A Perplexing Case of Bladder Mass Biopsy-Proven Neurosarcoidosis.

Introduction

Neurosarcoidosis is a challenging medical condition where up to 70% of patients present with neurological manifestations rather than already having a known systemic diagnosis [ 1 ]. It is difficult to diagnose as the disease can present in many different ways [ 2 ]. The diagnosis is usually one of exclusion as it often masquerades as other disorders, at times creating a lengthy differential and complicated diagnosis [ 3 ]. There is no cure, and most patients require long-term treatment with corticosteroids.

This case was previously presented as a poster at the Florida Society of Rheumatology Annual Fellow Poster Presentation on July 09, 2022.

Case presentation

A 55-year-old African American male, with a medical history of substance use, cerebrovascular accident, hepatitis B, recently diagnosed with right lower extremity deep venous thrombosis on anticoagulation presented to the hospital with complaints of dizziness, blurry vision and left-sided weakness of one-day duration. Of note, the patient had had multiple emergency department visits within the past month for similar left-sided leg pain and falls. He had been treated for cellulitis and pain. This time computed tomography (CT) of the brain was ordered and revealed large areas of white matter hypodensities in bifrontal lobes as well as small areas of cortical hypodensities in the right anterioinferior frontal lobe (Figure 1 ).

This was initially concerning for acute infarct versus subacute post-traumatic changes. Other possible differentials were reversible posterior leukoencephalopathy or neoplastic process given the local mass effect. Neurological examination was non-focal and cranial nerves II-XII were intact. A painful range of motion was noted in the lower extremity; however, muscle strength was noted to be 5/5. Additional findings on the physical examination included bilateral lower extremity edema left more than right, oral thrush and right axillary lymphadenopathy. The stroke protocol was initiated, and the patient was admitted to the hospital. Neurology and Hematology Oncology services were consulted for further evaluation.

Magnetic resonance imaging (MRI) of the brain with contrast revealed extensive enhancing dural nodularity along bilateral frontal convexities and anterior falx associated with extensive nodular leptomeningeal enhancement along the bilateral frontal lobes, suprasellar cistern, right sylvian fissure, and right basal ganglia with associated extensive bilateral frontal vasogenic edema and mass effect on lateral ventricles (Figures 2 , 3 ).

The differentials were narrowed down to central nervous system (CNS) lymphoma versus neurosarcoidosis. Due to concerns of CNS lymphoma, steroids were initially withheld pending cerebrospinal fluid (CSF) analysis. CT of the chest without contrast was done and revealed sub-centimeter mediastinal, bilateral hilar, and right axillary lymphadenopathy (Figure 4 ). A core needle biopsy of the largest axillary lymph node was performed that returned as benign and reactive. There was an insufficient sample for flow cytometry.

CT of the abdomen and pelvis with contrast was ordered for further assessment of lymphadenopathy that discovered a 2.6-cm bladder wall tumor concerning for neoplasm. There was also bilateral iliac chain and retroperitoneal adenopathy suspicious for metastatic disease. The patient underwent transurethral resection of the bladder tumor. The pathology revealed noncaseating granulomas (Figures 5 , 6 ).

On hospital day 7, the patient developed new-onset left-sided weakness including reduced grip strength and left-sided facial droop. Brain imaging revealed persistent vasogenic edema. After a discussion with all the specialists, the decision was made to initiate steroids prior to CSF analysis. Acid-fast bacilli (AFB) stains from the axillary lymph node as well as the bladder tumor returned negative. At this time, a lumbar puncture was performed that was negative for infection or malignancy. The CSF angiotensin-converting enzyme (ACE) levels were within normal limits (Tables 1 , 2 ).

The patient clinically improved after the initiation of steroids and a repeat MRI scan of the brain showed moderate interval improvement with persistent leptomeningeal enhancement and resolution of the previously present mass effect on frontal horns. The diagnosis of neurosarcoidosis was favored given bilateral hilar adenopathy on the chest CT scan, improvement in imaging findings following steroid administration, and noncaseating granulomas found in the bladder lesion. Neurosurgery and Oncology did not favor brain biopsy at this time. The patient was discharged on dexamethasone with instructions to follow up with Rheumatology as an outpatient.

Discussion

Up to 70% of patients with neurosarcoidosis present to medical care with their neurological manifestations rather than already having a known systemic diagnosis [ 1 ]. As the disease can present in many different ways without biopsy evidence, solitary nervous-system sarcoidosis is difficult to diagnose [ 2 ]. The diagnosis is usually one of exclusion as it often masquerades as other disorders, at times creating a lengthy differential and complicated diagnosis [ 3 ]. There is no cure and most patients require long-term treatment with corticosteroids.

Neurosarcoidosis exhibits variable degrees of infiltration in the brain resulting in focal or disseminated nodules or plaques affecting particularly the basal meninges. The granulomatous infiltration may extend into the cortex or white matter causing parenchymal lesions [ 4 - 8 ]. This pattern seen in imaging is generally indistinguishable from that seen with tuberculosis or lymphoma with leptomeningeal involvement [ 5 ]. Beside parenchymal lesions and meningeal masses, hydrocephalus may also be seen with MRI.

In 2018, the Neurosarcoidosis Consortium Consensus Group developed a diagnostic approach for neurosarcoidosis, adapted from 1999, that described possible, probable and definite neurosarcoidosis [ 9 - 10 ]. Alternative diagnoses like infection or malignancy must be ruled out and obtaining a tissue biopsy is recommended. A non-neural pathology confirming systemic sarcoidosis would support a diagnosis of probable neurosarcoidosis, whereas having a neural tissue showing noncaseating granulomas gives a definite diagnosis. If histology is not obtained, having at least two indirect indicators from a gallium scan, chest imaging, and serum ACE is accepted as the confirmation of systemic sarcoidosis. In recent years, F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scans have become an important tool to evaluate other sites of involvement in neurosarcoidosis and select more surgically accessible sites for biopsy [ 11 ]. If the clinical picture is suggestive of neurosarcoidosis but alternate diagnoses have not been ruled out, then a diagnosis of neurosarcoidosis is thought to be possible (Table 3 and Figure 7 ).

There are several conditions that neurosarcoidosis can mimic. One of them is multiple sclerosis (MS), given the radiologic findings on MRI besides relapsing-remitting course of the disease as well as dissemination of the MRI lesions in space and time. Cognitive and neuropsychiatric presentation in the context of parenchymal brain lesions argues against MS, and certainly, coexisting peripheral nervous system involvement or myopathies are distinctive features of neurosarcoidosis [ 10 ]. Additionally, neurosarcoidosis can present with weakness or dysarthria resembling a stroke. Transient ischemic attacks and ischemic stroke due to neurosarcoidosis have been reported [ 12 ]. Neurosarcoidosis may coexist with multiple myeloma or be confused with neuropathies secondary to monoclonal proliferation or paraproteinemic neuropathy. The enhancing parenchymal lesions may also be mistaken for neoplasms; however, the lack of central necrosis in histology distinguishes neurosarcoidosis from malignancy. CNS lymphoma is another possible differential diagnosis to keep in mind. There has been a case reported on neurolymphomatosis mimicking neurosarcoidosis. Neurolymphomatosis represents a unique subtype of extranodal lymphoma with localized invasion of cranial or peripheral nerves reported in patients with large B-cell non-Hodgkin's lymphoma [ 13 ].

This case is not only a diagnostic challenge but also a therapeutic one due to social constraints. Patient's comorbidities, in addition to homelessness, made it challenging to ensure follow-up with various specialists. Several works of literature have shown sarcoidosis to be a disease that affects those with health disparities [ 14 - 15 ]. According to Sharp et al., “worse dyspnea, lower health-related quality of life, and higher rates of mortality and hospitalization are more common among those who are black, female, or of low socioeconomic status” [ 14 ]. Low socioeconomic status is also associated with increased stress, and chronic stress has been shown to impact immune function. A study done by De Vries and Drent showed a direct relationship between stress and sarcoidosis [ 16 ]. Also, the economic burden was found to be higher during the first year after diagnosis [ 17 - 18 ].

Conclusions

Neurosarcoidosis poses a diagnostic challenge as it can imitate other neurological diseases, including CNS lymphoma and multiple sclerosis. In addition, the prognosis of neurosarcoidosis varies, with some recovering completely, while others have a chronically progressing, waxing, and waning course. Moreover, it imposes a significant economic burden on the payer, especially in the first year following diagnosis as patients require several specialist visits to manage sarcoidosis-related comorbidities, making it a therapeutic challenge.

No data sets were used except for the review of the medical record. Written informed consent was obtained from the patient to publish this report in accordance with the journal’s patient consent policy. Zainab Hanif and Keysha Gonzalez contributed equally to the work and should be considered co-first authors.

Human Ethics

Consent was obtained or waived by all participants in this study

The authors have declared that no competing interests exist.

References

1 Neurosarcoidosis: clinical review of a disorder with challenging inpatient presentations and diagnostic considerations Neurohospitalist Hoyle JC Jablonski C Newton HB 94 101 4 2014 24707339 10.1177/1941874413519447 PMC3975794

2 Neurosarcoidosis: a clinical dilemma Lancet Neurol Hoitsma E Faber CG Drent M Sharma OP 397 407 3 2004 15207796 10.1016/S1474-4422(04)00805-1

3 Neurosarcoidosis and the complexity in its differential diagnoses: a review Innov Clin Neurosci Spiegel DR Morris K Rayamajhi U 10 16 9 2012 https://pubmed.ncbi.nlm.nih.gov/22666636/ PMC3366456 22666636

4 Immunohistochemical characterisation and TNF-α expression of the granulomatous infiltration of the brainstem in a case of sudden death due to neurosarcoidosis Forensic Sci Int D'Errico S Bello S Cantatore S Neri M Riezzo I Turillazzi E Fineschi V 0 5 208 2011 10.1016/j.forsciint.2011.01.021 21353407

5 Imaging manifestations of neurosarcoidosis AJR Am J Roentgenol Smith JK Matheus MG Castillo M 289 295 182 2004 14736648 10.2214/ajr.182.2.1820289

6 Germ cell tumors masquerading as central nervous system sarcoidosis Arch Neurol Peeples DM Stern BJ Jiji V Sahni KS 554 556 48 1991 1850595 10.1001/archneur.1991.00530170118031

7 The clinical course of sarcoidosis: presentation, diagnosis, and treatment in a large white and black cohort in the United States Sarcoidosis Vasc Diffuse Lung Dis Judson MA Boan AD Lackland DT 119 127 29 2012 https://pubmed.ncbi.nlm.nih.gov/23461074/ 23461074

8 Neurologic manifestations in sarcoidosis: review of the literature, with a report of 23 cases Ann Intern Med Delaney P 336 345 87 1977 197863 10.7326/0003-4819-87-3-336

9 Definition and consensus diagnostic criteria for neurosarcoidosis: from the Neurosarcoidosis Consortium Consensus Group JAMA Neurol Stern BJ Royal W III Gelfand JM 1546 1553 75 2018 30167654 10.1001/jamaneurol.2018.2295

10 Neurosarcoidosis as an MS mimic: the trials and tribulations of making a diagnosis Mult Scler Relat Disord MacLean HJ Abdoli M 414 429 4 2015 26346790 10.1016/j.msard.2015.06.012

11 Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) computed tomography (CT) for the detection of bone, lung, and lymph node metastases in rhabdomyosarcoma Cochrane Database Syst Rev Vaarwerk B Breunis WB Haveman LM 0 11 2021 10.1002/14651858.CD012325.pub2 PMC8577863 34753195

12 Neuro-ophthalmologic signs in the angiitic form of neurosarcoidosis Neurology Caplan L Corbett J Goodwin J Thomas C Shenker D Schatz N 1130 1135 33 1983 6684247 10.1212/wnl.33.9.1130

13 Neurolymphomatosis mimicking neurosarcoidosis: a case report J Med Case Rep Santos E Scolding NJ 5 4 2010 20157431 10.1186/1752-1947-4-5 PMC2821394

14 Socioeconomic determinants and disparities in sarcoidosis Curr Opin Pulm Med Sharp M Eakin MN Drent M 568 573 26 2020 32732595 10.1097/MCP.0000000000000704

15 Mortality among African American women with sarcoidosis: data from the Black Women's Health Study Sarcoidosis Vasc Diffuse Lung Dis Tukey MH Berman JS Boggs DA White LF Rosenberg L Cozier YC 128 133 30 2013 https://pubmed.ncbi.nlm.nih.gov/24071884/ 24071884 PMC3801105

16 Relationship between perceived stress and sarcoidosis in a Dutch patient population Sarcoidosis Vasc Diffuse Lung Dis De Vries J Drent M 57 63 21 2004 https://pubmed.ncbi.nlm.nih.gov/15127976/ 15127976

17 Economic burden of sarcoidosis in a commercially-insured population in the United States J Med Econ Rice JB White A Lopez A 1048 1055 20 2017 28678623 10.1080/13696998.2017.1351371

18 Income and other contributors to poor outcomes in U.S. patients with sarcoidosis Am J Respir Crit Care Med Harper LJ Gerke AK Wang XF 955 964 201 2020 31825646 10.1164/rccm.201906-1250OC PMC7924656