Refractory Neurosarcoidosis Research Articles

Infliximab in neurosarcoidosis: a systematic review and meta-analysis.

To evaluate the clinical outcomes and relapse rates in neurosarcoidosis patients administered infliximab. A systematic review was conducted using the MEDLINE, EMBASE, SCOPUS, and Cochrane Library databases. The search included studies from their inception to March 2023. We included case-series studies with at least 10 neurosarcoidosis patients undergoing any treatment type. Studies were also required to report at least one of the following outcomes: response rate, overall survival rate, or relapse rate. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A random-effects model facilitated the analysis of proportional treatment outcomes. Study quality was evaluated using the modified Newcastle-Ottawa quality assessment scale, while a funnel plot helped detect any publication bias. Seven studies comprising 237 patients with neurosarcoidosis were included in the analysis. Of these patients, 184 (77.6%) received treatment with infliximab. The pooled proportion of patients showing clinical improvement after infliximab treatment was 0.74 (95% CI 0.64-0.84, I2 = 49.73%). Relapse rates, derived from four studies, stood at 0.38 (95% CI 0.22-0.55, I2 = 56.92%). Most studies reported successful tapering or cessation of corticosteroid dosage in patients receiving infliximab. Adverse effects were reported in 52 (29.4%) patients, of which 39 out of 54 events (72.2%) were linked to infections. Infliximab demonstrated potential improvement in clinical outcomes for patients with refractory neurosarcoidosis and showed potential for reducing the dosage of concurrent corticosteroids. However, a degree of relapse was observed, with infections being the primary concern for adverse events.

Epidemiology, clinical presentation, treatment, and outcome of neurosarcoidosis: A mono-centric retrospective study and literature review.

Neurosarcoidosis is a rare granulomatous disorder, and treatment guidelines are mainly based on retrospective studies. This retrospective study was performed to provide a detailed description of the clinical characteristics and treatment outcomes of patients with neurosarcoidosis followed at Cliniques Universitaires Saint Luc in Belgium. The second objective of our study was to perform a comparative literature review of neurosarcoidosis, with a focus on treatment outcomes with the use of TNF-α antagonist. Among 180 patients with sarcoidosis followed in our hospital, 22 patients with neurosarcoidosis were included in the final analysis. Our literature research identified 776 articles of which 35 articles met our inclusion criteria, including 1,793 patients diagnosed with neurosarcoidosis. In our cohort, the majority of patients (86%) were diagnosed with systemic sarcoidosis which was similar to that reported in the literature (83%). Serum CRP and calcemia were elevated only in 33 and 18% of patients, respectively. Serum lysozyme and angiotensin-converting enzyme were elevated in 79 and 16% of patients, respectively. Lumbar puncture and CSF fluid analysis were performed in 15/22 patients and were abnormal in all patients. Brain MRI was performed in 21/22 patients and showed abnormalities in 16 patients consisting of parenchymal lesions in 63%, hypothalamic-pituitary axis lesions in 38%, and meningeal enhancement in 31%. In both cohort patients, methotrexate was the most frequently used treatment (>45% of cases) with a favorable outcome in an average of 50% of patients. A TNF-α antagonist was administered in 9% of patients in our cohort and in 27% of patients in the literature review. The proportion of favorable outcomes in literature research was significantly higher in patients treated with TNF-α antagonists compared to methotrexate (p < 0.0001), mycophenolate mofetil (p < 0.0001), or azathioprine (p < 0.0001). The results of our cohort and literature review confirm that neurosarcoidosis occurred most frequently in the context of systemic sarcoidosis. Methotrexate is the most frequent second-line therapy. The effectiveness of therapy with TNF-α antagonists is well-demonstrated and associated with a better outcome. Their earlier use during the disease course among aggressive and/or refractory neurosarcoidosis should be considered.

Current treatment of sarcoidosis.

Sarcoidosis is a granulomatous systemic disease of unknown cause where the lung is the most frequently affected organ. Therapeutic management of the disease is challenging as clinical presentation and prognosis are very heterogeneous. In the present review, we will summarize the main advances in sarcoidosis therapy. Current sarcoidosis therapies are categorized in three lines: glucocorticoids (first line), immunosuppressants (second line), and biologics (third line). Recent glucocorticoid studies have reported that efficacy could be similar with high and low doses, but with an increase in side effects with higher doses. In immunosuppressants, recent publications in mycophenolate and repository corticotropin injection (RCI) have added more information in their use and efficacy. Finally, new evidence has been published in the use of antitumor necrosis factor (anti-TNFα) agents in refractory cardiac sarcoidosis and neurosarcoidosis. Sarcoidosis therapy is constantly evolving, and new drugs have been added to the recommended treatments. However, extensive clinical trials are still necessary to optimize the current recommendations.

Novel Use of Rituximab in Treatment of Refractory Neurosarcoidosis in an 11-Year-Old Girl

Novel Use of Rituximab in Treatment of Refractory Neurosarcoidosis in an 11-Year-Old Girl

Long-term outcomes of refractory neurosarcoidosis treated with infliximab.

Central nervous system localizations of sarcoidosis may be refractory to conventional treatment such as steroids and immunosuppressive drugs. Infliximab, a TNF-α antagonist chimeric antibody, has been shown to be effective for treatment of these localizations. The aim of this study was to evaluate the efficacy and safety, in particular the long-term outcomes, of the use of infliximab for the treatment of neurosarcoidosis. We retrospectively reviewed medical records of patients with neurosarcoidosis who had been treated with infliximab between 2009 and 2015. All patients had histologically proven non-caseating granulomas. Eighteen patients with histologically proven sarcoidosis were included in this study. All had neurological involvement consisting of meningeal (n=16), cerebral (n=10), spinal cord (n=6), and/or optic nerve (n=5) involvement. Sixteen patients had previously received at least one immunosuppressive drug in addition to corticosteroids, including cyclophosphamide in 11 patients. All patients received treatment with infliximab (3-7.5mg/kg) associated with corticosteroids (n=18), low-dose methotrexate (n=15), azathioprine (n=2), or mycophenolate (n=1). Sixteen out of 18 patients improved clinically (initial median modified Rankin scale score of 3, final median score of 1; p<0.0001). At 6months after initiation of infliximab, six patients obtained complete remission (33%), ten attained partial remission (56%), and two had stable disease (11%). The median follow-up time was 20months (range 6-93). Nine patients relapsed during follow-up (50%). Eight patients developed toxic side effects and seven of these side effects were infectious events. Infliximab is an efficacious treatment of refractory neurosarcoidosis. However, relapses frequently occurred during follow-up.

New-Onset Paresthesias in Inflammatory Bowel Disease

Question: A 44-year-old Caucasian woman with a history of ileocolonic Crohn's disease, currently in remission on infliximab and 6-mercaptopurine for the last 5 years, presented with paresthesias on her left below the waist, left lower extremity, and severe back pain. On examination, she demonstrated dysesthesia and hyperesthesia in the left hemibody below T4 level. Strength was normal. PET (Figure A) revealed moderately intense fluorodeoxyglucose activity (maximum standardized uptake value of 4.9) in the thoracic spinal cord extending from T3 to T9 correlating with the enhancing lesion seen on MRI (Figure B). Spinal cord biopsy was obtained. Extensive workup for infections including Mycobacterium tuberculosis by culture, polymerase chain reaction, and acid-fast smear was negative. QuantiFERON before initiation of infliximab 5 years ago had been negative. Chest CT and conjunctival biopsy were negative. What is the diagnosis? Look on page 907 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. The presence of nonnecrotizing granulomas on the spinal cord biopsy (Figure C) combined with the enhancing lesion seen on MRI (Figure B) and PET scan (Figure A) and in the absence of an infectious agent, is consistent with the diagnosis of neurosarcoidosis. Infliximab was discontinued immediately and high-dose glucocorticoids initiated. Follow-up in 3 months showed improvement of her neuroimaging (Figure D). Her Crohn’s disease has remained in remission while on high-dose prednisone and 6-mercaptopurine. Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that plays a major role in the pathogenesis of inflammatory bowel diseases (IBD). Anti–TNF-α therapy is recommended for treatment of moderate to severe IBD, either as monotherapy or in combination with thiopurines. Infliximab has been used for treatment of steroid-refractory neurosarcoidosis as well as cutaneous and joint involvement in this condition.1Pereira J. Anderson N.E. McAuley D. et al.Medically refractory neurosarcoidosis treated with infliximab.Int Med J. 2011; 41: 354-357Crossref Scopus (33) Google Scholar Recently, however, several case reports and series have demonstrated the development of sarcoidosis during treatment with TNF antagonists, with the most commonly affected organs including lungs, lymph nodes, and skin.2Cathcart S. Sami N. Elewski B. Sarcoidosis as an adverse effect of tumor necrosis factor inhibitors.J Drugs Dermatol. 2012; 11: 609-612PubMed Google Scholar TNF-α inhibitors have also been implicated in several other neurologic complications, including peripheral neuropathy, central demyelination, transverse myelitis, optic neuritis, leukoencephalopathy, chronic inflammatory demyelinating polyneuropathy, and posterior reversible encephalopathy syndrome.3Singh S. Kumar N. Loftus Jr., E.V. et al.Neurologic complications in patients with inflammatory bowel disease: increasing relevance in the era of biologics.Inflamm Bowel Dis. 2013; 19: 864-872Crossref PubMed Scopus (51) Google Scholar A 10-year review of the neurological complications of TNF alpha inhibitors from the Food Drug Administration Adverse Event Report System identified 528 cases, of which 17.4% were in patients with IBD. This case highlights the importance of recognizing the neurologic complications associated with TNF inhibitors, which are commonly prescribed in patients with IBD. Sarcoidosis is emerging as a new potential complication of this class of drugs and therefore should be considered in the differential of new-onset neurological symptoms.

Neurosarcoidosis

Neurosarcoidosis can involve either the central nervous system (CNS), the peripheral nervous system (PNS), or both. The clinical manifestations are varied and include cranial neuropathy, aseptic meningitis, hydrocephalus, headache, seizure, neuropsychiatric symptoms, neuroendocrine dysfunction, myelopathy, and peripheral neuropathy. Neurologic problems that develop in sarcoidosis patients should not be assumed to represent neurosarcoidosis, as they are often attributable to another cause. The diagnostic work up of neurosarcoidosis should include an evaluation for potential extra-neural involvement and histologic confirmation of sarcoidosis. If there is no appropriate extra-neurologic organ for biopsy, a biopsy from involved neural tissue needs to be considered. Biopsy of the dura and leptomeninges is less invasive than biopsy of the brain or spinal cord parenchyma. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain and spinal cord is the most sensitive test for neurosarcoidosis, while the diagnostic specificity of cerebrospinal fluid (CSF) analysis is limited. Corticosteroids are the mainstay of treatment for neurosarcoidosis. In general, oral corticosteroids are used for mild to moderate cases, while high-dose intravenous methylprednisolone is used in severe cases or refractory cases that fail to respond to oral corticosteroids. Immunomodulating and cytotoxic agents are often required for steroid-refractory neurosarcoidosis or for patients who develop significant corticosteroid adverse effects. Methotrexate is used as a first-line corticosteroid sparing agent. Tumor necrosis factor-alpha inhibitors, including infliximab, are effective for refractory neurosarcoidosis. Cyclophosphamide is also used for refractory neurosarcoidosis patients, but, because of the drug's significant toxicity, it is usually reserved for severe cases that have failed oral therapies when tumor necrosis factor alpha antagonists cannot be obtained. In addition to anti-granulomatous therapy, treatment is frequently required for neurosarcoidosis-associated conditions, such as epilepsy and neuroendocrine dysfunction. Surgical intervention is indicated for life threatening complications such as hydrocephalus, steroid-refractory spinal cord compression, or mass lesions causing increased intracranial pressure.

Reply: Treatment of refractory neurosarcoidosis with tumour necrosis factor inhibitors – what lies ahead?

Reply: Treatment of refractory neurosarcoidosis with tumour necrosis factor inhibitors – what lies ahead?

Treatment of refractory neurosarcoidosis with TNF‐inhibitors: what lies ahead?

We read with interest the case series on the treatment of refractory neurosarcoidosis with infliximab. We were interested to know whether the serum and cerebrospinal fluid angiotensin converting enzyme or other makers of sarcoidosis might have been ascertained (such as increased cerebrospinal fluid CD4/CD8 lymphocyte ratios, lysozyme and b2-microglobulin), as these can have a role in monitoring disease activity, and in supporting a diagnosis if a patient (e.g. Case 1) declines biopsy. Likewise, a gallium or positron-emission tomography scan may indicate accessible disease worthy of biopsy, for example, salivary glands or lymph nodes. Sarcoidosis refractory to glucocorticosteroids is an important and difficult area, and although there have not been any randomised controlled treatment trials for isolated neurosarcoidosis, there is now a large body of evidence from placebo-controlled studies that anti-TNF-a agents have a relatively modest effect in modulating this disease, which is disappointing given the logical choice of TNF antagonists in sarcoidosis. Nonetheless, individual trials of therapy may be worthwhile as in the refractory cases reported, if monitored carefully, and the therapy discontinued quickly if ineffective, particularly with the awareness that tuberculosis might be unmasked as being the true diagnosis, rather than sarcoidosis. We also note that Pereira et al. tested azathioprine in two of their patients although did not assess anti-malarials. Azathioprine, as well as chloroquine and hydroxychloroquine have also been reported as being useful in a few small case series of neurosarcoidosis, but no clinical trial data exist. Hopefully, better agents that target CD4+ type 1 helper T-cell (TH1) immunity and associated sarcoid inflammatory pathways will become available as the immunology of this fascinating disease becomes apparent.

Medically refractory neurosarcoidosis treated with infliximab

Neurosarcoidosis can worsen despite standard immunosuppressive therapy, a situation for which there is no established medical management. We present three cases of medically refractory neurosarcoidosis treated with infliximab. All three patients showed a clinical response to this treatment and side effects were limited. A summary of reported cases of neurosarcoidosis treated with infliximab is included. This case series supports a role for infliximab in the treatment of patients with medically refractory neurosarcoidosis.

Infliximab for Refractory Neurosarcoidosis

In this article, the authors report their experience with infliximab treatment in four patients with refractory neurosarcoidosis and discuss a possible

Dramatic response to infliximab in refractory neurosarcoidosis

Sarcoidosis is a systemic disease characterized by noncaseating granulomas in the involved organs. Neurologic manifestations involving the central and/or peripheral nervous system occur in about 5% of patients. Neurosarcoidosis is often refractory to conventional treatment and therefore more effective treatment options are needed. While the etiology of the disease is still unknown, there is now a better understanding of its pathogenesis on a molecular level. It is clear that tumor necrosis factor-α (TNFα) plays a pivotal role in the development of the granulomas and it is believed to be a key cytokine involved in the pathogenesis of the disease. Taking advantage of this better understanding of disease pathogenesis, anti-TNFα agents are being increasingly used to treat refractory sarcoidosis. We report a patient with refractory neurosarcoidosis who showed dramatic improvement in the clinical and radiological manifestations following treatment with infliximab; he suffered a relapse upon discontinuation of the medication.

15. A Case Series of Medically Refractory Neurosarcoidosis Treated with Infliximab

Introduction: Neurosarcoidosis is a granulomatous disease of postulated immune aetiology. Novel effective therapies are required as this disease often progresses despite standard treatment with a combination of steroids and immunosuppressive agents. Infliximab is a chimeric monoclonal antibody that inactivates the pro-inflammatory cytokine tumor necrosis factor alpha. It has a potential role in the treatment of medically refractory neurosarcoidosis based on animal data and a number of case series.

Treatment of CNS sarcoidosis with infliximab and mycophenolate mofetil

To describe the effects of the anti-tumor necrosis factor neutralizing antibody, infliximab, and the antiproliferative immunosuppressant, mycophenolate mofetil, in refractory neurosarcoidosis. We treated patients with biopsy-proven sarcoidosis and CNS involvement, who had failed treatment with steroids, with infliximab (5 mg/kg on weeks 0, 2, and 6, and then every 6-8 weeks thereafter). Six out of seven patients were co-treated with mycophenolate mofetil (1,000 mg PO BID). Patients underwent a review of symptoms and complete neurologic examination every 3 months and MRI scanning before and after 3-4 infusions of infliximab. All patients reported significant symptomatic improvement by the fourth infusion of infliximab, including relief of headache and neuropathic pain, reversal of motor, sensory, or coordination deficits, and control of seizure activity. Furthermore, infliximab therapy was universally associated with a decrease in lesion size or suppression of gadolinium enhancement as documented by MRI. A positive treatment response was attained irrespective of location or distribution of CNS involvement by sarcoidosis (dural/leptomeningeal based vs intraparenchymal; cord vs brain; single lesion vs multifocal). There were no serious adverse effects in a follow-up period spanning 6-18 months. Combination treatment with mycophenolate mofetil and infliximab is a promising therapeutic approach for neurosarcoidosis.

Treatment of refractory neurosarcoidosis with Infliximab

BackgroundNeurological involvement in sarcoidosis is serious and often aggressive. Many patients respond to steroids but some show a progressive course despite treatment with steroids and even more potent immunosuppressive drugs.ObjectiveThe...

Neurosarcoïdose réfractaire et infliximab : une expérience grandissante

Neurosarcoidosis is a rare disease that can involve all the nervous system with variable clinical onset and prognosis. The initial therapeutic approach is mainly based on corticosteroids and immunosuppressive agents. Treatment of refractory forms of neurosarcoidosis is not well established and emerging immunomodulating drugs like infliximab have been recently tested. The clinical report of a new case of neurosarcoidosis responding to infliximab is followed by a review of the new therapeutic agents available for the treatment of refractory neurosarcoidosis.

Remission of Refractory Neurosarcoidosis Treated With Brain Radiotherapy

Sarcoidosis is a chronic disease of unknown etiology characterized by the presence of T lymphocytes, mononuclear phagocytes, and noncaseating epithelioid granulomas in the tissues. Central nervous system involvement occurs in about 5% of the cases. The chronic form of neurosarcoidosis is particularly resistant to medical treatments. No universally accepted therapeutic protocols are currently available. Corticosteroids are the first line of therapy, but other immunosuppressive treatments are frequently added to the patient's regimen, although this strategy is not adequately supported by controlled clinical trials. For patients resistant to or not tolerating multiple alternate immunotherapeutic drugs, some authors suggest central nervous system radiotherapy. We present a case of a patient with neurosarcoidosis involving the hypothalamo-hypophyseal region and causing panhypopituitarism who had a poor response to and experienced severe side effects from conventional immunosuppressive treatments. The patient experienced a good clinical response to cranial irradiation. We review the literature on this subject.

Prognosis of refractory neurosarcoidosis altered by thalidomide: a case report

IntroductionSarcoidosis is a multisystem disease characterized by noncaseating granulomas in the lungs, skin, lymph nodes, and, rarely, the nervous system. Granuloma formation in sarcoidosis is mediated by increased secretion of interferon-gamma, interleukin-2, and tumor necrosis factor-alpha. 25% of patients with neurosarcoidosis are steroid resistant and another 20–40% are resistant to any conventional immunosuppression, but the typical agents suppress the immune system in a non-specific fashion. Thalidomide has been shown to have activity specific to the inflammatory mediators of sarcoidosis, has been shown to be beneficial in cutaneous sarcoidosis, and provides an interesting observation in our patient with refractory neurosarcoidosis.Case presentationA 40 year old African-american female presented with refractory neurosarcoidosis. Over the course of several years, the patient was treated with high dose steroids, imuran, cytoxan, and cyclosporine without benefit. Then, the patient received thalidomide, slowly escalating to 650 mg. After 2 months radiologic improvement was noted and after 6 months clinical stabilization and improvement became apparent.ConclusionOur case report presents a difficult, refractory case of neurosarcoidosis that demonstrates an altered prognosis based on the addition of thalidomide.

Dramatic MRI improvement with refractory neurosarcoidosis treated with infliximab

Neurosarcoidosis is often a devastating, refractory condition without definite pharmacotherapies beyond corticosteroids. To describe a case of steroid-refractory neurosarcoidosis with a marked clinical and radiological response to infliximab. We describe the case of a young female patient with biopsy-proven neurosarcoidosis leading to gait failure. She described significant corticosteroid-related side effects without clinical response to the therapy. Infliximab therapy was considered as a possible rescue medication. Within months of starting intravenous infliximab therapy, she regained her ability to walk and magnetic resonance imaging identified significant improvements over a sustained course of infliximab therapy, including loss of enhancing nodules and loss of meningeal enhancement. Mounting evidence suggests that infliximab is a valuable pharmacological agent in the management of patients with refractory and disabling neurosarcoidosis. Controlled studies of infliximab in this condition are needed.

Neurosarcoidosis

Neurosarcoidosis is an uncommon disorder and requires a careful clinical evaluation to reach a diagnosis. Generally, patients with peripheral symptoms, which include paresthesias, muscle weakness, and stocking glove deficits, have a better outcome compared with those with central nervous system involvement. Patients with mass lesions or hydrocephalus tend to have more relapses and are often more resistant to routine therapy. Neurosarcoidosis often responds to glucocorticoids, usually within days or weeks of initiating therapy. Patients are usually maintained on 40 to 80 mg per day for 4 to 6 weeks, which is then tapered slowly. Alternative treatments for refractory neurosarcoidosis, or to reduce or eliminate steroids, include methotrexate, cyclophosphamide, azathioprine, cyclosporine, infliximab, chlorambucil, chloroquine, and hydroxychloroquine.