This research review makes it very clear that people with EDS suffer a great deal of pain from the neck up, that EDS is a physically disabling condition, and that its effects are multi-systemic.
This is the article I will present to the new doctor that is taking over from the wonderful doctor who has been prescribing me sufficient opioid pain medication for the last 10 years. They work in the same medical group and this new doctor has on occasion refilled my opioid prescriptions when my regular doctor wasn’t available, so I hope she will continue doing so.
Just reading this review crushes any hope I’ve had of ever “getting better” because there are so many physical issues that arise when our body structures are held together (or rather, not held together) by defective connective tissue.
It seems very similar to what happens when a highrise is built with defective concrete. At first, it looks just fine, but in short order, cracks start appearing, doors don’t fit their frames right anymore, decorative parts fall off, then more critical parts collapse and the process of deterioration gathers speed as the building ages.
So be warned: reading this can be seriously depressing.
The Ehlers–Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin extensibility, and tissue fragility.
This communication briefly reports upon the neurological manifestations that arise including
- the weakness of the ligaments of the craniocervical junction and spine,
- early disc degeneration, and
- the weakness of the epineurium and perineurium surrounding peripheral nerves.
Entrapment, deformation, and biophysical deformative stresses exerted upon the nervous system may alter gene expression, neuronal function and phenotypic expression.
This report also discusses increased prevalence of
- idiopathic intracranial hypertension,***
- Tarlov cysts,
- tethered cord syndrome, and
where associations with EDS have been anecdotally reported, but where epidemiological evidence is not yet available.
*** Because I suffered from blinding headaches for a few years, I did a lot of research and found an explanation for their cause and also a method to prevent them.
My theory is that intracranial hypertension in people with EDS starts when we get a kink in our cervical vertebrae which then pinch the dura and prevent the free flow of cerebrospinal fluid (just like a tight band around your wrist will cause your hand to swell up).
This theory was supported by discovering that doing neck exercises to strengthen and stabilize those vertebrae prevented those terrible headaches. When my mother started having the same headaches, the same exercises helped her too.
Also, in a post from 2014, Craniospinal Hydrodynamics, the authors state that
“active distension of the ventricular system of the brain resulting from the inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation”
” in 2008 Williams proposed a unifying hypothesis for the cause of hydrocephalus, Chiari malformations, syringomyelia, anencephaly, and spina bifida based on dissociation of CSF flow between the cranial vault and spinal canal.”
There’s more information in these previous posts:
- Headache Research: Idiopathic Intracranial Hypertension
- The diag and mgmt of idiopathic intracranial hypertension
- Headache: Intracranial Hypertension – Pseudotumor Cerebri
Now, back to the original article:
Chiari Malformation Type I (CMI) has been reported to be a comorbid condition to EDS, and may be complicated by craniocervical instability or basilar invagination.
- Motor delay,
- headache, and
have been attributed to ligamentous laxity and instability at the atlanto‐occipital and atlantoaxial joints, which may complicate all forms of EDS.
Discopathy and early degenerative spondylotic disease manifest by spinal segmental instability and kyphosis, rendering EDS patients prone to mechanical pain, and myelopathy.
Musculoskeletal pain starts early, is chronic and debilitating,
and the neuromuscular disease of EDS manifests symptomatically with
- easy fatigability,
- limited walking,
- reduction of vibration sense, and
- mild impairment of mobility and daily activities.
Consensus criteria and clinical practice guidelines, based upon stronger epidemiological and pathophysiological evidence, are needed to refine diagnosis and treatment of the various neurological and spinal manifestations of EDS.
The above was only the abstract. This extremely long article covers the following EDS symptoms:
- HEADACHE IN EHLERS–DANLOS SYNDROME
- IDIOPATHIC INTRACRANIAL HYPERTENSION (IIH)
- CHIARI I MALFORMATION (CMI)
- ATLANTOAXIAL INSTABILITY
- CRANIOCERVICAL INSTABILITY
- SEGMENTAL KYPHOSIS AND INSTABILITY
- DYSTONIAS AND OTHER MOVEMENT DISORDERS
- NEUROMUSCULAR FEATURES OF EHLERS‐DANLOS SYNDROME
Extracts from the full article continue below:
The following article discusses the etiology and clinical findings related to neurological and spinal manifestations commonly observed, yet often poorly recognized, in EDS patients, and proposes treatment options and areas of research needed.
HEADACHE IN EHLERS–DANLOS SYNDROME
EDS patients commonly suffer a variety of headache types [Jacome, 1999; Martin and Neilson, 2014; Castori et al., 2015].
- headaches due to migraines,
- muscle tension,
- intracranial hypertension,
- craniocervical instability, and
- cervical spine disorders,
- temporomandibular joint disease,
- carotid dissection, and
- other physical conditions.
MIGRAINE IN EDS
Migraine often presents as a comorbid disorder with many other medical conditions [Schurks et al., 2009; Casucci et al., 2012; Pierangeli et al., 2012; Gelfand et al., 2013; van Hemert et al., 2014]. The final common pathway appears to be abnormal regulation of cerebral vasculature following a spread of depression of cortical electrical activity[Burstein et al., 2015; Ferrari et al., 2015].
Clinical and diagnostic findings
Defined as a primary headache disorder, with recurrent attacks of moderate or severe intensity, lasting 4–72 hr, migraine headaches are more often unilateral, pulsating, associated with nausea, photophobia, and phonophobia, which are disabling and worse with physical activity [Headache Classification Committee of the International Headache Society (IHS), 2013].
IDIOPATHIC INTRACRANIAL HYPERTENSION (IIH)
IIH, or pseudotumor cerebri, is a poorly understood entity characterized by an increased intracranial pressure (ICP), headaches, visual disturbances and photophobia, and occasionally tinnitus, nausea, and vomiting. Affected patients may have objective changes in vision with 10% developing blindness [Corbett et al., 1982].
Anecdotal reports from large case series have suggested an association between EDS and IIH, but no such association has been formally reported in the biomedical literature.
Hypotheses proposed for the etiology of IIH include
- excess cerebrospinal fluid (CSF) production,
- reduced CSF absorption,
- excessive brain water content, and
- increased cerebral venous pressure leading to reduced CSF reabsorption [Ball and Clarke, 2006].
Recent studies demonstrate that up to 93% of patients with IIH have focal venous sinus stenosis on MR venography, most commonly proximal to the transverse sigmoid sinuses junction, suggesting that venous abnormalities may play a role in the pathophysiology of IIH [Farb et al., 2003].
Treatments include lifestyle modifications targeting weight loss including bariatric surgery, decreasing CSF production with acetazolamide, or serial lumbar punctures, CSF diversion with a ventriculo‐peritoneal or lumbo‐peritoneal shunt, optic nerve sheath fenestration, or subtemporal decompression.
…or, as I discovered, strengthening the neck muscles to stabilize the cervical vertebrae.
CHIARI I MALFORMATION (CMI)
Chiari malformation Type I (CMI) has been reported as a comorbid condition in hypermobile EDS (hEDS) [Milhorat et al., 2007].
CMI is a mesenchymal disorder affecting the hindbrain, in which a developmentally small posterior fossa results in downward migration of the brainstem and cerebellar tonsils through the foramen magnum into the spinal canal [Batzdorf et al., 2015].
The herniation causes obstruction to the normal regional circulation of the cerebrospinal fluid (CSF) and compartmentalization of CSF circulation [Ellenbogen et al., 2000], which may result in suboccipital pressure headaches.
Obstruction of the CSF circulation may result in empty sella syndrome, with flattening of the pituitary gland and resulting hormonal changes.
A syrinx may form, which exerts a mass effect on the spinal cord
Milhorat et al. [2007, 2010] found a high prevalence of patients with hereditary disorders of connective tissue in their retrospective series of CMI post‐decompression failures that needed further intervention, including craniocervical fusion and/or tethered cord release.
Before rushing into surgery, I would suggest stabilizing the cervical spine by regular neck exercises instead of fusion.
While this may indicate a co‐existence of these conditions, it does not provide evidence of a causal relationship, but suggests that EDS and other disorders of connective tissue should not be overlooked in CMI.
Clinical and Diagnostic Findings
The CMI is traditionally defined radiologically by 5 mm of tonsillar herniation through the foramen magnum, though others have suggested a herniation of 3 mm, or 7 mm. The behavior of CMI is often unrelated to the size of the herniation, and CMI can be asymptomatic.
CM is best characterized by a tussive headache (worse with cough, strain, or yelling), dizziness, cerebellar findings—dysarthria, incoordination, imbalance, and unsteady gait—hearing and vestibular deficits. Romberg’s sign, and deficits of cranial nerves. There is sometimes trigeminal neuralgia [Milhorat et al., 1999; Tubbs et al., 2011a; Yarbrough et al., 2011].
Brainstem findings, such as sleep apnea and dysautonomia, are often found in CM that are complicated by craniocervical instability or basilar invagination, the so‐called “complex Chiari.”
There is no universally agreed upon surgical threshold for CMI, but surgery should be urgently performed in the presence of progressive neurological deficits, and expanding syringomyelia (Fig. 1) [Yarbrough et al., 2011].
The association of CMI and EDS is burdened by distinct management challenges, including craniocervical instability, and possibly an increased risk of CSF leaks.
Atlantoaxial instability (AAI) is a potential complication of all forms of EDS.
headache associated with “connective tissue pathological relaxation” and quadri‐paresis have all been attributed to ligamentous laxity and instability at the atlantooccipital, and atlantoaxial joints.
Exactly why strengthening the neck muscles can be so helpful.
A proclivity to ligamentous incompetence renders the atlanto‐axial joint a higher risk for instability.
The atlantoaxial junction (AAJ) is the most mobile joint of the body. The AAJ mechanical properties are determined by ligamentous structures, most prominent of which are the transverse and alar ligaments [Tubbs et al., 2011b].
Clinical and Diagnostic Findings
The diagnosis of AAI is predicated upon
- disabling neck pain or suboccipital pain, and
- history and clinical findings of cervical medullary syndrome, or syncopal (or pre‐syncopal) episodes,
- demonstrable neurological findings, and
- radiological evidence of instability or compression of the neuroaxis.
Neck pain and suboccipital headache are the most common findings, with the caveats that headache is a common occurrence in EDS patients [Castori and Voermans, 2014].
There may be symptoms referable to the vertebral artery blood flow, including visual changes, as well as headache resulting from vertebral artery torsion.
Other symptoms include
- sometimes facial pain,
- choking, and
- respiratory issues.
Symptoms usually improve with a neck brace.
Strong supporting muscles can accomplish the same thing.
Neurological examination demonstrates
- tenderness over spinous process of C1 and C2,
- altered mechanics of neck rotation,
- dysdiadochokinesia, and
- hypoesthesia to pinprick.
The difficulty of recognizing rotary instability on standard X‐ray, CT, and MRI images has resulted in failure to diagnose [Kothari et al., 2000].
The first line of treatment should be neck brace, physical therapy, and avoidance of activities that provoke exacerbation of the AAI symptoms.
If the non‐operative treatment fails, fusion stabilization of C1/C2 is required. Incompetence of the alar ligament requires dorsal surgical fusion [Menendez and Wright, 2007].
Occiput to C1/C2 fusion should be considered in the presence of craniocervical instability, basilar invagination, or complex Chiari malformation.
Craniocervical instability (CCI) is recognized as a manifestation of ligamentous laxity in EDS.
CCI is a pathological condition in which ligamentous connections from the skull to the spine are incompetent.
- Motor delay,
- developmental co‐ordination disorder, [I have this]
- headaches secondary to spinal compression, [and this]
- clumsiness, [and this] and
- the relatively high rate of dyslexia and dyspraxia
in the EDS population merit investigation as possible consequences of early onset degenerative changes resulting from ligamentous laxity upon the central nervous system [Nagashima et al., 1981; Adib et al., 2005].
The most prominent movement of the atlanto‐occipital joint is flexion‐extension; axial rotation is normally limited to <5 degrees of rotation [Dvorak et al., 1987].
There is increased recognition of mechanisms of neuronal injury that result from stretching, or deformative stress [Jafari et al., 1997; Maxwell et al., 1999; Shi and Whitebone, 2006].
Yes, “deformative stress” is exactly what I’m thinking of as the cause of my headaches.
Clinical andDiagnostic Findings
CCI‐related symptoms result from
- deformation of the brainstem and upper spinal cord,
- traction on the vertebral artery, and
- possibly from the consequences of altered venous or CSF outflow from the cranium.
CCI often occurs with basilar invagination or ventral brainstem compression, the findings of which are dominated by pyramidal and sensory changes:
- weakness of the limbs hyperreflexia and
- pathological reflexes (e.g., Babinski, Hoffman’s sign, absence of the abdominal reflex),
and a plethora of other symptoms—including
- sphincter problems,
- neck pain,
- altered vision, and hearing,
- syncope, emesis,
- altered sexual function,
- altered menses, and
- gait changes [Caetano de Barros et al., 1968].
These signs, in aggregate, constitute the cervical medullary syndrome [Batzdorf et al., 2015], elements of which are commonly recorded among EDS patients [Celletti et al., 2012].
Three metrics may be useful in the identification of CCI and basilar invagination:
- the clivo‐axial angle,
- the Harris measurement, and
- the Grabb, Mapstone, Oakes method [Batzdorf et al., 2015; NINDS Common Data Elements, 2016].
The Clivo‐axial angle (CXA) is the angle formed between the posterior aspect of the lower clivus and the posterior axial line. The CXA has a normal range of 145° to 160°, but an angle of less than 135° is pathological [Henderson et al., 1993; Henderson et al., 2010a; Batzdorf et al., 2015].
The second radiologic metric, the horizontal Harris measurement, is the distance from the basion to the posterior axial line (PAL) [Harris et al., 1994]. Instability is present when the basion to the PAL exceeds 12 mm.
This measurement, used in conjunction with dynamic flexion and extension images of the cervical spine, can also be used to measure the dynamic translation between the basion and the odontoid [Batzdorf et al., 2015; NINDS Common Data Elements, 2016].
In the normal individual, there should be no measurable translatory movement (sliding movement). Translation of greater than 1 mm between the basion and odontoid reflects craniovertebral instability, and may warrant stabilization (Fig. 3) [Wiesel and Rothman, 1979; White and Panjabi, 1990].
The third metric, the Grabb, Mapstone, and Oakes measurement predicts risk of ventral brainstem compression, and has been statistically correlated with clinical outcome [Grabb et al., 1999; Henderson et al., 2010b]. A measurement >9 mm suggests high risk of ventral brainstem compression [Grabb et al., 1999].
There is a relatively nascent recognition of the importance of dynamic imaging of the CCJ.
For example, the brainstem may appear normal on routine magnetic resonance imaging in the supine position, but show pathological ventral brainstem compression in the flexion view sitting upright [Klimo Jr et al., 2008; Henderson et al., 2010b; Milhorat et al., 2010].
“Functional” dynamic studies in flexion and extension are important to determine whether there is pathological hypermobility at the craniocervical junction [Klekamp, 2012].
Indications for surgery include
- symptoms which constitute the cervical medullary syndrome,
- neurological deficits referable to the brainstem and upper spinal cord,
- radiological findings of CCI, and
- failure of a reasonable course of non‐operative therapy.
SEGMENTAL KYPHOSIS AND INSTABILITY
discopathy and early degenerative spondylotic disease in hEDS and classical type EDS is well established. EDS is characterized by segmental instability, kyphosis, and scoliosis.
As a consequence of cervical and thoracic instability, and discopathy in EDS, there is loss of the normal cervical lordosis and an increasing kyphosis, rendering EDS patients prone to progressive myelopathy, and mechanical neck and chest pain.
The pathophysiology of segmental instability is well described: during flexion, there is deformation of the lateral and ventral columns of the spinal cord, directly related to the strain on the cord [Henderson et al., 2005; Shedid and Benzel, 2007].
Extension more often results in compression of the cord by buckling of the ligamentum flavum, resulting in myelopathic symptoms [Muhle et al., 1998].
The cervical spinal cord can be physiologically tethered in the sagittal plane, such that normal cord elongation in flexion is exaggerated by the kyphosis; this results in increased deformity and anatomic stretching of the cord.
Clinical and Diagnostic Findings
Clinical findings include pain and disability, as well as sensory, motor, and reflex changes.
Clinical differential diagnoses in the EDS population should be kept in mind:
- instability at the atlanto‐occipital and atlantoaxial joints,
- shoulder, clavicular and rib subluxations,
- brachial plexopathy,
- vascular anomalies,
- dissection or venous insufficiency,
- peripheral neuropathy,
- multiple sclerosis,
- amyotrophic lateral sclerosis,
- myasthenia gravis,
- myelopathy due to drugs—such as statins, colchicine, steroids‐
- vitamin deficiency, especially B12 and B3,
- mitochondrial dysfunction,
- stroke, and
- psychological disorders.
This is quite a long list of problems facing EDS patients and the last one seems almost unbelievable: that connective tissue dysfunction can physically lead to psychological problems, especially anxiety.
It’s difficult to convince a doctor that the anxiety isn’t a problem with your thinking, but rather a result of this genetic disorder.
Dynamic instability is unlikely to be demonstrated in a resting supine subject, and pathological instability will often become manifest only when the ligaments are placed under stress.
Though not yet validated, dynamic MRI in the upright position subjects the vertebral spine to physiological loading, and can be performed in the flexed and extended positions to demonstrate instability (Fig. 4) [Milhorat et al., 2010; Klekamp, 2012].
Initial management includes neck bracing and physical therapy with therapists who are knowledgeable regarding ligamentous laxity including EDS, attainment of a good sagittal balance, and avoidance of certain activities.
Rest will often improve symptoms.
Yes, but only while you’re resting, which does nothing to decrease the problematic instability. Once you get up and walk around, the problem might quickly reappear due to our nemesis: gravity.
If symptoms are refractory to conservative management, fusion, and stabilization of unstable levels may be indicated.
DYSTONIAS AND OTHER MOVEMENT DISORDERS
NEUROMUSCULAR FEATURES OF EHLERS‐DANLOS SYNDROME
EDS, especially hEDS, is associated with
- high prevalence of myalgia,
- nocturnal muscle cramps involving the calves,
- progressive muscle weakness,
- poorly developed musculature, and
- scapular winging,
which to some extent may be the result of avoidance of exercise due to hypermobility and instability of joints.
They left out the reason for the “avoidance of exercise”: outrageous pain. Without effective pain medication, I could not exercise enough to preserve the muscle strength that holds me upright.
Musculoskeletal pain starts early, is chronic and debilitating [Voermans et al., 2010].
I posted about this study: Pain in Ehlers-Danlos Syndrome Common & Severe. This is another good article to show your doctor to justify pain medication.
Neuromuscular disease manifests symptomatically with
- muscle weakness,
- easy fatigability, and
- limited walking distance;
physical findings include muscle weakness, reduction of vibration sense, and mild impairment of mobility and daily activities [Voermans et al., 2009b].
Brachial and/or lumbosacral plexus neuropathies and other compression mono‐neuropathies are not uncommon in EDS.
Some pathophysiologic studies are available on the relationship between tenascin‐x(TNX) deficient EDS and neuromuscular complications.
Human and murine studies suggest a correlation between TNX levels and degree of neuromuscular involvement, and a corresponding role of the extracellular matrix defect in muscle and peripheral nerve dysfunction in EDS [Huijing et al., 2010; Voermans et al., 2011].
However, TNX deficiency accounts for only a very small percentage of patients with hEDS.
The pathophysiological mechanism of peripheral neuropathy in hEDS appears, in part, to result from abnormal stretching and pressure upon peripheral nerves that results from joint subluxation.
A recent study on medical consumption and outcome reported the impact of pain upon daily functioning in hEDS.
Most patients (92%) used pain medications;
52% underwent physical therapy—including neuromuscular exercises, massage, and electrotherapy—of whom two thirds reported a positive outcome.
That would be me. Neck exercises weren’t suggested by a physical therapist, but my research on headaches and particularly “idiopathic intracranial hypertension” led me to try neck stabilization exercises. I was thrilled when they worked for both me and my mother.
Incompetent connective tissue results in
- lax ligaments within the axial skeleton,
- peripheral nerve sheaths, and
- possibly the architecture of the myoneural and muscular endplates.
Ligamentous laxity of the axial skeleton in particular, subjects the central and radicular nervous system to entrapment, deformation, and biophysical deformative stresses.
Biophysical stress is increasingly recognized in the alteration of gene expression, cellular function, and ultimately phenotypic expression.
Clinical practice guidelines, based upon stronger epidemiological and pathophysiological evidence, are needed for the diagnosis and treatment of the various neurological and spinal manifestations of EDS.