Prolotherapy for Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders

Prolotherapy for Ehlers-Danlos Syndromes

Ross Hauser, MD

In this article, we will lay the foundation for 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.

EDS and hypermobility is very treatable with Prolotherapy, see our main page Prolotherapy for EDS & Hypermobility pain for more information.

  • Note: The various subtypes of Ehlers-Danlos Syndromes require molecular testing to confirm diagnosis, except for the Hypermobile Ehlers-Danlos Syndrome (hEDS) type. This is an important point we will cover throughout this article.
  • As we are always updating research, a brief explanation of updated terminology is necessary. Ehlers-Danlos Syndrome is now known as the Ehlers-Danlos Syndromes. Various new designations for the subtypes also have new terminology. We will use this terminology in parenthesis when we discuss research from the past few years.

In 2017, the American Journal of Medical Genetics published an internationally agreed upon 2017 EDS Classification. This was the first such classification update since 1997. The new classifications seek to more specifically identify EDS patient symtopms and try to offer recommendation to treatment.

The 2017 international classification of the Ehlers-Danlos syndromes – helping identify hypermobile Ehlers-Danlos Syndrome (hEDS) type can be diagnosed without genetic testing

Nosology is the study of diseases. It derives from the greek Nosos (diseases) and logia, the study of. Nosologies for Ehlers-Danlos syndromes have been revised for decades.

In 1998 a landmark paper from Peter Beighton of the University of 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 of Ehlers-Danlos syndromes. Here are the highlights of that research.(1)

  • Categorization of the Ehlers-Danlos syndromes 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 replace the Berlin nosology. In it six subtypes of Ehlers-Danlos syndromes were described. Now Ehlers-Danlos syndrome became 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 called EDS3
    • Ehlers-Danlos syndrome type 3
    • Ehlers-Danlos syndrome hypermobility 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 (46) doctors and researchers co-published in the American journal of medical genetics: The 2017 international classification of the Ehlers-Danlos syndromes. 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 for 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).(2)
    • COMMENT: The various subtypes of Ehlers-Danlos Syndromes require molecular testing to confirm diagnosis, except for the hypermobile type.

The new classifications tries to address a stuck medicine and a stuck diagnosis waiting time


The patients could get better if they knew what their disease was and what how to come up with a more holistic (whole body) treatment approach

Doctors presenting in the American journal of medical genetics, present a summary of Ehlers-Danlos Syndromes and the problems of understanding. In this study, not only is joint hypermobility discussed, but the problems of headache and other head and neck problems related to cervical neck hypermobility / instability. Here are their learning points:

  • Ehlers-Danlos Syndromes may be thought of as an umbrella term for a growing group of hereditary disorders of the connective tissue mainly manifesting with generalized joint hypermobility, skin hyperextensibility, and vascular and internal organ fragility. 
  • Generalized joint hypermobility leads the patient challenges to also be called joint hypermobility syndrome (Hypermobility Spectrum Disorders).
  • The connective tissue of individuals with this syndrome neither forms nor heals properly.
  • Most (hEDS) patients share a nearly normal life span, but are severely limited by disabling features, such as pain, fatigue and headache.
    • Headache is reported in 1/3 of the patients. Migraine is the most common type.
    • Other possibly related headache disorders include tension-type headache, new daily persistent headache, headache attributed to spontaneous cerebrospinal fluid leakage, headache secondary to Chiari malformation, cervicogenic headache and neck-tongue syndrome, whose association still lacks of reliable prevalence studies. (Comment: Please watch the video below)
  • The underlying disease causing problems seems complex and variably associated with cardiovascular dysautonomia (the autonomic nervous system is disrupted causing irregular heartbeats and blood pressure drops), cervical spine instability and temporomandibular joint instability/dysfunction, meningeal fragility, poor sleep quality, pain-killer drugs overuse and central sensitization (A constant and heightened sense of pain). Particular attention is posed on a presumed subclinical cervical spine dysfunction.

The problem to these researchers as they state in their is shared by patients, “standard treatment is always symptomatic (just treats the symptoms) and usually unsuccessful.”(3)

An October 2017 study from university hospital researchers in Norway was published in the medical journal Disability 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 prognosis for these patients is poor.
  • The problem of patient information: Awareness of the complexity of the symptoms and disease could contribute with valuable information about these patients’ perceptions of their condition. Such information could in its turn be of value for clinicians as they work towards facilitating a more holistic treatment approach.(4)

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 what how to come up with a more holistic (whole body) treatment approach.


Medicine struggles for a better understanding of 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 suggests that medical research seems to be stuck. Here a reiteration of the problems expressed in the 2015 and 2017 studies listed above. This research come 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 on-line 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.(5)

Searching for a criteria for Ehlers-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 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 clinic 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 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 issue 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: Despite extensive 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.(6)

Comment: As above, we have a patient with a lot of health challenges. The many doctors and many tests they had came 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.

In this video, you will meet our patient, Louise, watch her brave battle with Ehlers-Danlos Syndrome, and see the courage it took for her and her family to travel from Europe to come to Caring Medical for Prolotherapy. Since her treatment she has been able to go back into sports she thought she would no longer be able to participate in. Louise is a wonderful example of the Prolotherapy as a treatment for Ehlers-Danlos Syndrome. We are grateful for her and her mother’s wish to share their story.

A brief summary of Hypermobile Ehlers-Danlos syndrome – making a diagnosis of hEDS in clinical evaluation as there is 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.(7)

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 does not include genetic testing

This is 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 which 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 the joint symptoms; they often impair daily life, and they should be considered and treated.(7)

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:

  1. One point if while standing forward bending you can place palms on the ground with legs straight.
  2. One point for each elbow that bends backwards.
  3. One point for each knee that bends backwards.
  4. One point for each thumb that touches the forearm when bent backwards.
  5. One point for each little finger that bends backwards beyond 90 degrees.

Criteria 2: Two or more of the following features must be present (A&B, A&C, B&C, or A&B&C):

Feature A—systemic manifestations of a more generalized connective tissue disorder (a total of 5 out of 12 must be present)


  1. Unusually soft or velvety skin
  2. Mild skin hyperextensibility
  3. 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.
  4. Bilateral piezogenic papules of the heel (solid painful pimples)
  5. Recurrent or multiple abdominal hernia(s) (e.g., umbilical, inguinal, crural)
  6. Atrophic scarring involving at least two sites (Atrophic scarring are depressions in the skin commonly referred to as pockmarks).
  7. 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
  8. Dental crowding and high or narrow palate
  9. Arachnodactyly (abnormally long and thin fingers), as defined in one or more of the following:
    1. positive wrist sign (Steinberg sign) on both sides (Your pinky and thumb can touch when your circle your wrist with them);
    2. 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)
  10. Your arm span is greater than your height
  11. Mitral valve prolapse (MVP) mild or greater based on strict echocardiographic criteria
  12. 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 ):


  1. Musculoskeletal pain in 2 or more limbs, recurring daily for at least 3 months
  2. Chronic, widespread pain for more than 3 months
  3. 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:

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.

Prolotherapy Treatment for hEDS

Let’s revisit the paper we cited above published in June 2016 in the medical journal Disability and rehabilitation. Let’s look at the problems of the treatment options noted in this reaserch.

“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, heat therapy, splints or braces and surgical interventions.”(5)

COMMENT:

  • With new research of 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 believe Prolotherapy 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 take splints 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.

Our research Prolotherapy and Ehlers-Danlos Syndrome (hEDS) and Joint Hypermobility Syndrome (Hypermobility Spectrum Disorders (HSD)).

This is research I presented with Hillary Phillips in the Journal of Prolotherapy in 2013. The full research 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 lifestyle advice, behavior modification, physiotherapy, taping and bracing, exercise prescription, functional rehabilitation and pain medications offer some symptomatic control, they do little in regard to curbing the progressive debilitating nature of the diseases.
  • The excessive joint mobility with its subsequent joint degeneration and multiple joint dislocations, can then lead the individual to seek out surgical intervention, which has suboptimal results in the hypermobile patient population versus the normal population. As such, some patients with 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 from generalized hypermobility because it is designed to successfully treat the ligament and tissue laxity that accompanies Ehlers-Danlos Syndrome and Joint Hypermobility Syndrome.
  • Prolotherapy works by initiating a brief inflammatory response, which causes a reparative cascade to generate new collagen and extra cellular matrix giving connective their strength and ability to handle strain and force.
  • Prolotherapy has a long history of success treating ligament injuries, including patients with joint hypermobility.
  • Studies on Prolotherapy have shown that it eliminates chronic pain even in those patients who have been told by their medical doctor(s) that surgery 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 (all or most joints can be treated at each visit),
  • is an outpatient procedure,
  • is cost effective (compared to surgery),
  • pain relief is often quick,
  • and it provides joint stabilization.

Perhaps its greatest asset is the fact that this one treatment modality can handle most of the painful
musculoskeletal conditions that occur in individuals with Ehlers-Danlos Syndrome and Joint Hypermobility Syndrome.

Case example of Kristle Lowell, Double Mini-Trampoline World Champion

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.

Figure 4.
Joint Hypermobility due to Ehlers-Danlos Syndrome

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 Regenerative Medicine Clinics in Chicagoland (second location in Fort Myers, Florida) 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.

Most patients require three to six sessions of Prolotherapy to resolve their joint instability. For over twenty years Caring Medical Regenerative Medicine Clinics have been treating EDS patients with Prolotherapy. When I wrote the book Prolo Your Pain Away! in 1995, I included a section on treating the pain and joint instability of EDS with Prolotherapy. (Available at Amazon.com and as a Free e-book) I have also had the opportunity to treat many of the sequelae of EDS, including postural orthostatic tachycardia syndrome (POTS) and dysautonomia. These conditions are often due to moderate to severe cervical instability, which can be treated successfully with Prolotherapy. (See Figure 5.)

To contact Kristle Lowell, you can follow her on Instagram and Youtube.

Rebecca the dancer’s story

If you have questions about Prolotherapy for Ehlers-Danlos Syndrome You can get help and information from our Caring Medical staff

1 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]

2 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]

3 Castori M, Morlino S, Ghibellini G, Celletti C, Camerota F, Grammatico P. Connective tissue, Ehlers-Danlos syndrome(s), and head and cervical pain. Am J Med Genet C Semin Med Genet. 2015 Feb 5. doi: 10.1002/ajmg.c.31426. [Google Scholar]

4 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]

5 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]

6 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]

7 Hypermobile Ehlers-Danlos syndrome, National Institute of Health, Rare Diseases Info.

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