Myopathy

Front 1

How has cornerstone of diagnosis of myopathy changed

Back 1

Gone from biopsy towards gentoyping

Front 2

What is waddling gait? Name and what occurs?

Back 2

Trendelenburg – pelvis tilts from side toside as walk

Front 3

What may lordosis indicate in myopathy?

Back 3

Lordosis can be a sign of axial muscleweakness or more distal as compensatory mechanism.

Front 4

Questions that need to be answered to work out which myopathy is responsible?

Back 4

1) Which part of the nervous system is invovled?

2) Which parts of musculature are affected?

3) What other organ systems are involved?

4) Is it acquired or inherited?

Front 5

Features if the following areas are affected:

a) higher centres/ supplemental motor areas

b) primary motor cortex/ brain stem/ spinal cord

c) peripheral nerve/ NMJ/ muscle

Back 5

a) inconsistent weakness, psychosocial factors

b) UMN – central symptoms, asymmetry, increasedreflexes, increased tone, up-going toes

c) LMN (motor unit) – autonomic symptoms, symmetry,reduced reflexes, muscle wasting, distal numbness

Front 6

What typifies myasthenia gravis/ congenital myashthaenic limb girdle syndromes?

Back 6

Fatiguing proximal weakness - worse towards end of the day

Front 7

4 typical features of myopathy?

Back 7

Weakness (usually proximal in the biggestmuscles so they have problems going up stairs and getting out of chairs,getting from floor i.e. Gower’s manouvere)

Weakness greater than wasting (often musclereplaced by fat)

Reflexes normal except when severely wasted

Sensory examination normal, if abnormalthen might not be muscle disease or might be secondary diagnosis of somethingelse (Exception – may get pain from secondary joint degeneration)

Front 8

typical investigations and findings?

Back 8

EMG – myopathic picture

CK – high (can be normal if slowprogressive inherited muscle disease)

Front 9

Other muscular systems affected?

Back 9

cardiac, respiratory, bulbar (speech andswallowing), extraocular (esp. in mitochondrial disease? And myasthenia)

Front 10

What breathing problems typically accompany myopathy?

Back 10

usually report inability to exercise rather thanshortness of breath like COPD patients would.

Orthopnoea especially withdiaphragmatic weakness and this may be suggested by tummy going in whenbreathing.

Trouble sleeping, sleeping during the day, headaches in morning allshould be asked about and do spirometry as minimum and if suggestion of problemthen overnight sleep study.

Front 11

Typical features of upper limb myopathy

Back 11

Proximal so difficulty in reaching above head

Front 12

Relationship of cancer and myopathy?

Back 12

Some inflammatory myopathies may be paraneoplastic

Front 13

What muscles/ nerves are affected typically in muscle and nerve disease?

Back 13

In muscle disease the biggest muscles areaffected most commonly (shoulder and hip girdle), in nerve disease the longestnerves are affected most commonly (nerves to the feet). Many exceptions tothese of course.

Front 14

What is the motor unit?

Back 14

Motor unit – single anterior horn cell(alpha) -> motor axon -> NMJ -> musclefibres

Front 15

What is a fasiculation?

Back 15

Spontaneous firing of a single motor unit

Front 16

Typical features of EMG in myopathy versus neuropathy

Back 16

EMG represents activity in motor unit. Inmyopathy there is a smaller motor unit because fewer healthy fibres and moreturns because muscle damaged and un-cordinated contraction. In neuropathy youget larger motor unit activity than normal because of cross sprouting from damageaxon to other axons. Main things looked at is amplitude and number of turns.

Front 17

Symtpoms, signs and tests for the following muscle systems:

Cranial

Limb

Cardiac

Respiratory

Back 17

Cranial – symptoms (swallowing difficulty,can’t whistle), signs (facial weakness, slurred speech), tests (EMG myopathic,MRI to rue out other causes)

Limb – symptoms (difficulty getting up fromthe floor and lifting heavy objects), signs (proximal weakness), tests (EMGmyopathic, muscle biopsy)

Cardiac – symptoms (heart failure, syncope(arrhythmia), sudden death), signs (cardiomegaly, heart failure), tests (ECG,echo, 24hr tape)

Respiratory – symptoms (orthopnoea, morninghedaches), signs (reduced vital capacity, paradoxical diaphragm movement),tests (spirometry, overnight oximetry)

Front 18

Myopathies that show typical myopathic weakness pattern?

Back 18

limb girdle muscular dystrophy,

duchennemuscular dystrophy,

mitochondrial myopathy,

statin myopathy,

polymyositis

Front 19

WHich myopathies show specific weakness patterns?

Back 19

facioscapulohumeral dystrophy,

myotnicdystrophy,

chronic progressive external opthalmoplegia,

distal myopathies,

inclusion body myositis

Front 20

Which myopathies show multi organ involvement?

Back 20

myotonic dystrophy,

duchenne muscular dystrophy,

mitochondrial disease,

HIV myopathy,

dermatomyositis

Front 21

Typical features of acquired myopathy?

Back 21

acute/ subacute, monophasic or relapsingremitting, exposure history, asymmetrical, adult onset

Front 22

Typical features of inherited myopathy?

Back 22

longstanding, progressive, family history,symmetrical, childhood onset

Front 23

Cranial, limb, cardiac, and respiratory involvement for Duchenne's

Back 23

Cranial – very late

Limb – age 3-5, lose ambulation early teens

Cardiac – teenage onwards (cardiomyopathy),most common cause of death

Respiratory – teenage onwards, oftenrequire respiratory support

Front 24

Typical features of Duchennes?

Back 24

pseudohypertrophy of calves, Gower’smanouvere (uses hand and crawls up legs)

Front 25

Biocehmical mechanism of Duchennes/ Beckers?

Back 25

No functional dystrophin in Duchenne’s butin Becker’s usually in frame mutation and therefore some dytrophin is producedbut truncated and milder phenotype. This is usually caused by in framemutation.

Front 26

Other organs involved Duchennes?

Back 26

Scoliosis

Cognitive impairment

Front 27

Specific pattern of weakness in Duchennes?

Back 27

No typical proximal

Front 28

Investigations in Duchennes?

Back 28

Investigations – CK very high severalthousand fold, biopsy – absent dystorphin staining (may omit and go straight togenotyping), genetic testing – dystrophin gene frameshift mutation

Front 29

Different treatment modalities and their value in duchennes? x3

Back 29

supportive (important and prolongs lifespan,such as cardiac and resp sreening, making sure nutrition correct, action planfor breathing/ infection, scoliosis surgery if necessary),

prednisolone (provenefficacy and prolongs ambulation),

experimental (anti sense oligonucleotide toblock a certain exon which restores reading frame for restoration of dystrophinalbeit truncated – should convert duchenne to Becker but phase III negative,ataluren licensed – this works for premature stop codons and it improves readthrough of premature stop signal and so you still make dystrophin)

Front 30

Inheritance? Exception?

Back 30

X linked so usually affects males but somefemale ‘carriers’ have severe phenotype due to x inactivation

Front 31

What may be used as outcome measure in Duchennes trials?

Back 31

MRI - muscle fat fraction

6 minute walk test

Front 32

What is diagnosis based upon?

Back 32

Clinical pictures, CK, genetics

Front 33

What is commonest and second most common and third most common msucular dystrophy

Back 33

Duchnnes -> Myotonic dystrophy -> FSHD

Front 34

Does myotonic dystrophy just affect skeletal muscle? How presentation varies with age

Back 34

No - multi system

can have congential forms with floppy baby andshort life expectancy or later on with facial muscle weaknes i.e. can’t raiseeyebrows, frontal baldness, wasting of pectoral muscles, distal upper limbwasting.

Front 35

Significance of whole exome screening in myotonic dystrophy and FSHD?

Back 35

Myotonic dystrophy and FSHD both havegenetic mutations not picked up by whole exome sequencing

Front 36

Myotonic dystrophy - genetic cause, significance of size of repeat, which line of inheritance shows anticipation and typical family tree?

Back 36

trinucleotide repeat in DMPK region innon-translated UTR region. Build up ox toxin in nuclei that affects splicing ofother genes – CLNC3. Repeat size correlates with onset and severity. Maternalanticipation. Classic grandmother cataracts, mother stiffness hand, childcongenital myotonic dystrophy.

Front 37

Cranial, limb, cardiac and respiratory features of myotonic dystrophy?

Back 37

Cranial – myopathic facies

Limb – distal upper limb weakness andmyotonia

Cardiac – arrhythmias, sudden death common,low threshold ICD

Respiratory – sometimes

Front 38

Other organ systems in myotonic dystrophy?

Back 38

frontal balding, cataracts, cognitive,hypersomnolence, diabetes, hypogonadism, apathy

Front 39

Specific weakness pattern myotonic dystrophy?

Back 39

Yes – face and finger flexion

Front 40

Investigations and findings myotonic dystrophy?

Back 40

EMG (myotonia), biopsy not needed, genetictesting DMPK gene

Front 41

3 treatment modalities and value?

Back 41

supportive (very important especiallyprophylactic),

genetic counseling (anticipation),

experimental (early phaseblock toxic RNA)

Front 42

What is aberrant splicing also a cause of?

Back 42

Abberant splicing seen in chloride channelgene responsible for myotonia congenital

Front 43

Clinical features of myotonic dystrophy? Systemic also?

Back 43

Distal upper limb weakness and myotonia(difficulty relaxing), cardiac particularly important so all myotonic dystrophy24hr tape every year and low threshold for ICD. Sudden cardiac death may bepresentation.

Front 44

Clinical features of facioscapulohumeral dystrophy?

Back 44

facial weakness (less wrinkles), scapularwinging bilaterally, need to look for this at shoulders. May also be weak infoot with foot drop, may also have wasting of pectoral muscles, Can’t get armsabove 90 degrees because can’t fix scapula.

Front 45

Pathological cause of myotonic dystrophy? Inheritance?

Back 45

Caused by several thousand base pair repeat atthe long arm of chromosome 4. In this there are actually fewer repeats so lessmethylation and expression of Dux4 gene which is not usually expressed.

Dominant inheritance although variable.

More than 95% of cases of FSHD are associated with the deletion of integral copies of a tandemly repeated 3.2kb unit (D4Z4 repeat) at the subtelomeric region 4q35 on Chromosome 4 of the human genome, of which a normal chromosome includes between 11-150 repetitions of D4Z4.[10] There are both heterochromatin and euchromatin structures within D4Z4 and one putative gene called DUX4.[10][11] Inheritance is autosomal dominant, though up to one-third of the cases appear to be from de novo (new) mutations. The heterochromatin is specifically lost in the deletions of FSHD while the euchromatin structures remain.[10] If the entire region is removed, there are birth defects, but no specific defects on skeletal muscle. Individuals appear to require the existence of 11 or fewer repeat units to be at risk for FSHD.In addition, a few cases of FSHD are the result of rearrangements between subtelomeric chromosome 4q and a subtelomeric region of 10q. This location contains a tandem repeat structure highly homologous to 4q35.[12] Disease occurs when the translocation results in a critical loss of tandem repeats to the 4q site.

Front 46

Prognosis?

Back 46

20% wheelchair but generally quite mild.

Rare cases may progress rapidly

Front 47

Cranial, limb, cardiac, respiratory features of facioscapulohumeral dystrophy?

Back 47

Cranial – facial weakness early

Limb – peri scapular, distal lower limb

Cardiac – 5% mid arrhythmias

Respiratory – rare but restrictivesecondary to kyphoscolisos

Front 48

Other systems that can be affected in FSHD?

Back 48

rare but deafness, retinal vasulopathy mayoccur

Front 49

Is there a specific pattern of weakness or FSHD?

Back 49

Yes – faces, scapular, often asymmetric

Front 50

Investigations for FSHD?

Back 50

CK moderate elevation, biopsy not usuallyneeded, genetic confirmation with D4Z4 repeat 4q. 95% have this 4q deletion.Second gene – Smlin 2 gene which also affects methylation.

Front 51

Treatmetn for FSHD?

Back 51

supportive (surgery to stabilize scapula),expeiremtnal techniques (lab stage)

Front 52

What is finding on biopsy?

Back 52

STIR hyperintensity associated withinflammation on biopsy

Front 53

Cranial, limb, cardiac and respiratory invovlement in dermatomyositis?

Back 53

Cranial – severe cases

Limb – Yes

Cardiac – No

Respiratory – Severe

Front 54

Other organ systems invovled in dermatomyositis? relationship with neoplasia?

Back 54

yes, rashes associated with malignancies,heliotrope rash on face and periorbital and extensor rash, paraneoplasticcondition (and cancer highr before/ after and if diagnosis made do full cancerscreen)

Front 55

Is there a specific pattern of weakness?

Back 55

No usually classical proximal pattern

Front 56

Investigations for dermatomyositsi?

Back 56

CK moderately elevated (useful formonitoring), biopsy needed for diagnosis (B cell mediated antibody productionvasculitis), in lecture says that proximal weakness and rash then you havediagnosis really but biopsy can be done

Front 57

Treatmetn for dermatomyositis?

Back 57

immunosuppression – good response, steroids 1stline then steroid sparring agents

Front 58

What is inflammatory myopathy in children most commonyl caused by?

Back 58

DM (juvenile DM)

Front 59

Who does dermatomyositis most commonly affect?

Back 59

Most commonly affects middle aged femaleslike most autoimmune conditions

Front 60

Use of imaging in DM?

Back 60

Imaging may be useful to guide biopsy toincrease yield

Front 61

Cranial, limb, cardiac and respiratory involvement in polymyositis?

Back 61

Cranial – severe cases

Limb – Yes

Cardiac – No

Respiratory – Severe cases

Front 62

How is polymyositis patholgoically different to DM

Back 62

Pathologically different to dermatomyositiswith inflamy cells throughout muscle fascicle and invasion of otherwise healthylooking muscle cells by lymphocytes. and no skin involvement,

Front 63

Are other organ systems invovled? Is there a specific pattern of wekaness

Back 63

No

No - classical proximal pattern

Front 64

Investigations for polymyositis?

Back 64

CK moderately elevated (useful formonitoring), biopsy for diagnosis

Front 65

Treatment?

Back 65

immunosuppression – good response, steroidsfirst line

Front 66

Who is usually affected by polymyositis?

Back 66

Usually middle aged women and associatedwith antibodies associated with other autoimmune conditions such as SLE.

Note - some argue it doesnt exist or is extremely rare

Front 67

Why iamging useful

Back 67

Biopsy yield

Front 68

Cranial, limb, cardiac and respiratory invovlement in inclusion body myositis?

Back 68

Cranial – swallowing

Limb – quadriceps and finger flexors

Cardiac – No

Respiratory – No

Front 69

Other organ systems involved?

Back 69

No

Front 70

Is there a specific pattern of weakness?

Back 70

Yes, quadriceps, long finger flexors thatbend the distal interphalengeal joint so weak grip, ankle dorsiflexors

Front 71

Investigations?

Back 71

CK slightly elevated (not useful for monitoring),biopsy needed for diagnosis

Front 72

Treatment for inclusion body myositis?

Back 72

immunosuppression – ineffective, currently noeffective therapy. So important to stop treatment if on treatment oncediagnosis made

Front 73

How do polymyositis and inclusion body myositis compare on biopsy?

Back 73

Looks a bit like polymyositis on biopsy butlater on you get something specific.

Front 74

In whom is inclusion body myositis most common in?

Back 74

Most common in older men (unlike otherinflammatory myopathies/ diseases)

Front 75

What imaging is done and how it helps?

Back 75

Inflammation on muscle MRI STIR

Front 76

Typical presentation of myopathy?

Back 76

Typical presentation of myopathy isproximal weakness with retained sensation and reflexes although this isvariable

Front 77

How to classify myopathies practically?

Back 77

– inherited versus acquired, typical versusspecific distribution, presence or absence of cardiac/ resp/ other systems

Front 78

What is cornerstone of diagnosis and when is it skipped?

Back 78

Muscle biopsy generally cornerstone ofdiagnosis but skipped in inherited myopathies if typical phenotype present(DMD, DM1, FSHD)

Front 79

How do the inflammatory myopathies differ?

Back 79

In inflammatory myopathies dermatomyositisand inclusion body myositis differ in patient demographic, pattern of weakness,biopsy findings, response to treatment