Rhabdomyolysis –

Causes, Tests and Management

Maria Elena Farrugia
Consultant Adult Neurologist, Glasgow
What is Rhabdomyolysis?
• A serious life-threatening condition due to direct or indirect injury to
muscle tissue

• Rapid breakdown and death of skeletal muscle fibres, leading to the

release of potentially toxic cellular contents into the circulation

• Should be distinguished from other causes of pigmentation in urine

eg drugs, haemolysis (breakdown of red blood cells) and porphyria
Rhabdo cont’d
• Creatine kinase levels rise to significant levels

• Normal range 40-320 U/L. In Rhabdo – CK can rise to x10 as much. We

have had patients with CKs rising to 1 million U/L.

• Can be a single event or recurrent

• If recurrent – genetic disorder more likely

Consequences
• Sarcolemmal injury results in Na/K- ATPase and Ca-ATPase pump
dysfunction
• High intracellular calcium levels enhance activation of calcium
dependent proteases and phospholipases with destruction of
myofibrillar, cytoskeletal and membrane proteins
• K+, PO4-, urate, aldolase, creatine kinase, myoglobin, AST and LDH
leak into circulation
• Myoglobin in excess precipitates in glomerular filtrate and can cause
Acute renal failure
Symptoms and complications
• Myalgia
• Muscle swelling
• Muscle Weakness
• Dark urine
Complications
• Renal failure with anuria
• Fever, nausea, anuria, confused/agitated
• Hypocalcemia
• Hyperkalemia, cardiac arrhythmia and death
• Hepatic inflammation can occur as a result of released proteases
• Liver failure
• Disseminated intravascular coagulation
• Compartment syndrome
• Death
Causes 1: intense exercise in healthy
subjects
1. An area of litigation in the military
2. Exertional rhabdo occurs as a physiological response to
unaccustomed, prolonged, repetitive exercise with eccentric
characteristics causing muscle tension, strain and injury
3. In the military there may be a metabolic component – energy
depletion since timings of meals/hydration are also tightly
controlled
4. This is a real threat to military population especially when
training under heat stress
Many publications in the literature…
• Rhabdo after crawling military training. Mil Med 2017
• Update: Exertional rhabdomyolysis, active component, US armed forces 2013-2017.
MSMR 2018
• A cluster of exertional rhabdo cases in a ROTC Program engaged in an extreme
exercise program. Mil Med 2018
• 11/44 cadets were hospitalised due to exertional rhabdo
• Twelve cases of exertional rhabdo in college football players from the same
institution over a 23-year span: a descriptive study.
• All black
• One had sickle cell trait
• 10/12 occurred in August (heat)
• CK average 14,850 U/L
Causes 2: Ischemia and Trauma

Multiple causes
• Falls
• Longlasting muscle compression eg after prolonged immobilisation after a fall
or lying unconscious on a hard surface during illness or after taking drugs or
alcohol
• Crush injuries
• Status epilepticus
• Electrical shock injury
• Third degree burns
• Lightning strike
• Venom from snake or insect bite
Causes 3: Drugs and Toxins
Drugs and toxins:
Alcohol, carbon monoxide, HIV drugs, herbal remedies, opiates, amphetamines, ask for over the counter remedies

Statins
Myalgia, HyperCKemia
Necrotising myopathy – CK around 10,000 with death of muscle fibres and poor prognosis for
Recovery
HMG CoA reductase antibodies

Neuroleptic malignant syndrome

A rare reaction to anti-psychotics
2/10,000 people
Causes 4: Autoimmune myositides
• Dermatomyositis
Necrotising myopathy (statins or
autoimmune or paraneoplastic)
Causes 5: Endocrinopathies and
Electrolyte disturbances
• Thyroid disease
• Diabetes
• Diabetes insipidus
• Pituitary dysfunction
• Diabetic ketoacidosis
• Profound hyokalemia eg in renal tubular dysfunction
• Adrenal pathology
• Hyponatremia and hypernatremia etc
Causes 6: Infection
1. Influenza A and other types
2. Coxsackie B virus
3. HIV and seroconversion
4. Others…
Causes 7: Genetic
1. Inherited metabolic myopathies
1. Glycolysis eg McArdle’s, Tarui’s
2. Fatty acid oxidation defect eg carnitine palmitoyl transferase II deficiency,
multiple Acyl Co A dehyrogenase deficiency
2. Mitochondrial disorders
3. Malignant hyperthermia (ryanodine mutations RYR1);
4. Dystrophinopathies (eg Becker’s muscular dystrophy, LGMD
especially related to ANO5, Dysferlin or Caveolin-3 mutations,
Sarcoglycanopathies, FKRP) – giving this pseudometabolic
presentation
The clue can be in the history and digging
for triggers…
• Infection and fever
• Fasting/Diet
• Trauma
• Exercise (unaccustomed, intense)
• Exercise-induced myalgia
• Probing for second wind (McArdle’s)
• Anaesthesia
• Medications including anti-psychotics, herbal remedies, recreational drugs,
alcohol, statins
• Background of exercise – induced myalgia
Physiology and pathology
• At rest muscles require energy from free fatty acid beta oxidation (and for low
intensity exercise and longer duration exercise)
• Starvation puts muscle under more stress and requires more beta oxidation
• In defects of Fatty Acid Oxidation: Symptoms occur if exercising while fasting, or
with simultaneous infection, or if exercising for longer duration, or if exercising for
30 minutes and is highly untrained/deconditioned
• Mismatch between ATP delivery to muscle and its needs. ATP falls and muscle
runs into crisis with fatigue and myalgia
• If individual continues to push, muscle seizes and goes into a contracture
• Carnitine palmitoyl transferase type 2 deficiency – commonest FAO defect
• Imports long chain fats in inner mitochondrial membrane
Multiple Acyl CoA dehdrogenase
deficiency
• Recessive FAO defect in Electron transfer flavoprotein
• Lipid storage myopathy responds to Riboflavin
• Extramuscular symptoms including cardiac, gastrointestinal,
neuropathy
• ETFDH gene mutations account for 90%

Vacuoles Oil red O showing lipid +

Glycogen storage/glycolytic disorders -
physiology
• Glycogen important fuel during moderate and intense exercise
• Exercise intolerance during early phases exercise
• If you run to a fire alarm, glycogenolysis starts within 2 seconds –
myophosphorylase is required – glycogen is broken down – lactate is
generated anaerobically
• If we continue to run, after some mins increase of delivery of oxygen
to muscles, energy through TCA cycle and mitochondria
• Commonest disorder is McArdle’s disease (myophosphorylase
deficiency)
Pathology
• Early on in exercise – severe cramp and muscle stiffness with
weakness
• Higher the intensity – symptoms come on almost immediately
• If the intensity is less – symptoms come on later
• Second wind: rest/slowing down, allowing blood borne glucose to be
delivered to muscle bypassing the myophosphorylase enzyme
activity/defect allowing them to continue activity because of
increased blood supply (during exercise) but at lower intensity
How to investigate rhabdomyolysis…
• If single episode, individual trains regularly and is of high fitness (+/-
occurring in context of unusual exercise) – maybe no investigations
required ????? (Difficult!)
 Current Investigations
• Baseline bloods
• NCS and EMG (generally unhelpful)
• Exercise test
• Aerobic defects (abnormality in acyl carnitine profile and urine organic acids, ↑ lactate)
• Beware ↑ lactate and deconditioning
• Glycolytic/glycogen storage defects (flat lactate)
• Muscle MRI
• This would detect changes in dystrophinopathies, ANO5 etc
• But some RYR1 patients can have normal MRI!
• Low threshold for testing for
• CPT2 deficiency (1 yield over 10 years! – after extended gene testing to detect 2nd mutation)
• ETFDH (multiple Acyl CoA dehydrogenase deficiency) – Riboflavin responsive myopathy
• Muscle biopsy (at least 1 month after rhabdo) - mitochondrial
• Genetic tests (other)
When to consider genetic testing
•R Recurrent (single episode there is an argument for not testing further)
•H HyperCK persists
•A No unusual exercise (absent)
•B Blood CK >50 UMNL
•D Drugs (absent)
•O Other family members (similar symptoms)
Rhabdomyolysis gene panel
• Sheffield
• 30 genes
• Also a Fatty acid oxidation gene panel
UKGTN Minimum criteria required for testing to be appropriate
Myalgia, muscle weakness, cramps, myoglobinuria, triggered by exercise/heat/fasting/infection
AND

Suggestive blood/urine tests: acylcarnitines, lactate, amino acids, organic acids, Creatinine Kinase
(CK) AND

Mitochondrial myopathy/dystrophinopathy unlikely/excluded AND

Common McArdle disease (PYGM)/CPTII deficiency (CPT2) mutations excluded, as appropriate
Yield from these panels is not great!
• Highly selective cohort, who had already been extensively investigated
• 31 patients WoS included in rhabdo/FAO gene panel
• 2 of these also recruited into MYOSEQ
• Another 6 patients recruited into MYOSEQ
• Indications
• Single or recurrent rhabdo
• Exercise induced myalgia (including a patient who left marines because of this)
• Muscle weakness and one patient with peripartum cardiomyopathy
Cohort
• Highly selected
• 89% (33) had abnormalities on biochemistry +/- muscle biopsy in
addition to persistence of muscle symptoms with exercise intolerance
• Abnormalities had been detected on muscle biopsy, acyl carnitines,
lactates (including flat)
• Individuals who never returned to previous exercise potential after
rhabdo episode (including one who left the Marines because of this)
• Patients with recurrent rhabdo and abnormalities on muscle biopsy
• Patient with peripartum cardiomyopathy
Results from the Sheffield gene panel (n=31)
• 3 possible/probable diagnosis
• 2 patients with probable MADD but only one gene mutation picked up
• Biopsy and biochemistry compatible
• 1 patient with hot VUS for RYR1 with phenotype and biopsy (cores)
compatible with this
• 4 patients incidental carriers but biopsy/biochemistry not compatible
with findings Overall results from WoS genetic panel testing

• 5 patients with VUS No. of definitive diagnoses 0

No. of possible/probable diagnoses 3

No. of presumed incidental carriers 3

No. of VUSs 5

  Pick up rate = 9.7%

MYOSEQ
• 8 patients
• 1 found to have variant in dysferlin (not compatible with
phenotype/biopsy/normal CK) and 2 pathogenic variants in RYR1
(compatible with phenotype)
• (from a recent batch, another 4 patients – negative results)
Sheffield lab results 300 cases across UK
Condition No. of cases

RYR1-related myopathy 16

CPTII deficiency 9

McArdle disease 6

Mitochondrial trifunctional protein deficiency 2

GSD type III 1

Pompe disease 1

GSD type VII 1

Polyglucosan body disease 1

Acute recurrent myoglobinuria (LPIN1) 1

38 cases/total 300 = 12.7%

Commonest disorder is RYR-1
How cost-effective are we in our
investigation of rhabdomyolysis?
Not very!
Cost implications of our tests
• Exercise test
• Admission to ward 68 = £500
• Biochemical tests = £500 (often mislabelled)
• Muscle MRI = £500 (usually unhelpful unless dealing with LGMD etc)
• EMG = £750
• Genetic testing = £1000
• Rhabdo panels = £750
• Muscle biopsy = £5000
Recurrent rhabdo…should we always be
concerned?

• Patient (now in 50s) – works as an architect

• Attends muscle clinic
• First presented with rhabdo 10 years ago
• Keen cyclist
• Lots of investigations (NAD)
• 3 Episodes in total
• Remains well and active in between
First rhabdo after going to the gym for
first time…
• 22 year old (overweight) girl decides to get a personal trainer and has
a gym session
• Feels unwell after, myalgia etc
• CK 107,000
• Sees me in clinic – CK 270. Normal muscle strength
• No symptoms before or after. No red flags. Never exercised
• What could this be?
Slight unusual way of investigating her..
• MRI muscles normal
• I omitted the exercise test initially
• CPT 2 – Genetics normal
• Muscle biopsy – abnormal
• Absent myophosphorylase
• I exercised her – flat lactate
• Genetics for McArdle’s – one PYGM gene mutation. Second mutation found after
extensive gene testing
• In retrospect still no second wind etc
• But brother in England similar symptoms and has had rhabdo and does not want
tests
Management of Rhabdomyolysis
• Preserve renal function
• Correct metabolic derangement
• Iv fluids ideally until CK drops to below 1000
• Alkalinisation of urine to promote myoglobin washout
• Bicarbonate corrects metabolic acidosis
• Keep an eye out for high K+
• Hemodialysis may be required
• DIC and compartment syndrome
Long term management of metabolic
myopathies
• Exercise + Diet

• Avoid exercise when running fever, dehydrated or fasting or metabolically

stressed
• Keep well hydrated
• Seek advice immediately if myalgia + dark urine
• Carnitine can help with chronic myalgia
• If there is a suggestion of Multiple Acyl Co A dehydrogenase deficiency
• Caution with persistent hyperemesis/weight loss/nutritional deficiency/pregnancy
• Riboflavin
Management for CPT2 deficiency
• Gradually increase exercise capacity
• After 2 months endurance training- increase in muscle glycogen –
greater buffer
• Careful controlled exercise
• Exercise preceded by carbohydrate intake and sometimes during
exercise
• High carbohydrate diet (but caution not to gain weight)
Management for McArdle’s
• Educate on second wind
• Exercise - Gradually increasing, allowing compensatory pathways to take effect,
threshold for symptom onset rises

• Pre-exercise carbohydrate 40 min before exercise shown to provide energy (glucose

enters system, goes into muscle, bypassing myophosphorylase defect, flux through
glycolysis allowing a source of carbohydrate and not requiring breakdown of glycogen
which is defective in McArdle’s
• 35g carbohydrate 20 min before exercise is as good as a higher dose given 40 min before
exercise

• Avoid chronic analgesia use and opiate dependence

Conclusions
• Many causes for rhabdomyolysis
• Acute management is same for all
• Investigation pathway needs some thought given that the current
yield of tests is very low
• Muscular dystrophies and mitochondrial disorders may rarely cause
rhabdo
• There are common metabolic disorders to be aware of – correct
advice on exercise and diet management