ENMC recommendations on optimal diagnostic pathway and management strategy for patients with rhabdomyolysis worldwide.

276th ENMC International Workshop:

Location: Hoofddorp, The Netherlands

Title: ENMC recommendations on optimal diagnostic pathway and management strategy for patients with exertional rhabdomyolysis worldwide

Date: 15.-17. March 2024

Organizers:
Salman Bhai (USA), Pascal Laforet (France), John Vissing (Denmark), Nicol Voermans (The Netherlands)

Early career researchers:
Nick Kruijt (The Netherlands), Felix Kleefeld (Germany) and Mads Stemmerik (Denmark)

Translations of this report by:
German by F. Kleefeld
Dutch by N. Kruijt
Danish by J. Vissing
Swedish by A. Oldfors
French by P. Laforet
Persian by F. Fatehi
Italian by G. Siciliano

Participants:

N. Kruijt (The Netherlands- Early-Career Researcher), P. Laforet (France), J. Vissing (Denmark), N. Voermans (The Netherlands), S. Bhai (USA), F. Kleefeld (Germany, Early-Career Researcher), M. Stemmerik (Denmark, Early-Career Researcher), B. Schoser (Germany), G. Siciliano (Italy), R. Quinlivan (United Kingdom), N. Roux-Buisson (France), G. Ravenscroft (Australia), A. Oldfors (Sweden), A. Roos (Germany), F. O'Connor (USA), S. Riazi (Canada), V. Gupta (USA), T. Liewluck (USA), F. Fatehi (Iran), G. McMahon (Australia, virtually), A. Lucia (Spain, virtually), E. Oates (Australia, virtually), A. Ferreiro (France), F. Sanders (The Netherlands, patient representative), J. Fonville (The Netherlands, patient representative)

Workshop summary

The 276^th ENMC workshop was held from March 15 to March 17, 2024. A total of 21 physicians and researchers from 12 different countries (Australia, Canada, Denmark, France, Germany, Italy, Iran, the Netherlands, Spain, Sweden, UK, USA) attended the workshop, as well as two patient representatives. The aim of the workshop was to define an optimal diagnostic pathway and management strategy for patients with exertional rhabdomyolysis (ERM). ERM is the uncontrolled breakdown of skeletal muscle due to exercise, which is a potentially life-threatening condition due to the risk of severe kidney failure. Nevertheless, the exact definition of the condition is topic of debate, resulting in very different diagnostic and treatment approaches worldwide. Therefore, guidelines have yet to be harmonized.

Day 1
In the workshop's opening session on Friday, unmet needs and open questions about rhabdomyolysis were presented and discussed. The participants agreed that no standardized approach to diagnosing and treating the condition exists.
Measuring muscle enzymes in the blood, including creatine kinase (CK), is widely used as a primary assessment in the diagnosis, but there is no consensus on which CK levels are within the limits of normal, and which levels should be considered rhabdomyolysis and subsequently treated. Therefore, many people receive unneeded treatment and would recover without such a treatment.

The next talk discussed the mechanism behind rhabdomyolysis and what distinguishes it from a normal response to excessive exercise. The event is a normal response if:

I)   CK values are less than 50 times the ‘upper limit of normal’ (<10,000 U/L);

II)  None of the following symptoms are present: muscle swelling, muscle weakness, or myoglobinuria (i.e., cola- or coffee colored urine)

III) The laboratory results show no signs of kidney injury or imbalance of electrolytes.

The experts discussed risk factors for the condition, such as type of exercise, environmental  factors, but also genetics and certain diseases. Specific diseases that can cause rhabdomyolysis that were discussed included glycogen storage disorders, fatty acid oxidation disorders, and mitochondrial diseases. It was also highlighted that patients suffering from muscular dystrophies (e.g., Limb Girdle Muscular Dystrophy, or Duchenne Dystrophy) are at a higher risk for developing rhabdomyolysis. In addition, rare cases of rhabdomyolysis in children were discussed, focusing on two inherited genetic causes in the RYR1 and LPIN1 genes, which cause a spectrum of symptoms, including severe rhabdomyolysis.

Day 2
On Saturday, after discussing the wide spectrum of causes, the participants discussed how physicians currently diagnose ERM. Before the workshop, a survey amongst 60 specialists was distributed. The survey results showed that different countries have very different approaches to rhabdomyolysis, so the discussion focussed on formulating very clear criteria for a diagnosis. Next, two patient/patient representatives shared their story and experiences, including the father of a young athlete who died from a heat stroke. A second representative shared his story on rhabdomyolysis while suffering from a heat stroke (severe overheating of the body temperature) during a marathon, even though he was a very well-trained athlete. The patient representatives expressed the importance of acquiring more reliable information, counseling, and psychological support. They expressed a clear wish that more frequent follow-up would have been beneficial for their recovery process; not only physically but also mentally. This was further discussed, as this was in line with one of recent studies that a participating physician performed amongst 60 athletes.

The following talks focused on new genetic tests and procedures that could help physicians diagnose a possible genetic cause for rhabdomyolysis. It was highlighted that the genes included in the genetic work-up of rhabdomyolysis currently need to be standardized. The role of muscle biopsies in the diagnostic process can be helpful in specific cases, but nowadays genetic testing should be the first approach.

A physician from the USA army discussed how rhabdomyolysis affects not only athletes but is an important problem amongst military personnel. They examined how intense exercise and heat can increase the risk of rhabdomyolysis, especially in these groups. Experts shared stories from the military and sports fields, discussing the unique challenges faced by these individuals and how to keep them safe, as well as from the perspective of occupational medicine to attempt to not let them drop out of their work as a military servant.

Lastly, it was discussed how to support people with rhabdomyolysis after recovery. This is important since there is a risk of developing a second event if individuals start too fast with their daily activities or sports. Managing ongoing symptoms and helping people get back to exercising safely is a topic that requires more attention in clinical practice.

Day 3

On Sunday, experts worked together to summarize the gaps in our knowledge about rhabdomyolysis, as a starting point for discussion to develop guidelines on improved ways to diagnose and treat it. In addition, this should ultimately help people with this condition to have better quality of life. It was concluded that the definition of ERM should include symptoms (e.g., muscle pain, swelling) and laboratory tests (e.g., CK, kidney function) to identify patients at risk of developing severe complications. At the same time, patients with chronic CK elevation and/or underlying conditions causing recurrent episodes should not be overtreated.

A full report on definitive diagnostic guidelines and therapeutic recommendations will be published in the medical journal Neuromuscular Disorders.