Hypertrophic chronic pachymeningitis as a localized immune process in the craniocervical region

Case report.

In 1991, a 54-year-old man was referred to an internal department with relapsing fever, weakness, myalgia, arthralgia, diplopia, conjunctivitis, and inflammation of the salivary glands. His medical history included cholesteatoma surgery, recurring otalgia, hearing loss, and diabetes mellitus for the previous 10 years. At that time, the findings from CT and gadolinium-diethylene-triamine-pentaacetic acid (Gd-DTPA)–enhanced MRI scans, CSF analysis, and liver biopsy were normal. A tentative diagnosis of unspecified autoimmune disease was made. The patient received prednisolone for several months and improved slowly. Later he developed penis ulcers followed by iridocyclitis, but no oral ulcers. Biopsy of the penis showed inflammatory granulomatous tissue. Cultures of smears from the ulcers grew methicillin-resistant Staphylococcus aureus. The patient was treated with rifampicin and doxycycline for several months.

Thickening of the dura of the craniocervical region was first documented by MRI in October 1996. HCP was diagnosed. The C-reactive protein (CRP) level was 5.5 mg/dL (normal, <0.8 mg/dL). The protein level was elevated on CSF examination. The serum immunoglobulin (Ig) G level was 1,760 mg/dL (normal, <1,600 mg/dL); the IgA level was 507 mg/dL (normal, <400 mg/dL); and the C3 level was 119 mg/dL (normal, <90 mg/dL). IgM and complement component C4 levels were normal. Serum was nonreactive to the Venereal Disease Research Laboratory (VDRL) test; fluorescent treponemal antibody, absorbed (FTA-ABS) test; Borrelia; and HIV-1 and HIV-2 antibodies. Antibodies to mycoplasma and Cryptococcus, antinuclear antibodies (HEp-2), rheumatoid factor, antibodies to Sm, double-stranded DNA, U₁RNP, Ro (SS-A), La (SS-B), Jo-1, and tumor markers were negative. Antineutrophil cytoplasmatic antibody (p-ANCA and c-ANCA), antiparietal cell antibody (APCA), antimitochondrial antibody (AMA), and antismooth muscle antibody (ASMA) were negative. Thyroid function was normal. Results of CSF cultures were negative. The creatine kinase level was elevated (250 U/L). A muscle biopsy showed non-specific, mild, myopathic changes. Abdominal CT revealed no abnormalities. Treatment with rifampicin and doxycycline was restarted, followed by long-term methylprednisolone administration.

In April 1998, the patient was admitted to a neurologic department for headaches, myalgia and confusion. Gd-DTPA-enhanced MRI again showed thickening of the dura in the craniocervical region ( figure 1A). Antibody titers were negative. The PCR for Mycobacterium tuberculosis DNA in CSF was also negative. Thoracic CT was normal. Clinical symptoms improved following IV high-dose steroid therapy. In May 1998 a ventricular-atrial shunt was inserted because the patient had developed obstructive hydrocephalus. A specimen of the dura taken from the frontoparietal region revealed no abnormalities.

Figure 1. (a) MRI 16 months before surgery. Sagittal T1-weighted scans after gadolinium-diethylene-triamine-pentaacetic acid (Gd-DTPA) administration demonstrates enhancement of the thickened dura in the craniocervical region. (b) Preoperative MRI shows compression of the spinal cord. (c) Postoperative MRI after 20 months of methotrexate therapy. Sagittal T1-weighted scans following Gd-DTPA administration demonstrate the synthetic patch and slight reduction of the meningeal mass in the clivus (arrow). (d) A fluorodeoxyglucose PET scan before treatment shows high activity in the clivus. (e) Nine months after treatment a reduction of activity in the clivus is shown.

The patient was readmitted to the neurologic department in August 1998 with frequently occurring headaches, cervical pain with bilateral arm radiation, gait difficulties, and confusion. Corticosteroids were gradually tapered because of intractable type II diabetes. The erythrocyte sedimentation rate was 80 mm/h and the CRP level was 5.3 mg/dL. Monoclonal gammopathy was excluded by serum immunoelectrophoresis. The CSF contained 9 white blood cells/mm³, 4.6 mmol/mm³ glucose, 1,640 mg/dL protein, and 1,081 mg/dL albumin. CSF and serum angiotensin-converting enzyme (ACE) findings were normal. Antihuman T-cell lymphotropic virus-I antibody was negative. Human leukocyte antigen (HLA) typing revealed DR2 and DR7. Purified protein derivative (PPD) skin testing was negative. Cultures of urine, CSF and sputum were negative for anaerobes, mycobacteria, and fungi. MRI showed marked enhancement of the thickened craniocervical dura (figure 1b). There was no intracerebral lesion on MRI scans. A fluorodeoxyglucose (FDG) PET study demonstrated extracerebral hypermetabolism at the clivus and the upper cervical spine (figure 1d).

The patient’s condition worsened until finally he developed acute quadriplegia with urine retention in September 1998. An emergency suboccipital craniotomy was performed, along with a C1 to C6 laminectomy. The entire posterior part of the dura was removed. Microscopic examination showed dense fibrous tissue with a granulomatous inflammatory reaction composed of a mixed granulo-lymphoplasmo-cellular infiltrate, and multinucleated giant cells of Langhans type ( figure 2). Perivascular accentuation and occasional invasion of small vessel walls by neutrophils was compatible with the histologic picture of leukocytoclastic vasculitis. Stains for bacteria (including Ziehl-Neelsen), fungi, and amyloid were negative.

Figure 2. Surgical specimen from cervical dura shows noncaseating epithelioid granulomatous tissue with giant cell of Langhans type (arrow) and mixed inflammatory infiltrate composed of neutrophils, lymphocytes, and plasmocytes. Hematoxylin and eosin ×110.

After surgery, immunosuppression with low dose methotrexate was started. The dose was gradually increased to 15 mg weekly. The patient was transferred to our neurorehabilitation department, and neurologic symptoms improved within 3 months. Since January 1999, he has remained in a stable clinical condition, and is able to walk with assistance and eat unassisted. MRI in September 1999 showed a slight regression of the thickened dura in regions where surgery had not been performed, and FDG-PET showed a reduction of activity (figure 1e). In December 1999, the patient was treated with antibiotics because of a suspected shunt infection, and recovered completely. MRI was repeated in June 2000 and again revealed regression of the thickened dura (figure 1c). In an FDG-PET scan, no activity at all could be detected (data not shown).

Discussion.

Exhaustive efforts to identify the cause of the dural thickening in our patient were unsuccessful. Focal inflammatory dural lesions have been described in the literature as radiologic features or occurring on autopsy.1 Whereas the frontoparietal part of the dura in our patient was unaffected (biopsy 1998), we found bioptic evidence for a localized granulomatous inflammatory process in the craniocervical region. There was no history of trauma or intrathecal drug administration. The patient had received several courses of antibiotic and antituberculous drugs, and intermittent corticosteroid treatment from 1991 on. He had multiple relapsing rheumatic symptoms, which could not be classified according to clinical or serologic criteria. Disorders such as rheumatoid arthritis, Wegener’s granulomatosis, polyarteritis nodosa, mixed connective tissue disease, orbital pseudotumor, and Behçet’s disease were excluded.

Four cases of craniocervical pachymeningitis have been reported in the literature.3-6⇓⇓⇓ The clinical courses of these patients suggested that cranial HCP extends downwards to the spine. In our case there was no neuroradiologic evidence for this pattern.

Medical treatment of HCP is not well defined due to the rarity and variability of the disorder. High-dose corticosteroid therapy is often effective initially, but usually there is progression of the disease. In addition, antituberculous, chloroquine immunosuppression, and radiation therapy have been discussed.7,8⇓ Methotrexate was chosen in our patient because of the granulomatous nature of the process.9,10⇓

Considering the possible irreversible damage to the CNS, the need for early extensive excision of the hypertrophic dura is mandatory in pachymeningitis in the spinal and craniocervical regions.2,6⇓ Biopsy is usually sufficient for pathologic confirmation of the diagnosis. Neurosurgery is required in patients with hydrocephalus. We are aware of the fact that methotrexate therapy does not cure HCP. However, the clinical improvement and reduction of metabolic activity as seen in the PET scan in the case presented demonstrate impressively the long-lasting effect of this drug in a clinical situation where corticoid treatment is not possible.