Neuromuscular Diseases Flashcards
what is a neuromuscular disease
any disease or condition that affects the PERIPHERAL nervous system
what components of the nervous system can be impacted by neuromuscular disease
-anterior horn cell (neuronopathy, motor neuron disease)
-dorsal root ganglia (neuronopathy)
-nerve root (radiculopathy)
-nerve plexus (brachial or lumbosacral plexopathy)
-entire nerve (polyneuropathy)
-neuromuscular junction
-muscle
neuronopathy
affects the cell body of a motor neuron or a sensory neuron
examples of motor neuron diseases
-amyotrophic lateral sclerosis (ALS)
-spinal muscular atrophy (SMA)
-poliomyelitis
amyotrophic lateral sclerosis (ALS) - epidemiology
-average age of onset = 60 (can get it at any age though)
-risk factors: older, men, smokers, and history of head/neck trauma
-increasing age is associated with increased risk of developing it
-aka Lou Gehrig’s disease
-most ALS is sporadic, but 2 types are hereditary
amyotrophic lateral sclerosis (ALS) - physical exam signs
*lower motor neuron findings (atrophy, fasciculations, weakness, decreased tone)
*upper motor neuron findings (hyperreflexia, increased tone)
*extremity weakness and affects cranial nerves (normal eye movements though)
*NO sensory involvement
NOTE: UMN and LMN findings in the SAME EXTREMITY
amyotrophic lateral sclerosis (ALS) - treatment
-riluzole (glutamate inhibitor)
-edaravone (free-radical scavenger)
-phenylbutyrate/taurursodiol
-tofersen (genetic tx for ALS - only for people with SOD1 mutations)
amyotrophic lateral sclerosis (ALS) - prognosis
*patients die from respiratory failure an average of 4 years after disease onset
amyotrophic lateral sclerosis (ALS) - pathophysiology
central AND peripheral motor neurons die
(amyotrophic = anterior horn cells dying off; lateral sclerosis = lateral corticospinal tracts are become sclerotic/scarred)
amyotrophic lateral sclerosis (ALS) - genes associated with hereditary types of ALS
*SOD1 mutation
*C9 mutation (hexanucleotide repeat; most common cause of hereditary ALS)
spinal muscular atrophy (SMA) - etiology
*autosomal recessive
*SMN1 (survival motor neuron 1) gene mutation
spinal muscular atrophy (SMA) - types
*type I (Werdnig-Hoffman) is most severe and affects infants
*type IV is the most mild (often adult-onset SMA)
spinal muscular atrophy (SMA) - pathophysiology
*anterior horn cells die off for unknown regions (lower motor neuron signs only)
*common cause of hypotonic infants
*most kids die before age 2 without treatment
spinal muscular atrophy (SMA) - treatments
*new treatments are extremely effective and kids no longer die from SMA and are “normal”!
-nusinersen (antisense oligonucleotide)
-onasemnogene (gene replacement therapy)
-risdipalm (small molecule)
*more effective when started early
poliovirus - etiology
*GI viral infection
poliovirus - pathophysiology
*anterior horn cells are killed
*causes focal LOWER MOTOR NEURON dysfunction (weakness and atrophy)
*very rare now, but older patients may still have effects from childhood infection (atrophic leg; post-polio syndrome)
radiculopathy
*result from injuries to peripheral nerve roots
*sometimes referred to as a “pinched nerve”
*causes pain, weakness, numbness, and tingling
*typically in the arms or legs
what causes a radiculopathy
*most often from mechanical causes (herniated disc, bone spurs)
polyradiculopathies
*multiple nerve roots affects
*can be from mechanical causes or pathology in the spinal fluid (infection or cancer)
plexopathy
*injury to nerves in either the brachial plexus or the lumbosacral plexus
birth trauma plexopathy
*Erb’s palsy (C5/6 and upper trunk plexopathy)
*commonly caused by birth trauma, especially if the shoulder gets stuck during birth (often with mom’s with gestational diabetes because the baby is large)
*“Waiter’s tip hand”
motor cycle accident plexopathy
*C8/T1 and lower trunk
*Klumpke’s palsy
*usually causes intrinsic hand muscle weakness
other causes of brachial or lumbosacral plexopathies
-metastases
-infection and post-infection
-diabetes
inherited polyneuropathy
*Charcot-Marie-Tooth disease
*usually autosomal dominant and demyelinating (but can be any inheritance pattern and can be axonal)
*long-standing neuropathy causes HIGH ARCHES and HAMMER TOES
overview of polyneuropathies
*very common (because of diabetes)
*can be categorized: inherited vs. acquired; sensory vs. motor vs. sensorimotor; axonal vs. demyelinating
*commonly causes a “stocking-glove” distribution of symptoms (numbness, tingling)
how do we determine if a polyneuropathy is axonal vs. demyelinating
*determined by nerve conduction studies & electromyography (EMG)
*very rarely by biopsy
demyelinating polyneuropathy
*rare
*nerve biopsy shows “onion bulbs”
*if you see a nerve biopsy on a test, it is probably demyelinating polyneuropathy
most common axonal causes of acquired polyneuropathies
**DIABETES (common, increases risk of amputation)
*B12 deficiency
*alcohol, toxins, drugs (chemotherapy)
acute inflammatory demyelinating polyneuropathy (AIDP or Guillain-Barre syndrome)
*follows GI or respiratory infection (often campylobacter jejuni) [usually within 4 weeks of inciting onset]
*usually ascending (starts in feet and works its way up)
*can cause complete paralysis
*patient will be AREFLEXIC EVERYWHERE
*treated with IVIG or plasmapheresis (NOT steroids)
*cytoalbuminologic dissociation (elevated protein but no WBCs) on lumbar puncture
what happens in diseases of the neuromuscular junction
*fluctuating weakness in face and extremities
*NO sensory involvement
examples of diseases of neuromuscular junction
*myasthenia gravis
*Lambert-Eaton myasthenic syndrome
*botulism
botulinum toxin
*most potent neurotoxin (affects NMJ)
*heavy chain binds to pre-synaptic terminal and is internalized
*light chain cleaves SNARE proteins (prevents vesicle from fusing with membrane so Ach cannot be released)
pyridostigmine
*acetylcholinesterase inhibitor
*used to treat MYASTHENIA GRAVIS
*more acetylcholine in the cleft allows for more muscle contraction
*works in about 30 min and lasts 2-4 hours
*excess can cause a cholinergic crisis (DUMBBELSS or SLUDGE)
succinylcholine
*depolarizing paralytic drug
*action is similar to an acetylcholine agonist (but channel stays open, putting them in a paralytic state)
*can cause malignant hyperthermia
rocuronium
*non-depolarizing paralytic
*competes with acetylcholine for binding to post-synaptic receptors but does NOT open the channels (competitive antagonist of acetylcholine)
*reversed by AchE inhibitors (increases Ach to displace the rocuronium)
myasthenia gravis - epidemiology
*bimodal distribution: common in young women and older men
myasthenia gravis - pathophysiology
*classic autoimmune disease - can cross placenta
*production of post-synaptic ACETYLCHOLINE RECEPTOR ANTIBODY
*long-term, the post-synaptic membrane becomes smoother (less complex), causing fewer available acetylcholine receptors, so less ability to cause muscle contraction
*the more you do, the worse your symptoms become (worse towards the end of the day)
acetylcholinesterase inhibitors & myasthenia gravis
*work quickly
*do not change the course of the disease
*can cause cramps and upset stomach
what treatment is used for a myasthenia gravis crisis
IVIG or PLEx
thymectomy & myasthenia gravis
*removal of thymus
*long course of action
*reserved for those with severe disease
immune suppressants & myasthenia gravis
*mainstay of treatment
*usually prednisone first
*other options include azathioprine, mycophenolate, eculizumab, efgartigimod
infantile myasthenia gravis
*occurs when mom has myasthenia gravis
*acetylcholine receptor antibodies cross the placenta and affect the fetus
*will go away
congenital myasthenia gravis
*extremely rare
*different inheritance patterns
*caused by DEFECTIVE or MISSING PROTEINS IN THE NMJ
Lambert-Eaton Myasthenic Syndrome - etiology
*usually paraneoplastic (cancer makes the antibodies against the calcium channel of the presynaptic neuron)
*can be autoimmune
Lambert-Eaton Myasthenic Syndrome - pathophysiology
*antibody against voltage-gated calcium channels of the presynaptic neuron
*presynaptic disease of the NMJ
Lambert-Eaton Myasthenic Syndrome - symptoms
*weakness
*weakness may improve with exercise
*typically have dry mouth and areflexia at patella
Lambert-Eaton Myasthenic Syndrome - treatments
*treat underlying malignancy
*immune suppression/modulation and 3,4 diaminopyridine
botulism - etiology
*caused by clostridium botulinum
*infantile (grows in intestines); foodborne (ingestion of spores/toxin); wound (black tar heroin)
botulism - symptoms
*flaccid paralysis
*ptosis
*dilated pupils
botulism - treatment
*antitoxin
*ventilator support
*induced vomiting/diarrhea
presynaptic vs postsynaptic diseases of the NMJ
*postsynaptic (myasthenia gravis) - the more you do, the worse your symptoms become (symptoms worse at the end of the day)
*presynaptic - doing more, you generally feel better (usually symptoms are better at the end of the day)
overview of inherited muscle diseases
*most affect children
*causes symmetric, proximal weakness without sensory involvement
*trouble going up/down stairs, lifting arms above head
muscular dystrophies
*result from an abnormality in the dystrophin complex (muscle cell membrane protein complex)
*a type of inherited muscle disease
Duchenne muscular dystrophy - epidemiology
*most common muscular dystrophy in kids
*x-linked recessive (affects boys predominantly)
Duchenne muscular dystrophy - clinical course
*calf psueodohypertrophy & weakness
*trouble walking by age 2
*in wheelchair by age 13
*death by age 30 (usually from cardiomyopathy or respiratory failure)
Duchenne muscular dystrophy - treatment
*prednisone slows down disease progression (prevents secondary inflammation)
antisense oligonucleotides (used for specific gene mutations)
**GENE THERAPY
Duchenne muscular dystrophy - goal of treatment
*switch from Duchenne phenotype to a Becker phenotype
*Becker is a less severe form of muscular dystrophy (“relative” absence of dystrophin - much better prognosis)
myotonic dystrophy - epidemiology
*most common adult-onset muscular dystrophy
myotonic dystrophy - genetic mechanism
*autosomal dominant
*trinucleotide repeat (demonstrates genetic anticipation)
myotonic dystrophy - symptoms
*causes myotonia (inability to RELAX muscle)
*low IQ
*cataracts
*diabetes
*cardiac conduction abnormalities (can lead to sudden cardiac death)
glycogen storage disease type 2 (Pompe)
*a type of inherited muscle disease
*can be treated with replacement of acid-alpha glucosidase
polymyositis
*an acquired inflammatory myopathy (autoimmune disease that attacks the muscle)
*symmetrical weakness of the proximal muscles of the limbs
*muscle biopsy with many WBCs (CD8+) in the ENDOMYSIUM
*treat with prednisone
dermatomyositis
*an acquired inflammatory myopathy (autoimmune disease that attacks the muscle)
*often paraneoplastic (need to look for cancer)
*causes HELIOTROPE RASH (purple discoloration over eyelids) & GOTTRON’S PAPULES
*CD4+, PERIMYSIAL INFLAMMATION
inclusion body myositis
*an acquired inflammatory myopathy (autoimmune disease that attacks the muscle)
*most common inflammatory myopathy
*occurs > age 50, more in men
*causes FINGER FLEXION WEAKNESS (unable to flex DIP joints)
*very slow progression
*often does not respond to treatment
blood work testing for neuropathy
*test for common and treatable etiologies of neuropathy:
-glucose (fasting of random blood sugar, 2 hour glucose tolerance test, Hgb A1C)
-B12 deficiency
-TSH
-paraproteinemia (SPEP, UPEP)
blood work testing for diseases of neuromuscular junction (NMJ)
*myasthenia gravis:
-acetylcholine receptor antibodies (sensitive and specific for MG; rapid turnaround time)
-MuSK (muscle-specific kinase antibody)
-about 10% of people with MG are seronegative
*Lambert-Eaton:
-P/G voltage-gated calcium channel antibodies (takes several weeks to process)
blood work for testing for muscle disease (myopathy)
*CK (creatine kinase) level is the starting point for ALL suspected myopathies
additionally:
*for muscular dystrophy: genetic testing
*for inflammatory myopathy: antibody testing (ANA, DS DNA, myositis panel, etc)
2 types of electrodiagnostic (EDX) testing
-nerve conduction studies (NCS)
-electromyography (EMG)
nerve conduction studies (NCS)
*stimulate a nerve transcutaneously and measure the response from either a different segment of the same nerve (sensory testing) or a distal muscle (motor testing)
*the speed of the conduction and amplitude of the response are the key parameters
*nerves conduct electricity at about 50 m/s (normal)
*demyelinating disease = slow
*axonal disease = low amplitude
electromyography (EMG) - overview
*a thin needle is inserted into muscle to record the electrical potential of the muscle cells
*at rest, muscle should be electrically silent
*then, patient is asked to contract the muscle and the voluntary motor units are recorded
electromyography (EMG) - abnormalities & findings of disease
*at rest: diseased muscle (from either a primary nerve or muscle etiology) will result in muscle fibers that fire spontaneously
*upon contraction: small units = muscle disease; large units = nerve disease and reinnervation
testing the neuromuscular junction
1) repetitive stimulation
2) tensilon test
3) ice pack test
4) single fiber EMG
repetitive stimulation - myasthenia gravis findings
*slow (3 Hz) stimulation results in a DECREMENT > 10% from baseline
*usually a “J-shaped” decrement curve
repetitive stimulation - Lambert-Eaton findings
*exercise or fast (50 Hz) stimulation results in an INCREMENT, usually > 200% above baseline
repetitive stimulation - botulism findings
*fast (50 Hz) stimulation results in an increment > 200% above baseline
tensilon test for testing the NMJ
*Edrophonium, fast-acting acetylcholinesterase inhibitor, is administered and almost immediately, the clinical weakness improves
*old-school test for myasthenia gravis
ice-pack test for testing the NMJ
cold improves neuromuscular junction transmission (because AchE is less active in the cold)
single fiber EMG for testing NMJ
*special type of needle EMG, used to assess and compare the firing rates of 2 muscle fibers in a single motor unit
*increased jitter is abnormal
peripheral nervous system imaging
*MRI neurography and tractography can depict nerves, but are mainly research techniques
*neuromuscular ultrasound can visualize small nerves and subtle muscle changes; now becoming a more common diagnostic test
myopathic findings on muscle biopsy
*central nuclei
*rounded atrophy
neuropathic findings on muscle biopsy
*fiber type grouping
*angular atrophy
