Immunoglobulin G4-related hypertrophic pachymeningitis

Case 1

A 55-year-old Caucasian male with a history of genetic hemochromatosis, diabetes mellitus, and high blood pressure presented with a progressive walking difficulty over a 2-week period. Clinical examination reported T2-T3 dorsalgia, severe paresis with pyramidal syndrome, decreased vibratory sensation of the lower limbs, and bladder dysfunction. There was no weight loss, asthenia, fever, or extra-neurologic abnormalities. Spinal cord MRI revealed many cervico-thoracic T2/fluid attenuated inversion recovery hyper intense signals from C3 to T3 that were all enhanced by gadolinium injection revealing active inflammatory myelitis. Spinal venous dilatation of the cervico-thoracic junction suggestive of dural fistula was also reported (figure 1, A). The brain MRI was normal as were visual evoked potentials. Blood tests did not reveal an inflammatory syndrome (the C-Reactive protein level was below 5 mg/L and fibrinogenemia was 3.15 g/L). Immunologic and infectious assessment did not help the diagnosis. Anti-aquaporin 4 and myelin oligodendrocyte glycoprotein auto-antibodies were negative. Analysis of the CSF revealed elevated protein levels (1.96 g/L) and lymphocytic meningitis (69 white blood cells [WBCs]/mm3 with 95% of lymphocytes). Viral PCR testing and CSF cytology were not informative. The CSF IgG index was 0.53 despite a high level of CSF IgG (18.7 mg/dL) and there was no oligoclonal band. CSF levels of Interleukin-6 were high at 1923 pg/mL.

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Figure 1 MRI of both patients with IgG4-HP and spinal cord arteriography of the first patient

(A) Multiple T2 hyperintense signals (white arrows) (A.a) all enhanced after gadolinium injection (A.b) of the posterior half of the cervico-thoracic spinal cord. T2 hypointense signal of the posterior subarachnoid space from C5 to D3 suggesting a dural fistula (red arrow) (A.c), confirmed by medullary arteriography (A.d) with opacification of a venous peloton opposite the meninge of the left lateral part of the dural sheath corresponding to the medullary veins visible on MRI. (B) Intra-ductal, intra-dural, postero-median, polylobulated tumor lesion, well-defined, in T1 isointense signal (B.a), intensely and homogeneously enhanced after injection of gadolinium (B.b), T2 hypointense signal (B.c), next to D2-D3 realizing a mass effect on the spinal cord. There is an extensive intramedullary edema supra and under-lesion (B.d). (C) Bi-frontal meningeal thickening enhanced by gadolinium invading the sheaths of optic nerves and cavernous sinuses (white arrows) (C.a and c). T2/FLAIR hyperintense signal of the left optic nerve testifying to radiologic optic neuritis, white arrows (C.b d). FLAIR = fluid attenuated inversion recovery.

Treatment with IV corticosteroids (1 g per day for 5 days) resulted in partial regression of neurologic signs. Spinal cord arteriography confirmed the diagnosis of a dural fistula that was treated by embolization (figure 1, A). Three months later, the MRI showed complete regression of spinal cord lesions. The patient was able to walk without limitation to the walking perimeter. Only mild proximal motor weakness and proprioceptive ataxia of the lower limbs persisted.

The same patient presented to our department 3 years later with similar neurologic features. The MRI of the spine found a posterior T1 isointense signal intensively enhanced with gadolinium and a T2 hypointense signal related to an intra-dural, extra-medullary, posterior, and compressive tumor-like lesion regarding T2-T3 surrounded with edema (figure 1, B). Surgical subtotal resection of the lesion was performed and confirmed its extramedullary location, originating from the dura and highly adherent to the spinal cord pia mater. Histopathologic examination of the surgical specimen identified a fibro-inflammatory lesion with dural thickening due to a lymphoplasmocytic infiltrate, storiform fibrosis, and obliterative vasculitis. Immunohistochemical analysis showed a polyclonal lymphocytic infiltration (expression of both kappa and lambda light chains) including 53 IgG4+ plasma cells per high-power field (HPF) and an IgG4+/IgG ratio greater than 40% (figure e-1a, links.lww.com/NXI/A115). There was no evidence of malignant, meningiomatous, or histiocytic disease (negativity of epithelial markers cytokeratin and Epithelial Membrane Antigen, progesterone receptors, protein S100, CD1a, langherin, and Anaplastic Lymphoma Kinase). Staining for microbial pathogens (Gram, Gomori-Grocott and Ziehl) was negative. Plasma IgG4 levels were, however, normal (59 mg/dL). There was neither eosinophilia nor complement consumption. [18F]-fluorodeoxyglucose positron emission tomography (FDG PET) (PET-CT) did not document other lesions. IgG4-HP was diagnosed based on histopathologic criteria.

Near-complete clinical recovery was achieved 3 months after surgery. Bladder dysfunction had subsided and walking did not require help. Nevertheless, proprioceptive disorders of the lower limbs persisted. The MRI did not find residual lesions. Given the patient's history of diabetes mellitus, steroids were not initiated, and a close follow-up attitude was adopted.

Case 2

A 66-year-old Caucasian male with a history of high blood pressure, dyslipidemia, and smoking presented to the emergency department for subacute onset of non-painful bilateral loss of vision. He had been suffering from chronic pulsatile headaches for many months. There was no fever or weight loss. Physical examination revealed ptosis and left reactive mydriasis with a decrease in bilateral visual acuity at 5/10 in the right eye and less than 1/20 (light perception) in the left eye. Neurologic and general somatic examinations were normal. Visual evoked potentials revealed a bilateral severe axomyelenic defect in both eyes. Funduscopic examination showed left temporal pale retina. A brain MRI found a gadolinium-enhanced, bi-frontal meningeal thickening invading the optic nerve sheaths and cavernous sinuses (figure 1, C). Microbial analyses and the immunologic bioassay were not informative. There was no inflammatory syndrome, eosinophilia, or complement consumption. Hypogammaglobulinemia was found on electrophoresis of plasma proteins. Plasma IgG4 levels were normal (40.1 mg/dL). The CSF opening pressure was normal and its analysis showed protein levels of 0.99 g/L without pleocytosis (2 WBC/mm³) or inflammatory markers (IgG index of 0.63 and CSF IgG-levels at 6.29 mg/dL). Interleukins-6 and -10 levels were also normal. Meningeal biopsy identified an inflammatory infiltrate rich in IgG4+ plasma cells with perivascular storiform fibrosis and obliterative phlebitis. Immunostaining showed more than 10 IgG4-positive plasma cells per HPF. The IgG4+/IgG ratio was greater than 40% (figure e-1b, links.lww.com/NXI/A115). PET-CT did not show pathologic hypermetabolism. The diagnosis of IgG4-HP was made.

Corticosteroid therapy (1 mg/kg/d) after pulse IV methylprednisolone for 5 days at 1 g q.d. was introduced, but it was ineffective. IV Rituximab (RTX) was started 12 months later (1 g day 1 and day 15) and was followed by maintenance treatment (M8). Fifteen months later, clinical and radiologic improvement was observed with partial regression of headaches and recovery of visual acuity at 10/10 in the right eye and less than 1/20 (movements of the hand perceived at 50 cm) in the left eye. At follow-up 1 year later, a brain MRI showed the complete regression of meningeal thickening.

Methods and definitions

We reviewed clinical cases and case-series of cerebral and spinal cord HP with histologically proven IgG4-RD that were published between January 2008 and September 2017 in the PubMed-NCBI database. The key words used in the search were “Pachymeningitis,” “IgG4-related disease,” “HP,” “IgG4-HP,” “IgG4 neurologic impairment,” and “IgG4 CNS.” Demographics, clinical and biological data, pathology features, and treatment strategies were collected for each patient, when available.

Diagnostic criteria are those of the Japan College of Rheumatology⁸:

1. A clinical study showed characteristic diffuse/localized swelling or masses in single or multiple organs

2. A hematologic study showed elevated levels of serum IgG4 (135 mg/dL or higher)

3. A histopathologic study showed the following 2 findings:

   • Histologic findings: marked lymphocyte and plasmocytic infiltration and fibrosis

   • IgG4-positive plasma cell infiltration: ratio of IgG4/IgG positive cell >40% and IgG4-positive plasma cells/HPF >10

When (1) + (2) + (3) are fulfilled, it is definite.

When (1) + (3) are fulfilled, it is probable.

When (1) + (2) are fulfilled, it is possible.

Isolated IgG4-HP was characterized by the absence of extra-meningeal organ-involvement (including the pituitary gland). Mutually exclusive lesions of the brain or spinal cord defined “single-organ pachymeningitis.” When extra-meningeal involvement was reported, IgG4-HP was defined as systemic IgG4-RD. Non-specified IgG4-HP was retained when data was lacking for classification.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials (e-references e1-e47, links.lww.com/NXI/A115).

Findings

We report findings from 60 patients that were taken from 42 case reports and 5 case-series. The complete list of bibliographical references is provided in the supplemental data online document.

Patients' characteristics

Brain involvement was mostly reported (49/60 cases). Spinal cord lesions were described in 16 cases, of which 9 were cervical. Thoracic and lumbar spinal cord lesions were described respectively in 8 and 5 cases. The disease affected both the brain and the spine in 5 patients. Systemic IgG4-RD was noted in 18 cases and mostly accompanied cranial manifestations of IgG4-HP. The extra-meningeal manifestations are reported in figure 2. Isolated meningeal damage was identified in 25 patients of whom 24 had single-organ IgG4-HP. Seventeen patients could not be classified because of a lack of data.

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Figure 2 Classification of IgG4-HP

^a–cOther locations of IgG4-RD involvement by patients: ^a1. Orbital pseudotumor, kidney and lung. 2. Pancreas. 3. Lymph nodes, submandibular glands and lung. 4. Retroperitoneal fibrosis. 5. Mastoid. 6. Retroperitoneal fibrosis. 7. Aortitis. 8. Episcleritis. 9. Hypophysitis. 10. Lacrymal and submandibular glands. 11. Orbital pseudotumor. 12. Maxillary pseudotumor. 13. Episcleritis. ^b1. Orbitory pseudotumor. 2. Pulmonary pseudo-tumor and hypophysitis. 3. Orbitary pseudotumor. 4. Retroperitoneal fibrosis. ^c1. Submandibular gland. IgG4-HP = IgG 4-related hypertrophic pachymeningitis; IgG4-RD = IgG 4-related disease; NS = non-specified.

The demographics, clinical, pathology, and blood work-ups are shown in table 1. Patients with IgG4-HP were mostly males with a male-to-female ratio of 2. Median age was 53 years (range: 19–82). Headache was common in cases of cerebral IgG4-HP. Visual impairment and cranial nerve palsy were each present in less than one-third of cases.

Plasma IgG4 levels of more than 135 mg/dL were found in 20 of the 36 patients for whom this information was available. The median level of plasma IgG4 levels was higher in patients with systemic IgG4-RD, whereas meningeal IgG4 infiltration was higher in isolated IgG4-HP. A biological inflammatory syndrome was inconsistently present (10/27 cases) and was more frequently found with systemic involvement. Eosinophilia was only reported in the case of a patient who also presented with eosinophilic granulomatosis with polyangiitis.

CSF analysis

CSF findings are presented in table 2. Aseptic lymphocyte meningitis was identified in more than half of the specimens with median CSF protein levels of 0.91 g/L and a median CSF white blood count of 19.5/mm3. The CSF profile was generally oligoclonal (5 cases). Intrathecal IgG synthesis was found in 11/13 patients. CSF IgG4 levels were only available for 4 patients, but they were significantly increased with a median value of 5.225 mg/dL—which is more than 10 times the upper limit of the normal range (0.32 mg/dL).

Treatment

Treatment strategies are presented for 53 patients in table 3. Nearly all patients received systemic steroids (48/53), of which 20 received pulse steroid therapy. Relapse occurred in 16 cases and was less frequent in the “pulse therapy” group (13/23 patients vs 3/15 patients). Relapse occurred less frequently when the steroid dose was greater than 49 mg/d (relapse rate was 52.6%, whereas it was 100% with lower dosages). In the same way, the occurrence of relapse was lower when steroid therapy was followed over a longer period of time (100% relapse for less than 6 months of steroid therapy vs 42.9% when steroids were continued over a year). All the steroid treatment specific data are available in table e-1, links.lww.com/NXI/A115.

Twenty patients were treated surgically, mostly in cases of cerebral involvement. Only 3 patients with systemic IgG4-RD required surgical treatment. Relapse occurred less often when surgery was done (33% vs 44% without surgery). Surgical treatment was in itself sufficient to achieve disease remission within 6 months (range: 3–12 months) in 4 cases of isolated IgG4-HP.

Twenty-five patients received an immunosuppressive drug, either as a steroid sparing agent (11/25) or after failure to achieve disease control (19/25). RTX was the most used immunosuppressant as first-line (10/25 patients) and second-line therapy (6/7 patients). The clinical response was reported for all patients with the first immunosuppressive therapy. The clinical response data for patients who received more than 1 immunosuppressant were available for 7 of the 8 patients. The overall clinical remission was obtained for 24 patients; 11 had isolated IgG4-HP, 11 had systemic IgG4-RD, and 2 had non-specified IgG4-HP. RTX (14 patients) and cyclophosphamide (CYC) (5 patients) were associated with the best response rate in comparison to other drugs. One patient died of an infection with RTX therapy.