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Cranial pachymeningitis: a rare neurological syndrome with heterogeneous aetiology
  1. Norbert Brüggemann1,
  2. Stefan Gottschalk2,
  3. Konstanze Holl-Ulrich3,
  4. Jan Stewen4,
  5. Wolfgang Heide4,
  6. Gunter Seidel1
  1. 1Department of Neurology, University of Lübeck, Lübeck, Germany
  2. 2Institute of Neuroradiology, University of Lübeck, Lübeck, Germany
  3. 3Institute of Pathology, University of Lübeck, Lübeck, Germany
  4. 4Department of Neurology, General Hospital Celle, Celle, Germany
  1. Correspondence to Professor Seidel, Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; guenter.seidel{at}neuro.uni-luebeck.de

Abstract

Cranial pachymeningitis is a poorly understood syndrome, defined by leptomeningeal thickening and typical gadolinium enhanced MRI. The heterogeneous clinical and aetiological features of five patients with both focal and diffuse pachymeningitis are presented. The initial symptoms included headache (n=3), sensory Jackson seizures (n=1), hemiparesis (n=1), episodes of short lasting hemiataxia (n=1), hemihypaesthesia (n=1), aphasia (n=1) and confusion (n=2). MRI scans revealed focal (n=3) or diffuse (n=2) leptomeningeal gadolinium enhancement and cortical swelling (n=4). In addition, one case presented with a subarachnoid and a second with an intracerebral haemorraghe. CSF findings were variable and showed clear lymphomonocytic pleocytosis in 3/5 cases. Infectious diseases were extensively excluded in all cases. Leptomeningeal biopsies of two cases revealed perivascular inflammation, indicating central nervous system vasculitis. In the cases presented, pachymeningitis was caused by primary central nervous system vasculitis (n=2) and rheumatoid arthritis (n=2). In one case, the cause remained unclear.

  • Infectious diseases
  • MRI
  • tuberculosis
  • vasculitis
  • central nervous system vasculitis
  • leptomeningeal enhancement
  • leptomeningeal inflammation
  • pachymeningitis
  • rheumatoid arthritis

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Cranial pachymeningitis is a rare neurological condition, typically characterised by diffuse or localised meningeal thickening and chronic inflammation. Frequent clinical features are caused by compression and include headache, cranial neuropathies, hemiparesis and seizures. Pachymeningitis is associated with granulomatous diseases such as tuberculosis1 2 and Wegener's granulomatosis3, rheumatoid arthritis (RA)4 5 and vasculitides, especially temporal arteritis.6–8 Our aim here is to delineate the heterogenous aetiological background of pachymeningitis by describing five new cases. The clinical characteristics, diagnostic findings and specific treatments are summarised in table 1.

Table 1

Clinical characteristics, laboratory findings, MRI, biopsy results and therapeutic options in five patients with pachymeningitis

Case reports

Case No 1

A 78-year-old woman suffering from headache for 3 weeks was admitted because of sudden onset of global aphasia and amentia with an otherwise unremarkable neurological examination. MRI scan revealed an extensive gyral swelling of the left parieto-occipital region with superficial gadolinium (Gad) enhancement (figure 1). Repeated lumbar punctures showed a distinct lymphomonocytic pleocytosis and massive dysfunction of the blood–CSF barrier. It was noteworthy that the first CSF analysis showed a sanguineous specimen with the detection of several siderophages, indicating an accessory (CT negative) subarachnoid haemorrhage. Microbiological examination of CSF and serum was unremarkable (see table 1). Blood chemistry showed increased erythrocyte sedimentation rate (ESR) and C reactive protein, as well as a slight leucocytosis. The remaining results were normal, including angiotensin converting enzyme and immunological parameters. Ultrasonography of the extracranial and intracranial arteries, including the temporal vessels, and arterial and venous magnetic resonance angiography (MRA) showed normal results. Biopsy of the temporal artery revealed no evidence of giant cell arteritis.

Figure 1

Brain MRI images and histological findings of patients with pachymeningitis. (A) The axial images reveal swelling of the left parieto-occipital cortex (FLAIR) and superficial gadolinium enhancement (T1+GAD) in patient No 1. (B, C) Haematoxylin–eosin staining (B, 1:100) and lymphocytic (CD3+) staining (C, 1:200) indicate perivascular lymphocytic infiltrates due to chronic inflammation of leptomeningeal and adjacent cortical tissue in keeping with a central nervous system vasculitis. (D) T1 weighted coronar axial image of patient No 5 shows a bilateral pachymeningitis with leptomeningeal thickening and considerable enhancement after GAD application. The T2* image illustrates the small right frontal haemorrhage.

Histopathological analysis of the leptomeningeal biopsy and adjacent cortical tissue indicated the presence of chronic inflammatory perivascular infiltrates due to small vessel vasculitis without amyloid deposition (see figure 1). We diagnosed a primary central nervous system vasculitis (PCNSV) with leptomeningeal and gyral manifestation. We initiated immunosuppressive therapy with methylprednisolone, initially with pulse therapy, and cyclophosphamide. Serial MRI follow-up under ongoing immunosuppressive treatment revealed distinct regression of the cranial lesions; the clinical symptoms disappeared except for the persistent headache.

Case No 2

A 76-year-old man reported experiencing a headache over several weeks and short lasting episodes of left-sided acroataxia. The medical history included clinically stable RA for 5 years. The clinical examination of the alert patient revealed hypaesthesia and reduced fine motor skills of the left extremities. Serial cranial MRI scans showed swelling and disturbed diffusion of the right temporal, parietal and occipital lobes, as well as focal leptomeningeal enhancement after Gad application. Duplex of the brain supplying arteries revealed marked arteriosclerotic plaques at the carotid bifurcation level but no evidence of vascular obliteration or stenoses. Lumbar puncture showed normal findings, except for an increased CSF protein level. CSF and serum results were negative for several infectious agents. There was no cytological evidence of carcinomatous meningitis. Further blood analysis showed a positive antinuclear antibody (ANA) titre and a high titre rheumatoid factor (RF) whereas further immunological markers were unremarkable. The patient declined leptomeningeal biopsy. Serial cranial MRI scans over the course of 2 years revealed stable findings; the clinical features fluctuated with the appearance of short lived, left-sided hemiparesis and suspected focal seizures under immunosuppressive treatment with oral low dose prednisolone, etanercept and methotrexate.

In summary, despite the absence of biopsy, we presume that the patient had rheumatic pachymeningitis. It is noteworthy that pulmonal squamous cell carcinoma was diagnosed 3 years after onset of the first symptoms at which stage the patient decided against further diagnostic and therapeutic approaches. Paraneoplastic CNS syndromes can occur up to 4 years before manifestation of carcinoma.

Case No 3

The third case describes an 83-year-old alert man who presented with a right-sided hemiparesis and slight dysdiadochokinesis on the right. His medical history included idiopathic polyneuropathy. Cranial MRI scan revealed leptomeningeal enhancement of the left central and precentral regions as well as a slight gyral bulging. CSF results were normal. The value for ANA was marginally increased and RF was qualitatively positive. The clinical profile, however, argued against systemic vasculitis and collagenosis. Chest CT revealed a possible tumour in the left lingula that did not change over 2 months. The patient was no longer available for pulmonal workup afterwards.

He was treated with a combination of intravenous ceftriaxon and methylprednisolone. Pragmatic antibiotic treatment was initially started because of elevated C reactive protein, highly increased ESR and a positive serum IgG against Borrelia burgdorferi. Hemiparesis and the MRI findings resolved after continuation of immunosuppressive treatment for 2 months, supporting the assumption of an autoimmunological cause for the leptomeningeal inflammation. Unfortunately, longer follow-up was not available. Nevertheless, despite normal CSF findings, a neoplastic process could not be definitely excluded. The patient declined leptomeningeal biopsy.

Case No 4

A 45-year-old patient experienced recurrent episodes of ascending left-sided numbness beginning in the leg, with each episode lasting several minutes. The symptoms were attributed to sensory epileptic Jackson seizures with the detection of an epileptogenic focus in the right frontal region. The neurological examination was unremarkable at each time. The medical history comprised RA since 1999 that involved joints only. Initially, brain MRI revealed leptomeningeal enhancement in the right frontal region. Over the course of 6 weeks, the process also began to affect the left frontal area on MRI. He also developed right-sided focal sensory seizures. CSF showed a lymphocytic pleocytosis. CSF cultures and further microbiological diagnostics were negative. A leptomeningeal biopsy specimen revealed mild chronic inflammation with consecutive fibrosis and subpial astrogliosis but no evidence of vasculitic changes. The patient experienced iatrogenic bacterial meningitis after biopsy and was successfully treated with a combination of antibiotics (intravenous application of meropenem 3×2 g, vancomycin 2×1 g, rifampicin 1×600 mg and fluconazole 1×200 mg for 12 days and subsequent imipenem 3×500 mg, clindamycin 3×600 mg and ampicillin 3×2 g for 12 days due to fever relapse).

In summary, after performing an extensive workup, we diagnosed the patient as having rheumatoid pachymeningitis. We have planned immunosuppressive therapy with cyclophosphamide and steroid pulses, and will perform serial clinical controls and MRI scans.

Case No 5

A 69-year-old woman developed headache, two episodes of ascending hemihypaesthesia and confusion associated with blurred vision caused by MRI proven diffuse pachymeningitis with leptomeningeal enhancement and cortical oedema overlying both hemispheres and a small haemorrhage in the right frontal region with a subarachnoid component (see figure 1). The medical history included breast cancer, which had occurred decades before. Subsequent CSF analyses showed lymphocytic pleocytosis with intrathecal Ig synthesis. The workup for infectious causes remained negative. A biopsy specimen showed vasculitis with perivascular infiltrates and necrotic as well as granulomatous components because of small vessel involvement while cerebral digital subtraction angiography of the left hemisphere excluded vasculitic changes. Although the serum ANA titre was elevated, we did not detect specific antibodies indicating collagenosis. Furthermore, recurrence of breast cancer with CNS manifestation was excluded by negative tumour markers as well as leptomeningeal biopsy, and we diagnosed the patient as having PCNSV. Immunosuppressive treatment with methylprednisolone resulted in obvious regression of MRI proven leptomenigeal enhancement. Headache and impaired vision resolved while confusion improved distinctively but persisted. CSF cell count decreased considerably from 180/3 to 72/3. Cyclophosphamide pulses in regular intervals of 4 weeks over 6 months and subsequent treatment with mycophenolate mofetil will be applied for therapeutic consolidation.

Discussion

Pachymeningitis consists of meningeal thickening due to chronic inflammation. Clinical symptoms of the affected brain or cranial nerves are not diagnostic. In most cases the condition is diagnosed by MRI. The spectrum of MRI findings includes focal (case No 1), hemispheric and bilaterally hemispheric (case No 5) meningeal enhancement and in part cortical swelling (case No 1) and focal brain oedema. Dependent on the aetiology, other MRI changes can be observed, such as haemorrhage (case No 5) and ischaemia in case of CNS vasculitis. Contrast enhanced MRA can reveal vasculitic changes of brain supplying arteries.

The causes of pachymeningitis are, among others, vasculitides, including primary9 10 and secondary CNS vasculitis such as temporal arteritis.6 7 8 An alternative classification distinguishes between systemic—for example, Wegener's disease,3—and local organ related vasculitides. Furthermore, both systemic and local inflammations are capable of inducing pachymeningitis, which is in part caused by infectious agents, such as tuberculosis.1 2 If the causes remain unclear, the disorder is identified as idiopathic hypertrophic pachymeningitis.11

Pachymeningitis should be considered as a neurological syndrome with heterogeneous aetiology attributed to one of the following causative groups: (a) PCNSV,9 10 (b) secondary CNS vasculitis,3 6 7 8 (c) general systemic inflammation, especially tuberculosis,1 2 (d) neoplastic disorders and (e) idiopathic causes.11

We suggest a gradual diagnostic workup for comparable patients, including MRI sequences T1±Gad, T2, FLAIR, DWI, T2* and CE-MRA as well as colour coded duplex sonography of extracranial and intracranial arteries and high resolution sonography of the temporal and occipital arteries. The next steps should involve transoesophageal echocardiography, 24 h ECG, chest x-rays, ultrasonography of the upper abdomen and tumour positron emission tomography in case of an assumed but not yet diagnosed neoplasm. Laboratory serum analysis should include screening for immunological disorders (ESR, C reactive protein, differential blood count, RF, ANA, anti-SS-A, anti-SS-B and anti-ds-DNA, cytoplasmic antineutrophil cytoplasmic antibodies, plasma antineutrophil cytoplasmic antibodies, antiphospholipid antibodies) and infectious diseases (serology for Treponema pallidum, B burgdorferi, hepatitis B and C, HIV, Mycoplasma, Chlamydia, Toxoplasma gondii). Furthermore, occult blood testing and urinalysis (proteinuria, erythrocyturia) should be performed. CSF should be examined for cell count, protein, lactate, glucose, ink stained microscopic slides (Cryptococcus) and other infectious agents (microscopy including acid resistant rods, PCR for Mycobacterium tuberculosis and HSV, serology for T gondii, culture (including culture for M tuberculosis)). Subsequent medical workup requires optional cerebral digital subtraction angiography (vasculitic changes), biopsy of the temporal artery and, as the gold standard, combined leptomeningeal and cortical biopsy. To emphasise, tuberculosis is very important in the differential diagnosis and should be definitively excluded before starting high dose immunosuppressive treatment. Specific treatment and prognosis depends on the underlying disease.

References

Footnotes

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.