Cerebrospinal fluid biomarkers implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody-related hypertrophic pachymeningitis.

OBJECTIVE: Hypertrophic pachymeningitis (HP) related to anti-neutrophil cytoplasmic antibody (ANCA) is the most frequently seen immune-mediated HP. We investigated cerebrospinal fluid (CSF) biomarkers related to the pathogenesis of ANCA-related HP (ANCA-HP). METHODS: The levels of B cell activation factor of the tumor necrosis factor family (BAFF), a proliferation-inducing ligand (APRIL), and transforming growth factor beta 1 (TGF-ß1) in the CSF were compared between patients with ANCA-HP (n = 12), other types of immune-mediated HP (other HP; n = 12), multiple sclerosis (MS; n = 14), and non-inflammatory neurological disorders (NIND; n = 10). In addition, we evaluated whether ANCA would be detected in CSF. RESULTS: CSF levels of BAFF, APRIL, and TGF-ß1 were significantly increased in ANCA-HP and other HP. In particular, BAFF and APRIL levels were significantly correlated with the IgG index in ANCA-HP. In other HP, BAFF and APRIL levels were significantly correlated with cell counts and protein levels in CSF. Of 12 patients with ANCA-HP, the CSF of 7 patients (58%) tested positive for myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA, while none of the CSF samples from other HP, MS, or NIND patients tested positive. CONCLUSION: The levels of BAFF, APRIL, and TGF-ß1 may serve as useful CSF biomarkers for assessing the disease activity of immune-mediated HP. Moreover, BAFF and APRIL in the CSF may be implicated in the pathogenesis of ANCA-HP via promoting autoreactive B cells, while detecting MPO- or PR3-ANCA in the CSF may be found in some patients with ANCA-HP.Key Points• CSF BAFF, APRIL, and TGF-ß1 levels increase significantly in immune-mediated HP.• CSF BAFF and APRIL levels are significantly correlated with IgG index in ANCA-HP.• Detection of MPO- or PR3-ANCA in the CSF is found in some patients with ANCA-HP.• BAFF, APRIL, and ANCA in the CSF may be implicated in the pathogenesis of ANCA-HP.

Neuronal surface antibody-mediated encephalopathy as manifestation of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Although it remained controversial for a long time, central nervous system (CNS) involvement of graft-versus-host disease (GVHD) is now becoming recognized as a real nosological entity. Previous case reports have suggested heterogeneous clinical presentations and it is not excluded that the whole spectrum of manifestations has not yet been fully described. Here, we report the case of a 58-year-old man with chronic GVHD who developed a rapidly ingravescent encephalopathy. There was no evidence for CNS immune-mediated lesions on conventional imaging nor for cellular infiltration in the cerebrospinal fluid. Serum analyses revealed the presence of anti-neuronal antibodies directed against anti-contactin-associated protein 2 (anti-Caspr2), a protein associated with voltage-gated potassium neuronal channels. Functional imaging with 2-deoxy-2-[fluorine-18] fluoro- d-glucose integrated with computed tomography (18F-FDG PET-CT) demonstrated diffuse cortical and subcortical hypometabolism. The patient was treated with a combination of immunosuppressive agents (corticosteroids, cyclophosphamide and rituximab) and progressively recovered normal neurocognitive functions. Taken together, these data suggest that CNS-GVHD may manifest as a reversible antibody-mediated functional encephalopathy. This report suggests for the first time the interest of screening for anti-neuronal antibodies and functional imaging with brain 18F-FDG PET-CT in diagnosing this severe complication of allogeneic hematopoietic cell transplantation (alloHSCT).

Increased BAFF and APRIL levels in the cerebrospinal fluid of patients with anti-neutrophil cytoplasmic antibody-related hypertrophic pachymeningitis.

Hypertrophic pachymeningitis (HP) is an inflammatory disorder involving intracranial or spinal thickened dura mater. It has been recognized that anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis may lead to HP; however, the immune-mediated pathogenesis of ANCA-related HP (ANCA-HP) remains elusive. In the present study, we analyzed B-cell activation factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) expression in the cerebrospinal fluid (CSF) and serum of patients with ANCA-HP, multiple sclerosis (MS), and non-inflammatory neurological disorders (NIND). BAFF and APRIL levels in the CSF were significantly higher in patients with ANCA-HP than in those with MS and NIND. In addition, a positive correlation between BAFF levels in the CSF and IgG-index was found in patients with ANCA-HP. On the other hand, no correlation was detected between CSF and serum levels of BAFF or APRIL. The results suggest that increased levels of BAFF and APRIL produced in the central nervous system may influence the development of ANCA-HP.

Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody.

The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting TH1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.

Motor-dominant chronic inflammatory demyelinating polyneuropathy.

We reviewed the clinical, electrophysiological an laboratory findings, plus the therapeutics and evolution of patients with motor-dominant Chronic inflammatory demyelinating polyneuropathy (CIDP) and compared them with those of other CIDP patients. Among 12 consecutive CIDP patients, we identified five patients with motor-dominant CIDP. The five patients with motor-dominant CIDP initially presented with weakness of the upper limbs. Cervical magnetic resonance imaging (MRI) examinations of the patients with motor-dominant CIDP showed that the most affected lesions are the cervical nerve roots and brachial plexus. The clinical course of these patients was relapsing-remitting, and they improved markedly after treatment by intravenous immunoglobulin (IVIg) infusion or plasmapheresis. However, they did not improve in response to corticosteroid therapy during the acute phase of relapses. The relapses frequently occurred within 2 years, but rarely occurred after that. The score in the modified Rankin disability scale (mRDS) at the last follow-up period was statistically lower for the patients with motor-dominant CIDP than for the other CIDP patients (P < 0.002). The characteristic clinical features, responsiveness to treatment, and prognosis suggest that motor-dominant CIDP is a distinct subtype of CIDP, with a specific immunological background. Repeated IVIg therapy is required to maintain the motor functions of patients with motor-dominant CIDP. We consider that treatment for recurrence prevention as an alternative to IVIg therapy is very important for patients with motor-dominant CIDP.

[Atypical headache and facial pain as a result of hypertrophic pachymeningitis in C-ANCA-positive Wegener's granulomatosis]. / Atypischer Kopf- und Gesichtsschmerz infolge hypertropher Pachymeningitis bei c-ANCA positivem Morbus Wegener.

BACKGROUND: Wegener's granulomatosis (WG) is a systemic vasculitis involving the nervous system in 20-54% of cases; lesions of peripheral nerves are commonest, while manifestation in the central nervous system (CNS) is rarer. Focal hypertrophic pachymeningitis is a very rare complication of WG. This inflammatory thickening and fibrosis of the dura mater is always associated with headaches, whereas cranial nerve lesions, cerebellar symptoms or epileptic seizures occur more rarely. CASE REPORT: A 67-year-old patient, in whom WG had been diagnosed 2 years earlier and who had been treated with immunosuppressants since then, complained of continuous severe, mainly left-sided headache and facial pain for weeks. Cranial MRI showed thickening of the left tentorium cerebelli with obvious contrast enhancement and led to the diagnosis of hypertrophic pachymeningitis. The inflammatory parameters and the C-ANCA (antineutrophil cytoplasmic antibodies) in the serum were raised and CANCA were detectable in the cerebrospinal fluid. The headaches subsided with several days of intravenous high-dose corticosteroids and a simultaneous increase in the immunosuppressive basic medication. On a follow-up MRI after 3 months, the magnetic resonance changes were less apparent, i. e., the hypertrophic pachymeningitis was resolving; C-ANCA were now no longer detectable in the cerebrospinal fluid. CONCLUSION: With newly occurring, unusually severe and persistent headaches in the presence of WG, the very rare complication of hypertrophic pachymeningitis should be considered.

[A case of hypertrophic spinal pachymeningitis associated with MPO-ANCA].

A 71-year-old man was admitted to our hospital, because of subacute progressive back pain and thoracic transverse myelopathy. Magnetic resonance imaging showed thickening with gadolinium enhancement of dura mater at the T1-T6 vertebrate levels. A dura biopsy specimen revealed fibrous thickening of the dura with the inflammatory changes, and diagnosis of hypertrophic spinal pachymeningitis was made. The cerebrospinal fluid (CSF) contained high titer of myeloperoxydase anti-neutrophil cytoplasmic antidody (MPO-ANCA), indicating that the antibody synthesized intrathecally. After treatment with oral prednisolone, 60 mg daily for a month, thickness of the dura and the CSF MPO-ANCA improved dramatically. This is the first report of hypertrophic pachymeningitis associated with MPO-ANCA localized exclusively in the spine. This report suggests that intrathecal MPO-ANCA synthesis is an index of disease activity as well as a diagnostic hallmark. Early corticosteroid therapy is recommended in this disorder.

Meningeal involvement in Wegener's granulomatosis confirmed and monitored by positive circulating antineutrophil cytoplasm in cerebrospinal fluid.

MRI and CSF investigations revealed meningeal involvement in a 29-year-old patient with biopsy-confirmed Wegener's granulomatosis. The intracranial manifestation of Wegener's granulomatosis was supported by the detection of pathologic circulating antineutrophil cytoplasm (c-ANCA) in the CSF. We monitored disease activity by c-ANCA measurement in the CSF. After repeated cycles of intrathecal administration of methotrexate and corticoids, progression of meningeal infiltration stopped, and CSF c-ANCA titers became negative.