Abstract We describe a clinical phenotype we have characterized and have been presenting over the past half-decade whereby the combination of a genetically vulnerable host and a chronic inflammatory state such as might occur from a chronic environmental toxic exposure leads to activation of mast cells and development of at least a localized hypermobility state including instability of anatomy in the craniofacio-cervical region. A cascade of events occurs from both the mast cell activation and unstable craniofacio-cervical structures that causes dysautonomia and hypopnea. These two phenomena lead to a large differential in daytime and nighttime blood carbon dioxide levels that cause an exaggerated increase in nighttime cerebral blood flow requiring rapid displacement of cerebrospinal fluid (CSF). The same unstable anatomy also prevents normal CSF and lymphatic drainage thereby causing an increase in intracranial pressure (the Spiky Phase). CSF pressure then pops-off through cranial nerve sheaths most notably through the olfactory nerve into sinus mucosa and into facial sinuses whereby it leaks out through the nose and ears, into facial tissue, or down the throat (the Leaky Phase). We call this Spiky-Leaky Syndrome and it may explain the vast collection of signs and symptoms co-segregating in these patients and also such other phenomena as cervical medullary syndrome, pseudotumor cerebri, idiopathic intracranial hypertension without papilledema, and occult tethered cord. Detailed data and theory are given as to why this has been difficult to detect to date as well as potential environmental toxins that may be responsible. Potential evaluations and therapies are posited Keywords: cerebrospinal fluid leak, mast cell activation syndrome, hypermobile Ehlers Danlos Syndrome, craniocervical instability, upper airway resistance syndrome, idiopathic intracranial hypertension without papilledema. Significance Statement: We hypothesize that Spiky-Leaky Syndrome is an important but yet to be recognized or fully described phenomenon that might explain a variety of poorly understood neurological phenomena involving increased intracranial pressure and cerebral spinal fluid leaks and might be the end result of an environmental exposure.