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This report concerns a 53-year-old male patient with idiopathic hypertrophic cranial pachymeningitis who presented with multiple cranial nerve palsies (I, II, III, IV, V, VI). Brain magnetic resonance imaging showed diffuse thickening and gadolinium enhancement of the cerebral dura mater. A biopsy of the cerebral dura mater showed granulomatous vasculitis with histiocyte infiltration. Although both the serum rheumatoid factor (RF) and matrix metalloproteinase-3 (MMP-3) were high, the patient showed no signs of arthritis. He was anti-cyclic citrullinated peptide antibody negative, which makes the presence of comorbid chronic rheumatoid arthritis (RA) unlikely. The aetiology of the pachymeningitis was unknown, which led to the diagnosis of idiopathic hypertrophic cranial pachymeningitis. Steroid pulse therapy successfully diminished the patient’s pachymeningitis and lowered both RF and MMP-3. High values of RF suggest the possible involvement of an autoimmune mechanism, and the MMP value may be an important indicator of the aetiology of pachymeningitis with granulomatous vasculitis.
Hypertrophic cranial pachymeningitis, which occurs in or near the cranial base, is a chronic inflammatory condition in the intracranial dura mater that causes various neurological symptoms, including cranial nerve impairment.1–3 Wegener’s granulomatosis,4 chronic rheumatoid arthritis (RA),5 periarteritis nodosa,6 bacteria, tuberculosis, syphilis, mycosis, and other infections, as well as malignant tumour infiltration, are among the diseases and underlying conditions that are known to cause chronic hypertrophic cranial pachymeningitis. Patients with no identified cause are categorised as idiopathic.2,3 Steroids are generally used for treatment, and while this therapy often proves effective during early treatment phases, the recurrence or progression of pachymeningitis may lead to a poor prognosis.2,3 Even when the condition is classified as idiopathic, detection of anti-neutrophil cytoplasmic antibodies (ANCA) by a serological test suggests the possible involvement of an autoimmune mechanism, such as vasculitis.7,8 Treatment with steroids or immunosuppressive drugs may be useful in such conditions.7,8
On the other hand, matrix metalloproteinase (MMP) is associated with tissue destruction and fibrosis in chronic RA and other collagen diseases.9–12 Recent studies have reported that serum concentrations of MMP-3 and other metalloproteinases increase in concert with the progression of vasculitis.11,12 The high concentrations of MMP-3 observed in this case are believed to be associated with conditions such as vasculitis. These findings have important implications in considering the aetiology of hypertrophic pachymeningitis with granulomatous vasculitis.
The case involves a 53-year-old man who, in October 2006, presented with symptoms including a throbbing headache, discomfort in the left frontal region of the head, and diplopia in all directions. However, by January 2007, his condition had improved without treatment. In March 2008, the patient developed diplopia and fatigability. In April, visual field defects and visual loss became evident. His vision impairment progressively worsened, and when he first visited our hospital in January 2009, he was found to have light perception vision in the right eye and hand motion vision in the left eye. A contrast brain magnetic resonance imaging (MRI) scan revealed diffuse thickening of the dura mater.
At the age of 23, the patient received a subtotal gastrectomy to treat a gastric ulcer. The patient had no noteworthy family history.
The patient’s body temperature was 36.4°C. Upon examination, he exhibited mild clouding of consciousness and some cranial nerve problems including impaired sense of smell in both nostrils, binocular blindness, ptosis, restricted eye movement in all directions, round pupils, reduced reaction to light, and numbness in the first branch of the left trigeminal nerve. His deep tendon reflex was normal without any pathological reflexes. No other neurological abnormalities were noted. The patient was able to walk without assistance.
The erythrocyte sedimentation rate (ESR) was 57 mm/h (normal <7), C reactive protein (CRP) was 3.82 mg/dl (normal <0.2), rheumatoid factor (RF) was 38 U/ml (normal <18), MMP-3 (latex agglutination immunoassay method) was 148 ng/ml (normal range 36.9–121), and the anti-cyclic citrullinated peptide (anti-CCP) antibodies were <0.6 U/ml (normal <4).
The patient tested negative for the following antibodies: antinuclear antibody, anti-DNA antibody, anti-SS-A/SS-B antibody, anti-myeloperoxidase ANCA, and anti-proteinase-3 ANCA.
The angiotensin converting enzyme value was within normal range.
An examination of the cerebrospinal fluid revealed the following results: initial pressure >220 mm H2O, mononuclear cells 5/mm3, protein 94 mg/dl (normal <40), glucose 75 mg/dl (non-fasting glucose 116 mg/dl), and culture negative for bacteria and acidophiles.
The patient’s brain MRI (fig 1A, E) showed oedematous swelling of the entire brain parenchyma, diffuse thickening with enhancement of the dura mater (see white arrow), and liquid retention in an epidural space (see red arrow). The patient underwent a cerebral dura mater biopsy (figs 2–4). During the biopsy, the thickening of the dura mater was confirmed macroscopically. Histological observation revealed multiple foci of granulomatous vasculitis and foamy histiocyte (CD68 positive macrophage) aggregation in the dura mater. No infiltration of the tumour cells was noted, and the tissue culture was negative for bacteria and acidophiles. The patient tested negative for tubercle bacillus using the polymerase chain reaction test.
Since the tests described above did not provide any clear indication of the cause of the patient’s condition, a diagnosis of idiopathic hypertrophic pachymeningitis was made.
Three courses of steroid pulse therapy (1000 mg methylprednisolone daily for 3 days) were administered, with 1 week between courses. After three courses of steroid pulse therapy, we began administering oral prednisolone (1 mg/kg/day), gradually tapering off the dosage.
The patient’s symptoms progressed even after hospital admission, and he lost sight in both eyes immediately before the initiation of steroid therapy. Although his symptoms improved quickly after the initiation of steroid pulse therapy, bilateral visual loss (light perception vision in the right eye and hand motion vision in the left eye) and numbness in the left trigeminal nerve region persisted. His brain MRI (fig 1B, F) after 2 months of treatment showed a reduced thickness of the dura mater. After 3 weeks of steroid pulse therapy, both ESR and RF decreased to about 20, and cerebrospinal fluid protein decreased to 45 mg/dl and remained stable afterwards. As the pachymeningitis worsened, the patient’s MMP-3 before treatment rose to 318 ng/ml but decreased to 272 ng/ml after a month of steroid treatment. After 9 months of steroid therapy (prednisolone 30 mg/day), his pachymeningitis worsened (fig 1C, G), and his peak value of MMP-3 was 595 ng/ml, indicating an increase. Moreover, cerebrospinal fluid protein increased to 68 mg/dl without new symptoms. Three courses of steroid pulse therapy for the revival of pachymeningitis were performed after the second hospitalisation. After 3 weeks of steroid pulse therapy, the revival of liquid retention in an epidural space (fig 1D, H) disappeared. His MMP-3 decreased to 365 ng/ml after 7 weeks of steroid therapy (prednisolone 30 mg/day).
Recent years have witnessed significant technological advancement in the diagnosis of chronic RA, with the establishment of new important markers that reflect the diagnosis and progress of the disease. Because RF has low disease specificity, anti-CCP antibodies, or autoantibodies other than RF, are often used in contemporary RA diagnosis.13 Anti-CCP antibodies have an excellent specificity of 90–100% in RA identification.14 No subjective or clinical symptoms of arthritis, including swelling, pain, and warmth of the joints, were observed. The patient was anti-CCP antibody negative, which makes the presence of comorbid chronic RA unlikely.
MMP-3 (stromelysin-1) is a component of the extracellular matrix and is produced by synovial cells, cartilage cells, fibroblasts, smooth muscle cells, and histiocytes. Possessing various MMP activities, including degradation of proteoglycan, laminin, fibronectin, and collagen, MMP-3 is believed to be involved in tissue destruction.15,16 In chronic RA, MMP-3 is a typical metalloproteinase involved in the destruction of articular cartilage. However, comorbid RA was unlikely in this patient, which suggests that the increase in MMP-3 was due to reasons other than the destruction of articular cartilage. As far as our investigation revealed, there has been no report to date suggesting an association between high values of MMP and hypertrophic pachymeningitis. Recent reports found high values of serum MMP-3 in diseases other than chronic RA that are accompanied by multisystemic vasculitis (Takayasu disease and Kawasaki disease), and suggested that MMP-3 concentrations may reflect the relative progress of these diseases.11,12 In the case described here, the comparison of RF and MMP-3 values before and after treatment revealed that, following the initiation of steroid pulse therapy, RF values changed in parallel with the prompt improvement in cranial nerve palsy. On the other hand, changes in MMP-3 values were slower and were more in line with the reduction in thickness of the dura mater rather than with improvement of the symptoms. Considering the fact that vasculitis is involved in the production of MMP-3,11,12 vasculitis with histiocyte proliferation may be associated with the high concentrations of MMP-3 observed in this case.
There are no previous reports of neuropathological findings involving granulomatous vasculitis in idiopathic hypertrophic pachymeningitis.2,3,17 This finding of vasculitis and histiocyte aggregation may indicate the presence of an autoimmune mechanism.
Liquid retention in an epidural space was detected by the MRI images. There are no previous reports of such MRI findings in hypertrophic pachymeningitis. We thought that these findings might indicate an intense inflammatory change in the dura mater.
To date, there have been several reports of RF positive patients presenting with hypertrophic cranial pachymeningitis that do not accompany chronic RA. As in the case described here, four of these reports noted the presence of cranial nerve palsy. In addition, although patients were RF positive, no involvement of autoimmune mechanisms was observed.18–21 The average age of the patients in these studies was 69 years, and most of them had RF concentrations of 100 IU/ml or higher. These reports noted improvement in the patients’ symptoms through steroids or immunosuppressive therapy, which suggests the possibility that positive RF test results may be associated with autoimmune mechanisms.
We thank Dr Akinori Sugaya (University of Tsukuba) for the treatment of the patient.
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.