Sarcoidosis is a granulomatous disorder of unknown cause that affects multiple organs. Estimates of its prevalence in the population range from 1 to 40 cases per 100,000 individuals, with a particular proclivity for adults aged under 40 years.10 The features of sarcoidosis are exceedingly variable. This disorder can affect virtually any part of the nervous system. Neurologic involvement occurs in 5%-16% of patients with sarcoidosis and is a significant cause of morbidity and mortality.5,9,19,23
Spinal cord sarcoidosis occurs rarely, although its diagnosis is frequently considered when patients present with subacute myelopathy. Knowledge about the neurologic localization of sarcoidosis comes from isolated case reports or small studies; therefore, management of this rare condition is mostly experience-based, rather than evidence-based.2,4,14,17,20 In particular, sarcoidosis remains a diagnostic dilemma and a therapeutic challenge.9
We conducted a multi-center, retrospective case-control study of 31 patients presenting with spinal cord sarcoidosis. The aims of this study were to describe the clinical, laboratory, and imaging features of spinal cord sarcoidosis and to compare them with those of myelopathy from other causes in order to define noninvasive diagnostic tools. Moreover, we assessed spinal cord sarcoidosis morbidity by describing long-term sequelae, and we tried to identify prognostic markers.
The study was entirely retrospective. Thirty-one patients with spinal cord sarcoidosis were recruited between 1993 and 2006 from the Neurology and Internal Medicine Departments, Pitié-Salpêtrière Hospital (Paris, France), and from the Pneumology Department, Avicenne Hospital (Bobigny, France). All of these clinical departments are tertiary care centers highly specialized in the treatment and management of sarcoidosis. The patients were chosen from the appropriate database of each department. A complete medical history was obtained for each patient from their medical records. Patients were included in the study if they met the following 4 criteria: 1) presented clinical features consistent with myelopathy (motor and/or sensory signs below the spinal cord level of the lesion and/or cortical tract syndrome and/or sexual or sphincter disturbances); 2) a spinal cord magnetic resonance imaging (MRI) revealed intramedullary involvement; 3) biopsy analysis revealed noncaseating granuloma or bronchioalveolar lavage (BAL) lymphocyte levels were between 30% and 50% with a CD4/CD8 ratio of >3.5;25 and 4) there was no alternative diagnosis, including other granulomatous disorders.
Clinical, Laboratory, and Radiographic Investigations
Complete demographic characteristics and the results of neurologic examinations were collected at baseline. In addition, laboratory analyses including serum angiotensin-converting enzyme (ACE) and cerebrospinal fluid (CSF) analyses were obtained. Chest X-rays were classified according to the Scadding stage method. Results of pulmonary function tests, thoracic computed tomography (CT) scans, bronchoscopies with BAL, cardiac investigations, tissue biopsies, and histologic analyses were recorded when available. The onset of neurologic disease was defined as acute when symptoms appeared in less than 24 hours, subacute when symptoms developed within 2 months, and chronic when they evolved over more than 2 months.
MRI features were reviewed by a neuroradiologist who had no knowledge of the patient's medical histories, as follows.
Baseline spinal cord and brain MRIs were reviewed for 26 patients; review was not possible for 5 patients because MRIs were not available or were of insufficient quality. However, for these 5 patients, imaging data from medical records were collected and compared to the reviewed patients' MRIs, and there were no significant differences. When available, spinal cord MRIs performed 1 month after starting corticosteroid therapy and during follow-up were also reviewed.
A brain MRI was considered abnormal if it displayed gadolinium enhancement, T2-weighted hyperintensities, or fluid-attenuated inversion recovery (FLAIR) hyperintensities of abnormal size, number, or localization, according to patient age and cardiovascular risk factors.
Treatment and Assessment of Outcome
Patients were managed by regular assessment and at time intervals based on their clinical status. Therapeutic strategies were based on local experience. Corticosteroids were considered effective if Modified Oxford Handicap Scale (MOHS) score (see below) improved after 1 month of treatment. Other immunosuppressive drugs were considered effective if the patient's condition improved or stabilized, without relapses, during treatment.
Clinical outcome at the end of follow-up was assessed according to the Modified Oxford Handicap Scale (MOHS), in which 0 = No symptoms, 1 = Minor symptoms that do not interfere with lifestyle, 2 = Minor handicap with symptoms leading to some restriction in lifestyle but not interfering with the patient's capacity to look after him/herself, 3 = Moderate handicap with symptoms that significantly restrict lifestyle and prevent totally independent existence, 4 = Moderately severe handicap with symptoms that clearly prevent independent existence though not needing constant attention, 5 = Severe handicap leading to total dependence and requiring constant attention during night and day, and 6 = Death. Recovery was defined by the complete resolution of neurologic signs and no disease recurrence for at least 12 months without treatment.
A monophasic course was defined by a unique flare without relapse. A flare can be defined by a progression of symptoms or new symptoms that occur in more than 24 hours and less than 1 month. A remitting-relapsing course was defined by flares (with or without sequelae) with no progression between 2 flares. A progressive course was defined by progression of symptoms without acute flare. Finally, a progressive course with flares was defined by progression of symptoms in addition to acute flares.
Control patients were recruited between 1999 and 2006 from the Neurology Department, Pitié-Salpêtrière Hospital, through a computerized database of diagnosis coding (PMSI). Complete information was obtained from the patient's medical records. Patients were included as controls if they met all following criteria: 1) their clinical findings were consistent with myelopathy for which they had been referred to the Neurology Department; 2) a spinal cord MRI revealed medullary involvement; 3) clinical, laboratory, and imaging results were consistent with a diagnosis other than sarcoidosis (including cervical degenerative myelopathy, optic neuromyelitis, definite multiple sclerosis, Sjögren disease, infectious disease, or a biopsy-proven spinal tumor). Patients were also included as controls if they suffered from myelopathy of unknown cause with a negative extensive workup that included at least 1 complete physical examination, serum ACE tests, chest X-rays, a thoracic CT scan with high resolution slices, and a labial biopsy and BAL. These parameters allowed for the exclusion of sarcoidosis as a diagnosis at the time the procedures were performed as suggested by the Transverse Myelitis Consortium Working Group.8 Patients with myelopathy of vascular origin were excluded as controls.
Clinical and laboratory data, including CSF analysis, were collected at baseline. Brain and spinal cord MRIs were reviewed in a blinded fashion by the same neuroradiologist who reviewed MRIs from spinal cord sarcoidosis patients.
Data collection ended in August of 2006. Results are expressed as the mean ± standard deviation or percentage. Qualitative values were compared with a chi-square test or the Fisher exact test for small sized samples. Quantitative values were compared with an unpaired t-test or nonparametric test (Mann-Whitney test), when appropriate. All tests were 2-sided. Prognostic markers were assessed using a linear regression model. P values were considered significant when < 0.05. Statistical analysis was performed with GraphPad Prism 5 (GraphPad software).
Demographic and Clinical Data
Thirty-one patients met the criteria required for inclusion in the spinal cord sarcoidosis (SCS) study group. Analysis of tissue biopsies revealed noncaseating granuloma for 22 patients. Patients with and without biopsy-proven noncaseating granuloma did not differ in terms of demographic, clinical, and imaging features or outcome (data not shown).
Demographic and clinical features are shown Table 1. Patients were mostly men, with a mean age of 41.6 ± 12.5 years at the onset of sarcoidosis. Nineteen of the patients were white (61%) and 12 were black (39%). Neurologic signs at onset were frequently subacute (23/31, 74%), or chronic (6/31, 19%). Two patients (7%) had an acute presentation.
Spinal cord involvement was the initial manifestation of sarcoidosis in 28 of the patients (90%). In the 3 remaining patients, spinal cord involvement occurred 2, 6, and 11 years after the first symptoms of sarcoidosis, which were, respectively, respiratory symptoms, uveitis, and arthritis. In these 3 patients, sarcoidosis was diagnosed before myelopathy became clinically apparent.
The mean time between the onset of symptoms and diagnosis of sarcoidosis for patients in whom sarcoidosis was revealed by neurologic signs was 15.1 ± 4.18 months.
All patients presented with clinical signs of myelopathy, which included sensory symptoms (25/31, 81%), motor deficit (23/31, 74%), cortical tract syndrome (24/31, 77%), sphincter disturbances (23/31, 74%), and sexual disturbances (11/31, 35%). In addition, pain, which consisted mostly of lesional syndrome (10/31), was frequently reported (14/31, 45%). Other neurologic signs were found infrequently (see Table 1).
In 9 patients, neurologic involvement was a unique manifestation of sarcoidosis (at onset and during follow-up). Of note, among these 9 patients, histologic confirmation from neurologic biopsy was obtained for 2. In 7 patients, BAL further disclosed the presence of significant lymphocytosis with a CD4/CD8 ratio of >3.5, although chest X-rays and high-resolution chest CT scans were normal.
In the 22 remaining patients, the most frequent extraneurologic localizations of sarcoidosis, at the onset of neurologic signs, included the lung and mediastinal lymph nodes as revealed by chest X-rays (n = 17); followed by the liver (n = 10); peripheral lymph nodes, eye, and skin (n = 2 each); and arthritis, bone, and sinuses (n = 1 each).
Laboratory and Other Analyses
The results of all laboratory data and cardiac and pulmonary tests are shown in Table 2. Laboratory blood test results were normal in 2 patients. The abnormality most frequently observed was elevated C-reactive protein (CRP) levels (54%).
CSF samples were obtained for 28 patients, and results were normal in 1 patient. Protein levels were elevated (>0.40 g/L) in 26 patients (mean, 1.94 ± 3.21 g/L). Total protein levels were greater than 1 g/L in 8 patients. White cell counts were elevated in 20 patients (mean, 100 ± 182 cell/mm3). Low CSF glucose levels were observed in 6/20 patients. CSF-ACE levels were normal in more than 50% of patients.
The results of tissue biopsy are shown in Table 3. The minor salivary glands were used for histologic examination in 21 patients, although noncaseating granuloma were found in only 6 patients. In contrast, peripheral and mediastinal lymph node biopsies displayed higher sensitivity. Neurosurgical biopsies were obtained for 5 patients (spinal for 3 patients, cerebral for 1, and optic nerve for 1). One patient underwent surgery for Arnold-Chiari disease, and noncaseating granulomas were discovered by histologic analysis. Surgical specimens displayed noncaseating granulomas in all but 1 patient. This patient had been on corticosteroid treatment during the previous 18 months. A laminectomy was performed due to the patient's progressive worsening despite treatment, and analysis of meningeal biopsy samples obtained during surgery displayed only inflammation without granulomas.
Spinal Cord and Brain MRI
Twenty-six spinal cord MRIs of patients with spinal cord sarcoidosis were initially reviewed (Table 4). All MRIs displayed T2-weighted hyperintensity lesions that were localized mainly in the thoracic (n = 17) and cervical (n = 15) areas (Figure 1). T2 hyperintensities were frequently not isolated, with at least 2 spinal cord lesions in 7 patients (27%), and heterogeneous (n = 8, 31%). Axial slides mostly showed central localization of the T2 hyperintensities. Twenty-three patients underwent gadolinium infusion. Among these patients, contrast enhancement was observed in 17 (74%). The appearance of gadolinium enhancement was heterogeneous in 5 patients and nodular in 3 (see Figure 1). In addition, spinal cord swelling was observed in 9 patients.
MRI findings improved after corticosteroid treatment in 10 patients, were unchanged in 3, and normalized in 5 (data not available for 8 patients). The changes observed by MRI did not always parallel the immediate clinical outcome of the patients. In addition, contrast enhancement diminished in 10 patients, was unchanged in 1, and disappeared in 2 (gadolinium infusion was obtained during follow-up in only 13 of 17 patients who underwent gadolinium infusion during the initial MRI). At the end of follow-up, MRI was normal in 5 of 16 patients and showed medullar atrophy in 5.
Initial brain MRIs were reviewed for all patients in the SCS group and were found to be abnormal in 17 (55%) patients. These abnormal MRIs showed mostly T2-weighted hyperintensities (n = 15) or meningeal contrast enhancement (n = 2). Additionally, 3 patients had pituitary involvement.
Table 5 shows the efficacy and side effects of different immunosuppressive treatments. Corticosteroids were used in all patients, except for 1 who improved spontaneously. Twenty-one patients received intravenous corticosteroids. The decision to treat a patient with corticosteroids was always justified by neurologic localization. One month after starting corticosteroids, 25 patients (83%) had improved, 4 (13%) were unchanged, and 1 was worse. The mean duration of corticosteroid therapy was 51 ± 7 months. Fifteen patients (50%) had side effects as a result of corticosteroid treatment, most of which involved metabolic disturbances, such as weight gain and high blood glucose levels, and infections.
Additionally, 12 patients were treated with methotrexate, which was stopped in 4 patients because of the presentation of side effects, which included hepatotoxicity for 3 patients and recurrent infections for 1. Ten patients received intravenous cyclophosphamide, 5 received hydroxychloroquine, and 4 were treated with mycophenolate mofetil. It is noteworthy that 1 patient was treated with anti-TNF-α antibodies (infliximab) due to the failure of other immunosuppressive drugs, but continued to worsen despite anti-TNF-α treatment.
The mean follow-up from the onset of neurologic signs was 64 ± 8 months. Twenty-eight patients were followed for more than 1 year and were included for further analysis.
Treatments at the end of follow-up included corticosteroids (n = 21), cyclosporine (n = 2), cyclophosphamide (n = 2), methotrexate (n = 2), mycophenolate mofetil (n = 2), and hydroxychloroquine (n = 1).
Approximately one-third of the patients each had a monophasic course (n = 11), a relapsing-remitting course (n = 10), or a progressive course of disease with or without relapses (n = 7) (Table 6).
Twenty-six patients presented neurologic sequelae at the end of follow-up (Figure 2). Two patients achieved total recovery from sarcoidosis. Patients who had a progressive course had higher MOHS at the end of follow-up. Using a linear regression model, we found no statistically significant association between MOHS at the end of follow-up and T2 or contrast enhancement extension in the spinal cord by MRI. We did find a slight association between MOHS and CSF white cell counts (p = 0.046) and a non-significant association between MOHS and CSF protein content (Figure 3).
We could not demonstrate an association between MOHS at the end of follow-up and the time between onset of neurologic symptoms and initiation of steroid therapy when using a linear regression model (p = 0.39).
Of note, 4 patients presented pulmonary embolism during follow-up. Of these, 1 had mild protein S deficiency.
Of the 137 screened, eligible patients, 68 met the inclusion criteria. Thirty-eight patients were excluded, because MRI results were not available for reviewing (5 patients) or because the data were too inconsistent to exclude sarcoidosis as a diagnosis in patients with myelopathy of unknown cause (30 patients). Three patients presented with vascular myelopathy and were also excluded from the analysis. Among the 30 remaining patients included for analysis in the control group, 16 were male and 14 were female (see Table 1).
The diagnoses for the patients in the control group included multiple sclerosis (n = 7), optic neuromyelitis (n = 4), degenerative myelopathy (n = 3), infectious disease (n = 2), Sjögren disease (n = 1), and a malignant tumor (n = 1). Twelve patients had myelopathy for which a known cause could not be identified despite extensive workup (see the Methods section).
The sex ratio and age at onset of neurologic signs were not statistically different. In addition, clinical presentation of the disease did not differ significantly between the SCS group and the control group (see Table 1).
Laboratory blood test results were more frequently normal in the control group (p < 0.0001). Control patients were less likely to have elevated blood CRP levels, elevated lactate dehydrogenase (LDH), lymphopenia, and hypergammaglobulinemia than were patients in the SCS group. In contrast, there were no differences in serum liver test abnormalities or serum ACE between the 2 groups (see Table 2).
Patients in the SCS group had higher CSF protein content and white blood cell counts than did the control patients. Low CSF glucose levels were never observed in the control group. Furthermore, the proportion of patients who had local immunoglobulin synthesis or increased CSF-ACE levels did not differ between the 2 groups.
When we compared MRI features, we found no difference in the repartition of T2 hyperintensities (cervical thoracic or conus) between the 2 groups (see Table 4). However, in the SCS group, the lesions were more extensive in T2-weighted imaging. The extension of contrast enhancement was also higher in the SCS group. T2 lesions were more likely to be central in axial slides in the SCS group. Brain MRIs were more frequently abnormal in the SCS group (p = 0.01).
Neurologic sarcoidosis represents an uncommon but serious manifestation of sarcoidosis that occurs in 5%-16% of patients.3,18,21,23,26 Virtually any part of the nervous system may be involved, including the peripheral nervous system, the cranial nerves, the cerebrum, and the spinal cord. Spinal cord sarcoidosis encompasses a large spectrum of manifestations, including arachnoiditis, extradural or intradural lesions, and intramedullary involvement.
Even in the largest studies of neurologic sarcoidosis, intraspinal sarcoidosis is rarely reported (0.1%-50% of neurologic sarcoidosis).5,6,13,22,23 Representing a rare manifestation of sarcoidosis, spinal cord sarcoidosis has been reported only in case reports or studies that focused on clinical features and descriptive MRI findings.11,12 To our knowledge, there is no controlled study of spinal cord sarcoidosis. Moreover, little is known about the clinical course, long-term follow-up, and neurologic sequelae of spinal cord sarcoidosis. Diagnosing sarcoidosis when myelopathy seems isolated is still challenging, as illustrated by the numerous studies reporting serendipitous findings of noncaseating granulomas from neurologic biopsies or postmortem examinations.7 Therefore, important areas of uncertainty persist. For example, which clinical, laboratory, or imaging clues lead to suspicion of sarcoidosis origin instead of myelopathy? Are there prognostic markers that are predictive of neurologic sequelae that could lead to intensive treatment? To address these questions, we conducted the current multicenter case-control study of 31 patients with definite intramedullary spinal cord sarcoidosis rather than myelopathy of other causes.
Diagnosis of Spinal Cord Sarcoidosis
Compared to other manifestations of sarcoidosis, spinal cord sarcoidosis has some peculiar features. In our study, the patients were mostly male, with a mean age of 41 years. However, sarcoidosis is more frequently seen among young women. In spinal cord studies, the proportion of males is frequently high, reaching 88% in 1 study.6
Neurologic signs are commonly the first symptoms of sarcoidosis, as reported in a large study of neurologic sarcoidosis.4,5,16 Clinical presentation is similar to other myelopathies, although pain is more frequent in spinal cord sarcoidosis. Spencer et al22 reported back pain corresponding to the level of spinal cord sarcoidosis involvement in 4/6 patients. Lung and mediastinal lymph nodes were involved in 55% of cases (as observed by chest X-rays), but these patients were largely asymptomatic. When chest X-rays were found to be normal (stage 0), chest CT scans were also normal, although BAL showed evidence of lymphocytosis.
Some elements may raise the suspicion of sarcoidosis instead of myelopathy, such as abnormal findings in laboratory blood tests, particularly elevated CRP levels, elevated LDH, hypergammaglobulinemia, or lymphopenia. The classical features of sarcoidosis (hypercalcemia, elevated liver enzymes, and elevated serum ACE) were not specific to sarcoidosis. Likewise, we confirmed that analysis of serum ACE has a poor predictive value in the diagnosis of sarcoidosis.23,24 Analysis of serum interleukin 2 receptor (IL-2R) levels has been reported to be better than serum ACE tests for monitoring the disease.9 Unfortunately, none of our patients had information on serum IL-2R levels. CSF analysis may provide important information. Patients in the SCS group had significantly higher CSF protein levels and white blood cell counts. In addition, low CSF glucose was very specific, since it was never observed in the control group. CSF-ACE and oligoclonal bands were not useful to differentiate the 2 groups. In other studies, about a third of the patients with neurosarcoidosis had normal CSF.26 In our study, all but 1 patient displayed abnormalities.
Imaging features also discriminated between myelopathy due to sarcoidosis versus other causes. Brain MRIs were more frequently abnormal in patients with spinal cord sarcoidosis. Spinal cord MRIs disclosed higher T2 hyperintensity lesions and higher contrast enhancement extension. In previously reported studies, spinal cord sarcoidosis was reported to involve the cervical area commonly.22 In our controlled study, this criterion was not sufficient to discriminate between sarcoidosis and non-sarcoidosis myelopathy. Axial slides may be of importance because they frequently show central lesions in patients with sarcoidosis myelopathy. As previously reported for neurologic sarcoidosis, about a third of the patients have multiple neurologic lesions (intraspinal and/or intracerebral).5 In our study, more than 50% of patients had multiple lesions. In the case of myelopathy, physicians should be aware that disseminated hyperintensities or gadolinium enhancement is not always suggestive of multiple sclerosis. Linear leptomeningeal enhancement was not observed, as previously reported.13 However, hyperintensities and gadolinium enhancement were highly heterogeneous. Spinal cord swelling was also a frequent finding. Some authors argue that leptomeningeal enhancement is specific for neurosarcoidosis.15 In our control group, leptomeningeal enhancement was also observed, although with a lower extension level.
Outcome of Spinal Cord Sarcoidosis
Our results largely confirm that the spinal cord is a debilitating localization of sarcoidosis. Only 2 of 31 patients underwent complete recovery from neurologic sarcoidosis. At the end of follow-up, 17 patients (61%) had a MOHS superior to 3, which indicates a moderate to severe handicap. Analysis of CSF seems to provide appropriate prognostic markers; patients who had the highest protein levels and white blood cell counts had the highest MOHS. However, this remains to be confirmed given the small sample size. Some groups have reported that early treatment resulted in a remarkable recovery from neurologic sarcoidosis. We failed to demonstrate such an effect, and found that the time between the onset of neurologic symptoms and treatment did not correlate with MOHS.
Spinal cord sarcoidosis mostly displayed a monophasic or relapsing-remitting course. Patients with a progressive course had higher MOHS at the end of follow-up.
Corticosteroids are efficient to treat spinal cord sarcoidosis, and patients may relapse when dosage is tapered.6 As previously reported, long-term steroid dependence is usual.1 In refractory neurosarcoidosis, infliximab has been shown to be effective in a few cases. However, infliximab was not effective for our patients. Of note, side effects from the use of these drugs were frequent (50% with corticosteroids and 33% with methotrexate).
MRI findings improved in some patients in response to corticosteroid therapy, although the clinical and imaging results did not always parallel the MRI findings. Some groups have reported that spinal cord gadolinium enhancement, spinal cord swelling, and hyperintensities always disappeared after corticosteroid therapy was initiated.13 We did not confirm such a result, since some patients displayed markedly improved MRI findings, while others did not.
This study was entirely retrospective in nature. Therefore, we cannot make any definitive conclusions with respect to the efficacy of the different treatments administered to the patients.
For 9 patients, we could not obtain histologic confirmation of noncaseating granulomas. However, these patients were recruited from highly specialized tertiary care centers, so that sarcoidosis diagnosis was considered reliable for these patients. Furthermore, our inclusion criteria were restrictive because, in addition to using specific clinical and laboratory criteria, we included only patients with lymphocytosis in BAL, which is very suggestive of sarcoidosis. Moreover, we compared these patients to those who had histologic confirmation of sarcoidosis and found no difference between them.
The control group was highly heterogeneous in terms of their diagnoses, which ranged from multiple sclerosis to degenerative myelopathy. Nevertheless, the control group is representative of a real-life scenario in which patients typically present with myelopathy as an initial feature.
Neurologic sarcoidosis is a disease that can involve any part of the central nervous system, producing protean clinical expressions. As in other neurosarcoidoses, spinal cord sarcoidosis has a peculiar proclivity for men aged under 40 years and is difficult to diagnose since it tends to mimic other neurologic diseases. Based on the results of the current study, we recommend analyzing inflammatory blood markers (CRP), serum LDH levels, protein electrophoresis, chest X-rays or CT-scans, and accessory salivary gland biopsies in patients with myelopathy of unknown cause. We suggest eliminating the analysis of CSF-ACE levels. In addition, we suggest paying careful attention to thromboembolism in patients who have simultaneous inflammatory disease, decreased mobility, and are being treated with corticosteroids.
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