Ross Hauser, MD.
Introduction: Ehlers-Danlos Syndrome (EDS) is a group of connective tissue disorders that have joint hypermobility as the central character but can also cause symptoms and complications of the skin, joints, blood vessels, and other organs throughout the body. When this instability is present in the cervical spine, the vertebrae can compress blood vessels or irritate nerves, causing symptoms like dizziness, facial pain, arm pain and numbness, and migraine headaches. The various disorders are characterized by a defect in collagen, a protein that provides strength and elasticity to the majority of our body parts from our ears to our toes. Those with EDS are often misdiagnosed because the array of systems involved often presents a challenge to physicians unfamiliar with the condition. Patients can suffer numerous dislocations and injuries because their ligaments, the soft connective tissue that connects bone to bone, are too elastic. While this can be an edge for some gymnasts, allowing them to bend and twist in amazing ways, this same feature makes their joints unstable and prone to injury.
In many of the Ehlers-Danlos Syndrome patients we see, there is a longing for understanding. This unfulfilled desire to know what was wrong with them has led these patients through a journey of years of bouncing between clinician and clinic, from doctor to alternative practitioner, from self-help guideline to self-help guideline with few answers and little help. This may be what is happening in your case.
Some of the emails we get reflect this desire in patients. Despite being a “complex,” or “difficult to manage case” many Ehlers-Danlos Syndrome patients have a simple goal:
- I just want to be able to function better and improve my overall quality of life.
- I just want to take care of my toddler for a day or two without help.
- I want to walk. Maybe one day run and jump again. But right now I just want to be able to walk without pain or fear of a dislocation.
- I want to get out of bed. Be able to sit in a chair, stand, and walk without my symptoms becoming worse.
As you can see in their comments, these once healthy active people have now been reduced to people who are barely able to walk because of excessive joint pain and excessive fatigue. They find themselves managing their energy enough to prioritize the daily tasks they must do and leave “non-essential” tasks to “better days.”
This article is part of a series of articles on Ehlers-Danlos Syndrome (EDS).
Please see these articles:
- TMJ, Joint Hypermobility Syndrome And Ehlers-Danlos Syndrome
- Ehlers-Danlos Syndrome, Atlanto-Axial Instability, And Craniocervical Instability
- Are Ehlers-Danlos Syndrome Headaches And Migraines Caused By Cervical Spine And Neck Instability?
- Ehlers-Danlos Syndrome And Knee Replacement Complications
- Ehlers-Danlos Syndrome And Hip Replacement Complications
- Ehlers-Danlos syndrome hypermobility type – Hypermobility Spectrum Disorder in children
- Shoulder Replacement Complications In The Ehlers-Danlos Syndrome Patient
- Whiplash And Post-Concussion Syndrome In The Ehlers-Danlos Syndrome Patient
- Hypermobile Ehlers-Danlos Syndrome, Joint Hypermobility, Lumbar Instability, And Low Back Pain
- Digestive Problems In The Hypermobile Ehlers Danlos Syndrome Patient
- Dystonic Storms In Four Patients With Hypermobile Ehlers-Danlos Syndrome
EDS is often a progressive disorder, especially when a joint becomes unstable. With smartphone and computer use, certain parts of everyone’s anatomy, especially the neck, are undergoing forces never before seen in human history. Cervical instability, the most disabling of all the instabilities that occur with EDS, can not only cause severe neck pain, dizziness, vertigo, and migraine-headaches but also some of the more devastating dysautonomias seen with EDS including POTS (postural orthostatic tachycardia syndrome) and MCAS (mast cell activation syndrome). Since joint instabilities are a progressive disorder, it is imperative that early recognition of these conditions and then appropriate treatments be given that can resolve the instabilities.
Article Outline:
- “I do not have a diagnosis, only a lot of theories. I have been seeking treatment for years. All the doctors and therapists can tell me is that all my problems are because I am too flexible.”
- The “unmet need of the patients”
- Patients still have trouble finding fast access to correct diagnosis and treatment.
- “Many needs are unfulfilled, including access to care and treatment, educational therapy, professional educational programs, and awareness.”
- Individuals living with EDS demonstrated a high degree of self-reliance
- “I have finally been diagnosed with Ehlers-Danlos Syndrome and I am just as confused as before.”
- The 2017 international classification of the Ehlers-Danlos syndrome – helps identify hypermobile Ehlers-Danlos Syndrome (hEDS) type that can be diagnosed without genetic testing.
- Doctors are trying to understand the “mental aspects” of hypermobility spectrum disorder and Ehlers-Danlos syndrome
- A brief summary of Hypermobile Ehlers-Danlos syndrome – making a diagnosis of hEDS in clinical evaluation as there is no specific test available– from the National Institutes of Health (NIH)
- Diagnostic guidelines recommended by the NIH for hEDS do not include genetic testing
- The new classifications try to address a stuck medicine and a stuck diagnosis waiting time
- Medicine struggles for a better understanding of the defective production of collagen and reduced musculoskeletal functioning by symptoms of joint laxity and frequent dislocations eventually leading to disability
- Searching for criteria forEhlers-Danlos Syndrome (hEDS) in Adolescents because standard care patients do not get better. Not to say anything about the toil on the family and the patient looking for answers
- Treatment strategies
- The problem of just treating symptoms
- Treating the symptom of pain: Research suggests overall expert consensus indicates that pain medications are often not effective in long-term treatment.
- Understanding pain, Managing pain, and Healing pain. Medicine searches for answers
- Physical therapy
- Prolotherapy Treatment for hEDS
- Our research: Prolotherapy and Ehlers-Danlos Syndrome (hEDS) and Joint Hypermobility Syndrome (Hypermobility Spectrum Disorders (HSD)).
- Can joint instability in hEDS be objectively measured?
“I do not have a diagnosis, only a lot of theories. I have been seeking treatment for years. All the doctors and therapists can tell me is that all my problems are because I am too flexible.”
In a younger more active group of patients, we will often hear a patient story that includes chronic joint dislocation.
- “I dislocated my shoulder while I was sleeping,” or
- “My hip popped out of place when I rolled over in bed.”
- Or we will hear that the patient, “blew out their knee, walking down a flight of stairs,”
- or that their elbow popped out while opening a door.
- We will also hear a lot about neck pain and headaches, dizziness, and sensory problems that seem to be “all in their head,” but may instead be “all in their neck muscles and ligaments.”
What we hear about the most, is that these people ask why it took years to figure out what was wrong with them. Why do they have so much pain? Why had they been to countless health care providers over years, and in some cases decades, and came out of all this no better, more confused, and seemingly hopeless that anything can help them?
We can only explain that medicine is still reaching for answers. These people are in our office because they have come to explore Prolotherapy, a treatment that they had never heard of, or been recommended to but they found out about in hEDS discussion groups or through their own internet research.
Injections may be one answer
In this article, we will lay the foundation for the treatment of patients suffering from Ehlers-Danlos syndrome, specifically Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders with Prolotherapy injections. The treatment is designed to stimulate connective tissue growth and rebuilding in damaged painful joints where there is collagen deficiency. Patient outcomes are described below. We will also discuss other treatments that may benefit the patient.
The “unmet need of the patients”
From a patient: “I was diagnosed with Ehlers-Danlos Syndrome and I was given a big package of information. The first thing I did was look at the treatments.”
- The “treatments for Ehlers-Danlos” was:
- an electric wheelchair
- an electric scooter
- braces and different things to hold you together
- and pain medication
Patients still have trouble finding fast access to correct diagnosis and treatment.
In October 2018, an extended team of European researchers working as the European Reference Network for “Rare and Complex CONnective tissue and musculoskeletal diseases NETwork (ReCONNET)”, published these findings on the unmet needs of the Ehlers-Danlos Syndromes patient in the journalRheumatic & Musculoskeletal Diseases Open. (1)
- Although the new 2017 EDS nosology has brought attention to EDS, patients still have trouble finding fast access to correct diagnosis and treatment.
- Not many physicians have been trained to recognize EDS or do not know how to treat it. In many European countries and beyond, there are no diagnostic centers or experts available to patients.
- Most patients with EDS suffer from generalized joint hypermobility, chronic widespread pain, and fatigue. Pain treatment is complex and usually requires the guidance of a specialized pain clinic and the support of an integrated rehabilitation program.
- Because of the tissue fragility, conservative treatment is preferred over surgery. To improve daily life functioning, many patients need orthotics to stabilize hypermobile joints, mobility aids, aids for self-care and household, etc.
- Unfortunately, the needs of patients are often misunderstood, because their main problems are ‘invisible’. For instance, joint hypermobility is difficult to observe, unless evaluated with specific clinical tests.
“Many needs are unfulfilled, including access to care and treatment, educational therapy, professional educational programs, and awareness.”
At present, EDS is not curable, but only ‘treatable’.
- Patients presenting pain require multidisciplinary care, including pain medication, intensive physiotherapy, podiatry, psychology, occupational therapy, and adequate bracing.
- Often a holistic or alternative approach is complementary to normal treatment.
- Unfortunately, many treatment options are not reimbursed, even when they improve the quality of life of patients with EDS significantly.
At present, a good number of patients are not taken seriously or even accused of hypochondria, Munchausen or Munchausen-by-proxy.
- As such, psychiatric diagnoses sometimes precede the actual diagnosis. Furthermore, psychological follow-up is sometimes needed, considering the fact that the long road to the correct diagnosis and correct treatment of the symptoms often contributes to anxiety and depression.
“In conclusion, there is a long road ahead for the EDS Community. Many needs are unfulfilled, including access to care and treatment, educational therapy, professional educational programs, and awareness.”
An October 2017 study from university hospital researchers in Norway was published in the medical journalDisability and Rehabilitation, in it the doctors made these observations:
- Adults with Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome-Hypermobile Type reported higher frequency and severity of health complaints (symptoms)
- Further, these patients reported low understanding of their illness and associated symptoms and moderate belief that their illness can be kept under control through self-management or (improper or ineffective) treatment. This may indicate one of the reasons why the prognosis for these patients is poor.
- The problem of patient information: Awareness of the complexity of the symptoms and disease could contribute to valuable information about these patients’ perceptions of their condition. Such information could in turn be of value for clinicians as they work towards facilitating a more holistic treatment approach. (2)
Comment: We have a patient with a lot of health challenges. They have been told to self-manage or get treatments, which we will cover below that were in many cases inappropriate. “This may indicate one of the reasons why prognosis for these patients is poor.” In other words, the patients do not get better. The patients could get better if they knew what their disease was and how to come up with a more holistic (whole-body) treatment approach.
Individuals living with EDS demonstrated a high degree of self-reliance
A January 2024 study in the journal Frontiers in Medicine (3) suggested however that “individuals living with EDS demonstrated a high degree of self-reliance and low expectations that the health care system would solve their problems. This contrasts with findings in other studies . . (this study’s participants generally continued to work despite significant disability, and had adapted and negotiated their work environment and the health care system’s formidable barriers.”
“I have finally been diagnosed with Ehlers-Danlos Syndrome and I am just as confused as before.”
One of the incredible things about Ehlers-Danlos syndrome is the amount of confusion it can create in some patients and their doctors. A patient will come into our clinics having an idea that there are different classifications of Ehlers-Danlos Syndromes but unsure which one impacts them. Once in a while, we will hear a patient say that they never got a classification because their primary doctor told them the classifications didn’t matter because there is nothing that can be done about it, there are no effective treatments.
Other patients will discuss their “medical team.” They have a neurologist, orthopedist, general practitioner, nutritionist, physical therapist, and others. The patients will say that these providers are all working hard for them but they are not getting any better.
There is also a question of confusion about genetic testing for Ehlers-Danlos Syndromes and what happens when that comes back “negative.”
The 2017 international classification of the Ehlers-Danlos syndrome – helping identify hypermobile Ehlers-Danlos Syndrome (hEDS) type can be diagnosed without genetic testing
In 2017, the American Journal of Medical Genetics published aninternationally agreed upon 2017 EDS Classification. This was the first such classification update since 1997. The new classifications seek to more specifically identify EDS patient symptoms and try to offer a recommendation toseek treatment.
Nosology is the study of diseases. It derives from the Greek nosos (diseases) and logia, the study of. Nosologies forEhlers-Danlos syndromes have been revised for decades.
In 1998 a landmark paper fromPeter Beighton of the Universityof Cape Town, South Africa published in the American Journal of Medical Genetics gives a history up until that time and the challenges of the 1998 doctor and defines new criteria in the diagnosis ofEhlers-Danlos syndromes. Here are the highlights of that research.(4)
- Categorization of the Ehlers-Danlos syndrome began in the late 1960s and was formalized in the Berlin nosology in 1988.
- Over time, it became apparent that the diagnostic criteria established and published in 1988 did not discriminate adequately between the different types of Ehlers-Danlos syndromes or between Ehlers-Danlos syndromes and other phenotypically related conditions. (This includes Marfan syndrome, a connective tissue disorder characterized by tall thin patients with long, disproportionately, long arms, legs, fingers, and toes. Some have speculated Abraham Lincoln had Marfan syndrome.)
Dr. Beighton proposed a revision of the classification of the Ehlers-Danlos syndromes based primarily on the cause of each type.This became the Revised Nosology, Villefranche 1998 to replacetheBerlin nosology. In it, six subtypes of Ehlers-Danlos syndromes were described. Now Ehlers-Danlos syndrome has become Ehlers-Danlos syndromes.
- The type we are discussing in this article is hypermobile Ehlers-Danlos syndrome (hEDS) which has also been tagged with these diagnostic terms:
- Hypermobile EDS formally calledEDS3
- Ehlers-Danlos syndrome type 3
- Ehlers-Danlos syndromehypermobility type
- Hypermobile EDS
- A common, more layperson description is that of being “double jointed.”
Why look back to 1988?
If you are in your 40s, or 50s, or older you can offer a better answer to anyone. For some of you, it took decades to get a diagnosis. Back in 1988, you were one of the people that Dr. Beighton and his colleagues were looking to find a more specific term to describe what you had.
In 2017, forty-six doctors and researchers co-published in the American Journal of Medical Genetics: The 2017 international classification of the Ehlers-Danlos syndromes.(5) Their reasons for this new nosology are given below:
- Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of Ehlers-Danlos syndromes.
- The International Ehlers-Danlos Syndromes Consortium proposes a revised Ehlers-Danlos syndromes classification, which recognizes 13 subtypes.
- For each of the subtypes, we propose a set of clinical criteria that are suggestive of the diagnosis. However, in view of the vast genetic heterogeneity (the great variation in gene mutation in hereditary situations) and phenotypic (characteristic) variability of the Ehlers-Danlos Syndromes subtypes, and the clinical overlap between Ehlers-Danlos Syndromes subtypes, but also with other heritable connective tissue disorders, the definite diagnosis of all Ehlers-Danlos Syndromes subtypes, except for the hypermobile type, relies on molecular conformation with identification of (a) causative genetic variant(s).
- COMMENT: The various subtypes ofEhlers-Danlos Syndromes require molecular testing to confirm the diagnosis, except for the hypermobile type.
Doctors are trying to understand the “mental aspects” of hypermobility spectrum disorder and Ehlers-Danlos syndrome
In May 2019, a team of international researchers published a paper in the journal Disability and Rehabilitation.(6) The summary points of this paper point to the doctor’s need to understand all aspects of the patient’s problems. Here is what they wrote:
“The tissue fragility characteristic of this condition leads to multi-systemic symptoms in which pain, often severe, chronic, and disabling, is the most experienced. Clinical observations suggest that the complex patient with EDS hypermobility-type is refractory (does not respond) toward several biomedical and physical approaches . . . the identification of psychological aspects involved in the pain experience can be useful to improve interventions for this under-recognized pathology.
As in other chronic pain conditions, these aspects should be more explored in EDS hypermobility-type, and integrated into chronic pain prevention and management programs. Implications for Rehabilitation Clinicians should be aware that joint hypermobility may be associated with other health problems, and in its presence suspect a heritable disorder of connective tissue such as the Ehlers-Danlos syndrome (EDS) hypermobility-type, in which chronic pain is one of the most frequent and invalidating symptoms.
It is necessary to explore the psychosocial functioning of patients as part of the overall chronic pain management in the EDS hypermobility-type, especially when they do not respond to biomedical approaches as psychological factors may be operating against rehabilitation.”
In April 2023, doctors in Italy wrote in the journal Healthcare (7) that many hEDS sufferers have “a nonspecific symptom and cannot be considered among the diagnostic criteria” for hEDS guidelines, However, the pain is there and does cause a negative quality of life of patients with EDS… In real-world terms, examining the previously published research, the study authors found that in self-reported questionnaires, hEDS patients showed higher levels of anxiety and depression with a correlation between fears and anxiety and hypermobility of joints, even without any psychiatric disorders. The researchers summarized that doctors should pay “particular attention” to the diagnosis of (hEDS) whose symptoms, often vague and poorly defined, create confusion, diagnostic delay, and therapeutic errors that do nothing but worsen the health condition of these subjects, with both physical and psychological implications.
A brief summary of Hypermobile Ehlers-Danlos syndrome – making a diagnosis of hEDS in clinical evaluation as there is no specific test available– from the National Institutes of Health (NIH)
According to the United States Department of Health National Institute of Health, Hypermobile Ehlers-Danlos syndrome (hEDS) is diagnosed based on the presence of characteristic signs and symptoms, because there is no specific test available.
Some of the signs and symptoms of hypermobile Ehlers-Danlos syndrome vary but may include:
- Joint hypermobility affecting both large (elbows, knees) and small (fingers, toes) joints
- Frequent joint dislocations and subluxations (partial dislocation), often affecting the shoulder, kneecap, and/or temporomandibular joint (jaw)
- Soft, smooth, elastic skin that may bruise easily
- Chronic musculoskeletal (muscle and bone) pain
- Early-onset osteoarthritis
- Dysfunction of the autonomic nervous system (This is part of what we described above relating to headaches and cervical neck instability)
Diagnostic guidelines recommended by the NIH for hEDS do not include genetic testing
This is also from the NIH website:
“Tenascin X genetic testing is available outside of the United States, but the frequency of this abnormality in patients with hypermobility EDS is not known.”
There is a range of conditions that can accompany hEDS, although there is not enough data for them to become diagnostic criteria. While they’re associated with hEDS, they’re not proven to be the result of hEDS and they’re not specific enough to be criteria for diagnosis. Some of these include sleep disturbance, fatigue, postural orthostatic tachycardia (POTS), functional gastrointestinal disorders, dysautonomia, anxiety, and depression. These conditions may be more debilitating than the joint symptoms; they often impair daily life, and they should be considered and treated.
Criteria 1: Generalized joint hypermobility (small and large joints) which is assessed by using the Beighton Score system and a questionnaire.
The Beighton score is calculated as follows:
- One point if while standing forward bending you can place palms on the ground with legs straight.
- One point for each elbow that bends backward.
- One point for each knee that bends backward.
- One point for each thumb that touches the forearm when bent backward.
- One point for each little finger that bends backward beyond 90 degrees.
Criteria 2: Two or more of the following features must be present (A and B, AandC, B
and C, or A andB andC) –
Feature A—systemic manifestations of a more generalized connective tissue disorder (a total of 5 out of 12 must be present)
- Unusually soft or velvety skin
- Mild skin hyperextensibility
- Unexplained striae (stretch marks) or rubrae (lines) at the back, groins, thighs, breasts, and/or abdomen in adolescents, men, or prepubertal women without a history of significant gain or loss of body fat or weight.
- Bilateral piezogenic papules of the heel (solid painful pimples)
- Recurrent or multiple abdominal hernia(s) (e.g., umbilical, inguinal, crural)
- Atrophic scarring involves at least two sites (Atrophic scarring are depressions in the skin commonly referred to as pockmarks).
- Pelvic floor, rectal, and/or uterine prolapse in children, men, or nulliparous (never given birth) women without a history of morbid obesity or other known predisposing medical condition
- Dental crowding and high or narrow palate
- Arachnodactyly (abnormally long and thin fingers), as defined in one or more of the following:
- positive wrist sign (Steinberg sign) on both sides (Your pinky and thumb can touch when you circle your wrist with them);
- positive thumb sign (Walker sign) on both sides (You can fold your thumb into your closed fist and the thumb tip extends outside the fist)
- Your arm span is greater than your height
- Mitral valve prolapse (MVP) mild or greater based on strict echocardiographic criteria
- Aortic root dilatation with Z-score > +2 (A tool to measure aortic elasticity)
Feature B—positive family history, with one or more first-degree relatives independently meeting the current diagnostic criteria for hEDS.
Feature C—musculoskeletal complications (must have at least 1 of 3 ):
- Musculoskeletal pain in 2 or more limbs, recurring daily for at least 3 months
- Chronic, widespread pain for more than 3 months
- Recurrent joint dislocations or frank joint instability (partial dislocations), without trauma injury (a or b)
a. Three or more dislocations without trauma injury in the same joint or two or more atraumatic dislocations in two different joints occurring at different times
b. Medical confirmation of joint instability at two or more sites not related to trauma.
Criteria 3: All these prerequisites must be met:
The absence of unusual skin fragility, exclusion of other heritable and acquired connective tissue disorders including autoimmune rheumatologic conditions, and exclusion of alternative diagnoses that may also include joint hypermobility due to poor muscle tone (hypotonia) and/or connective tissue laxity.
In the image below we present a single case. This patient was diagnosed with all these symptoms and a history including 18 surgeries. We were able to assess her “ground zero” as cervical spine instability leading to compression of the vagus nerve.
In the above image we see that the patient was diagnosed with:
- EDS – hypermobility
- Celiac Disease – gene 1 variant HLA DQA1 the gene mutation is causing damaging inflammation in the intestinal digestive tract. A December 2020 study (11) from Italian university researchers published in the journal Cell Reports suggested vagus nerve stimulation could reverse problems of Celiac Disease.
- MTHFR or Methylenetetrahydrofolate reductase. A common genetic mutation that can be responsible for problems usually identified with hEDS, such as Mast cell activation syndrome (MCAS), digestive, neurological, urinary-like disorders, cardiovascular-like attacks, heart palpitations and blood pressure problems, among many other challenges.
- SIBO Small intestinal bacterial overgrowth – Please see our article SIBO: Small intestinal bacterial overgrowth and the Vagus nerve. The problem of nerve compression.
- Tested for HLA DBR1, and BBR 345 (autoimmune disorders causing inflammatory bowel and digestive diseases).
- Acid Reflux
- Hiccups. please see our article Hiccups, Neck Pain, and Vagus and Phrenic Nerve Injury
- Bloating / Gas
- Constipation
- Colonic diverticula / diverticulitis
- Cyst on the right lobe of the liver
- Cyst on right ovary
- Chronic fatigue. Please see our article Can Chronic Fatigue Syndrome and Myalgic Encephalomyelitis Be Caused by Cervical Stenosis and Cervical Spine Instability?
- Lactose intolerance
- TOS. Please see our article Neurogenic and Nonspecific-type thoracic outlet syndrome – Diagnosis and treatment.
- Muscle pain, stiffness and tightness
- Hip popping, clicking frequent dislocations
- Hypertension – Please see our two articles Cervical Spine Instability, Vein blockage, fluid build-up and intracranial hypertension and Dysautonomia, POTS, and the hEDS patient.
- Joint Pain
- Memory Loss
- Eyesight deterioration. Please see our article Chronic Neck Pain and Blurred or Double Vision Problems.
- Osteopenia
- Arthritis
- Stomach pain
- Neuropathy
- Allergies
- Migraines. Please see our article Are Ehlers-Danlos Syndrome Headaches and Migraines Caused by Cervical Spine and Neck Instability?
We are frequently asked about how Prolotherapy works for Ehlers-Danlos Syndrome or other disorders when there is a known collagen defect. Ross Hauser, MD discusses the various types of collagen that are involved with ligaments and other tissues in the body.
Dr. Hauser refers to this chart in the video.
The chart shows the different types of collagen:
- Type 1 collagen makes up the bones, the skin layers, tendon,s and ligament tissue.
- Type 2 collagen is found in Hyaline cartilage, and fibrocartilage (which is the type of cartilage found in the spinal discs and at the insertions (enthesis) of ligaments and tendons. The enthesis is the attachment of the tendon and the ligament to the bone. In regenerative medicine, where injections are given to rebuild collagen, Type 2 collagen renewal is the focus.
- Type 3 collagen (and Type 5) defects or genetic mutation are associated with vascular problems including aneurysms and intestinal problems in Ehlers–Danlos syndrome, vascular deficiency, and aortic and arterial aneurysms. Type 3 collagen only makes up five to 9% or so of the collagen in the ligament.
- Type 4 collagen makes up the important basement membrane. Basement membrane is a type of extracellular matrix, it is a secretion that as its name implies provides the foundation for other cells to build on.
- Type 5 collagen makes up the lungs, cornea, and bone
- Type 6 collagen makes up the Dermis, lungs, blood vessel walls, and the discs of the spine.
The new classifications try to address a stuck medicine and a stuck diagnosis waiting time
Medicine struggles for a better understanding of the defective production of collagen and reduced musculoskeletal functioning by symptoms of joint laxity and frequent dislocations eventually leading to disability
The papers listed above and this paper published in June 2016 in the medical journal Disability and Rehabilitation (8)suggest that medical research seems to be stuck. Here is a reiteration of the problems expressed in the 2015 and 2017 studies listed above. This research comes from Appalachian State University whose doctors sought to help provide answers for patients. Here are their bullet points.
- “Ehlers-Danlos Syndrome is a complex, multi-systemic condition that can be difficult to diagnose and poses challenges for healthcare practitioners who engage with Ehlers-Danlos Syndrome patients in holistic care.
- Improved healthcare provider knowledge of Ehlers-Danlos Syndrome is needed, and additional research on the co-occurring diagnoses with EDS may assist in comprehensive pain management for Ehlers-Danlos Syndrome patients.
- Ehlers-Danlos Syndrome is a group of connective tissue disorders associated with defective production of collagen, which can dramatically reduce musculoskeletal functioning by symptoms of joint laxity and frequent dislocations eventually leading to disability.
- Respondents to an online survey reported having to seek out confirmation of their Ehlers-Danlos Syndrome diagnosis with multiple physicians, which implies the difficulty many people with Ehlers-Danlos Syndrome face when trying to gain access to appropriate treatment.
Searching for criteria forEhlers-Danlos Syndrome (hEDS) in Adolescents because standard care patients do not get better. Not to say anything about the toil on the family and the patient looking for answers
Doctors at Boston’s Children’s Hospital and Harvard University have published their research in the February 2017 edition of the Journal of Pediatrics (9)which describes the typical experience of an adolescent with Ehlers-Danlos Syndrome type syndromes:
The researchers examined the medical records of 205 patients with EDS (ages 6-19 years) seen in sports medicine or orthopedic clinics at a large pediatric hospital over a 5-year period.
- Female (147) and male (57) patients were identified (mean age 12.7 years old).
- The most common EDS subtype (55.6%) was the hypermobility type.
- Patients had between 1 and 69 visits (average 4), and 764 diagnoses were recorded.
- most commonly laxity/instability,
- pain,
- subluxation,
- and scoliosis/spinal asymmetry.
- Nearly one-half of patients (46.8%) received a general diagnosis of pain because no more specific cause was identified.
- in addition to 8.3% who were diagnosed with chronic pain syndrome.
- The most common sites of presenting issues were:
- knee (43.4%),
- back (32.2%),
- and shoulder (31.2%).
- Over three-fourths (77.1%) of patients had imaging.
- Most (88.1%) were prescribed physical therapy and/or other conservative measures, such as rest (40.5%), orthotics (35.6%), and medication (32.2%). Surgery was recommended to 28.8% of the study population.
The researchers concluded that despiteextensive workup, the etiology of pain may not be identified. Large numbers of office visits, imaging studies, treatment prescriptions, and specialist referrals indicate considerable use of medical resources.
Comment: As above, we have a patient with a lot of health challenges. The many doctors and many tests they had come up with no answers. Referring to the Norwegian study above: “This may indicate one of the reasons why prognosis for these patients is poor.” In other words, the patients do not get better. Not to say anything about the toil on the family and patient.
Treatment strategies
Let’s start here with a June 2023 paper from Dr. Matthew B. Carroll published in the journal Rheumatology and Immunology Research (10). Dr. Carroll’s paper outlines treatment suggestions and provides clinicians with the rationale for the update in treatments and understanding the musculoskeletal and extra-articular manifestations of the subtypes of HSDs, considerations when making the diagnosis, and treatment.
Writes Dr. Carroll: “Pharmacologic treatment strategies are similar to that for other chronic pain conditions with avoidance of opioids and deference toward non-steroidal anti-inflammatory drugs (NSAIDs)/acetaminophen, topical NSAIDs, and antidepressants (particularly serotonin and norepinephrine reuptake inhibitors (SNRIs) or low-dose tricyclic antidepressants (TCAs). Muscle pain or spasms may be treated with antispasticity agents such as baclofen or tizanidine, although patients with exercise intolerance or orthostatic symptoms may not tolerate TCAs or tizanidine. Patients with comorbid fibromyalgia may benefit from gabapentin or pregabalin.
He concludes: “The current treatment of pain borrows from studies using older nomenclature (diagnostic labels) as well as management of other chronic pain syndromes. A multidisciplinary approach is likely optimal, incorporating specialists such as physical therapists and mental health specialists to address the regional and chronic pain that patients with subtypes of HSD experience.”
An August 2023 paper (11) led by the KITE Research Institute, Toronto Rehabilitation Institute – University Health Network, and the University of Toronto identified the nature and extent of the evidence on psychological interventions among individuals with Ehlers-Danlos Syndrome (EDS) and Hypermobility Spectrum Disorder (HSD). The researchers here expressed a “critical need for high-quality research surrounding psychological interventions for individuals with EDS/HSD. Psychological interventions for these individuals are understudied and existing studies lack validity.”
The problem of just treating symptoms
When there is confusion as to the cause of the patient’s problems and there is confusion with how to treat this patient, the fallback, as many of you know, is to treat the symptoms until hopefully an underlying cause can be found. Sometimes all there is is treating symptoms with the hope of improving the person’s daily quality of life.
An April 2021 paper in the journal of the American Academy of Family Physicians (12) offered guidance to general practitioners on looking beyond joint dislocation and joint pain. Here the study authors suggested the role of the family doctor in helping patients with Hypermobile EDS.
“Hypermobile EDS and, less commonly, hypermobility spectrum disorders may also be associated with several extra-articular symptoms, including anxiety disorders, chronic pain, fatigue, orthostatic intolerance, functional gastrointestinal disorders, and pelvic and bladder dysfunction.
The central goals of therapy are managing symptoms, preventing joint injury, and educating patients about their condition.
Based on limited evidence, patients with hypermobile EDS/hypermobility spectrum disorders may benefit from physical and occupational therapy, psychological support, and self-management. Primary care physicians play a key role not only in initial recognition, diagnosis, and patient education, but by virtue of their ongoing relationship they can also help oversee and coordinate the multidisciplinary team many of these patients require.”
The suggestion here is that the family doctor help coordinate and evaluate the patient’s treatment as many times the patient will see specialist after specialist and as you yourself may know first-hand, sometimes the specialists do not communicate and the patient is now thrown into a situation of isolated treatments without an understanding of the overall or holistic experience.
Treating the symptom of pain: Research suggests overall expert consensus indicates that pain medications are often not effective in long-term treatment.
The idea that Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders can be managed long-term with pain medications, anti-inflammatories, and opioids is being discredited. These pain medications can be beneficial in the short-term, and detrimental in the long-term.
In November 2018, a review of patient outcomes and the medical research surrounding the management of pain was published in the medical journal Medicine(13) by a team of Canadian researchers. This review is a guide to helping other doctors understand the pain challenges ofEhlers-Danlos Syndromes patients.
Here are some of the learning points shared with clinicians:
- Chronic pain is common in EDS, particularly in the hypermobility type.
- According to one study, nearly 90% of patients report some form of chronic pain.
Some of the things doctors should look for:
- Nociceptive, joint pain (acute pain following an injury that sometimes does not go away after the injury has healed). This the researchers suggest is usually the first manifestation of pain in EDS
- These injuries are usually joint traumas such as dislocations and sprains as well as “growing pains.”
- The most commonly involved joints are the shoulder (80%), hands (75%), and knees (71%).
- “Clumsy” or “Klutzy” behavior. The researchers suggest that patients will often describe themselves in this manner because, among balance issues (poor proprioception see below), they are constantly dropping things.
- The recurrent dislocations due to joint laxity and associated trauma are further amplified by poor proprioception, (the body’s sense of awareness in space and movement and communication, or lack of coordination to the limbs to keep the body steady and no fallover.) This leads patients to have a fear of falling and kinesiophobia (being afraid to move) which are common complaints. Catastrophizing thoughts are also present.
- Doctors should look for TMJ pain which can also be a significant source of disability in 70% of Ehlers–Danlos patients.
- Severe chronic fatigue is now considered a common accompanying feature of EDS. It is reported in up to 95% of patients and in many cases was reported by patients to be more debilitating than pain. The frequency of fatigue is influenced by age.
- Psychological distress, fatigue, and sleep disturbances are common
- High prevalence of anxiety and panic disorders.
What type of pain medications should be offered?
- Tylenol and nonsteroidal anti-inflammatory medications (NSAIDs) are suggested for mild to moderate pain. However, the use of NSAIDs is limited due to poor tolerance secondary to comorbid gastrointestinal issues in EDS patients.
- Opioids may be an option, but only for a short duration. There is good evidence that long-term treatment with opiates is not a viable option and may lead to central pain sensitization. Tramadol could be considered as an alternative.
- Steroids have been found to be helpful in acute exacerbation of joint pains. However, care must be taken to avoid long-term use to prevent steroid-related side effects.
- For nerve-related pain tricyclic antidepressants, anticonvulsants, serotonin, and norepinephrine reuptake inhibitors, and other antidepressants may be used with caution given an increased risk of dysautonomia in EDS.
- Muscle relaxants such as baclofen can be helpful for painful muscle spasms but are discouraged for routine use due to the theoretical risk of increasing joint instability and consequently worsening pain.
- No evidence exists regarding the use of medical marijuana in the treatment of EDS patients. Anecdotally it works better than opioids.
- Overall expert consensus indicates that pharmacological treatments are often not effective in long-term treatment.
In 2013, Caring Medical research led by Ross Hauser, MD, published in the Journal of Prolotherapy(14) made these same points and added that many of these medicines accelerate joint destruction.(15)
“Pain management is a critical element in the treatmentof hypermobility. While physical therapy and exercise may lend some degree of pain relief, individuals withhypermobility often require additional measures tomanage joint pain. Patients with hypermobility disordersare often prescribed large doses of pain medication,such as acetaminophen, muscle relaxants, NSAIDs, and
antidepressants; over time, stronger medications (includingnarcotics) and higher doses may be required to deal withthe effects of chronic pain.
These medications are helpfulin the management of symptoms that prohibit patients fromcarrying out certain activities, but they have no effectin treating the underlying pathology of hypermobilityand, in some cases, they may actually have a negativeeffect on joint tissues.
Non-steroidal anti-inflammatorydrugs (NSAIDs) are one class of medications commonlyprescribed for joint pain but can have a combativeeffect on joint health, due to their role in inhibiting thesynthesis of collagen and articular cartilage synthesis.This can cause not only weakness in ligaments, but also in cartilage, tendon, and bone cells, contributing to anoverall weakening of the joint.”
Understanding pain, Managing pain, and Healing pain. Medicine searches for answers
When we see patients with Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders we understand the amount of pain that can be involved, we also need the patient to understand what we are going to try to do is get rid of the pain by regenerating and repairing and healing connective tissue with Prolotherapy injections. The way we go about pain management is we try to heal joint and connective tissue damage. Understanding the treatment program is crucial.
Physical therapy
A June 2021 study in the American Journal of Medical Genetics Part A (16) comes to us from a team of Belgium researchers and physical therapists. The objective of this paper was to investigate the effect of the different physiotherapy (PT) techniques related to children and adult patients with hEDS. To do this the researchers compiled dates from six previously published studies.
Here are the learning points of the researchers:
- Physiotherapy techniques are regularly prescribed for the hypermobile type Ehlers-Danlos syndrome (hEDS) and they are appreciated by the patients.
- However, there were vast differences in the types of physical therapy prescribed without a true standardization
- The duration of the program was from 4 to 8 weeks.
- Pain or proprioception demonstrated significant improvements in the intervention group regardless of the type of intervention.
- A benefit of the inspiratory muscle training was observed in functional exercise capacity. The quality of life was systematically improved. Physiotherapy benefits proprioception and pain in patients with hEDS even if robust randomized control studies are missing.
Prolotherapy Treatment for hEDS
Let’s revisit the paper we cited abovepublished in June 2016 in the medical journal Disability and Rehabilitation. Let’s look at the problems of the treatment options noted in this research.
“Participants with Ehlers-Danlos Syndrome reported the most helpful methods for managing acute pain were opioids, surgical interventions, splints and braces, heat therapy, nerve blocks, and physical therapy, while chronic pain was treated most effectively with opioids, heattherapy, splints or braces and surgical interventions.”
COMMENT:
- With new research on the hazards and side-effects or opioids and other painkiller medications can we really call a lifetime dependency on medications the MOST effective treatment?
- Surgeries may be risky due to very sensitive inner organs as well as an inclination to sprains and dislocations.
- Nerve blocks may be effective for those with multiple failed treatments or “no other way,” to alleviate their pain.
We believeProlotherapy offers great hope to those with symptoms of hypermobility because it is designed to successfully treat the ligament and tendon laxity that accompanies Ehlers-Danlos Syndrome and Joint Hypermobility Syndrome, as well as strengthen the joints in the body.
If we takesplints and braces, heat therapy, and physical therapy treatments at face value we find a group of treatments that seek to stabilize a painful joint (hold it together with splints and braces), bring circulation to the joint, (heat therapy), stresses movement (physical therapy) to build up strength in the joint. These are all part of the therapeutic properties of Prolotherapy injections.
- Symptoms of EDS are from a progressive destructive ligament problem
- Symptoms of joint instability are from a progressive destructive ligament problem causing ligament laxity and hypermobility.
- Unresolved or untreated joint instabilities lead to progressive joint destruction and the rapid development of osteoarthritis.
- Progressive joint destruction is not limited to the affected joint, a knee for example, but progressive joint destruction influences on degenerative knee disease and can cause a cascading effect that leads to rapid development of the adjacent joints such as degenerative hip disease, degenerative disc disease, and degenerative ankle disease.
- When progressive destructive ligament problems impact the cervical spine the neurological system of the entire body becomes compromised. We often see patients with a myriad of symptoms that include the blockage of cerebral spinal fluid, tension on the cervical spinal cord, and brainstem compression of the vertebral basil artery and compression of the vagus nerve.
- Multiple joint instabilities cause most of the disabling symptoms from EDS. Repairing these multiple joint instabilities would resolve most of the horrific symptoms of EDS.
- Prolotherapy causes joint tightening. Prolotherapy should be considered for joint instability including those who have EDScauses joint instability from ligament laxity ligaments are the primary stabilizers of the joint so in other words it’s really the ligaments that control the motion of the joint if someone has ligament laxity the joints are going to move in a destructive manner most of the nerve endings that give pain in the joints are in the ligament so it means that if somebody has pain you have joint pain whether you have eds are you have any kind of joint instability the actual pain is stemming from the nerve endings in the ligament the articular cartilage itself has no nerve endings
Our research Prolotherapy andEhlers-Danlos Syndrome (hEDS) and Joint Hypermobility Syndrome (Hypermobility Spectrum Disorders (HSD)).
Above we cited this research in the Journal of Prolotherapy in 2013. The fullresearch can be downloaded as a PDF file – Treatment of Joint Hypermobility Syndrome, Including Ehlers-Danlos Syndrome, with Hackett-Hemwall Prolotherapy.
Here are our bullet points:
- While traditional medical treatments including education and lifestyleadvice, behavior modification, physiotherapy, taping and bracing,exercise prescription, functional rehabilitation and pain medicationsoffer some symptomatic control, they do little in regard to curbingthe progressive debilitating nature of the diseases.
- The excessivejoint mobility with its subsequent joint degeneration and multiplejoint dislocations, can then lead the individual to seek out surgicalintervention, which has suboptimal results in the hypermobile patientpopulation versus the normal population. As such, some patientswith Ehlers-Danlos Syndrome (hEDS) and Joint Hypermobility Syndrome (HSD) are seeking alternative treatments for their pain,including Prolotherapy.
- Prolotherapy offers great hope for those with symptoms fromgeneralized hypermobility because it is designed to successfullytreat the ligament and tissue laxity that accompanies Ehlers-Danlos Syndrome and Joint Hypermobility Syndrome.
- Prolotherapy works by initiating a brief inflammatory response, whichcauses a reparative cascade to generate new collagen and extra cellular matrix giving connective tissue strength and ability to handle strain and force.
- Prolotherapy has a long history of success treatingligament injuries, including patients with joint hypermobility.
- Studieson Prolotherapy have shown that it eliminates chronic pain even inthose patients who have been told by their medical doctor(s) thatsurgery was the only treatment option for their pain.
Some of the rationale for using Prolotherapy for patients with Ehlers-Danlos Syndrome and Joint Hypermobility Syndrome include that it has:
- a high safety record, is comprehensive (allor most joints can be treated at each visit),
- is an outpatient procedure,
- is cost effective (compared to surgery),
- pain relief is often quick,
- andit provides joint stabilization.
Perhaps its greatest asset is the factthat this one treatment modality can handle most of the painfulmusculoskeletal conditions that occur in individuals with Ehlers-Danlos Syndrome and Joint Hypermobility Syndrome.
Case example of Kristle Lowell, Double Mini-Trampoline World Champion
https://members.usagym.org/pages/athletes/nationalTeamTT.html?id=601791
- 2022 U.S. double mini silver medalist
- 2018 World double mini bronze medalist
- 2018 U.S. double mini bronze medalist
- 2016 U.S. double mini champion
- 2015 World double mini team bronze medalist
- 2015 U.S. double mini silver medalist
- 2013 World double mini & double mini team champion
- 2013 U.S. double mini champion
- 2012 U.S. double mini bronze medalist
- 2011 World double mini team bronze medalist
- 2011 U.S. double mini silver medalist
Ehlers-Danlos Syndrome causes pain when the force on the joint tissues is greater than the strength of those tissues. When the ligaments can no longer hold the adjacent bones in place, the medical condition is called joint instability. The extreme form of joint instability is joint dislocation. Kristle Lowell, the 2013 World Champion in Double Mini-Trampoline can dislocate many of her joints. (See Figure 4.) Her story is a common one heard from those suffering from EDS.
When Kristle started gymnastic training as a child, she knew she had excessive flexibility, but this also helped her excel. Her flexibility allowed her to perform certain maneuvers that the other children could not. She suffered her first serious injury in 2014, a severe ankle sprain. Afterward, the ankle would pop and click constantly, and the pain was extreme with sprinting, which is a vital component of double mini-trampoline. The sprint is what provides the momentum to do all the turns and flips during the routine. Sprinting and landing became extremely painful, enough so that the injury precluded her from competing at the 2014 World Championships. It was during this time that she was diagnosed with EDS.
Kristle received corticosteroid shots, which provided temporary relief, however, the ankle pain and instability progressed. She tried physical therapy, though it did not help. The ankle pain and clicking were constant. Like many with EDS, she lived with the fear that at any moment her ankle would sublux and possibly dislocate. Sometimes, just the simple act of getting out of bed would cause the ankle to move out of its normal location. Depression started to set in.
Kristle came to Caring Medical for an evaluation. Upon physical exam and MRI review, it was clear that she had significant ligament damage in both the front and back of her ankle. Her most significant instability was in the posterior ankle. As her physician, I was confident Prolotherapy could help her. She received her first Prolotherapy session in March of 2015. Over the course of the next weeks, she reported a tightening of her ankle to the point where it was no longer dislocating. She was able to return to training full-time. After Prolotherapy, she came in second in double mini-trampoline at the 2015 USA Gymnastics Championships, which are the national championships for trampoline/tumbling, acrobatic gymnastics, and rhythmic gymnastics. She qualified for the U.S. World Championships Team for the 2015 World Championships in Odense, Denmark. After the national competition, she came in for one more Prolotherapy treatment to help tighten her ankle ligaments so they could withstand the rigor of training for the World Championships.
Since receiving Prolotherapy, Kristle continues to receive both National and International competitions including placing first in the 2017 Winter Classic in Battle Creek, Michigan and first in the 2016 USA Gymnastic Championships in Providence, Rhode Island.
Can joint instability in hEDS be objectively measured?
Joint instabilities can be objectively documented with motion ultrasound and digital imaging (fluoroscopy). Peripheral joints are typically examined under ultrasound and the amount of joint instability recorded, measured and documented.
As the patient is treated with Prolotherapy, the improvement in the joint stability can also be objectively measured. Treatment is normally continued until joint stability has been restored.
Joint instability in the spine is documented through digital motion imaging (fluoroscopy). Typically when a patient is scanned on the first visit, instabilities at multiple levels are found.
This information is key because it helps in treatment by:
- Documenting where the instabilities are located.
- Verifying if a patient is a Prolotherapy candidate (versus a surgical candidate).
- Establishing the severity of the instability.
- Demonstrating the instability to the patient, their family, and their health providers.
- Assisting in key decision making including whether the instability is so severe that bracing or curbing of certain activities is necessary.
- Validating that the Prolotherapy treatments are working as the patient is re-scanned (mini-scan) after every two visits.
- Confirming joint stabilization so the patient can be discharged.
Joint instability can be objectively measured and treatment efficacy validated. These are key components of the Prolotherapy regimen at Caring Medical.
Our specialists can help you relieve pain and improve your joint stability, whether you need an official evaluation for EDS and diagnosis, or if you have already been to 10+ providers, and want to see if you are a good candidate for Prolotherapy.
References
1 Sulli A, Talarico R, Scirè CA, Avcin T, Castori M, Ferraris A, Frank C, Grunert J, Paolino S, Bombardieri S, Schneider M. Ehlers-Danlos syndromes: state of the art on clinical practice guidelines. RMD open. 2018 Oct 1;4(Suppl 1):e000790.[Google Scholar]
2 Hope L, Juul-Kristensen B, Løvaas H, Løvvik C, Maeland S. Subjective health complaints and illness perception amongst adults with Joint Hypermobility Syndrome/Ehlers–Danlos Syndrome-HypermobilityType–a cross-sectional study. Disability and Rehabilitation. 2017 Oct 17[Google Scholar]
3 Schubart JR, Mills SE, Francomano CA, Stuckey-Peyrot H. A qualitative study of pain and related symptoms experienced by people with Ehlers-Danlos syndromes. Frontiers in Medicine. 2024 Jan 3;10:1291189.
4 Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology. am J Med genet. 1998 Apr;77(1):31-7. [Google Scholar]
5 Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M. The 2017 international classification of the Ehlers–Danlos syndromes. In American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2017 Mar 1 (Vol. 175, No. 1, pp. 8-26).[Google Scholar]
6 Baeza-Velasco C, Bulbena A, Polanco-Carrasco R, Jaussaud R. Cognitive, emotional, and behavioral considerations for chronic pain management in the Ehlers–Danlos syndrome hypermobility-type: A narrative review. Disability and rehabilitation. 2019 Apr 24;41(9):1110-8. [Google Scholar]
7 Guerrieri V, Polizzi A, Caliogna L, Brancato AM, Bassotti A, Torriani C, Jannelli E, Mosconi M, Grassi FA, Pasta G. Pain in Ehlers–Danlos Syndrome: A Non-Diagnostic Disabling Symptom?. InHealthcare 2023 Mar 24 (Vol. 11, No. 7, p. 936). MDPI. [Google Scholar]
8 Arthur K, Caldwell K, Forehand S, Davis K.Pain control methods in use and perceived effectiveness by patients with Ehlers-Danlos syndrome: a descriptive study.Disabil Rehabil. 2016 Jun;38(11):1063-74.[Google Scholar]
9 Stern CM, Pepin MJ, Stoler JM, Kramer DE, Spencer SA, Stein CJ. Musculoskeletal Conditions in a Pediatric Population with Ehlers-Danlos Syndrome. J Pediatr. 2017 Feb;181:261-266. doi: 10.1016/j.jpeds.2016.10.078.[Google Scholar]
10 Carroll MB. Hypermobility spectrum disorders: A review. Rheumatology and Immunology Research. 2023 Jul 22;4(2):60-8. [Google Scholar]
11 Song JZ, Luong D, Feldman EC, Tran S, Perrier L, Eubanks K, Bayley M, Kastner M, Slepian M, Munce SE. Psychological interventions for individuals with Ehlers-Danlos syndrome and hypermobility spectrum disorder: a scoping review. Orphanet Journal of Rare Diseases. 2023 Aug 31;18(1):254. [Google Scholar]
12 Yew KS, Kamps-Schmitt KA, Borge R. Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders. American Family Physician. 2021 Apr 15;103(8):481-92. [Google Scholar]
13 Zhou Z, Rewari A, Shanthanna H. Management of chronic pain in Ehlers–Danlos syndrome: Two case reports and a review of literature. Medicine. 2018 Nov;97(45). [Google Scholar]
14 Hauser R, Phillips HJ. Treatment of joint hypermobility syndrome, including Ehlers-Danlos syndrome, with Hackett-Hemwall prolotherapy. J Prolotherapy. 2011 May;3:612-29.[Google Scholar]
15 Hauser RA. The acceleration of articular cartilage degeneration in osteoarthritis by nonsteroidal anti-inflammatory drugs. Journal of Prolotherapy. 2010;2(1):305-22.[Google Scholar]
16 Reychler G, De Backer MM, Piraux E, Poncin W, Caty G. Physical therapy treatment of hypermobile Ehlers–Danlos syndrome: a systematic review. American Journal of Medical Genetics Part A. 2021 Oct;185(10):2986-94. [Google Scholar]