Rhabdomyolysis – Causes, Tests and Management - PowerPoint Presentation

Slide1

Rhabdomyolysis – Causes, Tests and Management

Maria Elena Farrugia

Consultant Adult Neurologist, Glasgow

Slide2

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

Slide3

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

Slide4

ConsequencesSarcolemmal

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

Slide5

Symptoms and complications

Myalgia

Muscle swelling

Muscle Weakness

Dark urine

Slide6

ComplicationsRenal 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

Slide7

Causes 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

Slide8

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

Slide9

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

Slide10

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

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Causes 4: Autoimmune myositides

Dermatomyositis

Slide12

Necrotising myopathy (statins or autoimmune or paraneoplastic)

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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

Slide14

Causes 6: Infection

Influenza A and other types

Coxsackie B virus

HIV and seroconversion

Others

…

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Causes 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

Slide16

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

Slide17

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

Slide18

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 +

Slide19

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)

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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

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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!)

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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 2

nd

mutation)

ETFDH (multiple Acyl CoA dehydrogenase deficiency)

–

Riboflavin responsive myopathy

Muscle biopsy (at least 1 month after

rhabdo

) - mitochondrial

Genetic tests (other)

Slide23

When 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)

Slide24

Rhabdomyolysis 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

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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

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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

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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

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%

Slide28

MYOSEQ8 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)

Slide29

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

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How cost-effective are we in our investigation of rhabdomyolysis?

Slide31

Not very!

Slide32

Cost 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

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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

Slide34

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?

Slide35

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

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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

Slide37

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

Slide38

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)

Slide39

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

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ConclusionsMany 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