Beyond biopsy for neurosarcoidosis: A review of blood and CSF biomarkers.

Neurosarcoidosis, a rare granulomatous disease, causes inflammation and damage to the central nervous system (CNS). A major diagnostic challenge in neurosarcoidosis is the absence of well-defined biomarkers. The need for biopsy to make the diagnosis can lead to delays and misdiagnosis if histopathology is inaccessible or indeterminate, highlighting the need for more accessible diagnostic indicators. The current gold standard for a "definite" neurosarcoidosis diagnosis requires biopsy of CNS tissue revealing non-caseating granulomas. However, such biopsies are inherently invasive and carry associated procedural risks. Notably, angiotensin-converting enzyme (ACE), commonly associated with systemic sarcoidosis, is recognized as a poor biomarker for neurosarcoidosis due to its lack of accuracy in the context of CNS involvement. Furthermore, imaging in neurosarcoidosis, while widely utilized and important for narrowing the diagnosis, lacks specificity. Decades of research have yielded molecular and immunologic biomarkers-soluble interleukin-2 receptor (IL-2R), serum amyloid A1, the CD4/CD8 ratio, neopterin, interferon-gamma (IFN-γ), and chemokine ligand 2 (CCL2)-that hold potential for improving diagnostic accuracy. However, these biomarkers are not yet established in clinical care as they may be difficult to obtain and are derived from small studies. They also suffer from a lack of specificity against other inflammatory and infectious central nervous system diseases. New biomarkers are needed for use alongside those previously discovered to improve diagnosis of this rare disease. This review synthesizes existing literature on neurosarcoidosis biomarkers, aiming to establish a foundation for further research in this evolving field. It also consolidates information on biomarkers of systemic sarcoidosis such as IL-8 and soluble CD40L that have not yet been studied in neurosarcoidosis but hold potential as markers of CNS disease.

Adalimumab as treatment for neurosarcoidosis: A case series.

Sarcoidosis is a disease characterized by non-caseating granulomas that can involve the central nervous system as neurosarcoidosis. This challenging disease is currently managed with high dose steroids, and sometimes the addition of infliximab. Other TNA-alpha inhibitors have not been studied as rigorously. We discovered ten neurosarcoidosis patients who were on an alternative TNA-alpha inhibitor, adalimumab. Eight patients had a positive response clinically and radiographically to adalimumab.

A Novel, Possibly Pathogenic, COL4A1 Gene Variant (c.3698G>A) in a Family With Childhood Epilepsy and Leukoencephalopathy.

This case report explores the clinical presentation and genetic findings of a 44-year-old male with a history of pediatric epilepsy. The patient's daughter, recently diagnosed with autism, underwent genetic testing, revealing a variant of uncertain significance (VUS) in the type IV collagen alpha 1 (COL4A1) gene. The male patient reported a spectrum of neurological symptoms, including chronic migraines, exertional weakness, and sensory disturbances. Detailed neurological examination findings were within normal limits, but a brain MRI unveiled confluent deep white matter T2/fluid-attenuated inversion recovery (FLAIR) signal abnormalities with basal ganglia involvement. Genetic testing identified a novel COL4A1 gene variant, c.3698G>A (p.Gly1233Glu), in the patient, which was also carried by his daughter. The nature and clinical implications of this VUS in the context of the family's clinical history are discussed in this case report, emphasizing the potential significance of this genetic variant in understanding the etiology of the patient's neurologic symptoms. Further research and correlation with clinical findings are needed to elucidate whether this is a pathogenic variant.

Neurosarcoidosis causing hydrocephalus: A case series.

Sarcoidosis is a granulomatous inflammatory disease that rarely affects the central nervous system as neurosarcoidosis. Neurosarcoidosis can affect any part of the nervous system causing a wide variety of clinical presentations ranging from seizures to optic neuritis. Here, we highlight rare cases of obstructive hydrocephalus in patients with neurosarcoidosis to make clinicians aware of this potential disease complication.

Neurosarcoidosis: Diagnostic Challenges and Mimics A Review.

PURPOSE OF REVIEW: Neurosarcoidosis is a rare manifestation of sarcoidosis that is challenging to diagnose. Biopsy confirmation of granulomas is not sufficient, as other granulomatous diseases can present similarly. This review is intended to guide the clinician in identifying key conditions to exclude prior to concluding a diagnosis of neurosarcoidosis. RECENT FINDINGS: Although new biomarkers are being studied, there are no reliable tests for neurosarcoidosis. Advances in serum testing and imaging have improved the diagnosis for key mimics of neurosarcoidosis in certain clinical scenarios, but biopsy remains an important method of differentiation. Key mimics of neurosarcoidosis in all cases include infections (tuberculosis, fungal), autoimmune disease (vasculitis, IgG4-related disease), and lymphoma. As neurosarcoidosis can affect any part of the nervous system, patients should have a unique differential diagnosis tailored to their clinical presentation. Although biopsy can assist with excluding mimics, diagnosis is ultimately clinical.

Leber's Hereditary Optic Neuropathy Plus Causing Recurrent Myelopathy due to an MT-DN1 Mutation at G3635A.

A 51-year-old man with known Leber's hereditary optic neuropathy (LHON) presented with worsening lower extremity weakness and numbness. Following an episode of myelopathy two years before, he had been ambulating with a walker but over two weeks became wheelchair bound. He also developed a sensory level below the T4 dermatome to light touch, pinprick, and vibration. MRI of his cervical and thoracic spine showed a nonenhancing T2 hyperintense lesion extending from C2 to T12. At his presentation two years earlier, he was found to have a longitudinally extensive myelopathy attributed to his LHON. Genetic testing revealed a 3635 guanine to adenine mutation. MRI at that presentation demonstrated a C1-T10 lesion involving the central and posterior cord but, unlike the new lesion, did not involve the ventral and lateral horns. Given the similarity to his prior presentation and a negative evaluation for alternative etiologies, he was thought to have recurrent myelopathy secondary to Leber's Plus. To our knowledge, recurrent myelopathy due specifically to the G3635A mutation in Leber's Plus has not been reported previously.

Negative Diffusion Weighted Imaging on Magnetic Resonance Imaging of the Brain in Creutzfeldt-Jakob Disease.

A 76-year-old Caucasian woman initially presented to the Duke Memory Disorders clinic with a 9-month history of a rapid decline in cognitive, motor, and neuropsychiatric function. On initial presentation, the patient required assistance with activities of daily living. On neurological examination, she was found to have Gerstmann's syndrome along with appendicular apraxia. A positional tremor was noted without myoclonus or fasciculations. She had a paucity of speech and was unable to write her own name. Snout and grasp reflexes were present. Episodes of inappropriate laughter were noted during the exam. She was admitted to the inpatient neurology service for further evaluation. The Diffusion Weighted Imaging sequence on Magnetic Resonance Imaging of the brain was negative for restricted diffusion. An electroencephalogram was unremarkable. Cerebrospinal fluid analysis for Real-Time Quaking-Induced Conversion assay was positive along with an elevated 14-3-3 and increased total Tau protein levels. There was no family history of Creutzfeldt-Jakob disease. The cerebral spinal fluid results were consistent with a diagnosis of Creutzfeldt-Jakob disease, despite the negative MRI brain findings.

Adhesive and Cohesive Peel Force Measurement of Human Airway Mucus.

In health, the high-speed airflow associated with cough represents a vital backup mechanism for clearing accumulated mucus from our airways. However, alterations in the mucus layer in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) leads to the mucus layer adhered to the airway surfaces, representing the nidus of chronic lung infection. To understand what is different about diseased mucus and why cough clearance is defective, there is a need for techniques to quantify the strength of the interactions limiting the ability of airflow to strip mucus from the airway surface (i.e., adhesive strength) or tear mucus apart (i.e., cohesive strength). To overcome the issues with measuring these properties in a soft (i.e., low elastic modulus) mucus layer, we present here novel peel-testing technologies capable of quantifying the mucus adhesive strength on cultured airway cells and cohesive strength of excised mucus samples. While this protocol focuses on measurements of airway mucus, this approach can easily be adapted to measuring adhesive/cohesive properties of other soft biological materials.

Roles of mucus adhesion and cohesion in cough clearance.

Clearance of intrapulmonary mucus by the high-velocity airflow generated by cough is the major rescue clearance mechanism in subjects with mucoobstructive diseases and failed cilial-dependent mucus clearance, e.g., subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Previous studies have investigated the mechanical forces generated at airway surfaces by cough but have not considered the effects of mucus biophysical properties on cough efficacy. Theoretically, mucus can be cleared by cough from the lung by an adhesive failure, i.e., breaking mucus-cell surface adhesive bonds and/or by cohesive failure, i.e., directly fracturing mucus. Utilizing peel-testing technologies, mucus-epithelial surface adhesive and mucus cohesive strengths were measured. Because both mucus concentration and pH have been reported to alter mucus biophysical properties in disease, the effects of mucus concentration and pH on adhesion and cohesion were compared. Both adhesive and cohesive strengths depended on mucus concentration, but neither on physiologically relevant changes in pH nor bicarbonate concentration. Mucus from bronchial epithelial cultures and patient sputum samples exhibited similar adhesive and cohesive properties. Notably, the magnitudes of both adhesive and cohesive strength exhibited similar velocity and concentration dependencies, suggesting that viscous dissipation of energy within mucus during cough determines the efficiency of cough clearance of diseased, hyperconcentrated, mucus. Calculations of airflow-induced shear forces on airway mucus related to mucus concentration predicted substantially reduced cough clearance in small versus large airways. Studies designed to improve cough clearance in subjects with mucoobstructive diseases identified reductions of mucus concentration and viscous dissipation as key therapeutic strategies.