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Man presents with chronic headaches and progressive vision loss

Visual acuity, extraocular motility and the optic nerve were worse in the right eye than the left eye.

A 60-year-old Hispanic man presented to the emergency department for evaluation of worsening chronic headaches and vision loss in the right eye more than the left eye. He had headaches for many years and had been managed with oral steroids by an outside neurologist. He began having vision loss 1 year before presentation.

At age 16, the patient was diagnosed with pulmonary tuberculosis and was treated for 1.5 years. His medical history was significant for diabetes for which he was taking metformin, hypertension, pancreatitis of unknown cause, and deep venous thrombosis treated with warfarin.

Examination

The patient’s visual acuity was no light perception in the right eye and 20/80 in the left eye. There was a right relative afferent pupillary defect. He had reduced extraocular motility in the right eye more than the left eye. Color vision was decreased to 2/10 Ishihara plates in the left eye. External examination and IOPs were within normal limits. On slit lamp biomicroscopy, the anterior segment was unremarkable. The right optic nerve was diffusely pale. The left optic nerve was normal. The retinal examination was unremarkable. Humphrey visual field testing of the left eye showed peripheral constriction. Cranial nerve examination was normal aside from mild hearing loss.

MRI demonstrated thickening of the pachymeninges, which was particularly pronounced around the optic nerve on the right side more than the left side (Figure 1). Lumbar puncture was performed, and opening pressure was normal at 18 cm of water. Cerebrospinal fluid (CSF) showed mildly elevated nucleated cells, elevated IgG index and oligoclonal bands. Gram stain and CSF cultures were negative. Serum C-reactive protein (CRP) was elevated. High-dose steroids were started, and a temporal artery biopsy was obtained, which was not consistent with giant cell arteritis. Serum testing for anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, anti-Ro, anti-La, anti-DNA, cyclic citrullinated peptide, rheumatoid factor and anti-myeloperoxidase was unremarkable. IgG4 subclass measurement was 22 mg/dL (range: 7 mg/dL to 89 mg/dL). Treponemal and HIV tests were normal. Meningeal biopsy was obtained. Histopathological examination revealed a lymphocytic and lymphoplasmacytic chronic inflammatory infiltrate without organisms or granulomata. IgG4 plasma cells were quantified at 15% to 20%.

In the left eye, vision improved to 20/25 on high-dose oral steroids. It declined to 20/40 with worsening visual field deficit with attempted tapering of steroids.

Figure 1. T1-weighted axial MRI demonstrating meningeal thickening (left). T1-weighted coronal post-contrast MRI demonstrating meningeal thickening surrounding the optic nerves (right).

Image: Branchini L, Sitko K

What is your diagnosis?

Headaches, vision loss

Ophthalmic examination and visual field testing revealed a progressive optic neuropathy with severe vision loss and optic atrophy in the right eye. MRI showed thickening of the meninges, leading to a diagnosis of compressive optic neuropathy from IgG4-related hypertrophic pachymeningitis.

The differential for IgG4-related hypertrophic pachymeningitis is broad and includes infectious causes such as tuberculosis and syphilis; inflammatory etiologies such as microscopic polyangiitis, Wegener’s granulomatosis, rheumatoid arthritis, sarcoidosis and giant cell arteritis; and neoplastic causes such as meningioma, lymphoma and metastatic carcinoma. Additionally, local meningeal thickening in areas adjacent to inflammatory foci could present with a similar picture. The laboratory findings, imaging studies and meningeal biopsy were together suggestive for IgG4-related pachymeningitis.

Discussion

Pachymeningitis was first described by Charcot and Joffroy in 1869. Compression of multiple nerves leading to cranial and spinal neuropathies is the hallmark of this process. Elevated CRP has been described in idiopathic pachymeningitis. Consequently, its presentation often raises concern for temporal arteritis, as was the case with this patient.

IgG4-related pachymeningitis was first described in 2003 by Kamisawa and colleagues who reported characteristic histopathologic findings in multiple lesions in different organ systems in the setting of autoimmune pancreatitis. Demographically, this disease affects men between the ages of 58 years and 69 years most frequently. It has been reported to cause hepatitis, chronic sclerosing sialadenitis, tubulointerstitial nephritis, retroperitoneal fibrosis, aortitis, pericarditis, prostatitis and thyroiditis, along with lung, skin and breast nodules. Of concern to an ophthalmologist, pachymeningitis, chronic sclerosing dacryoadenitis, and inflammatory orbital pseudotumor and pituitary hypophysitis have all been described.

Histopathologically, lesions consist of diffuse lymphoplasmacytic infiltrates with abundant IgG4-positive plasma cells. Obliterative phlebitis along with varying degrees of fibrosis correlating to the extent of disease can also be seen. Polyclonal elevations of serum IgG4 are found in most, but not all, patients. It is common for patients with IgG4-related disease affecting only one body system to have normal serum levels of IgG4. In the setting of pachymeningitis with other systemic manifestations of the disease, characteristic findings on meningeal biopsy are found half of the time. In our case, some but not all of the described findings were observed. Our patient had been on therapeutic doses of steroids before this biopsy had been taken, and this could have influenced the histologic findings.

Although there are no clinical trials, experts agree that this disease responds well initially with corticosteroids and may be resistant to steroid tapering. Significant morbidity may be avoided if therapy is initiated before the onset of tissue fibrosis. Serum IgG4 concentrations have been shown to decrease with initiation of glucocorticoid therapy. However, the incidence of symptomatic relapse after steroid taper has been reportedly as high as 47%. Immunomodulatory therapy with azathioprine, 6-mercaptopurine, mycophenolate mofetil or rituximab has had reported benefits for long-term therapy. Rituximab has shown the most promising results for IgG4-related hypertrophic pachymeningitis in particular.

This case was felt to represent IgG4-related hypertrophic pachymeningitis based on the lack of evidence for an alternative cause of hypertrophic pachymeningitis after extensive serum, CSF and tissue studies, the associated history of idiopathic pancreatitis, and the borderline pathologic findings, which were consistent with IgG4-related disease.

Follow-up

In the context of presumed IgG4-related disease, therapy with rituximab was initiated, and the patient’s steroids are being slowly tapered. Visual acuity had stabilized at 20/50 in the left eye at the time of the last visit but with a marked improvement in visual field testing, and his left optic nerve has residual mild temporal pallor.

A 60-year-old Hispanic man presented to the emergency department for evaluation of worsening chronic headaches and vision loss in the right eye more than the left eye. He had headaches for many years and had been managed with oral steroids by an outside neurologist. He began having vision loss 1 year before presentation.

At age 16, the patient was diagnosed with pulmonary tuberculosis and was treated for 1.5 years. His medical history was significant for diabetes for which he was taking metformin, hypertension, pancreatitis of unknown cause, and deep venous thrombosis treated with warfarin.

Examination

The patient’s visual acuity was no light perception in the right eye and 20/80 in the left eye. There was a right relative afferent pupillary defect. He had reduced extraocular motility in the right eye more than the left eye. Color vision was decreased to 2/10 Ishihara plates in the left eye. External examination and IOPs were within normal limits. On slit lamp biomicroscopy, the anterior segment was unremarkable. The right optic nerve was diffusely pale. The left optic nerve was normal. The retinal examination was unremarkable. Humphrey visual field testing of the left eye showed peripheral constriction. Cranial nerve examination was normal aside from mild hearing loss.

MRI demonstrated thickening of the pachymeninges, which was particularly pronounced around the optic nerve on the right side more than the left side (Figure 1). Lumbar puncture was performed, and opening pressure was normal at 18 cm of water. Cerebrospinal fluid (CSF) showed mildly elevated nucleated cells, elevated IgG index and oligoclonal bands. Gram stain and CSF cultures were negative. Serum C-reactive protein (CRP) was elevated. High-dose steroids were started, and a temporal artery biopsy was obtained, which was not consistent with giant cell arteritis. Serum testing for anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, anti-Ro, anti-La, anti-DNA, cyclic citrullinated peptide, rheumatoid factor and anti-myeloperoxidase was unremarkable. IgG4 subclass measurement was 22 mg/dL (range: 7 mg/dL to 89 mg/dL). Treponemal and HIV tests were normal. Meningeal biopsy was obtained. Histopathological examination revealed a lymphocytic and lymphoplasmacytic chronic inflammatory infiltrate without organisms or granulomata. IgG4 plasma cells were quantified at 15% to 20%.

In the left eye, vision improved to 20/25 on high-dose oral steroids. It declined to 20/40 with worsening visual field deficit with attempted tapering of steroids.

Figure 1. T1-weighted axial MRI demonstrating meningeal thickening (left). T1-weighted coronal post-contrast MRI demonstrating meningeal thickening surrounding the optic nerves (right).

Image: Branchini L, Sitko K

What is your diagnosis?

Headaches, vision loss

Ophthalmic examination and visual field testing revealed a progressive optic neuropathy with severe vision loss and optic atrophy in the right eye. MRI showed thickening of the meninges, leading to a diagnosis of compressive optic neuropathy from IgG4-related hypertrophic pachymeningitis.

The differential for IgG4-related hypertrophic pachymeningitis is broad and includes infectious causes such as tuberculosis and syphilis; inflammatory etiologies such as microscopic polyangiitis, Wegener’s granulomatosis, rheumatoid arthritis, sarcoidosis and giant cell arteritis; and neoplastic causes such as meningioma, lymphoma and metastatic carcinoma. Additionally, local meningeal thickening in areas adjacent to inflammatory foci could present with a similar picture. The laboratory findings, imaging studies and meningeal biopsy were together suggestive for IgG4-related pachymeningitis.

Discussion

Pachymeningitis was first described by Charcot and Joffroy in 1869. Compression of multiple nerves leading to cranial and spinal neuropathies is the hallmark of this process. Elevated CRP has been described in idiopathic pachymeningitis. Consequently, its presentation often raises concern for temporal arteritis, as was the case with this patient.

IgG4-related pachymeningitis was first described in 2003 by Kamisawa and colleagues who reported characteristic histopathologic findings in multiple lesions in different organ systems in the setting of autoimmune pancreatitis. Demographically, this disease affects men between the ages of 58 years and 69 years most frequently. It has been reported to cause hepatitis, chronic sclerosing sialadenitis, tubulointerstitial nephritis, retroperitoneal fibrosis, aortitis, pericarditis, prostatitis and thyroiditis, along with lung, skin and breast nodules. Of concern to an ophthalmologist, pachymeningitis, chronic sclerosing dacryoadenitis, and inflammatory orbital pseudotumor and pituitary hypophysitis have all been described.

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Histopathologically, lesions consist of diffuse lymphoplasmacytic infiltrates with abundant IgG4-positive plasma cells. Obliterative phlebitis along with varying degrees of fibrosis correlating to the extent of disease can also be seen. Polyclonal elevations of serum IgG4 are found in most, but not all, patients. It is common for patients with IgG4-related disease affecting only one body system to have normal serum levels of IgG4. In the setting of pachymeningitis with other systemic manifestations of the disease, characteristic findings on meningeal biopsy are found half of the time. In our case, some but not all of the described findings were observed. Our patient had been on therapeutic doses of steroids before this biopsy had been taken, and this could have influenced the histologic findings.

Although there are no clinical trials, experts agree that this disease responds well initially with corticosteroids and may be resistant to steroid tapering. Significant morbidity may be avoided if therapy is initiated before the onset of tissue fibrosis. Serum IgG4 concentrations have been shown to decrease with initiation of glucocorticoid therapy. However, the incidence of symptomatic relapse after steroid taper has been reportedly as high as 47%. Immunomodulatory therapy with azathioprine, 6-mercaptopurine, mycophenolate mofetil or rituximab has had reported benefits for long-term therapy. Rituximab has shown the most promising results for IgG4-related hypertrophic pachymeningitis in particular.

This case was felt to represent IgG4-related hypertrophic pachymeningitis based on the lack of evidence for an alternative cause of hypertrophic pachymeningitis after extensive serum, CSF and tissue studies, the associated history of idiopathic pancreatitis, and the borderline pathologic findings, which were consistent with IgG4-related disease.

Follow-up

In the context of presumed IgG4-related disease, therapy with rituximab was initiated, and the patient’s steroids are being slowly tapered. Visual acuity had stabilized at 20/50 in the left eye at the time of the last visit but with a marked improvement in visual field testing, and his left optic nerve has residual mild temporal pallor.