Non-inflammatory Myopathies Flashcards
What NM diseases are caused by damage to the anterior horn cells or motor neurons?
so called motor neuron diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis (this also affect the upper motor neurons).
In these conditions, the motor axons and the muscle fibers innervated by them are also secondarily affected.
What are peripheral neuropathies?
these involve not only motor axons, but also other various types of nerve fibers such as those that carry pain and proprioceptive sensations, and autonomic fibers, so peripheral neuropathies also cause sensory or autonomic problems.
What is a common disease of the neuromuscular junction?
also called disorders of neuromuscular transmission such as myasthenia gravis.
The most common symptom of neuromuscular disease is ____
weakness
What is Gower’s Sign?
In myopathic disease, weakness primarily affects the proximal muscles. Such patients have difficulty arising from the floor because of hip muscle weakness or raising the arms above their head. In this, because of hip muscle weakness, the patient needs to use his hands to raise from the floor shown in figure 1 and then ”climb over his legs” in figures 2, 3, and 4 (Gower’s sign) to achieve the standing position in figures 5 and 6.
What does this image show?
Patients with myopathies also have proximal muscle atrophy and weakness, as is shown in the next patient with shoulder atrophy at arrow 1 and “winging” of the scapula at arrow 2. Winging of the scapula occurs because the weak muscles cannot fix the scapula to the rib cage.
What is a characteristic finding poly-peripheral neuopathies?
Distal Leg Wasting. These patients typically also have decreased sensation and depressed reflexes
Patients with _____________ do not have sensory deficits as those disorders affect only the motor axons.
motor neuron diseases
What is a mononeuropathy?
Neuropathies that affect individual nerves
What is characteristic of a myasthenia gravis (MG) patient following sustained upward gaze?
Ptosis. This is characteristic of myasthenia gravis, a disease of neuromuscular transmission in which muscle fatigue is a hallmark.
What would a symmetric pattern of muscle weakness, with fasciculations, decreased muscle stretch relfexes, and no sensory loss suggest?
Motor neuron Disease?
What is one motor neuron disease that doesnt present normally?
ALS- still see fasciculations and no sensory loss BUT weakness patterns are asymmetric and muscle stretch reflexes are increased
What categories of NMD would present more commonly with distal patterns of weakness over proximal?
Polyneuropathies
How do Polyneuropathies present?
distal pattern of weakness, with decreased or absent muscle stretch reflexes, sensory loss and fascicualtions sometimes
What are some common characteristics of diseases of neuromuscular junction and myopathies?
both predominantly involve proximal over distal patterns of weakness, and you do NOT see fasciculations or sensory loss
What diseases of the neuromuscular junction present with normal muscle stretch reflexes?
POST-synaptic disorders such as myasthenia gravis
What diseases of the neuromuscular junction present with decreased muscle stretch reflexes?
Lambert-Eaton myastenic syndrome and botulism
Are muscle stretch reflexes present in myopathies?
Normal Initially, may be decreased in later stages (ankle reflexes often preserved until late)
What are motor unit action potentials (MUAPs).
When the motor neuron depolarizes, it causes the muscle fibers of that motor unit to also depolarize and their individual action potentials summate (A+B+C+D) forming the potentials
What is electromyography?
A diagnostic tool which detects MUAPs close to a needle electrode inserted in the muscle and connected to an oscilloscope. Analysis of the characteristics of the motor unit action potentials, their size, and numbers is a very important diagnostic tool in neuromuscular disease.
What is this?
Normal muscle histology (trichrome stain)
What is this showing?
Normal muscle biopsy stained with alkaline ATPase. Note that the type I muscle fibers stain pale while the type II fibers are dark. Fibers of either type are innervated by one type of motor neuron (motor unit). Here, fibers of various motor neurons, either type I or II, are intermixed in an almost checkerboard pattern.
T or F. A motor neuron and the fibers that it innervates belong to only one type
T, and the physiological and histological characteristics are determined by the motor neuron and its firing pattern. In humans the checkerboard pattern is seen in most muscles, with some having more of one fiber type depending on the muscle function.
What happens when a muscle loses it’s innervation through some injury, for example by trauma to its axon, a peripheral neuropathy or damage to the motor neuron?
the muscle fibers become atrophic and angulated.
slide: esterase stain
What is fiber type grouping?
When axons are damaged there is sprouting of axons from the other intact neurons that take over and reinnervate previously denervated fibers, thus more fibers of single neurons remain, forming groups of both fiber types seen histologically.
How does an EMG change in peripheral nerve injury with fiber type grouping?
The action potentials generated by these will be larger, as more muscle fibers innervated by a single motor neuron will be detected by the needle electrode during muscle contractions using EMG recording. However, the total number of action potentials will be decreased (fewer number of motor neurons).
Thus, in peripheral nerve injury with denervation and reinnervation there are fewer, but larger, motor unit action potentials on EMG.
T or F. In myopathies, the muscle fibers are not atrophic and angular.
T. In this case, they are necrotic (appearing pale here) from an autoimmune myopathy. In other myopathies, there could be structural abnormalities.
Where is the defect in myopathies?
the individual muscle fibers are ill or nonfunctional (thus when a muscle contracts the motor unit action potentials are smaller)
T or F.
In myopathies, the number of motor units is not decreased, unlike neurogenic disorders
T., because the number of motor neurons or axons are normal. (It is the number of individual fibers of the motor unit that are nonfunctional or dead). Even when the muscle contraction is very weak, there is a normal number of motor unit action potentials (this might appear increased for a weak muscle).
What are some serum markers of myopathies?
The sick, necrotic muscle fibers leak some of the sarcoplasmic components such as enzymes like creatine kinase (CK or CPK). Because of this, the enzymes are elevated in serum.
EMG changes in myopathies?
The motor unit action potential is small.
This is also polyphasic because the damaged individual fibers fire asynchronously.
Motor Conduction Velocity
stimulation of the ulnar nerve at the wrist on left and the elbow on the right with recordings at the adductor digiti quinti muscle. In the middle, notice the compound muscle action potential (summation of all motor units generated by a maximal nerve stimulation). One can also observe the latencies and measure the amplitudes.
Conduction velocities are calculated by dividing the distance between the two stimulation electrodes by the difference of their latencies = distance/latency 1 – latency, 2 = CV (conduction velocity).
In the bottom, notice the very slow prolonged latency and small compound muscle action potential in a demyelinating neuropathy.
Serum muscle enzymes are elevated in what kinds of NMD?
mildly in anterior horn disease and elevated in myopaties
Nerve conduction studies are only abnormal in what type of NMD?
peripheral neuropathy results in slow conduction
How is an EMG changed in anterior horn disease or peripheral neuropathy?
Decreased number of motor units, evidence of denervation & some reinnervation (large motor units)
How does an EMG change in myopathy?
Normal number of motor units, of short duration & low amplitude & frequently polyphasic
Repetitive Nerve stumulation test is abnormal in what type of NMD?
Neuromuscular transduction defects-
CMAPs at low rate of stimulation, ,decrease in amplitude, increment at fast rates in presynaptic disorders
Classic findings of myopathy?
- Proximal (and usually symmetric) weakness
- Normal sensation and reflexes
- Elevated muscle enzyme in serum (CK or CPK)
- Small (brief) motor unit potentials on EMG, with normal or “increased” recruitment on maximal effort or polyphasic
- Abnormal muscle biopsy, depending on the type of myopathy (i.e., inflammation, glycogen storage)
T or F. In myopathies, Motor Unit Action Potentials are not decreased in number
T. thus when the muscle contracts, even if weak, many motor units are recruited.
Remember that the reason that the numbers of Motor Units are not reduced (unlike in neuropathies) is because the number of motor neurons and their axons are not reduced, yet they are small because there is a lesser number of functional muscle fibers per unit.
What are the congenital myopathies?
These appear as floppy infants (weakness, hypotonia) at birth; e.g.
central core disease,
myotubular myopathy,
“nemaline” or “rod” myopathy and
congenital muscular dystrophy
shown. A Floppy Infant With Infantile Acid Maltase Deficiency
What are the muscular dystrophies? When do these initially present?
These are hereditary and progressive conditions and start during childhood or later and eventually cause weakness and atrophy
e.g., Duchenne’s, Becker’s,
limb girdle, fascioscapulohumeral and oculopharyngeal dystrophies
What are the myotonic dystrophies?
Myotonic dystrophies are also hereditary and progressive, but in addition to weakness they also have difficulty relaxing their muscles associated with abnormal electrical activity of muscle.
This difficulty with relaxing the contracted muscle is called myotonia.
What is Duchenne’s Muscular dystrophy?
An X-linked recessive lethal childhood disorder caused by a gene mutation resulting in lack of the protein, dystrophin
How does Duchenne’s Muscular dystrophy present?
There is progressive muscle weakness that progresses to necrosis and atrophy of muscle
as well as heart abnroamlities, low IQ, and pseudohypertrophy
What is this muscle biopsy showing?
Muscle biopsy of a child with Duchenne’s dystrophy.
Note the bluish fibers with a prominent nuclei - they are regenerating fibers. Also there is prominent connective tissue between fibers and one necrotic fiber undergoing phagocytosis (yellow arrow).
What is this?
Immunoperoxidase stain for dystrophin – notice the normal staining in the muscle membrane in a control (left), and a very abnormal muscle without dystrophin from a child with Duchenne’s dystrophy (right)
How does a lack of dystropin affect muscle?
the absence of dystrophin causes a membrane defect that causes intracellular Ca2+ to rise, Ca2+ activation of neutral proteases that digest troponin and Z-bands and overall degradation of strucural proteins leading to MUSCLE ATROPHY
What is a novel treatment for Duchenne’s dystrophy?
Exon skipping to restore the reading frame producing a message that although smaller, makes sense, so this could be a smaller yet functional protein.
How can exon restoring be performed?
injection of a morpholino, which is an antisense oligonucleotide that restores the reading frame (in clinical trials now)
What is Becker’s Muscular Dystrophy?
milder case similar to Duchenne’s
Image: Note the lordosis and the calf hypertrophy.
What is this?
muscle biopsy of a Becker’s patient stained for dystrophin. Notice that several muscle fibers still have the protein, i.e., not an absence as in Duchenne’s dystrophy.
What is the MOI of myotonic dystrophies?
AD
Myotonic dystrophy
Photograph of a mildly affected female with myotonic dystrophy and her two children who much more affected - note the elongated faces. As in most autosomal dominant diseases there is anticipation with increased repeat expansions and more severe phenotypes in younger generations.
What are inflammatory myopathies?
These are acquired diseases mostly autoimmune (polymyositis, dermatomyositis, inclusion body myositis, sarcoidosis) or caused by infections (trichinosis).
What are metabolic myopathies?
The metabolic myopathies are caused by enzyme deficiencies that blocks the metabolic pathways, depriving muscle cells of energy for muscle contraction and relaxation and to maintain their membrane integrity.
How do metabolic myopathies present?
Some manifest by weakness, but the majority by episodes of muscle pain and breakdown (rhabdomyolysis) and excretion of muscle proteins in the urine (myoglobinuria) when the energy demands increase such as during exercise.
What is McArdle’s disease?
muscle pains during exercise caused by muscle phosphorylase deficiency from which glycogen can not break down during exercise to produce ATP, lactate and pyruvate necessary for oxidative metabolism.
Measurement of serum lactate shows the lack of normal increase, particularly during ischemic exercise when glycogenolysis is normally utilized as an energy source.
What is this?
Biopsy of a patient with McArdle’s disease in center, showing lack of phosphorylase staining (blood vessels but not muscle stain positive, compared with the normal muscle on the left)
How do endocrine myopathies present?
Endocrine disorders can cause proximal muscle weakness and their muscle biopsies show non-specific findings and only selective type II muscle fiber atrophy.
What are the causes fo endocrine myopathies?
Cushing’s disease and hypothyroidism
Hyperparathyroidism might present with severe weakness resembling amyotrophic lateral sclerosis.
Hypothyroidism patients present with muscle spasms but not weakness, and could have a very high serum creatine kinase levels, so this should be suspected in obese patients with hyperlipidemia and high serum creatine kinase.
Some selective things that cna cause toxic myopathies?
- ethanol
- anesthetics like lidocaine
- Cholesterol-lowering agents like statins
- glucocorticoids
What are the disorders of neuromuscular transmission?
Such disorders include acquired diseases like Myasthenia Gravis, disorders caused by toxins such as Botulism, or hereditary diseases such as Congenital Myasthenic Syndromes.
How does neuromusuclar transmission occur?
a) The acetylcholine vesicles in the nerve terminal.
b) The nerve action potential.
c) The voltage gated calcium channels that open after the arrival of the nerve action potential initiateing acetylcholine release at the neuromuscular junction.
e) The acetylcholine molecules attach to their receptor in the muscle area of the junction, which then triggers the opening of its ionic channel. This produces an end plate potential (EPP).
f) If the EPP is of sufficient magnitude, it causes the opening of the muscle sodium channels. This, in turn, initiates a muscle action potential that propagates and then triggers the mechanism of muscle contraction.
What is a MEPP?
Spontaneous release of acetylcholine that does not trigger a muscle action potential is called a miniature end plate potential (MEPP).
What happens to used Ach?
Acetylcholine is removed from the synaptic cleft from hydrolysis by cholinesterase to choline and acetate and passive diffusion of the neurotransmitter from the area.
Choline is then transported actively to the nerve terminal for resynthesis of acetylcholine.
How can you test the function of the neuromuscular junction, and to diagnose diseases of neuromuscular transmission?
Nerves are stimulated with a series of stimuli.
In normal muscle the compound muscle action potential does not change in amplitude during these several stimuli.
In neuromuscular transmission disorders such as myasthenia gravis, the amplitude becomes smaller during slow, repetitive stimulation.
In presynaptic disorders the compound action potential becomes larger during fast stimulation rates
What is Myasthenia Gravis?
An acquired disease caused by impaired neuromuscular transmission due to blockade of acetylcholine receptors by auto-antibodies characterized by fluctuating muscle weakness that worsens with muscle activity and at the end of the day when patients typically are weaker than in the morning.
Presentation of MG? Classic signs?
Patients frequently have droopy eyelids (ptosis) which increases with sustained upward gaze. They may also have double vision and proximal limb weakness and may develop difficulty swallowing and breathing.
Treatment of MG?
-Anticholinesterase drugs such as pyridostigmine
-Corticosteroids (suppress Ab production)
-Immunosuppressants (suppress Ab production):
azathioprine, cyclophosphamide, mycophenolate mofetil
-Thymectomy
-Plasma exchange (removed Abs)
-Immunoglobulin infusions (block Abs)
This figure shows the features of the compound muscle action potential during slow (left) and fast (right) stimulation rates. With fast stimulation rates the recording of the potentials is seen as straight vertical lines because of technical changes in the recordings.
On the bottom recordings in a normal individual, the potentials do not change in amplitude or shape at slow and fast stimulations.
In the middle are recordings from patients with botulism or Eaton Lambert Syndrome ( presynaptic); the potentials are small, and they may get smaller with slow stimulation rates, but there is a large increment in their amplitude during fast stimulations.
In Myasthenia gravis (top), the amplitude of the action potentials get smaller at slow stimulation rates, and also during fast stimulations for a while, then there may be a small increment and a late reduction in amplitude. Any increments are mild and not as larges as in presynaptic disorders. In myasthenia, the test could be repeated after exercise which makes the decremental response more pronounced.
What is Eaton Lambert Syndrome?
Disease in which antibodies block the release of acetylcholine by blocking the presynaptic voltage gated calcium channels that impair the release of acetylcholine .
Symptoms of ELS (Botulinum)
- lung tumors common (not all)
- proximal limb weakness
0small and poorly reactive pupils from impaired sympathetics
- difficulty with activity or difficulty rising from sitting position
- decreased saliva production; metallic taste
Why do you see decreased saliva production in ELS?
Decreased salivation is explained because the antibodies affect not only the neuromuscular transmission (nicotinic), but also affect the autonomic ganglia synaptic (muscarinic) receptors.
In contrast, in Myasthenia Gravis the antibodies only affect neuromuscular transmission (nicotinic).
Signs of ELS?
Proximal limb weakness (legs > arms)
Reduced muscle stretch reflexes
Transient improvement in muscle power following exercise
How is ELS treated?
REMOVAL OF ASSOCIATED NEOPLASM
“SYMPTOMATIC “ BOOST OF NEUROMUSCULAR TRANSMISSION
Cholinesterase inhibitors (pyridostigmine)
3,4- diaminopyridine (availability)
IMMUNOSUPPRESSIVE THERAPY
High-dose, long-term corticosteroids
Azathioprine
Plasmapheresis
Ancillary tests:
- muscle enzymes were normal
- Maximum motor nerve conduction were 30m/sec in the ulnar nerve (normal greater than 50m/sec) and 27m/s in the peroneal nerve (normal greatre than 45 m/sec)
- EMG disclosed fibrillations, large and long motor action potentials and recruitment
DX?
Step page gait= when walking patient has to raise the leg and has foot drop
Case 1 continued
Fibrillations are signs of denervated muscle due to sensitized receptors to Ach
This is a peripheral neuopathy
Why is he having weakness noted in climbing stairs?
serum CPK is 350 (elrvated)
nerve conduction studies were normal and number of recruited studies were normal and the number of receruited motor units action potentials for the degree of effort were increased on EMG
Muscle weakness of the pelvic girdle
In what disease category would ‘ragged-red fibers be seen on a muscle biopsy?
mitochondrial disorders
serum CK was 25000 IU/L (normal less than 200)
Why is the urine dark?
the muscle fiber is damaged here and the dark urine is due to myoglobin in the urine
What will you in muscle biopsy in this patient?
muscle necrosis and phosphorylase deficiency
4.
Repetitive nerve stimulation test in myasthenia gravis
Characteristic of a pre-synaptic disease
How does Botulinum present?
this needs to be in the DDx of ELS (pre-synaptic)
patients get areflexia, large pupils, xerostomia
