The peripheral cerebrospinal fluid outflow pathway – physiology and pathophysiology of CSF recirculation: A review and hypothesis

An anatomical connection from subarachnoid spaces along nerves into peripheral tissues represents an important route for CNS antigens release, termed here peripheral cerebrospinal fluid outflow pathway (PCOP), is assumed analogous to mammals in humans: CSF leaves the subarachnoid spaces along nerves and joins respective interstitial tissue fluids, then the lymph then blood; in detail, flowing from the subfrontal subarachnoid spaces through the cribriform plate near olfactory nerves to nasal submucosa to the cervical lymph system, along cranial nerves and spinal nerves into respective peripheral tissues. Microanatomic details and relative shares of outflow volumes at various parts of the PCOP as compared to CSF reabsorption volumes into the venous system remain to be determined.Beyond, CSF functions as a third signaling system involving all CNS structures preferably surfaces, including spinal cord and nerve roots. But CSF may interact also with all cranial and peripheral nerves via the PCOP, and related peripheral tissues connected by nerves, e.g. subcutaneous tissues, muscles or neuronal ganglia, and even, a special case, the eye. PCOP associated pathomechanisms might arise with any abnormal pathogenic CSF contents including solutes and cells in various diseases, relevant especially in acute neuroinflammation, possibly in systemic inflammation, likely in chronic neuroinflammation and possibly in low level neuroinflammation. The latter may include subgroups of psychiatric disorders. PCOP associated pathomechanisms might explain for example the surprising muscle involvement in depression and schizophrenia, or diffuse pain or dysautonomia. PCOP associated pathomechanisms should generally relate to PCOP anatomy and the CSF outflow physiology respectively pathophysiology.

► Cerebrospinal fluid signaling plays underestimated role in neuropsychiatric diseases.
► Cerebrospinal fluid outflow along nerves is involved in peripheral pathologies.
► Role of CSF signaling in classical neuroinflammation or low level neuroinflammation.
► CSF associated pathologies in schizophrenia, depression, other psychiatric disorders.