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Alteration of IgG4 levels in cerebrospinal fluid in IgG4‐related disease

2015; Wiley; Volume: 20; Issue: 11 Linguagem: Inglês

10.1111/1756-185x.12739

1756-185X

Andreu Fernández‐Codina, M. Hernández, Roser Soláns-Laqué, Segundo Buján-Rivas, Miquel Vilardell‐Tarrés, Fernando Martínez‐Valle,

Neuroendocrine Tumor Research Advances

Dear Editor, Immunoglobulin G4-related disease (IgG4-RD) is an uncommon condition characterized by fibrosis and IgG4 lymphoplasmacytic infiltrates in diverse organs of unknown aetiology. Ig4-related pachymeningitis has been rarely described, but it can account for up to one-third of idiopathic hypertrophic pachymeningitis.1, 2 Dural biopsy is the gold standard for the final diagnosis. Pathological diagnostic criteria have been proposed by Lu et al.3 Della Torre et al.4, 5 are the only group who have studied the usefulness of cerebrospinal fluid (CSF) IgG4 determination as a diagnostic tool for central nervous system (CNS) IgG4-RD. A 55-year-old man consulted his general practitioner for progressive headache, horizontal gaze impairment, liquid dysphagia and scapular palsy. Cranial magnetic resonance imaging (MRI) showed focal meningeal thickening adjacent to the jugular posterior foramen (Fig. 1a). Meningeal biopsy was dismissed because of high risk for local complications. A few months later, as neurological deficits worsened, the patient developed fever and right pleural effusion appeared in the chest X-ray. 18-fluorodeoxyglucose positron emission tomography/computed tomography scan only revealed high glucose uptake in the right pleura. Antinuclear antibodies, extractable nuclear antigen antibodies, antineutrophil cytoplasmic autoantibodies and microbiological studies all resulted negative. A surgical pleural biopsy discarded malignity. A surgical review was performed due to hemothorax, and a pleuro-pulmonary cyst was resected. The pathological examination of the sample showed fibrous margins and a rich IgG4 lymphoplasmacytic infiltrate. Serum IgG4 by immunonephelometric assay (BN II System, Siemens, Munich, Germany) was 308 mg/dL (normal range [NR] 5–156 mg/dL). A review of the pleural samples revealed lymphoplasmacytic infiltrates, storiform fibrosis and 180 IgG4+ cells/high power field. IgG4/IgG ratio was not available due to technical limitations. The result was consistent with IgG4-related pleural and lung disease.3 The patient received three intravenous pulses of methylprednisolone 1 g followed by oral prednisone 60 mg/day during 4 weeks with a torpid neurological course and persistent fever. A new cranial MRI showed nodular-shaped dural and leptomeningeal thickening of the left cerebellopontine angle and in the petrous apex (Fig. 1b). At that time, total serum IgG was 921 mg/dL (NR 700–1600 mg/dL) and serum IgG4 was 91 mg/dL. The CSF exam obtained by lumbar puncture showed hyperglycorrhachia, hyperproteinorrhachia, leukocyte count of 43 cells/μL (lymphocytes 71%), erythrocyte count of 3 cells/μL, adenosin deaminase 4 UI/L (NR < 6.5 UI/L). Cultures (including Löwenstein), RNA amplification techniques for herpesvirus, cytomegalovirus, bacteria, tuberculosis and the cytological examination were all normal, as well as a reagin test for syphilis. The IgG and IgG4 CSF levels were 9.69 mg/dL and 1.44 mg/dL, respectively. The Delpech and Lichtblau index (IgGCSF/IgGserum : albuminCSF/albuminserum) was used to assess immunoglobulin production in CSF (overproduction >0.7). Results for IgG, IgG1, IgG2, IgG3 and IgG4 were 1.176, 1.529, 0.588, 0.882 and 1.859, respectively. He was diagnosed with IgG4-related disease with pleural, lung and pachymeningeal involvement.3 A ventricle-peritoneal shunt was placed because of persistent high intracranial pressure assessed by MRI. Due to persistence of neurological manifestations despite the use of steroids, a 2 g intravenous rituximab course was administered (1 g pulse on days 0 and 14). Six months later, the neurological manifestations had disappeared and thoracic computed tomography scan and cranial MRI revealed resolution of pleural and meningeal thickening (Fig. 1c). No CSF samples were obtained during follow-up. IgG4-related pachymeningitis is a rare manifestation of IgG4-RD. At disease onset, the CNS may be involved on its own or along with other organs. Tissue IgG4 determination is the cornerstone for diagnosis, although obtaining samples, especially from meningeal tissues, may entail a high risk of potential side effects or contraindications. We have reported a patient with biopsy-proven diagnosis of IgG4-RD with pleural and lung involvement, who developed dural thickening and clinical neurologic symptoms, consistent with pachymeningitis. We demonstrated overproduction of all CSF immunoglobulin subclasses. Among them, IgG4 was the most elevated subclass in absolute terms. These findings, in a patient previously diagnosed with systemic IgG4-RD, support Della Torre's hypothesis that the determination of CSF IgG4 levels (in this case applying the IgG4 index [Delpech and Lichtblau]) may be a diagnostic tool for IgG4-related pachymeningitis. The reason why the IgG4 index score in this patient resulted under the median value of Della Torre′s study5 (n = 3) may be due to the previous treatment. The optimal treatment for IgG4-related pachymeningitis has not been established. Rituximab has shown promising results treating some forms of IgG4-RD.2 A few cases have been described as refractory to this drug.6 In this case, rituximab was chosen because of the presence of systemic disease. During follow-up, we monitored serum IgG4 levels and systemic symptoms. However, serial determinations of CSF IgG4 in CSF might be useful to assess the therapeutic effect in localized forms of IgG4-related pachymeningitis.7 In conclusion, IgG4 CSF determination could drive a safer and effective diagnostic approach in IgG4-related pachymeningitis. More case reports are required in order to confirm these results. We would like to thank Carla Vert MD (Radiology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain) and Mònica Velasco-Nuño MD (Nuclear Medicine Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain) for their kind collaboration with the images and Cristina Eve Hidalgo MD (Internal Medicine-Hepatology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain) for her careful review of the work. AFC, MHG and FMV collected the data. All authors contributed equally in the design, interpretation and writing of the paper. None.