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A mysterious back pain H Chen1, D Gnepp2, J Paul1, S Borra11 Department of Medicine, Kingsbrook Jewish Medical Center, Brooklyn, New York, USA 2 Department of Pathology, Rhode Island Hospital, Providence, Rhode Island, USA
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.128816
IgG4-related disease is a fibroinflammatory condition that affects many different organs. The common pathological findings of this disease include storiform fibrosis and dense infiltration of lymphocytes rich in IgG4-positive plasma cells. We herein presents the diagnosis and treatment of a case with a newly recognized condition - IgG4-related pachymeningitis. Keywords: Diagnosis, IgG4 disease, pachymeningitis, treatment
Hypertrophic pachymeningitis, first described by Charcot and Joffroy in the 19 th century, refers to a condition characterized by diffuse inflammatory fibrosis of the dural mater. It is an uncommon cause of spinal cord compression, and its etiology is often obscure.
A 49-year-old male presented to the Emergency Department because of worsening pain at the midline of his upper thoracic back and right leg. This pain was dull and constant, and it had started approximately a year ago but became more intense recently. He lately noted difficulty in standing or walking for long periods of time as well as mild decrease in sensation and strength on his right leg. He reported no fever, cough, trauma, changes in weight, or bowel/urinary incontinence. His past medical history was significant for HIV infection. Highly active antiretroviral therapy (HAART) was started approximately 10 years ago, but had been discontinued after a new onset of jaundice one year ago for unclear reasons. His tuberculin skin test was positive many years ago and he completed a 9-month course of isoniazid. He denied prior history of blood transfusions, tobacco, alcohol, or illicit drugs. On examination, he was in moderate distress because of pain. His vital signs were in normal range. The positive findings included icteric sclera, tenderness at the T3 spine on palpation, and positive straight leg raise test at 45 degrees on the right side. No deficiency in muscle strength or sensation was appreciated. Deep tendon reflexes were present and symmetric, and Babinski sign was flexor on both sides. What are the differential diagnoses? Back pain is one of the leading reasons for medical visits. It is most often caused by musculoskeletal or nerve root disorders. However, other causes should also be considered, such as aortic dissection, esophageal disease, abdominal aortic aneurysm, and kidney problems. It is important to characterize a patient's back pain. There are three different types of back pain: Local, mechanical, and radicular pain. Local pain is often described as a persistent aching pain. It may be caused by stimulation of the pain fibers within the spinal periosteum by stretching (e.g., metastasis or infection in a vertebral body) or a local inflammatory process. Mechanical pain, such as muscle strain, is usually relieved by rest and worsened by movement. Radicular pain is caused by compression of a nerve root and manifests as a shooting/stabbing pain in the dermatomal distribution of the affected nerve. One should be vigilant for red flag symptoms/signs that are suggestive of spine cord compression, such as motor/sensory dysfunction and bladder/bowel incontinence. This patient began with local pain in the upper thoracic region and later developed radicular lower back pain. Discontinuation of HAART therapy in a human immunodeficiency virus (HIV)-infected patient increases risks for infections and malignancies, [1] either of which could be the cause of his chronic back pain. The presence of both jaundice and back pain should raise the suspicion of primary pancreatic/hepatocellular cancer or metastatic malignancy. Case details (continued) Results of initial laboratory investigations were as follows: Hemoglobin 10.1 g/dL, hematocrit 29%, platelet count 156,000/mm 3 , white cell count 5100/mm 3 with neutrophil 47.3% on differentials; total bilirubin 6.5 mg/dL (normal: 0.2-1.0 mg/dL), direct bilirubin 3.8 mg/dL (normal: 0-0.2 mg/dL), alkaline phosphatase 415 unit/L (normal: 32-92 unit/L), alanine aminotransferase 275 unit/L (normal: 10-40 unit/L), and aspartate aminotransferase 162 unit/L (normal: 10-42 unit/L); serum total protein and albumin were 8.9 g/dL (normal: 6.0-7.8 g/dL) and 2.5 g/dL (normal: 3.5-4.8 g/dL), respectively. Urine analysis and chest X-ray were unremarkable. A gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI) revealed a longitudinal hyperintense mass at the extramedullary epidural space from T1 to T3 compressing the contiguous spinal cord, and a second hyperintense mass at the ventral epidural space of L4 level impinging the right-sided L5 nerve root [Figure 1]. The computed tomography (CT) of the abdomen with intravenous contrast did not demonstrate any abnormalities in the pancreas, liver, and biliary tract.
What could be the differential diagnoses now? In HIV-infected patients, infectious processes (nontuberculous and tuberculous) and tumors are the two most common etiologies of epidural masses. Nontuberculous bacterial abscesses are often seen in patients with a history of intravenous drug abuse or venous indwelling catheters. The infection often presents as spondylodiscitis with epidural extension. Mycobacterium tuberculosis  ten causes vertebral infections (Pott's disease) and paraspinal abscesses. Classically, spinal tuberculosis first damages the anterior inferior portion of the affected vertebral body and then spreads to the adjacent vertebral bodies through the space underneath the anterior longitudinal ligament. [2] The above typical imaging findings were not present in this case. The incidence of neoplastic extradural disease is also increased in HIV-infected individuals. In a retrospective study of the acquired immunodeficiency syndrome (AIDS) patients with neurological symptoms/signs suggestive of spinal diseases, lymphoma and metastatic carcinoma were the two most common causes. [3] Most metastasized cancers affect the body of vertebrae first, then extend into the spinal canal and cause compression of the spinal cord. In contrast, lymphomas often extend from paravertebral lymph nodes into the canal via intervertebral foramina. In our case, no lesion in the vertebral bodies or enlarged paravertebral lymph nodes was identified. Case details (continued) The further workup revealed a HIV virus load of 198,322 and CD4 count of 281 cells/μL (normal range: 490-1740 cells/μL). Tuberculin skin test reading was positive 8 mm. Antinuclear, cryptococcal, and toxoplasma IgM antibodies were all negative, and rapid plasma reagin test was nonreactive. Hepatitis immunology panel reported positive hepatitis B core antibody, but negative hepatitis B surface antigen and antibody; hepatitis C antibody was also negative. Serum hepatitis B DNA was not detectable. Liver biopsy was recommended, but the patient refused it. Intravenous dexamethasone was started after the admission. On hospital day 6, he underwent a T3 dorsal laminectomy. A pale whitish mass continuous with the dura at left T3 nerve root was found. The bulk of the mass was excised and the left T3 nerve root was left intact. The hematoxylin and eosin staining of the surgical specimen revealed extensive fibrosis with prominent inflammatory cell infiltration in some areas [Figure 2]. No granuloma, acid-fast bacteria, or fungi were evidenced on special staining, nor did any organism grow in culture. The diagnosis of idiopathic spinal hypertrophic pachymeningitis was made.
Oral steroids were continued postoperatively. Because of his immunocompromised state and positive tuberculin skin test, tuberculosis infection could not be ruled out. Review of literature uncovered a case report of cranial 'idiopathic' hypertrophic pachymeningitis that responded to antituberculous therapy. [4] Empirical treatment was administered with isoniazid, rifabutin, pyrazinamide, and ethambutol for 2 months, followed with the former two medications for another 4 months. During the antituberculous therapy, his liver function tests were closely monitored. On hospital day 9, his liver function improved but did not normalize, with total bilirubin 2.8 mg/dl, alkaline phosphatase 372 unit/L, alanine aminotransferase 354 unit/L, and aspartate aminotransferase 193 unit/L. He subsequently underwent physical rehabilitation therapy and was discharged home with a tapering dose of oral steroids. HAART therapy was resumed shortly after discharge. What is hypertrophic pachymeningitis? Hypertrophic pachymeningitis is characterized by chronic inflammatory fibrosis of the dural mater with compression of contiguous brain/spinal cord. In a review of 42 case reports on hypertrophic pachymeningitis, Guidetti et al. found that most of cases had no identifiable cause except that a few cases were associated with tuberculosis, syphilis, fungi, sarcoidosis, and rheumatoid arthritis. [5] MRI has been an important noninvasive tool to differentiate hypertrophic pachymeningitis from other causes of spinal cord compression. Hypertrophic pachymeningitis characteristically manifests as thickened dura spanning multiple spinal levels on MRI. Treatment includes steroids therapy and correction of underlying cause if known. Additional immunosuppressive treatment (e.g., methotrexate, azathioprine, or cyclophosphamide) may be considered when the disease becomes refractory to steroid therapy. Case details (continued) At a follow up 8 months after discharge, this patient's back pain was minimal and the jaundice had not worsened. However, he reported a 3 × 2 cm lump, which was noticed in the subcutaneous tissue on the left side of his neck. A biopsy was recommended but declined by the patient. It was at this moment that our attention was brought to a newly recognized condition, IgG4-related disease. IgG4-related disease is characterized by dense fibroinflammatory change in histology and capable of affecting almost every organ system. We entertained the possibility that his subcutaneous neck lesion and the pachymeningitis might be caused by the same fibroinflammatory change and IgG4-related disease could likely be the cause. Workup revealed elevated levels of serum IgG 3350 mg/dL (normal range: 694-1618 mg/dL) and IgG4 183.1 mg/dL (normal range: 4-86 mg/dL); retrospective immunohistochemical staining of the epidural specimen revealed the presence of abundant IgG4-positive plasma cells [Figure 3]; and a repeated MRI of the spine revealed complete resolution of the epidural mass. A final diagnosis of IgG4-related disease with dura mater and possible lymphoid tissue involvement (pseudolymphoma) was concluded. Prednisone was restarted at 20 mg daily. One month later, his neck lesion resolved, and the serum IgG4 level decreased to 127 mg/dL. Prednisone was slowly tapered off in the following 2 months. Six months after discontinuation of prednisone, his neck lesion did not relapse and his liver function remained stable with total bilirubin 3.5 mg/dL, direct bilirubin 1.6 mg/dL, alanine aminotransferase 66 unit/L, and aspartate aminotransferase 131 unit/L.
What is IgG4-related pachymeningitis? IgG4-related disease is a newly recognized fibroinflammatory condition that affects many different organs and may manifest as, but is not limited to, autoimmune pancreatitis, Riedel's thyroiditis and retroperitoneal fibrosis. [6] The common pathological findings of this disease include 'storiform' fibrosis and dense infiltration of lymphocytes rich in IgG4-positive plasma cells. [6] In 2009, Chan et al. reported the first case of IgG4-related pachymeningitis. [7] Since then, many cases have been reported. The information on the clinical, histological, radiological, and prognostic features from the reported cases are summarized in [Supplemental Table 1]. [Additional file 1] In a national survey from 2005 to 2009 in Japan, 8.8% of hypertrophic meningitis cases were related to IgG4/multifocal fibrosclerosis. [8] The significance of HIV infection in IgG4-related pachymeningitis is unclear, since HIV status was not provided in most of the case reports. {Table 1} In 2012, an international symposium on IgG4-related disease formulated a consensus statement on the diagnostic criteria for IgG4-related disease. [9] The diagnostic criteria for IgG4-related disease at a new organ/site, such as IgG4-related pachymeningitis, are as follows:
Our case meets all the diagnosis criteria. Recently, a new diagnostic method was developed to diagnose IgG4-related hypertrophic pachymeningitis by measuring IgG4 concentration in cerebral spinal fluid and serum. [10] The first-line treatment for IgG4-related pachymeningitis is steroids. Almost all patients in the published case reports responded well to steroids, except that a few patients later became refractory to steroids. The relapse rate after tapering of steroids therapy is unknown, as the follow up times for many case reports were short. Other treatment options after relapse include azathioprine, mycophenolate mofetil, methotrexate, and rituximab. [6] Teaching points 1. IgG4-related pachymeningitis is a fibroinflammatory thickening of dural mater with dense infiltration of IgG4-positive plasma cells. It is believed to be the cause of some previously considered 'idiopathic pachymeningitis'. 2. IgG4-related pachymeningitis has an insidious onset and is often mistaken as malignancy. On MRI, it is found as thickened dura spanning multiple spinal levels without lesions in vertebrae or paraspinal lymph nodes. Measuring IgG4 levels in serum and cerebral spinal fluid help diagnose this condition. 3. IgG4-related pachymeningitis has an excellent response to steroids. Prognosis and relapse rate after tapering of steroids is currently unknown.
We thank Dr. Chi P. Cheung for his expert discussion as well as Dr. Firozali Panjvani for reviewing the pathological slides.
[Figure 1], [Figure 2], [Figure 3]
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