Whole genome sequencing identifies variants associated with sarcoidosis in a family with a high prevalence of sarcoidosis.

OBJECTIVE: We studied genetic risk factors associated with sarcoidosis within a family with a high prevalence of this disease. METHODS: We studied 41 members of a family with a high rate of sarcoidosis, including an index patient with treatment-resistant neurosarcoidosis. Whole genome sequencing was performed for six affected family members and variations associated with loss of function were filtered out as candidate genes. Findings were validated by using amplicon sequencing within all 41 family members with DNA available and candidate genes were screened on absence and presence within the sarcoidosis affected and non-affected. RESULTS: Family members (n = 61) from 5 generations were available for participation including 13 subjects diagnosed with sarcoidosis (20%). Analyses identified 36 candidate variants within 34 candidate genes. Variations within three of these genes (JAK2, BACH2, and NCF1) previously have been associated with autoimmune diseases. CONCLUSIONS: We identified 34 genes with a possible role in the etiology of sarcoidosis, including JAK2. Our results may suggest evaluation of JAK inhibitors in treatment-resistant sarcoidosis. Key Points • JAK2 has a potential role in the etiology of sarcoidosis and is a potential therapeutic target. • We identified 33 additional candidate genes of which BACH2 and NCF1 have been previously associated with autoimmune disease.

Infliximab treatment in pathology-confirmed neurosarcoidosis.

OBJECTIVE: To assess the efficacy and risks of treatment with infliximab (anti-tumor necrosis factor alpha) in pathology-confirmed neurosarcoidosis. METHODS: In a retrospective study in 2 tertiary referral centers in the Netherlands, we analyzed clinical characteristics, complications, and outcome of patients with neurosarcoidosis treated with infliximab. RESULTS: Twenty-eight patients were identified with a mean age of 42 years. Neurosarcoidosis presented with a cerebral parenchymal localization in 16 (59%), pituitary gland/hypothalamic sarcoidosis in 15 (54%), peripheral nerve involvement in 12 (43%), and chronic meningitis in 11 patients (41%). Initial treatment response after the start of infliximab was complete remission in 6 (21%) and improvement in 14 (50%), whereas 7 patients had stable disease (25%), and 1 (4%) deteriorated and died. At the end of follow-up, with a median of 32 months, 5 patients (18%) had died, and 2 (40%) were using infliximab at the time of death. Tapering or discontinuation of corticosteroids without a relapse was achieved in 19 of 28 patients (68%). In patients with decreasing dosing or discontinuation of infliximab, a relapse occurred in 5 of 19 patients (26%). Complications of infliximab were reported in 10 of 28 patients (36%) and mainly consisted of infections in 8 (29%). CONCLUSION: Infliximab is an effective treatment in neurosarcoidosis leading to remission or improvement in 70%. The mortality rate in infliximab-treated patients was substantial, indicating the severity of disease and treatment-associated complications. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in people with pathology-confirmed neurosarcoidosis, infliximab is beneficial.

Many faces of neurosarcoidosis: from chronic meningitis to myelopathy.

PURPOSE OF REVIEW: Neurosarcoidosis occurs in 5% of patients with sarcoidosis and can be difficult to diagnose. In this review we discuss the most recent advances in our understanding of the disease, describing clinical characteristics, diagnostic process, treatment, and prognosis. RECENT FINDINGS: Clinical presentation is heterogeneous with most patients presenting with cranial nerve palsy, headache, or sensory abnormalities. Patients are classified according to probability of the diagnosis with the Zajicek criteria. In these criteria, histopathological confirmation of noncaseating granulomas in affected tissue outside the nervous system is key. Radiological abnormalities on neuroimaging are nonspecific. No biomarkers have been described that adequately identify patients with sarcoidosis. However, soluble interleukin-2 receptor is a relatively novel biomarker that may be useful. In addition to HRCT scan, F-FDG PET-CT scanning can identify occult locations of disease activity and aid in obtaining pathological confirmation. Despite the use of new therapies, still a third of patients remains stable, deteriorate, or die. SUMMARY: Diagnosing and treating patients with neurosarcoidosis remains a challenge. Long-term prospective studies evaluating patients suspected of neurosarcoidosis are needed to assess sensitivity and specificity of ancillary investigations and diagnostic criteria. Furthermore, future studies are needed to evaluate the prognosis and the optimal treatment strategy.

Small fiber neuropathy: a disabling and underrecognized syndrome.

PURPOSE OF REVIEW: To discuss cause, clinical manifestations, diagnostics, and treatment of small fiber neuropathy (SFN). The diagnosis is difficult and can be easily missed. RECENT FINDINGS: SFN causes high morbidity with disabling symptoms and impact on quality of life. Patients may benefit from being diagnosed with SFN, even if no underlying cause is identified and no specific treatment is yet available. Recently, genetic mutations as a possible cause of SFN were identified. Clinical diagnostic criteria have been proposed, but no gold standard exists, and each test has its limitations. The diagnosis requires a combination of typical symptoms, abnormal neurologic findings, and absence of large fiber involvement. Clinicians should be aware of overlapping symptoms of SFN and fibromyalgia. Treatment is often difficult, even when the underlying cause is identified and appropriately treated. Usually, only symptomatic relief of complaints is available. SUMMARY: Awareness of SFN and related symptoms is of great clinical relevance. Guidelines for appropriate diagnostic workup using a stepwise approach involving a combination of tests are warranted. Even if no treatment is available, patients may benefit from timely recognition of SFN.

Clinical features, treatment and outcome in neurosarcoidosis: systematic review and meta-analysis.

BACKGROUND: Neurosarcoidosis is a rare variant of sarcoidosis and is only described in small cohort studies. We define clinical features, treatment and outcome of patients with neurosarcoidosis over the last 35 years. METHODS: We performed a systematic review and meta-analysis of studies on neurosarcoidosis published between 1980 and 2016. Studies were included if they reported at least 5 cases. Studies describing one specific neurological presentation were excluded. RESULTS: We identified 29 articles describing 1088 patients diagnosed between 1965 and 2015. Neurosarcoidosis occurred in 5% of patients with systemic sarcoidosis. Mean age at presentation was 43 years and neurological symptoms were the first clinical manifestation of sarcoidosis in 52%. The most commonly reported feature of neurosarcoidosis was cranial neuropathy in 55%, with the facial and optic nerve most commonly affected, followed by headache in 32%. Pleiocytosis and elevated CSF protein were found in 58 and 63%. MRI of the brain showed abnormalities in 70%. Chest X-ray, chest CT, or gallium-67-scintigraphy showed findings consistent with sarcoidosis in 60%, 70% and 69%, respectively. First line therapy with corticosteroids was initiated in 434 of 539 patients (81%). Second and third line therapy was started in 27 and 9%. Outcome consisted of complete remission in 27%, incomplete remission in 32%, stable disease in 24%, deterioration in 6% and death in 5%. CONCLUSION: Neurosarcoidosis has a heterogeneous clinical presentation and the diagnosis can be difficult because of low sensitivity of ancillary investigations. New treatments have emerged, but nevertheless one third of patients do not respond to treatment. Prospective cohort studies and RCTs on treatment are urgently needed.

Cryptococcal meningitis complicating sarcoidosis.

BACKGROUND: Cryptococcal meningitis is an uncommon but severe complication of sarcoidosis. METHODS: We present 2 patients with cryptococcal meningitis complicating sarcoidosis and compared findings with 38 cases reported in the literature. RESULTS: When analyzing our patients and 38 cases reported in the literature, we found that median age of sarcoidosis patients with cryptococcal meningitis was 39 years (range 30-48); 27 of 33 reported cases (82%) had a history of sarcoidosis. Only 16 of 40 patients (40%) received immunomodulating therapy at the time of diagnosis of cryptococcal meningitis. The diagnosis of cryptococcal meningitis was delayed in 17 of 40 patients (43%), mainly because of the initial suspicion of neurosarcoidosis. Cerebrospinal fluid (CSF) examination showed mildly elevated white blood cell count (range 23-129/mm). Twenty-nine of 32 cases (91%) had a positive CSF culture for Cryptococcus neoformans and 25 of 27 cases (93%) had a positive CSF C neoformans antigen test. CD4 counts were low in all patients in whom counts were performed (84-228/mL). Twelve patients had an unfavorable outcome (32%), of which 7 died (19%) and 24 patients (65%) had a favorable outcome. The rate of unfavorable outcome in patients with a delayed diagnosis was 7 of 17 (41%) compared to 5 of 28 (21%) in patients in whom diagnosis was not delayed. CONCLUSION: Cryptococcal meningitis is a rare but life-threatening complication of sarcoidosis. Patients were often initially misdiagnosed as neurosarcoidosis, which resulted in considerable treatment delay and worse outcome. CSF cryptococcal antigen tests are advised in patients with sarcoidosis and meningitis.

Neurosarcoidosis in a Tertiary Referral Center: A Cross-Sectional Cohort Study.

The aim of this study was to evaluate clinical characteristics, diagnostic strategy, and treatment in patients with neurosarcoidosis in a tertiary referral centre.In a cross-sectional study, we included all patients with neurosarcoidosis treated at our tertiary referral center between September 2014 and April 2015.We identified 52 patients, among them 1 patient was categorized as having definite neurosarcoidosis, 37 probable neurosarcoidosis, and 14 possible neurosarcoidosis. Neurologic symptoms were the first manifestation of sarcoidosis in 37 patients (71%). Chronic aseptic meningitis was the most common presentation (19/52 patients [37%]), followed by cranial neuropathy (16/52 patients [31%]). Serum angiotensin-converting enzyme and lysozyme levels were elevated in 18 of 41 (44%) and 12 of 26 cases (46%). Pulmonary or lymph node sarcoidosis was identified by chest X-ray in 21 of 39 cases (54%) and by computed tomography of the chest in 25 of 31 cases (81%); Fluorodeoxyglucose-Positron emission tomography showed signs of sarcoidosis in 15 of 19 cases (79%). Thirty-one of the 46 cases receiving treatment (67%) improved, 13 cases (28%) stabilized, and 2 cases (4%) deteriorated. First-line treatment with corticosteroids resulted in satisfactory reduction of symptoms in 21 of 43 patients (49%). Seventeen patients (33%) needed second-line cytostatic treatment, and 10 patients (19%) were treated with tumor necrosis factor-α inhibitors.The majority of patients with neurosarcoidosis present with chronic meningitis without a history of systemic sarcoidosis. The diagnosis can be difficult to make because of the poor sensitivity of most diagnostic tests. Half of patients had a satisfactory reduction of symptoms on first-line therapy.

Dexamethasone and long-term survival in bacterial meningitis.

BACKGROUND: Data on the long-term effect of dexamethasone on survival in bacterial meningitis are lacking. METHODS: A long-term follow-up study of the European Dexamethasone in Adulthood Bacterial Meningitis Study was performed. In this double-blind, randomized clinical trial, 301 patients were randomly assigned to receive adjunctive dexamethasone (n = 157) or placebo (n = 144) between June 1993 and December 2001. We obtained survival data of patients using the Dutch Municipal Population Register. RESULTS: Death had occurred in 32 of 301 included patients (11%) at the primary outcome measurement 8 weeks after randomization. Follow-up was obtained for 228 of 246 evaluable patients (93%), with median follow-up of 13 years. Overall, 31 of 144 patients (22%) in the dexamethasone group died and 44 of 134 patients (33%) in the placebo group died (log-rank p = 0.029). After the primary end point of the study at 8 weeks, 20 patients in the dexamethasone group died and 23 patients in the placebo group died (log-rank p = 0.27), with age being the sole predictor of death (p < 0.001). CONCLUSIONS: In adults with community-acquired bacterial meningitis, the survival benefit from adjunctive dexamethasone therapy is obtained in the acute phase of the disease and remains for years. CLASSIFICATION OF EVIDENCE: This study of a population of Dutch patients shows Class III evidence that dexamethasone provides an extended survival benefit in patients treated for bacterial meningitis, and this survival benefit extends as long as 20 years.

Intracerebral hemorrhages in adults with community associated bacterial meningitis in adults: should we reconsider anticoagulant therapy?

OBJECTIVE: To study the incidence, clinical presentation and outcome of intracranial hemorrhagic complications in adult patients with community associated bacterial meningitis. METHODS: Nationwide prospective cohort study from all hospitals in the Netherlands, from 1 March 2006, through 31 December 2010. RESULTS: Of the 860 episodes of bacterial meningitis that were included, 24 were diagnosed with intracranial hemorrhagic complications: 8 upon presentation and 16 during clinical course. Clinical presentation between patients with or without intracranial hemorrhage was similar. Causative bacteria were Streptococcus pneumoniae in 16 patients (67%), Staphylococcus aureus in 5 (21%), Pseudomonas aeruginosa and Listeria monocytogenes both in 1 patient (4%). Occurrence of intracranial hemorrhage was associated with death (63% vs. 15%, P<0.001) and unfavorable outcome (94% vs. 34%, P<0.001). The use of anticoagulants on admission was associated with a higher incidence of intracranial hemorrhages (odds ratio 5.84, 95% confidence interval 2.17-15.76). CONCLUSION: Intracranial hemorrhage is a rare but devastating complication in patients with community-associated bacterial meningitis. Since anticoagulant therapy use is associated with increased risk for intracranial hemorrhage, physicians may consider reversing or temporarily discontinuing anticoagulation in patients with bacterial meningitis.