Neurological manifestations of Ehlers-Danlos Syndrome

Neurological manifestations of Ehlers-Danlos syndrome(s): A review – Oct 2014

The term “Ehlers-Danlos syndrome” (EDS) groups together an increasing number of heritable connective tissue disorders mainly featuring joint hypermobility and related complications, dermal dysplasia with abnormal skin texture and repair, and variable range of the hollow organ and vascular dysfunctions.

Although the nervous system is not considered a primary target of the underlying molecular defect, recently, increasing attention has been posed on neurological manifestations of EDSs, such as musculoskeletal pain, fatigue, headache, muscle weakness and paresthesias.

The emerging picture defines a wide spectrum of neurological manifestations that are unexpectedly common and potentially disabling.

Their evaluation and correct interpretation by the clinical neurologist is crucial for avoiding superfluous investigations, wrong therapies, and inappropriate referral.

Features are organized under various subheadings, including pain, fatigue, headache, stroke and cerebrovascular disease, brain and spine structural anomalies, epilepsy, muscular findings, neuropathy and developmental features.

A set of basic tools for patient’s recognition is offered for raising awareness among neurologists on this underdiagnosed group of hereditary disorders.

Introduction

the definition of Ehlers-Danlos syndrome (EDS) is significantly changed and actually refers to an expanding spectrum of heritable connective tissue disorders sharing the variable triad of (i) generalized joint hypermobility and related osteoarticular complications, (ii) dermal dysplasia extending from minor changes of skin texture to clinically relevant skin fragility and defective scarring, and (iii) vascular and internal organ fragility with proneness to traumatic injuries and spontaneous ruptures, dissections and prolapses

The question whether EDS-HT and JHS are also identical at the molecular level is still a matter of debate

presumed cumulative frequency of 1 in 5000 individuals in the general population for EDS9 is likely an underestimation

for JHS/EDS-HT, musculoskeletal pain, fatigue and headache represent the master contributors to patients’ referral to the practitioner and quality of life deterioration

In this paper, we review pertinent literature reporting a seemingly increased rate of neurological features in EDS. Our aim was to offer a practical reference to the clinical neurologist in considering this condition in subjects with an apparently primary neurological condition, as well as to those taking part to the multidisciplinary team involved in the management of EDS patients

Search Methods

This work was intended as a narrative review summarizing actual evidence on nervous system involvement in EDS. A PubMed search was carried out matching the terms “EDS” OR “hypermobility syndrome” with the following: central nervous system, brain, myelum, spine, stroke, epilepsy, muscle, myopathy, peripheral nerve(s), polyneuropathy, (peripheral) nervous system, and nerve.

Pain

Pain is now accepted as a common and potentially disabling feature of various forms of EDS, especially JHS/EDS-HT. This is testified by the inclusion of chronic musculoskeletal pain as a major item in the Brighton criteria for JHS

Conversely, in the early EDS literature, pain was recognized as a marginal finding, usually

In 1994, Lumley et al. first pointed out a possible role of chronic pain in the quality of life of EDS patients

Furthermore, the repeated evidence of resistance to local anesthetics in both EDS-HT and JHS suggests a more complex effect on pain perception and modulation processes in EDS

Interestingly, pain seemed more severe in EDS-HT than classic and vascular types, and pain severity was correlated with hypermobility, dislocations and previous surgery. This preliminary observation prompted the same research group to state that pain and fatigue are possible important determinants of disability of EDS-HT.

chronic-recurrent joint pain is the most common presentation of pain in JHS/EDS-HT,

Additional manifestations of musculoskeletal pain in JHS/EDS-HT and perhaps other EDS subtypes include muscle cramps, fibromyalgia and compression/peripheral neuropathies

Pain is not limited to the musculoskeletal system and often presents with visceral involvement

Headache is also common in EDS

pain is a changing feature in EDS and its functional consequences are influenced by the adaptation strategies that the various structures of the affected individual develop, as a whole, to face repetitive pain perception.

presence of hyperalgesia in EDS-HT. This finding may represent a preliminary proof for the action of central sensitization processes in those EDS patients who develop the most severe disabilities associated to pain.

Fatigue

Though largely ignored in the past, severe fatigue is now considered a common accompanying feature of EDS, particularly EDS-HT, as it is reported in up to 84% of the patients

In JHS/EDS-HT, the impact of fatigue on daily life is often equal or more dramatic than the impact of pain; a fact that underscores the importance of fatigue for both assessment and treatment planning in these patients

Some possible contributors to fatigue-related disability have been investigated in EDS and include sleep disturbances, concentration problems, social functioning, self-efficacy concerning fatigue, and pain severity

Recently, dysautonomia was recognized as one of the most relevant pathogenic factors influencing fatigue onset and evolution. This feature, mostly studied in JHS/EDS-HT, often presents with orthostatic tachycardia syndrome and/or orthostatic intolerance

Headache and Head Pain

neck pain and headache is present in 30-40% of cases.

high prevalence of headache in JHS/EDS-HT

many EDS patients may develop chronic or recurrent headache,

possible associations between localized or generalized joint hypermobility and specific subsets of primary and secondary types of headache, including new daily persistent headache and headache attributed to spontaneous (idiopathic) cerebrospinal fluid leakage.

Cervical spine hypermobility/dysfunction is also anecdotally considered a predisposing factor for cervicogenic headache and neck-tongue syndrome

Stroke and Cerebrovascular Disease

Most reports on stroke and cerebrovascular disease in EDS concern vascular EDS and include intracranial aneurysms, subarachnoid hemorrhage, spontaneous arterial dissection and cavernous sinus fistula. In patients with classic EDS, aneurysms occasionally occur, whereas other vascular abnormalities are rare. In fact, the presence of stroke in patients with cutaneous features of classic EDS should prompt to molecular investigation for the classic variant with arterial rupture due to mutations in COL1A1

Although uncommon, vascular EDS is a potential cause of stroke in young people

Brain and Spine Structural Anomalies

Brain magnetic resonance imaging (MRI) is usually unremarkable for major structural anomalies in EDS. Therefore, with the exception of acute presentations with the suspect of cerebrovascular disease, such an investigation usually does not take place in the baseline assessment of EDS patients

The concurrence of Chiari malformation (Type I) is a further apparently underreported feature of EDS, as to date observed in single patients only

a surgically-oriented paper on hundreds of patients originally ascertained for symptomatic Chiari malformation, a subgroup of them, … presented minor, but measurable neuroradiologic features of occipitoatlantoaxial instability: posterior gliding of the occipital condyles, and reduction of the clivus-axis angle, clivus-atlas angle, and atlas-axis angle in the upright position

Epilepsy

The mechanisms explaining the possible association between EDS and seizures are likely heterogeneous

Muscular Findings

EDS is associated with a variety of neuromuscular features, and vice versa, a variety of congenital myopathies display joint hypermobility and, to a lesser extent skin changes

It was suggested that the muscle hypotonia might have a basis in the abnormality of the collagen in muscle sheaths rather than in the muscle fibers itself,

The presence of marked muscle hypoplasia with hypotonia led to the initial diagnosis of primary muscle disease; later, he was found to have hyper-extensible and fragile skin and hyper mobile joints, and EDS was diagnosed

muscle weakness was primarily due to the alterations in the connective tissue surrounding the muscle cells

mild-to-moderate neuromuscular involvement is common in various types of EDS

Another finding in this study was the remarkable relation between residual TNX levels and degree of neuromuscular involvement, compatible with a dose-effect relation. This points to the role of the extracellular matrix defect in muscle and peripheral nerve dysfunction in EDS

Neuropathy

Brachial and/or lumbosacral plexus neuropathies and compression mononeuropathies have been reported in several types of EDS

Conclusion

This overview on neurological manifestations of EDS demonstrates a largely unrecognized set of central and peripheral nervous system features in patients with heritable connective tissue disorders. The familiarity that any neurologist has with some of these manifestations when reported in the general population, such as cerebrovascular disease, headache, myalgia and fatigue, poses neurologists in a privileged position for promptly recognizing EDS.

It seems we should be seeing neurologists to be evaluated for EDS, not rheumatologists (people with EDS seem routinely misunderstood and misdiangosed with Fibromyalgia by rheumatologists)

“Red flags” for suspecting Ehlers-Danlos syndromes

 

 

 

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