Augusta University
Neurology and Neurosurgery

THE RELATIONSHIP BETWEEN CHIARI MALFORMATIONS AND CONNECTIVE TISSUE DISORDERS: Is it casual or causal?

Recently, there has been much interest in the association between Chiari malformations and connective tissue disorders (CTD) such as Ehlers-Danlos syndrome. Whereas treating one of these disorders is in itself challenging, when they occur simultaneously, the decision is even more complex. Chiari malformations are a group of disorders with a broad range of signs and symptoms at presentation. A great deal of knowledge and experience is required of the clinician to determine if a correlation exists and if aggressive (surgical) treatment is an option. Further complicating the situation is the fact that the subset of patients with CTD are at high risk of treatment failure with the standard surgical treatment. This article will help the clinician to better understand these disorders, how to diagnose them properly, and will explore the different treatment options – both conservative and surgical.

Chiari malformations

Chiari malformations are a heterogeneous group of disorders that produce herniation of the cerebellar tonsils below the level of the foramen magnum.

Increasingly, type III (cerebellar herniation into a high cervical meningocoele) and type IV (cerebellar agenesis) are thought to be due to a distinct dysembryogenesis from types I and II. Chiari malformation type II is generally found in association with spina bifida aperta. Type I is a relatively rare disorder with an estimated prevalence in the range of one in 1000-5000. Although most cases are sporadic, familial inheritance either by an autosomal recessive or autosomal dominant with incomplete penetrance mechanism have been reported. This disorder is generally understood as one of unbalanced development of the paraxial mesoderm of the posterior fossa relative to the intracranial contents, resulting in a “too small” cavity for the cerebellar contents and resultant herniation. The most common complaint is headache, classically described as occurring suboccipitally with radiation to the vertex and behind the eyes. In many cases, the headaches are exacerbated by Valsalva maneuvers such as sneezing, coughing or straining. Nearly any neurologic sign or symptom can be a part of the initial presentation. It is imperative that the treating physician be familiar with the disease to discern whether the symptoms are in fact due to the compression from the tonsillar herniation or are merely coincidental and not related. While some symptoms may respond to conservative treatment for which a trial may be appropriate prior to contemplating surgical intervention, other symptoms are best appropriately addressed surgically.

Ehlers-Danlos syndrome

The Ehlers-Danlos syndrome (EDS) is a heterogeneous group of disorders of collagen metabolism which manifest through a wide variety of symptoms. The cardinal features include joint hypermobility, as well as skin hyperextensibility and fragility. This is a rare disease, which occurs in 1:5000 individuals. It is divided into six subtypes according to the Villefranche classification with the classical, hypermobile, and vascular types being the most common. The genetic basis for these disorders are quite diverse, and in some instances, the exact genetic mutation is unknown. Where the mutation is known, it usually involves dysfunction in either the formation or crosslinking of collagen fibrils.

As the principle manifestation of this disease is joint hypermobility, the Beighton scale is used to assess the degree of hypermobility. As patients grow older, there is a tendency for flexibility to decrease; however, for children, generally a score of at least 5 out of 9 is considered diagnostic. Another characteristic of the disease is that patients frequently complain of joint pain and are prone to injuries such as joint subluxation and torn ligaments and tendons. Cutaneous manifestations such as marked skin hyperextensibility, widened atrophic cutaneous scars, and easy bruising with skin staining due to hemosiderin deposits are also prevalent. Furthermore, subcutaneous spheroids and molluscoid pseudotumors with scars over the knees and elbows can also be seen. Due to the connective tissue abnormality, children with these disorders can experience problems with motor development, muscle weakness and proprioception. Additionally, patients may be more prone to developing functional somatic syndromes such as fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome and orthostatic intolerance to name a few.

Connective tissue disorders and headaches

Headache and neck pain are common symptoms that patients with EDS report. The types of headaches they most commonly experience are migraines, cervicogenic headache, intracranial hypotension and new daily persistent headaches. The incidence of migraine headaches has been shown to be increased in EDS patients. It is speculated that this may be related to abnormalities in TGF-β  signaling, such as has been found in patients with Marfan syndrome.

Cervicogenic headaches are experienced in the occipital region and tend to be mild to moderate in intensity. In children, this may be due to C2 neuralgia, mechanical instability or functional instability. In older patients, degenerative disease such as disc herniation, facet arthropathy, spinal stenosis or cervical spondylosis can be the cause. Cervical disc disease is known to be increased in these patients and is postulated that it is due to hypermobility and/or spinal deformity causing abnormal stress on the disc and supporting structures, leading to herniation.

New daily persistent headaches begin on a specific day and are then continuous. They are bilateral 64 percent of the time and are described as throbbing or pressure in nature. They are usually located in the occipitonuchal or retro-orbital region but can be generalized in 18 percent of cases. It is postulated that cervical hypermobility and resultant brain stem compression may be causative in some cases by activating cervical afferents that converge on the spinal nucleus of 5.

Connective tissue disorders may predispose patients to dural laxity or ectasias. CSF leaks are known to occur at sites of ectasias, resulting in intracranial hypotension. These headaches tend to be position dependent and are worse sitting up and relieved while the patient lies flat.

Association between Chiari malformation and EDS

The association between Chiari malformation type I and connective tissue disorders (CTD) was initially described by Milhorat et al in 2007. In their cohort of patients, family history data appeared to show a relationship between CMI and CTD. They observed that a subset of Chiari patients who also had CTD appeared to have what they referred to as functional cranial settling. This was manifested by a reducible increase in the basion-dens interval and posterior gliding of the occipital condyles. This led to the conclusion that these patients suffer from occipitoatlantoaxial hypermobility, which is responsible for the treatment failure from decompression surgery in these patients. As a result, a belief that these patients require occipito-cervical fusion operations in order to achieve symptomatic relief has been developed. Although their manuscript illustrated the dynamic changes which occur in patients with occipitoatlantoaxial hypermobility with the use of vertical or sitting MRI, further studies have not demonstrated the utility of upright MRI. Henderson has described the potential harmful effects of this type of cranial settling. In a finite analysis model, when the clivo-axial angle is less than 125 degrees, the forward angulation produces a distracting force on the neural elements, which can result in neurologic dysfunction. Other authors sought to elucidate which patients would benefit from a decompression alone and which patients would progress to treatment failure if their surgical intervention did not include an occipital-cervical fusion. Brockmeyer et al. determined that a subgroup of “complex” pediatric Chiari malformation patients exist that indeed have a higher rate of requiring occipital-cervical fusion. These patients include those that present with basilar invagination, Chiari malformation 1.5 (tonsillar herniation along with brainstem herniation), and a clival-axial angle less than 125 degrees. Although it was initially thought that ventral brainstem compression, as defined by the pB-C2 line, is an independent predictor for treatment failure, further studies have not shown this to be the case. However, the pB-C2 line is still useful as a quantitative measure of ventral brainstem compression.

Treatment of EDS-related, CM1-related symptoms

For many patients, the initial treatment strategy employed is one of conservative management. Physiotherapy is an option for most patients as it has been shown to improve muscle tone, thereby stabilizing joints and reducing postural sway. With respect to the cervical spine, treatment strategies are employed to improve proprioception in addition to activity modification and postural training to stabilize the hypermobile cervical segments. In addition, many patients with a hypermobile spine tend to have tightened muscle groups, in particular the trapezius, which may require controlled stretching.

With respect to headaches, different treatments are available for migraines. Topiramate, tricyclic antidepressants, gabapentin and valproic acid are good preventative agents. Angiotensin receptor blockers have been shown to be effective migraine preventative agents in patients with Marfan syndrome due to abnormalities in TGF-β  signaling. As there is speculation that there are many similarities between Marfan’s and the other CTD, it is possible that these agents may be efficacious in these disorders as well.

As previously mentioned, those patients with dural ectasia or laxity may develop intracranial hypotension due to CSF leakage. The primary treatment is with caffeine, hydration and a lumbar epidural blood patch. If a definitive leak site can be identified, a targeted epidural blood patch can be tried, or direct surgical repair can be performed.

Patients who suffer from dysautonomia (postural orthostatic tachycardia syndrome or POTS) often develop a variant of migraines called “coat hanger” headaches. These are described as occurring in the occiput, neck and shoulders and occur while sitting or arising. β-blockers in small doses can be used to treat both the headaches and the dysautonomia. Other treatment options include support stockings, fludrocortisone or midodrine.

Given the chronic nature of CTD and the multiple pain-producing conditions that are associated with it, many patients ultimately suffer from the effects of polypharmacy. Where possible, it is best to avoid narcotics and instead use nonsteroidal anti-inflammatory medications. Conservative treatments such as physical therapy, biofeedback and acupuncture should be utilized in an attempt to avoid medications. When medications are required, those that are preventative in nature should be employed. Many of these patients suffer from diffuse pain throughout the body and should be evaluated for central sensitization syndrome. Central sensitization is a chronic pain condition where the functional state of sensory neurons is altered such that the central nervous system abnormally amplifies sensory input. This leads to patients having a hypersensitivity to nonpainful stimuli or experiencing the “gain” being turned up on painful stimuli. Although complex, identifying patients with central sensitization is the first step in treatment.

Surgical treatment

The symptoms that respond most optimally to surgical intervention are those related to neural compression and CSF circulation disturbance. Ataxia, hyperreflexia, swallowing dysfunction and central sleep apnea are examples of neural compression symptoms that are amenable to surgical decompression. Headaches that are related to perturbations in CSF flow, such as those that are worsened by coughing, sneezing or straining, many times respond favorably to a posterior fossa decompression.

Although many different variations of this procedure exist, generally the objective of any surgical correction is to relieve the neural compression at the foramen magnum and to restore normal anatomy and CSF circulation across the craniovertebral junction. When the intracranial pressure is elevated, an underlying defect in CSF absorption may be present, which usually responds well to CSF shunting. Intracranial hypotension responds well to a lumbar epidural blood patch or, when the actual leakage point can be discerned, direct repair.

When significant instability is present preoperatively or if the risk of developing it postoperatively is high, the decompression is paired with an instrumentation and fusion procedure (Figure 1). To treat cranial settling, the techniques described by Rekate and others to reduce the deformity are performed as part of the procedure prior to the instrumentation. If there is cranial settling or other anterior compression present that is not reducible, then an anterior decompression should be considered in addition to the posterior fusion. When a posterior fusion is contemplated for a patient with CTD, a longer construct than would otherwise be thought necessary should be considered. Due to connective tissue laxity in these patients, the ligaments at adjacent spinal levels to the fusion construct may not be strong enough and fail, leading to adjacent level failure and instability (Figure 2).

Case vignette

Patient BW is a complex patient who presented at the age of 8 with headaches that were refractory to conservative treatment. His initial surgical procedure involved a posterior fossa craniectomy with C1 laminectomy and duraplasty only involving the outer layer of dura. Initially, his headaches resolved, but ultimately, they returned along with upper extremity dysesthesias. His decompression was therefore revised, where a duraplasty, lysis of adhesions and tonsillar shrinkage was performed. Subsequently, he underwent a vascular bypass procedure for symptomatic vascular insufficiency, and a ventriculoperitoneal shunt was performed for hydrocephalus. He developed intractable neck pain for which an O-3 fusion was performed. His symptomatic improvement was short lived as he developed signs of cervical instability at the adjacent level (Figure 2). A C4/5 ACDF and extension of his posterior fusion to the thoracic spine (Figure 3) was required to achieve stability and symptomatic improvement.

Conclusion

When treating patients with Chiari malformations, it must be considered that a subset of patients will also meet the diagnostic criteria of connective tissue disorders such as EDS. Failure to recognize this can easily lead to treatment failure. The well-educated and experienced clinician will evaluate the patient for both of these conditions, as treatments may change depending on their presence or absence. If evaluated properly, many conservative as well as surgical treatments are available with good outcomes should these patients be diagnosed appropriately.

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