Maria Elena Farrugia Consultant Adult Neurologist Glasgow What is Rhabdomyolysis A serious lifethreatening condition due to direct or indirect injury to muscle tissue Rapid breakdown and death ID: 920300
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Slide1
Rhabdomyolysis – Causes, Tests and Management
Maria Elena Farrugia
Consultant Adult Neurologist, Glasgow
Slide2What 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
Slide3Rhabdo 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
Slide4ConsequencesSarcolemmal
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
Slide5Symptoms and complications
Myalgia
Muscle swelling
Muscle Weakness
Dark urine
Slide6ComplicationsRenal 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
Slide7Causes 1: intense exercise in healthy subjects
An area of litigation in the military
Exertional
rhabdo
occurs as a physiological response to
unaccustomed, prolonged, repetitive exercise with eccentric characteristics
causing muscle tension, strain and injury
In the military there may be a metabolic component
–
energy depletion since timings of meals/hydration are also tightly controlled
This is a real threat to military population especially when training under heat stress
Slide8Many 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
Slide9Causes 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
Slide10Causes 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
Slide11Causes 4: Autoimmune myositides
Dermatomyositis
Slide12Necrotising myopathy (statins or autoimmune or paraneoplastic)
Slide13Causes 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
Slide14Causes 6: Infection
Influenza A and other types
Coxsackie B virus
HIV and seroconversion
Others
…
Slide15Causes 7: Genetic
Inherited
metabolic myopathies
Glycolysis
eg
McArdle’s,
Tarui’s
Fatty acid oxidation defect
eg
carnitine
palmitoyl
transferase II deficiency, multiple Acyl Co A
dehyrogenase
deficiency
Mitochondrial disorders
Malignant hyperthermia (ryanodine mutations RYR1);
Dystrophinopathies
(
eg
Becker’s muscular dystrophy, LGMD especially related to ANO5,
Dysferlin
or Caveolin
-
3
mutations
,
Sarcoglycanopathies
, FKRP)
–
giving this
pseudometabolic
presentation
Slide16The 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
Slide17Physiology 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
Slide18Multiple 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 +
Slide19Glycogen 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)
Slide20Pathology
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
Slide21How 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!)
Slide22Current 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 2
nd
mutation)
ETFDH (multiple Acyl CoA dehydrogenase deficiency)
–
Riboflavin responsive myopathy
Muscle biopsy (at least 1 month after
rhabdo
) - mitochondrial
Genetic tests (other)
Slide23When to consider genetic testingR
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)
Slide24Rhabdomyolysis gene panelSheffield
30 genes
Also a
F
atty 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
Slide25Yield 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
Slide26Cohort 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
Slide27Results 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
5 patients with VUS
Overall results from
WoS
genetic panel testing
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%
Slide28MYOSEQ8 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)
Slide29Sheffield 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
Slide30How cost-effective are we in our investigation of rhabdomyolysis?
Slide31Not very!
Slide32Cost implications of our testsExercise 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
Slide33Recurrent 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
Slide34First 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?
Slide35Slight 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
Slide36Management 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
Slide37Long 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
Slide38Management 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)
Slide39Management 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
Slide40ConclusionsMany 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