of these patients have substantial comorbidities (e.g., diabetes, obesity, osteoporosis, and hypertension) which make steroid therapy unsuitable in these patients. Some have progressive and steroid refractory disease, as was the case in our patient. Biological disease modifying anti-rheumatic drugs, particularly a B-cell depleting (BCD) agent should be considered if available, in such cases. Rituximab has emerged as a treatment of choice for IgG4 RD even without concomitant glucocorticoid therapy, as per a prospective open label trial by Carruthers et al., in 2015. Ebbo et al., in a study observed that rituximab therapy was shown to induce responses in over 90% of patients. Rituximab is given at dose of 1 g every 2 weeks, and can be repeated at six monthly intervals, as required. BCD interrupts antigen presentation to CD4 cytotoxic T cell lymphocytes, decreases tissue fibrosis, and achieves reduction of serum IgG4 concentrations. We too, managed our patient with rituximab, in view of persistent symptoms. Given the effectiveness of medical management, complete surgical excision does not constitute the initial goal of therapy, particularly for skull base lesions, in view of their intimate relationship with critical neurovascular structures that surround these tumors. Radiotherapy too does not have any beneficial role as was observed by Marinelli et al., in their study. Differential diagnoses for such lesions comprise malignancies such as lymphoma, sarcoma, and nasopharyngeal carcinoma, autoimmune diseases such as neurosarcoidosis, granulomatosis with polyangiitis, Langerhans cell histiocytosis and benign skull base tumors, all of which were ruled out in our case too using histopathology and serology, before assigning a diagnosis of IgG4 RD.
Our case had a rapid clinical deterioration, with the development of multiple cranial nerve palsies despite steroids and rituximab in optimal dosing, and with a supportive evidence of fungus (candida albicans) being cultured from the ear discharge, a possibility of super added infection like disseminated candida in the background of poorly controlled type 2 diabetes mellitus, cannot be discounted in this case, as a probable cause for clinical deterioration. Furthermore, a possibility of steroid and rituximab resistant IgG4RD cannot be ruled out, although the authors could not come across a single reference in contemporary literature for such an entity. In cases of middle ear and mastoid infections/inflammation, there can be retrograde thrombophlebitis through emissary veins and sigmoid sinus, and this can lead to the development of central venous sinus thrombosis (CVT), as was there in our case. On the corollary, CVT thrombosis can develop secondary to SBO, which can lead to mastoid and middle ear effusion due to inability of these areas to drain, and this effusion can also get secondarily infected.
| Conclusion|| |
IgG4 related SBO is a rare presentation in the rheumatologist's clinic. Clinical manifestations include headache, otalgia, and lower cranial nerve palsies. Biopsies are difficult to obtain owing to fibrotic nature of tissue at skull base and serum IgG4 levels are an important adjunct towards successful diagnosis. Treatment modalities include steroid and rituximab. Final outcomes could be fatal unless diagnosed early and aggressively treated. Superadded infections due to glucocorticoid use and comorbid conditions like diabetes mellitus can contribute to poor outcomes.
Written informed consent was taken from the patient's relatives.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initial will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]