The Complex Path to Intracranial Hypertension and CSF Leak in those with Hypermobility and Dysautonomia; The Theory of Spiky-Leaky Syndrome

Andrew J. Maxwell *, Deborah Wardly¹

1. Deborah Wardly, M.D. FACC, Pollock Pines, CA.

*Correspondence to: Andrew J. Maxwell, M.D. FACC, Clinical Instructor Emeritus, Stanford University School of Medicine & University of California, San Francisco Medical Center. ORCID: 000-003-1280-5474 Pediatric Cardiologist, Heart of the Valley Pediatric Cardiology, 5933 Coronado Lane, Suite 104, Pleasanton, CA. amaxwell@heartofthevalley.us

Copyright

© 2024: Andrew J. Maxwell. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 15 February 2024

Published: 15 March 2024

DOI: https://doi.org/10.5281/zenodo.10836612

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.

Abbreviations:

ADI: atlas-dens interval

ANS: Autonomic Nervous System

ASGP-R 1 and 2: asialo-glycoprotein receptors 1 and 2

AXA: atlas-axis angle

B2T: Beta-2-transferrin (asialo-transferrin)

BAI – basion-axial interval

BBB: blood-brain barrier

BDI: basion-dens interval

C0/C1/C2: atlantooccipital and atlantoaxial or first and second cervical joints

CAA: clivo-atlas angle

CANS: Childhood acute neuropsychiatric syndromes

CBAI: Chronic biotoxin-associated illness

CBCT: Cone-beam computerized tomography

CBF: cerebral blood flow

CCI: craniocervical instability

CCJ: craniocervical junction

CSF: cerebral spinal fluid

CN: cranial nerve

CN IX: Glossopharyngeal nerve

CN X: Vagus nerve

CN XI: Accessory nerve

CNS: central nervous system

CXA: clivo-axial angle

DAI: dens-axial interval

DMX: Digital-motion X-ray or videofluoroscopy

ETCO2: End-tidal carbon dioxide concentration

HBGAB: Harmful blue-green algae bloom

hEDS: Hypermobile Ehlers Danlos Syndrome

ICP: intracranial pressure

IH/IIH: intracranial hypertension, idiopathic intracranial hypertension

IIHWOP: Idiopathic intracranial hypertension without papilledema

IJV: internal jugular vein

IL2, IL3, IL4, IL5 IL6: interleukins, 2, 3, 4, 5, and 6

JVP: jugular venous pressure

LP: lumbar puncture

MCAS: mast cell activation syndrome

MCMRS: Mast Cell Mediatory Release Syndrome

ME/CSF: myalgic encephalomyelitis/chronic fatigue syndrome

NML: nasal mucosa lymphatics

OCD: obsessive-compulsive disorder

OMT: orofacial myofunctional therapy

ONSC: olfactory nerve sheath cuff

ONSCJ: olfactory nerve sheath cuff junction

OSA: obstructive sleep apnea

pCO2/pO2: partial pressure of carbon dioxide or oxygen

paCO2/paO2: partial pressure of carbon dioxide or oxygen in arterial blood

PANS: Pediatric acute neuropsychiatric syndrome

PET: patulous Eustachian tube

POTS: postural orthostatic tachycardia syndrome

QEESI: Quick Environmental Exposure and Sensitivity Inventory

SLS: Spiky-Leaky Syndrome

SIBO: small intestinal bacterial overgrowth

Tf/ asialo-Tf/ sialo-TF: transferrin, asialo-transferrin, sialo-transferrin

TILT: toxicant-induced loss of tolerance

TM: tympanic membrane

TMJ; temporomandibular joint

TNFα: Tumor Necrosis Factor alpha

TTTS: tonic tensor tympani syndrome

UARS: upper airway resistance syndrome

 

Terms Introduced in this Manuscript:

Carpal Tunnel Syndrome of the Neck

Eagle Space

Metabolic localized hypermobility/ hypermobile Ehlers Danlos syndrome

Occult CCI

Olfactory Nerve Sheath Cuff Junction

Pathologic cervical hypermobility

Pentad Super-syndrome

Pseudo-Eagle Syndrome

Pseudo-tethered cord

Spiky-Leaky Syndrome

The Zipper Model of Olfactory Nerve Sheath Cuff Junction

Wardly Phenomenon

 

Introduction

Over the past decade caring for pediatric and young adult patients with cardiac manifestations of a dysfunctional autonomic nervous system, otherwise known as dysautonomia, it became clear that most of these patients also had an underlying chronic inflammation and very often also had elements of connective tissue hypermobility. They often also had significant gastrointestinal dysmotility with abdominal pain and seem to also have a higher incidence of expressing autoimmunity. From that frequent association of those 5 entities arose the term “The Pentad Super-syndrome” (1) and these patients were being referred from the corresponding author’s practice area daily. The symptoms of dysautonomia most commonly manifest as orthostatic intolerance with or without postural orthostatic tachycardia (POTS) and with or without myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (2-4). Nearly all of these patients scored significantly high on the Afrin/Molderings/Weinstock Mast Cell Mediatory Release Syndrome (MCMRS) Inventory (5, 6), as well as the Quick Environmental Exposure and Sensitivity Inventory (QEESI) (7, 8), and met the clinical diagnosis of the condition known as mast cell activation syndrome (MCAS) while many had serum and urine markers consistent with this (9). About a third of these patients demonstrated joint hypermobility and other signs consistent with hypermobility syndrome or hypermobile Ehlers Danlos (hEDS) although few met the 2017 diagnostic criteria for hEDS which is consistent with the demographics of other large young dysautonomia populations (4, 10-12). This co-segregation of these particular entities is not unique to this author’s practice and has been observed and described by many others outside of the literature and now recently in literature (13-15).

Further work with these patients revealed that a majority of these patients that demonstrated MCAS and hypermobility also displayed symptoms and findings consistent with cranial settling, cervical medullary syndrome, and craniocervical instability (CCI) (16-19). Often times the hypermobility was quite subtle with normal Beighton scores (20) and little other findings of hEDS but yet had complaints of temporomandibular joint (TMJ) dysfunction, physical exam findings consistent with cranial settling, and symptoms consistent with CCI and sometimes but not often with abnormal traditional craniocervical MRI measurements (18). For these patients, it is as if they have a localized hypermobility or hEDS within their craniocervical region at least early in the progression of their illness.

Of the subset of these Pentad patients with evidence of CCI, there is yet a smaller subset that also complains of headaches that are sometimes consistent with increased intracranial pressure and other times consistent with a CSF leak. They curiously describe that on the days they have a CSF leak-type headache they leak fluid from their nose and ears and taste a salty metallic taste in the back of their throat. These are our Spiky-Leaky Syndrome (SLS) patients. From an unpublished review of a cohort of the patients from this population, 206 were found to have dysautonomia significant enough to interfere with daily function (Functional Grade III dysautonomia (1)), about 1/3rd have hypermobility (~70) and, of these, 30 were found to have at least major elements of SLS (Figure 1). From these data it might be considered that 1/3 of those with hEDS and 1 out of 7 patients with at least Grade III dysautonomia might be progressing towards SLS. The remainder might be at risk of developing SLS.

While SLS could be an unrecognized global phenomenon, alternatively, this may be a phenomenon unique to this author’s geography where an ‘epidemic’ form of the Pentad is arising secondary to unique environmental exposure. It may very well be that SLS is uniquely a pathology of this particular environmental exposure. Our current suspicion is that those with genetic variants, the “canaries in the coal mine”, that are exposed to mold, cyanobacteria, and their respective biotoxins, and perhaps any other toxins or stealth infections that chronically activate mast cells are at risk.

What became apparent with these patients is that geographic relationships between them seemed as significant as familial relationships. While many patients had a parent or one or more sibling with a “Pentad presentation”, it was just as often that the corresponding author was seeing patients who are neighbors or classmates with each other. This prompted us to map the homes of where they first became ill and this revealed a strong geographical relationship. Many of these patients live in towns that bordered farmlands and the San Joaquin Delta and its canals. Indeed, many of the corresponding author’s patients turn out to live in neighborhoods with several other patients. Within a half kilometer radius of one patient lives 10 other patients with The Pentad. Others have homes nearly adjacent to each other. This led to the realization that there was an environmental trigger behind much of this illness with mold, mold toxins, cyanotoxins from harmful blue-green algae blooms (HBGABs), products of coccidioides, industrial toxins such as herbicides and farm run-off, and products and consequences of the recent epidemic of California wildfires as candidate culprits making this perhaps a type of chronic biotoxin-associated illness (CBAI) (21). Exposure to stealth microorganisms and electric and magnetic fields (EMFs) has also been considered and not ruled out nor has the role of poor posture from excessive forward head tilt such as from excessive cell phone viewing. Exactly which of these or if there are multiple responsible is still under investigation. We are particularly compelled to consider cyanobacteria and their cyanotoxins from worsening HBGABs as a cause for many, but not all, of these patients and this is the subject of a separate theoretical paper.

In any case, the Pentad presentation and SLS are appearing to be common in the corresponding author’s practice and in this geography. Since this original revelation of the SLS phenotype and theory and our first presentations at international conferences focusing on Ehlers Danlos syndrome, sleep disorders, airway physiology, and CSF Leak beginning in 2019, (1, 22-32), other geographic hotspots outside Northern California have been identified by these authors and other providers learning of this theory. These patients merit understanding and a solution to these yet undescribed phenomena.

Signs and Symptoms of Spiky-Leaky Syndrome
We have noted that the SLS population has some unique features that set them apart from other patients with dysautonomia syndromes. Their characteristics are enumerated in Table 1. The full Spiky-Leaky Syndrome phenomenon is laid out as a schematic sequence of events in a schematic as per Figure 2 which helps to place how such signs and symptoms fit into the full syndrome. The essential elements of the theory are laid out in a simpler schematic “The Roadmap to Spiky-Leaky Syndrome” for ease of understanding of theory (Figure 3).  This is presented more visually as a summary in Figure 27.

Table 1:  Signs and Symptoms of Spiky-Leaky Syndrome

Figure 1: Overview Schematic of Spiky-Leaky Syndrome

Figure 2:  Overview Schematic of Spiky-Leaky Syndrome

Figure 3: Simplified Schematic; The Roadmap to Spiky-Leaky Syndrome

Anatomy of the Craniocervical Region Relevant to SLS

The division between the larger population that presents with combinations of dysautonomia, MCAS, and hypermobility, and the subpopulation of those well on their way to SLS appears to be with the onset of CCI. We have observed that the patients who have the potential for developing SLS, have a close temporal relationship of the onset of dysautonomia with a set of related cranial nerve dysfunctions, specifically those of the glossopharyngeal, vagus and accessory nerves (CNS IX, X, and XI). A very detailed discussion of the anatomy in this region is in order because we believe that many of signs and symptoms observed in our patients arise from injury in this region and, to our knowledge, it does not appear that a description of these specific injuries with resultant signs and symptoms has been described before in this context. An understanding of the anatomy of this region also provides an explanation for many other signs and symptoms of SLS enumerated in Table 1.

Figure 5 Craniocervical Instability with Vascular Compressions:

Figure 6  CT Angiogram with 3D Reconstruction of Eagle Space:

Eagle Syndrome, Pseudo-Eagle Syndrome and the Eagle Space
CNs IX, X, and XI exit together through the jugular foramen not far from the atlantooccipital joint (C0-C1) as shown in Figure 4b (33, 34). The jugular foramen also provides exit for the inferior petrosal dural venous sinus and the sigmoid dural venous sinus which drain cerebral blood flow and filtered cerebrospinal fluid (CSF) into the internal jugular vein. The 3 nerves together traverse away from the jugular foramen following the course of the internal jugular vein and common carotid artery for a short distance. It is along this route that these nerves commingle and share nerve fibers to create the pharyngeal plexus (Figure 4c). This is a delicate region as all these structures (internal jugular vein, pharyngeal plexus, as well as the lymphatics that drain the sinus tissues and face) fit in a small space bordered by the structures of the airway medially, the spinal column postero-medially, the transverse processes of cervical bones posteriorly, the posterior border of the mandible and the hyoid bone anteriorly, and the styloid process and styloid ligament antero-laterally (Figure 4a). Therefore, if the mandible is dislocated backward and/or the cervical vertebrae are displaced anteriorly (Figure 5), then all of these structures can be compressed, injured, and create symptoms indistinguishable from the condition known as Eagle syndrome (35).
True Eagle syndrome or stylohyoid syndrome is an impingement of  the glossopharyngeal nerve by an abnormally long styloid process which causes sudden intense sharp nerve-like pain in the jaw and the back of the throat and base of the tongue which can be triggered by swallowing, moving the jaw or turning the neck (36) (34, 37) (38). However, in the case of our SLS patients, the styloid process might be quite normal in length. Rather, the compromise is hypothesized to be with either the posterior displacement of the mandible and perhaps hyoid bone and/or anterior displacement of the atlas as discussed later (39-41). Therefore, we consider this pseudo-Eagle syndrome and we have coined the term Eagle Space for want of any other term not found in literature. We posit that the soft tissue compromise and injuries within the Eagle Space arising from repetitive motions of unstable adjacent joints leads to chronically waxing and waning degrees of multiple nerve, vascular and lymphatic dysfunctions and might be thought of as a “carpal tunnel syndrome of the neck”. We can occasionally see the radiographic consequences of this chronic injury by the appearance of a calcification of the hyoid ligament which is often reported by the radiologist as elongated styloid bone consistent with Eagle syndrome. However, if analyzed closely, the osseous portions of the ligament might be separate from the styloid bone revealing their nature as being calcification (Figure 6). 

Craniocervical Instability Injury to Pharyngeal Plexus 
Of the adjacent joints that are unstable, perhaps instability of the craniocervical joints is most relevant in our patients. CCI is an instability of the atlantooccipital (C0-C1) and the atlantoaxial (C1-C2) joints by laxity of the ligaments responsible for stabilizing these structures. CCI is a common albeit likely underappreciated consequence of hypermobility syndrome and hEDS (18, 42) and this instability can injure many of these nearby structures together. The atlantoaxial joint is the most mobile joint of the human body. Its mechanical properties are determined by ligamentous structures, most prominent of which are the transverse, alar, and accessory ligaments and anterior and posterior longitudinal ligaments (43, 44). Capsular and inter-spinous ligaments are important as well.  The cervical spinal cord is protected within the spinal canal created by the arches of these cervical vertebrae. The cord is protected within a thecal sac which must adjust to this mobility. Therefore, it is not firmly attached to the spinal canal at this level. Instead, a variety of suspension ligaments, such as the Hofmann ligaments and myodural bridges, tether the thecal sac to the spinal canal and deep suboccipital musculature (42, 45-47). The spinal cord, in turn, is tethered to the thecal sac by the dentate ligaments and further tethered to the spinal canal below C2 by spinal nerve roots egressing through the intervertebral foramina (48, 49). 
Injury in this region can happen in at least 3 major ways. Two of these, direct concussive injury to the brainstem and vertebrobasilar insufficiency, collectively termed cervical medullary syndrome, are discussed below.  The third mechanism of injury in CCI is injury to the nearby nerves. The pharyngeal plexus, the occipital nerve, and spinal nerves C1 and C2 are at particular risk of injury arising from increased laxity of any and all of these connective tissues in those at risk for CCI. However, because of this uniquely flexible arrangement of these ligaments and bridges, the risk is not always apparent by standard radiographic procedures. Thus, CCI in these patients often remains elusive (42, 50).
This use of the term CCI deserves detailed consideration. Mao et al recently stated that the benign hypermobility of hEDS is often mistakenly classified as CCI (19). Their distinction seems to be in whether the craniocervical junction (CCJ) hypermobility causes transient neurologic symptoms versus a major risk of permanent deficits or death and most patients with hEDS do not risk death from their CCJ hypermobility (51). We posit that there is middle ground. Our experience is that patients with hEDS have significant neurologic symptoms that are essentially unrelenting if not permanent if left unmanaged even though there may not be a risk of death directly from CCI. A suitable analogy might be carpal tunnel syndrome of the wrist which is not life-threatening and not necessarily in need of urgent surgical correction but it is also not benign nor transient if left untreated. It is a serious medical issue causing major dysfunction and occupational limitation, pain, and is life-altering. It requires medical evaluation and appropriate treatment – even if not surgery. It also has little radiologic evidence at times. Applying this analogy to the neck, (carpal tunnel syndrome of the neck) and the dysfunction and limitation is an order magnitude greater.  This middle ground might be better termed “pathologic cervical hypermobility” or “occult CCI” but CCI nonetheless. Therefore, we elect to retain this use of the term CCI in the patients we observe. 

Localizing Injury of Pharyngeal Plexus
The specific location within the Eagle Space of nerve injury can be deduced by considering the following. Although pharyngeal plexus injury from CCI likely occurs near the jugular foramen, it is not likely immediately proximal to the foramen. The presentation we observe in our patients is distinctly different from nerve palsies or complete paralysis of these 3 nerves at the level of the jugular foramen, a condition known as Jugular Foramen Syndrome or Vernet’s Syndrome (52, 53). Among other signs and symptoms, jugular foramen syndrome presents as paralysis of the laryngeal muscles leading to hoarseness and nasal pitch, loss of sensation to the posterior aspect of the tongue, reduced parotid secretions, loss of gag reflex, and weakness of the sternocleidomastoid and trapezius muscles (52). While many of the other signs and symptoms are observed, these particular signs are not observed in our patients. Furthermore, vocal cord paralysis associated with signs implicating injury also to CN IX may be regarded as a lesion seated in or above the jugular foramen (54). Since vocal cord paralysis or hoarseness, soft palate paralysis, and swallowing difficulties are not observed in our patients, we conclude the injury is distal to the branching of these fibers. With respect to the type of injury, rather than a complete palsy or paralysis, there is a neuralgia, or irritation, or stretch of these nerves; the difference being much the same analogy as paralysis of the hand versus the symptoms of carpal tunnel syndrome. Instead, we propose that pharyngeal plexus injury occurs at the level of the transverse processes of C1. We postulate that the atlas intermittently slips anteriorly causing its transverse processes to impinge on these nerves as well as compromise internal jugular vein and lymphatic flow by pressing them against the stylohyoid ligament within the Eagle Space (Figures 4 and 5). 

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