Nervous System Sarcoidosis Research Articles

Central Nervous System Sarcoidosis: A National-Basedregistry study.

Sarcoidosis of the central nervous system (CNS) often presents deleterious effects on affected patients. Data and available literature discussing the diagnosis and treatment of this condition are scarce and inconsistent. In this study, we aim to shed light on demographics, management, diagnostics, and clinical complications of CNS sarcoidosis patients within the United States (US) based on a nation-wide registry questionnaire. Our retrospective study was conducted based on a national registry investigating 3,835 respondents to the Foundation for Sarcoidosis Research Sarcoidosis Advanced Registry for Cures Questionnaire (FSR-SARC). This national registry data was collected during the period of June 2014 to August 2019. We performed propensity score matching, summary, univariate, and multivariate analyses to establish a comparison between the presence and absence of central nervous system sarcoidosis. We identified a total of 420/3634 (11.55%) patients having CNS sarcoidosis; 296 (70.5%) were females, 307 (73.1%) were Caucasian and 81 (19.3%) were African American. The mean (±SD) age at diagnosis of CNS sarcoidosis was 43.3 (±12) years old. Multiorgan involvement (≥3 organs) was present in 318/420 (75.7%) patients. Brain magnetic resonance imaging was the most common ancillary diagnostic modality used and reported to be abnormal 251/328 (76.5%). Corticosteroids were the most used treatment by CNS sarcoidosis patients 206/420 (49.0%) followed by cytotoxic agents 180/420 (42.9%). CNS sarcoidosis prevalence in our cohort was similar to what has been described previously. The most prevalent imaging modality used was cranial MRI. Corticosteroids were the most used medications. Lastly, CNS sarcoidosis showed a propensity to cause several clinical complications such as chronic pain syndrome and disability.

Cerebrospinal Fluid Cytokine and Chemokine Profiles in Central Nervous System Sarcoidosis: Diagnostic and Immunopathologic Insights.

To evaluate the cerebrospinal fluid (CSF) cytokine/chemokine profile of central nervous system (CNS) neurosarcoidosis (NS), and its utility in differential diagnosis, treatment, and prognostication. In this case-control study, we validated 17 cytokines/chemokines (interleukin [IL]-1-beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17A, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and tumor necrosis factor [TNF]-alpha) in a multiplexed automated immunoassay system (ELLA; Bio-Techne, Minneapolis, MN, USA), and assessed them in CSF and serum of symptomatic patients with probable or definite CNS NS (01/2011-02/2023) with gadolinium enhancement and/or CSF pleocytosis. Patients with multiple sclerosis, primary CNS lymphoma, aquaporin-4 immunoglobulin G positivity, non-inflammatory disorders, and healthy individuals were used as controls. A total of 32 NS patients (59% women; median age, 59 years [19-81]) were included; concurrent sera were available in 12. CSF controls consisted of 26 multiple sclerosis, 8 primary CNS lymphoma, 84 aquaporin-4 immunoglobulin G positive, and 34 patients with non-inflammatory disorders. Gadolinium enhancement was present in 31 of 32 NS patients, and CSF pleocytosis in 27 of 32 (84%). CSF IL-2, IL-6, IL-10, IL-13, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and TNF-alpha levels were significantly higher in NS patients compared with non-inflammatory controls (p ≤ 0.02); elevations were more common in CSF than serum. Concurrent elevation of IL-6, CXCL9, CXCL10, GM-CSF, interferon-gamma, and TNF-alpha was present in 18 of 32 NS patients, but only in 1 control. Elevated IL-6, IL-10, IL-13, CXCL9, CXL10, GM-CSF, and TNF-alpha associated with measures of disease activity. NS CSF cytokine/chemokine profiles suggest T cell (mainly T helper cell type 1), macrophage, and B-cell involvement. These signatures aid in NS diagnosis, indicate disease activity, and suggest therapeutic avenues. ANN NEUROL 2024.

Approaching an undetermined diagnosis in the aftermath of rhombencephalitis: A case report

A 49-year-old male patient manifested acute onset increased imbalance, quadriparesis, and speech impairment 1 month after undergoing ventricular-peritoneal shunt for normal pressure hydrocephalus (although magnetic resonance imaging [MRI] of the brain with contrast was otherwise normal), which showed improvement afterward. He had hypercalcemia and elevated erythrocyte sedimentation rate. Repeat brain MRI revealed pachymeningitis coupled with rhombencephalitis, while cerebrospinal fluid study unveiled only increased protein level without evidence of active infection. Given these findings, neurosarcoidosis was preliminarily considered a plausible cause of the recent clinical manifestations, and the patient was prescribed methylprednisolone, which led to significant improvement. However, the steroid treatment was discontinued on the revelation that the patient grappled with severe sepsis. Despite an initial improvement following a post-management of sepsis, his condition deteriorated, and he became lost to follow-up after 4 months of initial presentation. An infective etiology was ruled out since his condition improved with steroid. Precluding vasculitis or demyelinating disorder left the physicians with primary central nervous system (CNS) lymphoma or sarcoidosis as a proper diagnosis based on the fact that the patient experienced deterioration when steroid was excluded from the treatment regimen. This case study portrays a need to conduct a more specific and elaborate investigation, driven by a strong perception to both primary CNS lymphoma and sarcoidosis, to optimize clinical diagnosis, which facilitates the formulation of an appropriate treatment regimen.

Steroid-Resistant Central Nervous System Sarcoidosis: The Selections of Multi-Agent Combination as the Initial Treatment

Sarcoidosis is a granulomatous multiorgan disease of unknown etiology that commonly affects the respiratory system, eyes, and skin, and less commonly affects the nervous system. Because of its rarity, a standard treatment for central nervous system (CNS) sarcoidosis has not yet been established. Corticosteroids remain the cornerstone of CNS sarcoidosis treatment. However, CNS sarcoidosis, other than isolated facial nerve paralysis, is often refractory to treatment and requires long-term corticosteroid treatment. In particular, patients with hydrocephalus have a high mortality rate and a lack of response to this treatment. Therefore, immunosuppressants, including TNF-α inhibitors and corticosteroids, should be considered as the initial treatment. For older patients, it is important to pay attention to infection as an adverse event and to the toxicity of the therapeutic agents. Because steroid-related adverse events are more common in the older patient group, the lowest effective dose should be used, and the treatment duration should be kept as short as possible after careful evaluation of disease activity. Corticosteroid-sparing agents are effective at reducing the cumulative toxicity of corticosteroids. Recently, various new potential agents have emerged and their efficacy has been assessed. It is expected that more treatment options will be available for CNS sarcoidosis in future.

Sarcoidosis

Sarcoidosis is a granulomatous systemic disease of unknown etiology most commonly affecting the lungs and thoracic lymph nodes. The diagnosis is based on typical clinical radiologic appearance and histology with evidence of noncaseating epithelioid cell granulomas without central necrosis. In the acute form, Löfgren's syndrome, histologic confirmation may not be necessary. Approximately half of patients may develop a chronic form, and extrathoracic organ involvement should be investigated during the course. Indications for therapy are based on functional limitations, marked organ-related or systemic symptoms, and life-threatening organ manifestations (cardiac, central nervous system, renal, and ocular sarcoidosis). To date, there is no approved drug therapy for sarcoidosis. Administration of immunosuppressants such as glucocorticosteroids and as add-on or sequential, methotrexate, azathioprine or mycophenolate mofetil is recommended in the currently published international guideline.

Adalimumab for CNS sarcoidosis: single-center experience and literature review.

Tumor necrosis factor (TNF) alpha is critical in the development of granulomas and multiple recent reports have highlighted the role of infliximab, an infused TNF alpha inhibitor, in the treatment of neurosarcoidosis. As a self-injected TNF alpha inhibitor, adalimumab has certain advantages over infused medications, including greater patient freedom and autonomy. Experience with adalimumab is not well reported in the literature. To report clinical experience with adalimumab in the treatment of central nervous system (CNS) sarcoidosis by combining observations in our center with those that have been reported in the literature. Patients were identified from the Mass General Brigham Research Patient Data Registry and in the literature by searching PubMed. Patients with CNS manifestations of sarcoidosis treated with adalimumab were included for retrospective review and analyzed for baseline characteristics, treatment indications, outcomes, and adverse effects. Adalimumab was commonly started after failure of or intolerance to infliximab and methotrexate. Of those with adequate follow-up, 5/10 ultimately improved, remission was maintained in 3/10, and 2/10 with active disease remained stable without further worsening. One patient suffered a relapse, likely multifactorial in etiology, but has remained relapse free on adalimumab for 10months subsequently. Three patients ultimately discontinued adalimumab. Preliminary evidence suggests that adalimumab may be a reasonable therapeutic option for patients with neurosarcoidosis affecting the CNS, including those with medically refractory disease.

Clinical characterization and outcomes of 85 patients with neurosarcoidosis

To analyze the frequency and clinical phenotype of neurosarcoidosis (NS) in one of the largest nationwide cohorts of patients with sarcoidosis reported from southern Europe. NS was evaluated according to the Diagnostic Criteria for Central Nervous System and Peripheral Nervous System Sarcoidosis recently proposed by Stern et al. Pathologic confirmation of granulomatous disease was used to subclassify NS into definite (confirmation in neurological tissue), probable (confirmation in extraneurological tissue) and possible (no histopathological confirmation of the disease). Of the 1532 patients included in the cohort, 85 (5.5%) fulfilled the Stern criteria for NS (49 women, mean age at diagnosis of NS of 47.6 years, 91% White). These patients developed 103 neurological conditions involving the brain (38%), cranial nerves (36%), the meninges (3%), the spinal cord (10%) and the peripheral nerves (14%); no patient had concomitant central and peripheral nerve involvements. In 59 (69%) patients, neurological involvement preceded or was present at the time of diagnosis of the disease. According to the classification proposed by Stern et al., 11 (13%) were classified as a definite NS, 61 (72%) as a probable NS and the remaining 13 (15%) as a possible NS. In comparison with the systemic phenotype of patients without NS, patients with CNS involvement presented a lower frequency of thoracic involvement (82% vs 93%, q = 0.018), a higher frequency of ocular (27% vs 10%, q < 0.001) and salivary gland (15% vs 4%, q = 0.002) WASOG involvements. In contrast, patients with PNS involvement showed a higher frequency of liver involvement (36% vs 12%, p = 0.02) in comparison with patients without NS. Neurosarcoidosis was identified in 5.5% of patients. CNS involvement prevails significantly over PNS involvement, and both conditions do not overlap in any patient. The systemic phenotype associated to each involvement was clearly differentiated, and can be helpful not only in the early identification of neurological involvement, but also in the systemic evaluation of patients diagnosed with neurosarcoidosis.

Peripheral Blood Transcriptome in Patients with Sarcoidosis-Associated Uveitis

ABSTRACT Purpose To identify peripheral blood transcriptome differences in uveitis patients with sarcoidosis compared to those with Vogt-Koyanagi-Harada (VKH) syndrome and controls. Methods Ten patients with uveitis compatible with sarcoidosis (eight with pulmonary sarcoidosis, one with central nervous system sarcoidosis, and one with conjunctival sarcoidosis), nine patients with VKH, and nine healthy controls were prospectively enrolled. Results Ten genes exhibited a four-fold difference in expression in sarcoidosis patients compared to controls, many being involved in regulating inflammatory processes or cellular responses to microbes. Conclusions This research suggests that the transcriptome in sarcoidosis is robust enough to be detected in the peripheral blood and that sarcoidosis can be distinguished from healthy controls. Differentially expressed genes may serve as candidates warranting further investigation with respect to disease pathophysiology and may provide additional information, such as ability to stratify patients based on associated disease severity and anatomical location of inflammation within the eye.

A multi-center case series of sarcoid optic neuropathy

ObjectiveThe diagnosis of sarcoid optic neuropathy is time-sensitive, as delayed treatment risks irreversible vision loss. We sought to analyze its characteristics and outcomes. MethodsWe performed a multi-center retrospective study of sarcoid optic neuropathy among 5 USA medical centers. Inclusion criteria were: 1) clinical optic neuropathy; 2) optic nerve/sheath enhancement on neuroimaging; 3) pathological confirmation of systemic or nervous system sarcoidosis. ResultsFifty-one patients were included. The median onset age of sarcoid optic neuropathy was 50 years (range, 17–70 years) and 71% were female. The median visual acuity at nadir in the most affected eye was 20/80 (range, 20/20 to no-light-perception). Thirty-four of 50 (68%) patients had radiologic evidence of other nervous system involvement and 20 (39%) patients had symptoms/signs of other cranial nerve dysfunction. Cerebrospinal fluid analysis revealed an elevated white blood cell count in 22 of 31 (71%) patients (median: 14/μL; range: 1–643/μL). Pathologic confirmation of sarcoidosis was by biopsy of systemic/pulmonary site, 34 (67%); optic nerve/sheath, 9 (18%); or other nervous system region, 8 (16%). Forty patients improved with treatment (78%), 98% receiving corticosteroids and 65% receiving steroid-sparing immunosuppressants, yet 11/46 patients (24%) had a visual acuity of 20/200 or worse at last follow-up. ConclusionsSarcoid optic neuropathy frequently occurs with other clinical and radiologic abnormalities caused by neurosarcoidosis and diagnostic confirmation occasionally requires optic nerve/sheath biopsy. Improvement with treatment is common but most patients have some residual visual disability. Improved recognition and a more expeditious diagnosis and treatment may spare patients from permanent vision loss.

Altered retinal oxygen metabolism in patients with combined ocular and central nervous system sarcoidosis.

To evaluate retinal oxygen metabolism by retinal oximetry for ocular and CNS diseases in a cross-sectional study of sarcoidosis. Overall 201 eyes from 103 biopsy-verified sarcoidosis patients were included and divided into four groups depending on the organ affection: (i) sarcoidosis without ocular or CNS affection, (ii) ocular sarcoidosis, (iii) CNS sarcoidosis, and (iv) combined ocular and CNS sarcoidosis. Retinal oximetry was obtained and analysed, with the mean retinal arteriolar and venular saturation as well as arteriovenous difference as principal outcomes. Comparison between groups was done in a multi linear regression model adjusted for age, sex, duration of sarcoidosis, best corrected visual acuity and retinal oximetry quality. Mean (s.d.) age was 50.5 (13.4) (95% CI: 47.9, 53.1) years and 52.2% were males. Eyes of the combined Ocular/CNS group had a higher retinal arteriovenous difference than eyes of the Non-ocular/no-CNS group (42.1% vs 37.7%, P = 0.012) but did not differ between other groups. Eyes in the four groups (Non-ocular/no-CNS, Ocular, CNS and Ocular/CNS) did not differ according to retinal arterial (94.5%, 93.5%, 93.5% and 94.5%, respectively) or venular (57.5%, 56.4%, 55.0% and 52.5%, respectively) oxygen saturation. The results of this study suggest that eyes of sarcoidosis patients with combined ocular and CNS affection have an altered oxygen metabolism indicating a subclinical eye affection that is not recognized by conventional screening methods.

Sarcoidosis and the Nervous System.

This article provides an overview and update on the neurologic manifestations of sarcoidosis. The 2018 Neurosarcoidosis Consortium diagnostic criteria emphasize that biopsy is key for diagnosis and determines the level of diagnostic certainty. Thus, definite neurosarcoidosis requires nervous system biopsy and probable neurosarcoidosis requires biopsy from extraneural tissue. Without biopsy, possible neurosarcoidosis can be diagnosed if the clinical, imaging, and laboratory picture is compatible and other causes are ruled out. Recent large retrospective studies from the United States and France established that infliximab appears to be efficacious when other treatments are inadequate. Sarcoidosis is a multisystem noninfectious granulomatous disorder that is immune mediated, reflecting the response to an as-yet unidentified antigen or antigens. Neurosarcoidosis refers to neurologic involvement due to sarcoidosis that clinically manifests in 5% of cases of sarcoidosis, with asymptomatic involvement in as many as another one in five patients with sarcoidosis. Sarcoid granulomas can occur in any anatomic substrate in the nervous system, causing protean manifestations that have earned neurosarcoidosis the sobriquet the great mimic. Nevertheless, central nervous system sarcoidosis occurs in well-defined presentations that can be classified as cranial neuropathies, meningeal disease, brain parenchymal (including pituitary-hypothalamic) disease, and spinal cord disease. In addition, the peripheral nervous system is affected in the form of peripheral neuropathy and myopathy. Glucocorticoids are the cornerstone of treatment, especially in the acute stage, whereas steroid-sparing agents such as methotrexate, mycophenolate mofetil, and azathioprine are used for prolonged therapy to minimize steroid toxicity. Anti-tumor necrosis factor agents may help in refractory cases.

CSF TO ACE THE DIAGNOSIS

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Sarcoidosis is a granulomatous disorder characterized by noncaseating granulomas affecting involved organs. Although the majority of sarcoidosis is diagnosed as pulmonary sarcoidosis incidentally on chest imaging, extrapulmonary sarcoidosis is the presenting symptom for approximately 30% of all cases, with 5-10% affecting the nervous system. Angiotensin Converting Enzyme can be produced by granulomas, with 55% of cases demonstrating positive ACE levels within cerebrospinal fluid. CASE PRESENTATION: A 28 year old man with no past medical history presented with bilateral lower extremity weakness and numbness, gradually worsening over four weeks, starting in the pelvic area causing urinary urgency and painful defecation with distal spread. Over the few days prior to admission his family had also noticed dysarthria. Physical exam was notable for anisocoria, dysarthria, ataxic gait, diminished lower extremity reflexes, and saddle anesthesia. Serum was unremarkable except a sed rate of 39 and a positive ANA. Lumbar puncture showed an elevated white count of 43 cells/uL, predominantly lymphocytes, and an elevated protein at 336mg/dL. CSF ACE level was elevated (7.0 units/L). An MRI of the brain and spine showed diffuse nodular leptomeningeal enhancement of the entire spinal cord and brain. A CT of chest abdomen and pelvis was obtained which demonstrated innumerable pulmonary nodules and masses in a perilymphatic distribution with upper lobe predominance and subcarinal, pelvic and abdominal lymphadenopathy. Endobronchial biopsies of right mainstem bronchus nodularity and EBUS guided transbronchial needle aspiration of the subcarinal lymph node revealed granulomatous inflammation. He was treated with IV pulsed Solumedrol for 3 days with improvement in his neurologic symptoms. He was discharged on prednisone 1 mg/kg and methotrexate 15 mg weekly. Repeat MRI 5 days post treatment showed improvement of leptomeningeal enhancement. DISCUSSION: In this case, we observed a young man who developed neurologic symptoms as his first sign of sarcoidosis. Neurosarcoidosis can effect any portion of the peripheral or central nervous system. Cranial mononeuropathy, cognitive deficits, radiculopathy, and aseptic meningitis are common manifestations, wherever a granuloma can obstruct a nerve. A helpful diagnostic cue is angiotensin I-converting enzyme within the CSF itself, as granulomas synthesize this enzyme which can diffuse into various fluid compartments. The mainstay of treatment for any neurologic symptom is to treat the underlying sarcoidosis with steroids, as was done on our patient. CONCLUSIONS: In a younger patient with a pulmonary nodules and masses with associated neurologic complaints, neurosarcoidosis is a unique diagnosis that physicians should consider on their differential, while excluding malignancy. Angiotensin Converting Enzyme in CSF can be a helpful diagnostic cue. Reference #1: "Neurosarcoidosis” by Burns, Arch Neurol. 2003 Aug;60(8):1166-8. Reference #2: "Clinical characteristics of patients in a case control study of sarcoidosis” by Baughman, Teirstein, Et Al. Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1885-9. Reference #3: "Cerebrospinal fluid angiotensin-converting enzyme for diagnosis of central nervous system sarcoidosis.” By Khoury, Wellik, Et Al. Neurologist. 2009 Mar;15(2):108-11. https://doi.org/10.1097/NRL.0b013e31819bcf84. DISCLOSURES: No relevant relationships by Elena Burke, source=Web Response no disclosure on file for Christine Fleury; No relevant relationships by Kellen Mulhern, source=Web Response

64-Year-Old Man With Subacute Altered Mental Status and Headache

64-Year-Old Man With Subacute Altered Mental Status and Headache

BIOPSY-PROVEN CENTRAL NERVOUS SYSTEM AND PULMONARY SARCOIDOSIS: FIRST REPORTED CASE IN HONG KONG

SESSION TITLE: Pulmonary SESSION TYPE: Global Case Reports PRESENTED ON: 10/10/2018 01:00 PM - 02:00 PM INTRODUCTION: Lung is the commonest organ to be involved by sarcoidosis. Nervous system is involved in around 5% of cases only. [1] Due to rarity, neurosarcoidosis has never been reported in Hong Kong Chinese patients. CASE PRESENTATION: A 34-year-old Chinese clerk lady presented with headache and personality changes. CT brain showed hydrocephalus and MRI showed ill-defined T2 hyper-intense lesion without enhancement at superior-dorsal aspect of pons. (Fig.1) Endoscopic third ventriculostomy with brain biopsy found granulomatous inflammation with negative mycobacterial tuberculosis polymerase chain reaction (MTB-PCR). CT thorax showed numerous tiny pulmonary nodules with extensive mediastinal lymphadenopathy. (Figs 2,3)She was managed as miliary tuberculosis (TB) with central nervous system (CNS) involvement. Cognitive symptoms persisted despite 8 months of TB treatment and interstitial involvement worsened on CT thorax. Further investigations with transbronchial biopsy and endobronchial ultrasound guided needle aspiration of station 7 lymph node confirmed granulomatous inflammation with negative MTB-PCR. After multi-disciplinary team discussion, diagnosis was revised to be sarcoidosis. TB medications were stopped and she was started on oral prednisolone. The cognitive problem improved and repeat CT 3 months after steroid treatment showed reduced extent of bilateral lung nodules and lymphadenopathy. DISCUSSION: Sarcoidosis was thought to be rare among Asians. The incidence rate ranged from 0.027 (Taiwan) to 2 (Japan) per 100000. Reports in Chinese patients were scarce. The epidemiology in Hong Kong is unknown but there were a number of case reports over last 30 years showing it is not that rare.Diagnosis remained by exclusion from compatible clinical and radiological picture with histology of noncaseating granuloma. [2] This highlighted the diagnostic challenge: TB notification rate was 58.27 per 100000 in Hong Kong; that is 50-2000 times more common than sarcoidosis. Two diseases can overlap, making it more complicated. [3] Many cases therefore received TB treatment during pursuit of diagnosis. Symptoms and signs are non-specific. Usually patients need to have symptoms for more than 3 months, and require three or more encounters with health care providers before arriving diagnosis.Nervous system sarcoidosis is even rarer but it can be first symptoms before systemic disease. Imaging findings are also non-specific. It is difficult to obtain biopsy and some can only be found in autopsy. It is one of the most fearful complications of sarcoidosis as it can carry mortality up to 18%. More aggressive immunomodulating treatment are needed. CONCLUSIONS: Sarcoidosis is still rare but is likely under-recognized. Diagnosis can be challenging in particular to exclude TB. We presented the first biopsy-proven case of central nervous system sarcoidosis in Hong Kong Chinese patient with successful treatment. Reference #1: 1. Dominique V, Antje P, Hilario N, et al. Sarcoidosis. Lancet 2014; 383: 1155–67 Reference #2: 2. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999; 160: 736–55. Reference #3: 3. Wong CF et al. A case of concomitant tuberculosis and sarcoidosis with mycobacterial DNA present in the sarcoid lesion. Chest 1998; 114:2; 626-9 DISCLOSURES: No relevant relationships by Yu Hong Chan, source=Web Response no disclosure on file for Yiu Cheong Yeung

A pragmatic approach to diagnosing and treating neurosarcoidosis in the 21st century

Neurosarcoidosis may be a serious complication of sarcoidosis. As the presentation of neurosarcoidosis is manifold, solitary nervous system sarcoidosis without systemic activity remains a difficult diagnosis. Appropriate treatment may be a dilemma. Most neurosarcoidosis patients present with neurological symptoms as the first manifestation. Whole-body fluorodeoxyglucose positron emission tomography has been found useful in neurological patients suspected of sarcoidosis. Small-fiber neuropathy is commonly associated with sarcoidosis and can cause significant morbidity to afflicted patients. New drugs such as antitumor necrosis factor alpha have been proven valuable in the treatment of neurosarcoidosis in different locations. Progressive multifocal leucencephalopathy should be considered in neurosarcoid patients, especially when treatment fails. In this paper an update on clinical manifestations of neurosarcoidosis, diagnostic dilemmas, and therapeutic options is provided.

Treating CNS sarcoidosis with infliximab and mycophenolate mofetil

Introduction: Neurosarcoidosis is a complication of systemic sarcoidosis that is frequently diffi cult to manage. Manifestations of central nervous system (CNS) sarcoidosis are quite variable. They include infi ltration of the optic nerve, perivascular retinopathy, leptomeningitis and pachymeningitis, chiasmal and hypothalamic lesions, cortical en plaque meningioma-like lesions, and spinal cord and cauda equina nodules and infi ltration. The rarity of this condition (5%– 10% of all sarcoidosis) makes any systematic randomized masked trial of treatment alternatives problematic. Most patients with neurosarcoidosis are treated with systemic corticosteroids with fair success. Problems arise when the neurosarcoidosis fails to yield to corticosteroids or fl ares as the corticosteroids are tapered, leading to the use of a long list of variably effective immunosuppressant alternative or adjunctive treatments [1]. None of these anecdotally recommended drugs have been subjected to a randomized prospective study. The paper by Moravan and Segal is typical of reports published since 2002 on the use of infl iximab as a next step in the treatment of corticosteroidand immunosuppressant drug–resistant CNS sarcoidosis.

Neurosarcoidosis presenting as spontaneously remitting hypersomnia

A 38-year-old woman was first admitted to our hospital in November 2007 because of excessive daytime somnolence and short-term memory disturbance. She reported that her speech had gradually become slower starting in April 2007. Severe fatigue and somnolence had developed at the beginning of August 2007. She felt very sleepy and had to take long naps, generally sleeping all day except for at meal times, and she was therefore unable to do housework. Hypersomnia and chronic fatigue persisted after she was admitted to the hospital. On admission, her body temperature was 35.8 C, heart rate was 99 beats/min, and blood pressure was 118/56 mm Hg. Physical and neurological findings were uninformative with the exception of mild cognitive dysfunction; her MiniMental State Score was 23/30. She had daytime somnolence and her Epworth Sleepiness Score [4] was 18 points. Blood cell counts and serum levels of sodium, potassium, creatinine, and urea nitrogen as well as liver enzymes, glucose, angiotensin-converting enzyme (ACE), and adenosine deaminase (ADA) were all within normal ranges. However, cerebrospinal fluid (CSF) cell count (17/ll) and protein level (139 mg/dl) were elevated. Activity of ACE (0.2 U/l) and ADA (2.2 IU/l) in the CSF were within the normal range, and CSF culture and cytology were negative. CSF hypocretin-1 (orexin A) concentration was decreased (82.8 pg/ml: lower limit of normal = 110 pg/ml) [5]. T2-weighted magnetic resonance imaging (MRI) showed high-intensity signals in the brainstem, hypothalamus, basal ganglia, and white matter surrounding the lateral ventricle (Fig. 1a). Gadolinium-enhanced T1weighted MRI (Gd-MRI) demonstrated numerous small spots of high intensity in the bilateral thalamus, hypothalamus, and basal ganglia (Fig. 1b). Bilateral hilar lymphadenopathy (BHL) was absent on chest X-ray. Neither chest computed tomography (CT) nor whole body gallium scanning revealed abnormal lesions. The patient was clinically diagnosed with central nervous system (CNS) sarcoidosis associated with secondary hypersomnia, although the diagnosis was not confirmed by laboratory data at that time. The hypersomnia spontaneously and gradually improved. Therefore, no medication was initiated, and she was discharged from the hospital in December 2007. Six months later, the hypersomnia and memory disturbance had disappeared completely. The high-intensity areas in the bilateral thalamus and basal ganglia on MRI T2-weighted imaging, as well as the numerous small spots on gadolinium-enhanced T1-weighted imaging, had disappeared by May 2008 (Fig. 1c, d). Mild memory disturbance recurred in September 2008, and new bilateral cerebral white matter lesions were seen on brain MRI, which demonstrated foci of abnormal signal intensity in the bilateral white matter; these showed decreased signal Y. Nakazato (&) S. Kondo A. Ohkuma Y. Ito N. Tamura N. Araki Department of Neurology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Iruma-gun, Saitama 350-0495, Japan e-mail: nakachan@saitama-med.ac.jp

Spontaneous Remission of Diabetes Insipidus Due to CNS Sarcoidosis

Central nervous system (CNS) sarcoidosis is a crucial disease and has a poor prognosis. A 58-year-old woman had acute development of polydipsia and polyuria. Her pituitary MRI demonstrated a swelling of pituitary gland and hypophyseal stalk. She was diagnosed as central diabetes insipidus (CDI) due to CNS sarcoidosis based on the examinations and pituitary MRI findings as well as a result of cutaneous biopsy. Uveitis and bilateral hilar lymphadenopathy were observed mildly throughout. However, CDI and pituitary MRI findings were getting recovered spontaneously without steroid treatment in a couple of months, suggesting an atypical clinical course of CNS sarcoidosis.

Infliximab therapy rescues cyclophosphamide failure in severe central nervous system sarcoidosis

Central nervous system involvement is a severe manifestation of sarcoidosis that often requires aggressive immunosuppressive therapy. The most efficacious approach for refractory disease is unknown. We reviewed the cases of four subjects who demonstrated active progression of neurosarcoidosis while under treatment with cyclophosphamide, and who were subsequently treated with infliximab. All four subjects demonstrated rapid and substantial reversal of their clinical course. Radiologic findings were concordant with the clinical responses. There were no notable toxicities. Treatment with infliximab may be more effective than cyclophosphamide for refractory central nervous system sarcoidosis. A larger, prospective study is warranted.

Isolated central nervous system sarcoidosis: A great mimicker

A patient is described who presented with focal brain lesion considered to be a tumor and later developed disseminated white matter disease. After 21 years of clinical and MRI follow up, the diagnosis of isolated neurosarcoidosis was confirmed by histology. The follow up of more than 21 years in this patient supported the existence of isolated neurosarcoidosis as a separate disease entity.