A 54 Year‐Old Man with Progressive Vision and Hearing Loss

Clinical History

A 54 year‐old man with past medical history significant for hypertension and gastro‐esophageal reflux (GERD) presented with several months of sinus complaints (headaches, nasal drainage, sinus pain) requiring several courses of antibiotics and a right‐sided tympanostomy tube placement. Over the last 2–3 months he developed bilateral eye pain with progressive vision loss, to the point of becoming blind in both eyes. He also had an unintentional weight loss of nearly 100 pounds. On physical examination no other motor, sensory, or cranial nerve deficits were seen. A CT scan of the brain showed a right frontoparietal subdural fluid collection, consistent with a hematoma, measuring up to 1 cm in thickness. This was associated with minimal midline shift and compression of the right lateral ventricle. A bilateral temporal artery biopsy and a turbinate biopsy showed no evidence of vasculitis. He underwent drainage of the hematoma without significant improvement of his symptoms. A brain MRI was performed. The T1 image revealed bilateral subdural collections, with associated diffuse meningeal thickening, (Fig 1a, 1b). There was a 1.5 cm lesion with restricted diffusion in the right parietal lobe and associated contrast enhancement, morphologically suspicious for a lymphoma. A FLAIR sequence showed no discrete mass corresponding to the area of restricted diffusion. In addition there was patchy mass‐like effect, and mild herniation of the right parietal lobe into the burr hole.

Figure 1.

 

A subsequent lumbar puncture showed a mildly elevated protein level and a negative cytology. The cell count was normal. A CT scan of the chest, abdomen and pelvis demonstrated no evidence of lymphadenopathy. A bone marrow biopsy was obtained (due to the concern for lymphoma), which showed normocellular marrow with multilineage hematopoiesis and no lymphoma (flow cytometry performed on the sample was also negative). Laboratory findings were significant for anemia and mild thrombocytosis (Hemoglobin 8.8 and Platelets 606). In addition, normal IgG levels with elevated IgG3 (108 mg/dl; nl range = 18.4 – 106 mg/dl) and IgG4 (148 mg/dl; nl range = 2.4 – 121 mg/dl) subclasses were seen. A biopsy of the putative enhancing lesion and the meninges was taken under MRI‐guidance.

Microscopic Pathology

Histologically, the right dura was thickened and showed an infiltrate composed predominantly of small to medium‐sized lymphocytes with clumped chromatin and abundant small, mature‐appearing plasma cells (Figs 2a,b,c)). In some areas the infiltrate appeared to be more pronounced around some blood vessels that were otherwise unremarkable. No vasculitis or necrotizing granulomatous inflammation was seen. By immunohistochemistry the lymphoid infiltrate was composed of a mixture of CD3+ T‐cells (Fig. 3a) and CD20+ B‐cells (Fig. 3b). Rare larger CD20+ cells were occasionally seen, intermixed with the smaller lymphocytes. CD138 (Fig 3c) showed an increased number of plasma cells, both singly scattered and clustered, which comprised approximately 30% of the cells in the infiltrate. In‐situ hybridization for kappa and lambda revealed that the plasma cells were polytypic, with a kappa to lambda ratio of 3–4:1 (Figs. 4a and b). An IgG4 immunostain (Fig. 5a) showed numerous positive plasma cells, comprising approximately 40% of that cell population. In several high‐power fields there were over 10 IgG4+ cells (approximately 15–20 per HPF). IgG (Fig. 5b) stained relatively fewer plasma cells, representing 10–20% of the cells. The IgG4 to IgG ratio was markedly increased (>1). In‐situ hybridization for EBER was negative. Molecular PCR studies were negative for IGH clonal rearrangement. What is your diagnosis?

Figure 2.

 

Figure 3.

 

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Figure 5.

 

Diagnosis

IgG4‐related meningeal disease, previously classified as idiopathic hypertrophic pachymeningitis (IHP).

Discussion

Idiopathic hypertrophic pachymeningitis (IHP) was originally described by Charcot and Joffroy in 1869 with many subsequent reports. Patients typically present with headaches, along with ataxia and various cranial nerve palsies. On MRI examination, it is characterized by a marked thickening of the dura that enhances along the edges. The cervical spine and thoracic cord are more commonly involved, and intracranially, it's typically seen along the base of the brain. Microscopic examination of these sites revealed extensive fibrotic tissue with a chronic inflammatory infiltrate containing small lymphocytes, plasma cells and rare eosinophils. More recently, Chan et al (1) described a 37 year‐old man with spinal cord compression at the thoracic level, an elongated dural mass on MRI and a biopsy showing a dense lymphoplasmacytic infiltrate with a significant subset of the plasma cells being immunoreactive for IgG4, and a high IgG4 to IgG ratio. Chan proposed that a subset of those cases previously described as IHP might represent part of the spectrum of IgG4‐related disorders (1).

IgG4 was first recognized as being associated with sclerosing disorders in 2001, when Hamano et al reported that patients with autoimmune pancreatitis had elevated serum levels of IgG4 in comparison to patients with other causes of chronic pancreatitis (4). Since then a number of different disorders, predominantly idiopathic in nature, emerged as a spectrum of diseases linked to the IgG4 subclass (2, 5, 7).

Within the central nervous system, IgG4‐related meningeal disease has been recently recognized as a distinct entity. Lindstrom et al (7) described 5 patients with intracranial disease, all of which exhibited the typical lymphoplasmacytic infiltrate and fibrosis of IgG4‐related sclerosing diseases, along with increased number of IgG4+ plasma cells. The mean number of IgG4+ cells was 36.2/HPF and the percentage (IgG4/IgG ratio) was 42%. The plasma cells were characteristically polytypic by in‐situ hybridization. In addition, there was no evidence of a clonal IGH gene rearrangement by PCR analysis. The authors recommended the use of 10 IgG4+ plasma cells/HPF, as a cutoff, for a diagnosis of IgG4‐related meningeal disease. It is now recognized that IgG4 antibodies can be detected in patients with IgG4 pachymeningitis (3). MALT lymphomas can enter in the differential diagnosis, and a recent study by Venkataraman et al (8) has shown that an increased number of IgG4‐plasma cells can be seen in intracranial MALTs. The treatment recommendations include high‐dose corticosteroid therapy and decompressive surgery if emergently required. The response to steroids is variable (7).

In summary, this case represents one of a few cases of IgG4‐related meningeal disease reported. Our patient presented with the typical clinical features of IHP, including visual and hearing loss with associated diffuse leptomeningeal thickening and enhancement. The typical histologic features of IgG4‐related meningeal disease were also seen in our case (lymphoplasmacytic infiltrate with fibrosis). Molecular studies and in‐situ hybridization confirmed the lack of a clonal population of B‐cells or plasma cells. These features along with the high serum IgG4 levels and rich IgG4+ infiltrate were diagnostic of the disease.

A more complete discussion and additional references can be found at http://path.upmc.edu/divisions/neuropath/bpath/cases/case275.html.