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Intracranial spread of IgG4-related disease via skull base foramina
  1. C M Rice1,2,
  2. T Spencer1,
  3. G Bunea3,
  4. N J Scolding1,2,
  5. P Sloan4,
  6. U Nath5
  1. 1Department of Neurology, North Bristol NHS Trust, Bristol, UK
  2. 2Clinical Neuroscience, School of Clinical Sciences, University of Bristol, Bristol, UK
  3. 3Department of Radiology, Sunderland Royal Hospital, Sunderland, UK
  4. 4Department of Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
  5. 5Department of Neurology, Sunderland Royal Hospital, Sunderland, UK
  1. Correspondence to Dr Claire Rice, Department of Neurology, Southmead Hospital, Bristol, BS10 5NB, UK; c.m.rice{at}bristol.ac.uk

Abstract

IgG4-related disease (IgG4-RD) is a newly recognised, multiorgan, inflammatory disease, and its full clinical spectrum remains undefined. We present a biopsy-proven case of IgG4-RD presenting with a parapharyngeal mass with intracranial extension and possible involvement of the brain parenchyma. We highlight the importance of considering the diagnosis in those presenting with tumefactive lesions, leptomeningitis or pachymeningitis and emphasise the value of securing a tissue diagnosis so that appropriate long-term treatment can be instigated and complications avoided.

  • IgG4-related disease
  • NEUROIMMUNOLOGY
  • dacryosialoadenopathy
  • pachymeningitis
  • leptomeningitis

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Introduction

IgG4-related disease (IgG4-RD) was recognised only relatively recently as a distinct entity, and its complete clinical spectrum is still not determined. It typically causes painless swelling affecting either one organ in isolation or multiple organs.1 ,2 Fever, malaise, sweats and weight loss are less common. Here, we present a man with both intracranial and extracranial manifestations of IgG4-RD with spread of the disease via the skull base foramina.

Case report

A 46-year-old right-handed male construction worker presented with a 12-month history of fatigue, weight loss (25 kg), headache, right-sided facial numbness and diplopia on gaze to the right. On examination, there was right-sided trigeminal sensory impairment, partial right sixth nerve palsy and right-sided tongue wasting.

His peripheral blood markers of inflammation were elevated. Screening for immunodeficiency and mycobacterial infection was negative. Chest X-ray and CT scans of chest, abdomen and pelvis were normal.

An MR scan of the brain (figure 1A–D) showed an enhancing soft tissue mass involving the right posterior nasopharynx with intracranial spread through the right carotid canal, jugular foramen and foramen ovale. There was basal pachymeningitis and leptomeningitis in the middle cranial fossa with high signal in the overlying temporal lobe. There was no significant lymphadenopathy. MR venogram confirmed that the major dural venous sinuses were patent. Biopsy of the parapharyngeal space on two occasions was non-diagnostic.

Figure 1

MR imaging (A and B) showing an enhancing soft tissue mass involving the right posterior nasopharynx with infiltration laterally and posteriorly into the right prevertebral strap muscles and through the pharyngobasilar fascia to involve the medial and lateral pterygoids. The right carotid and internal carotid arteries were ensheathed and there was abnormal tissue in the right carotid canal and jugular foramen. The right cavernous sinus was involved via perineural spread through the foramen ovale. There was basal pachymeningitis and leptomeningitis along the floor of the right middle cranial fossa with high signal in the overlying temporal lobe (C). There were progressive changes in the pterygomaxillary fissure, the muscles of the masticator compartment and throughout the temporalis muscle on the right at the time of re-presentation (D). (E–G) Biopsy of anterior temporalis and posterior maxilla showed a diffuse plasma cell-rich, chronic inflammatory cell infiltrate with prominent stromal fibrosis/hyalinisation, fat necrosis and focal granulation tissue. Immunocytochemistry showed numerous IgG and IgG4 positive plasma cells (F and G).

Three months later, he developed worsening headache with bilateral haemorrhagic papilloedema. Following treatment with intravenous methylprednisolone (1 g) for 3 days and then oral prednisolone 60 mg daily he showed symptomatic and radiological improvement, but developed corticosteroid-induced diabetes mellitus. While reducing prednisolone to 15 mg over 9 months he developed right-sided facial swelling consistent with dacryosialoadenopathy. His diplopia reappeared together with reduced left-sided visual acuity, consistent with optic neuropathy. Sensation was reduced in the maxillary and mandibular branches of the right trigeminal sensory distribution and there was right-sided tongue wasting. Weber's sign localised to the right. His limbs showed clinical signs of peripheral neuropathy but were otherwise normal.

Repeat MR imaging (figure 1D) showed resolution of the previously abnormal right temporal lobe and there was stable disease along the tentorium and in the cavernous sinus; however, he had progressive changes in the pterygomaxillary fissure, the muscles of the masticator compartment and throughout the temporalis on the right.

Biopsy of anterior temporalis and posterior maxilla found a diffuse plasma cell-rich, chronic inflammatory cell infiltrate. There was prominent stromal fibrosis/hyalinisation, fat necrosis with focal granulation tissue and numerous IgG and IgG4-positive plasma cells (figure 1E–G).

After restarting high-dose corticosteroids his signs resolved within a fortnight. Fluorodeoxy-glucose-positron-emission tomography (FDG-PET) after restarting corticosteroids showed no enhanced uptake. He started azathioprine and gradually reduced the dose of prednisolone to 10 mg daily over 1 year with no recurrence of clinical signs.

Discussion

IgG4-RD has only recently been appreciated as a distinct clinical entity although the same pathological changes occur in several long-recognised conditions such as Mikulicz syndrome,3 autoimmune pancreatitis4 and Riedel's thyroiditis.5 While the full spectrum of the clinical phenotype remains undetermined, there are descriptions of the characteristic histopathological findings in almost every organ.1 ,6 ,7 In the central nervous system (CNS), there may be leptomeningitis and pachymeningitis as well as hypophysitis, pseudotumours and cranial neuropathy but brain parenchymal involvement is rare.8 ,9 There has been a single previous case report documenting intracranial extension of disease via the foramen ovale along the trigeminal nerve.10

Finding an elevated serum IgG4 concentration supports the diagnosis of IgG4-RD but is not a constant finding.2 It is uncertain whether IgG4, a relatively weak activator of effector cells, is pathogenic.11

In the head and neck, hypointense T2 lesions on MR are typical, sometimes with gadolinium enhancement.12 11C-methionine (MET) PET may be better than 18F-FDG PET in detecting CNS disease.13 Nonetheless, with the possible exception of autoimmune pancreatitis,14 the radiological features are not pathognomonic and cannot reliably differentiate IgG4-RD from other inflammatory, multiorgan diseases such as granulomatosis with polyangiitis (Wegener's granulomatosis) and Sjögren's syndrome.

The diagnosis of IgG4-RD therefore relies on histology. The consensus diagnostic criteria are based on morphological appearances, including the presence of a dense lymphoplasmacytoid infiltrate, fibrosis (usually storiform) and obliterative phlebitis.15 There may be an eosinophilic infiltrate but this is not a prerequisite for the diagnosis.

IgG4-RD typically responds to treatment with glucocorticoids but corticosteroid-sparing agents such as azathioprine, methotrexate or mycophenolate mofetil may be required to reduce the risk of relapse with corticosteroid withdrawal.6 There are also reports of patients with CNS IgG4-RD responding successfully to rituximab.8

We present a case of IgG4-RD with contiguity of intracranial and extracranial disease via skull base foramina. Although there was radiological evidence of cerebral parenchymal involvement, this may be due to vasogenic oedema or direct brain involvement; in this case, we elected to biopsy the extracranial disease given the associated lower risk of complications. Nonetheless, this case adds to the reported clinical spectrum of IgG4-RD, a relatively newly recognised clinical entity where appropriate long-term immunosuppression can avoid serious complications.

Key points

  • IgG4-related disease should be considered in the differential diagnosis of central nervous system pseudotumour, cranial neuropathy, hypophysitis and leptomeningitis or pachymeningitis.

  • IgG4-related disease may present with a combination of intracranial and extracranial manifestations.

  • Early recognition of IgG-related disease and establishing appropriate long-term treatment may avoid unnecessary investigations and morbidity.

  • Histological findings in IgG4-RD typically include a lymphoplasmacytoid infiltrate, storiform fibrosis and obliterative phlebitis. An elevated serum IgG4 concentration is supportive of the diagnosis.

  • IgG4-RD is typically a corticosteroid-responsive disease but may require additional immunomodulatory therapy.

Acknowledgments

We thank the patient for permission to publish the report and the ENT team (Mr S Carrie) in obtaining tissue samples.

References

Footnotes

  • Contributors UN was the treating neurologist with input from the authors. CMR, TS and NJS were responsible for the first drafts of the manuscript. Radiology and pathology analyses were performed by GB and PS respectively. All authors reviewed and contributed to the manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review. Not commissioned; externally peer reviewed. This paper was reviewed by Jeremy Chataway, London, UK.

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