Blood-spinal cord barrier disruption in degenerative cervical myelopathy

Abstract

Degenerative cervical myelopathy (DCM) is the most prevalent cause of spinal cord dysfunction in the aging population. Significant neurological deficits may result from a delayed diagnosis as well as inadequate neurological recovery following surgical decompression. Here, we review the pathophysiology of DCM with an emphasis on how blood-spinal cord barrier (BSCB) disruption is a critical yet neglected pathological feature affecting prognosis. In patients suffering from DCM, compromise of the BSCB is evidenced by elevated cerebrospinal fluid (CSF) to serum protein ratios and abnormal contrast-enhancement upon magnetic resonance imaging (MRI). In animal model correlates, there is histological evidence of increased extravasation of tissue dyes and serum contents, and pathological changes to the neurovascular unit. BSCB dysfunction is the likely culprit for ischemia-reperfusion injury following surgical decompression, which can result in devastating neurological sequelae. As there are currently no therapeutic approaches specifically targeting BSCB reconstitution, we conclude the review by discussing potential interventions harnessed for this purpose.

Keywords: Blood-spinal cord barrier; Cell therapy; Cervical decompression; Degenerative cervical myelopathy; Gene therapy; Inflammation; Ischemia.

Fig. 1

Pathophysiology of degenerative cervical myelopathy

Fig. 2

Blood spinal cord barrier disruption during and after cervical decompression in degenerative cervical myelopathy. Spinal cord perfusion is maintained by the anterior spinal artery, left/right posterior spinal arteries, and their associated veins. Chronic cervical cord compression (schematically represented as anterior compression alone) causes pathological changes to these supplying vessels and disrupts the BSCB. Spinal cord tissues remain hypoperfused despite vascular remodeling. Following surgical decompression, there is sudden restoration in blood flow but the BSCB remains hyperpermeable. This predisposes the cord to reperfusion injury and impairs neurological recovery, although the underlying mechanical compression has been relieved. Bright red and blue colors denote healthy blood vessels, while dark red and blue colors indicate blood vessels with compromised blood supply. Pink-shaded regions indicate mildly hypoxic regions, while darker pink-shaded regions indicate ischemic regions with severe ischemia

Fig. 3

Components of the blood spinal cord barrier (BSCB) and therapeutic strategies for BSCB reconstitution in degenerative cervical myelopathy (DCM). Left panel—At the BSCB, the presence of non-fenestrated endothelial cells establishes tight junctions that heavily restrict paracellular transport. At the capillary level, the basement membrane is closely associated with astrocyte end-feet, resulting in the elimination of the perivascular space. Pericytes, embedded within the basement membrane, assume a crucial role in facilitating endothelial cell maturation, supporting the basement membrane, and potentially modulating blood flow. Disruption of the BSCB integrity is characterized by the thickening or swelling of the basement membrane, endothelial cells, pericytes, and astrocytes. Deterioration of the tight junctions leads to the leakage of serum contents into the surrounding tissues. Inflammation leads to the transient formation of the perivascular space at the capillary level, thereby enabling leukocytes infiltration into the spinal cord parenchyma. Right panel—The treatment modalities mentioned in this figure are elaborated in the main text