What is the difference between a myopathy, segmental demyelination and axonal degeneration?
In a myopathy, there is degeneration in the muscle fiber, segmental demyelination leaves the axon alone but gets rid of myelin and axonal degeneration results in loss of axon innervation.
Which of these is a normal axon?
The one on the left, it has a thick myelin sheath with Schwann cells clustered nearby. The one one the right shows signs of remyelination and a very thin myelin sheath.
Which of these pictures indicated reinnervation and which indicates pathological atrophy?
Center picture = reinnervation due to clumping of fibers. Right = atrophy due to shrunken fibers and centrally located nuclei
A patient comes to see you complaining of rapid ascending paralysis starting with foot drop a couple days ago and now he is struggling getting out of a chair. The only thing different he can think of is getting a vaccine a couple days ago. What is the likely diagnosis and pathophysiology? How would you treat this patient?
Guillian-Barre Syndrome. Inflammation and demyelination of spinal nerve roots and peripheral nerves. Treat with plasmaphoresis then IVIG.
You are doing a service mission in India and see a patient with dry, scaly, asymmetric lesions on his limbs. He says he cannot feel the lesions. Biopsy of the lesions shows granulomatous inflammation with no evident microbes. What is causing the lesions in this patient?
Tuberculoid leprosy mediated by CD8+ T-cells
You are doing a service mission in India and see a patient with symmetrical loss of sensation in the hands and feet. What cells were likely invaded by what microbe in this patient?
He has lepromatous leprosy which would mean his Schwann Cells were invaded by Mycobacterium leprae.
A diabetic patient comes to see you presenting with this on his foot. What is causing this and how might it affect his autonomic nervous system?
Loss of circulation in the extremities in diabetics results in peripheral neuropathy. Patients can no longer feel ulcerations in their feet. Autonomic nerves can also be affected and yield postural hypotension, decreased bladder control and sexual function.
A 55 year old construction worker presents with carpal tunnel syndrome. Why does his nerve biopsy look like this?
With trauma to nerves, you get discontinuity of proximal and distal segments. The axons then branch out and form random clusters as seen in this biopsy. This is how a normal axon should appear.
A mother brings her 5 year old boy to see you who is having difficulty keeping his balance when walking. You take a biopsy of the muscle in his leg and see this. What protein is mutated in this boy?
Dystrophin, which is commonly deleted in X-linked Duchenne Muscular Dystrophy. Note centrally located nuclei in large fibers and atrophic fibers mixed in.
Why might a patient with the condition that yielded this histology experience hypertrophy of calf muscles later on in life? What is a simple test to lead you in your diagnosis?
Muscular dystrophy leads to proliferation of endomysial connective tissue that causes pseudohypertrophy of fibers, which will eventually lead to replacement of muscle with fat and CT. You could look for creatine kinase levels in blood to confirm muscle fiber death.
What is the difference between Becker Muscular Dystrophy and Duchenne Muscular Dystrophy?
Becker has a mutation in dystrophin which lessens the symptoms. Patients usually lead normal lives.
A patient comes to see you with a lilac rash around their eyelids complaining of slow onset of muscle weakness that has made it difficult for her to get up out of a chair. What is the likely diagnosis? What is the likely pathophysiology of her condition?
Dermatomyositis. T-cell mediated destruction of muscular capillaries leads to perifascicular atrophy, causing her symptoms of proximal paralysis.
A patient comes to see you with double vision and respiratory problems. You prescribe acetylcholinesterase inhibitor to test out your suspicion and it helps. What can you do to further your treatment?
Plasmaphoresis to get rid of the antibodies against ACh receptors in Myasthenia Gravis. You could also remove his thymus,
What contributes to the loss in checkerboard pattern of these muscle fibers?
Reinnervation of muscle fibers. The motor neuron determines the type of fiber it innervates. Since neighboring fibers reinnervate fibers that lost innervation, they lose their checkerboard appearance.
What type of muscle fiber atrophy is most commonly attributed to disuse?
A patient comes to see you complaining of rapid ascending paralysis. One week earlier he was diagnosed with a CMV infection. Deep tendon reflexes are 0/2 in right and left LE. What might you expect to see in a tissue sample of a peripheral nerve?
This sounds like Guillain-Barre Syndrome, which is an immune-mediated demyelinating neuropathy. In a tissue sample you might see endoneural lymphocyte/macrophage infiltration and macrophages stripping away myelin at the nodes of Ranvier.
A patient comes to see you complaining of relapses and remissions of mixed sensorimotor polyneuropathy over the past 5 years. Biopsy of the patient's sural nerve shows well-developed onion bulb structure. How do you treat this patient?
This sounds like Chronic Inflammatory Demyelinating Polyradiculoneuropathy. Patients can go into remission with steroid treatment and plasmapheresis.
You see a patient with large ulcers in his extremities. He says that he has lost feeling in the distal portions of his extremities in symmetric fashion. What infectious disease could be causing his condition?
Mycobacterium leprae in Leprosy. Endoneurial fibrosis and perineurial sheath thickening contribute to symmetric polyneuropathy.
A mother brings her unvaccinated child to your clinic complaining of weakness and paresthesia down both legs. You notice the child is having difficulty maintaining his balance. What is your diagnosis?
Diptheria toxin is damaging this child's nervous system
A patient comes to see you with erythematous, blistering rash following a dermatomal distribution around her ribcage. How did the causative agent get to her skin and what would a biopsy of the affected nerves look like?
This is shingles. The virus traveled through the neuron and infected epidermal cells to create the blistering effect. A biopsy of the nerve would show mononuclear infiltrate in the affected ganglia.
What are the different types of hereditary sensory and autonomic neuropathies (HSANs)?
I: AD sensory neuropathy. II: AR sensory neuropathy. III: AR autonomic neuropathy. IV: AR congenital insensitivity V: AR congenital insensitivity
What hereditary neuropathies predominately affect strength and sensation?
Hereditary motor and sensory neuropathies (HMSNs)
A mother brings her 2 year old child to see you complaining of progressive muscular atrophy below the knee and distal muscle weakness. On PE you notice his foot looks like this and can palpate enlarged peripheral nerves. Tissue sample of the enlarged nerve shows a well-developed onion bulb pattern. What is the molecular basis of her child's disease? Is it likely that one of his parents has a similar condition?
This is HMSN 1, which is a result of mutated PMP22 or MPZ proteins that cause demyelination of axons when mutated. This is an autosomal dominate disease so it is likely one of his parents will have the same condition.
A mother brings her 2 year old child to see you complaining of progressive muscular atrophy below the knee and distal muscle weakness. On PE you cannot palpate any enlarged peripheral nerves and tissue sample of peripheral nerves shows loss of myelinated axons. Is it likely that one of the child's parents will have the same condition?
Yes. This is HMSN II, which is an autosomal dominate condition.
A mother brings her 4 year old child to see you complaining that he has failed to reach developmental motor skill milestones. PE shows absence of deep tendon reflexes, enlarged palpable peripheral nerves and generalized muscle weakness in his trunk and limbs. Tissue sample of peripheral nerves shows abundant onion bulbs and diminished axons. Is it likely this child's parents have this condition also?
No. This is HMSN III, which is an autosomal recessive disorder where PMP22 or MPZ are mutated.
A 65 year old female with a history of diabetes comes to see you complaining of diminishing distal sensorimotor function and ulcerations on the soles of her feet. What autonomic abnormalities might you find when taking her history?
Postural hypotension, recurrent UTIs due to incomplete bladder emptying, and sexual dysfunction.
What is the mechanism behind neuropathic beriberi?
A 70 year old patient comes to your clinic complaining of numbness and paresthesias in her LE for the past 10 months. She has a 30 year history of smoking and you suspect paraneoplatic effect from small-cell lung carcinoma. What clinical test could you do to test out your diagnosis?
IgG titer. IgG antibodies made against the tumor also bind to the dorsal root ganglia, causing the neuropathy.
Which patient had her nerve damaged during a surgery one year ago?
The bottom, notice disordered axons intermixed with connective tissue
A new mother brings her 1 month old complaining that her baby is very "floppy" and has difficulty breathing. Below is a tissue sample of the child's muscle. What determines the severity of disease in this baby?
The slide shows panfascicular atrophic fibers and a few giant muscle fibers characteristic of spinal muscular atrophy. The severity of this disease is determined by the number of copies of the SMN2 gene that is homologous to the deleted SMN1 gene that causes disease.
What muscular dystrophies are most common in men? What gene is responsible for these conditions?
X-linked Duchenne Muscular Dystrophy and Becker Muscular Dystrophy. These are from DMD gene mutations that cause absence or mutation of dystrophin.
A mother brings her 6 year old boy in to see you complaining of clumsiness and inability to keep up with the boys on his soccer team. Physical exam shows hypertrophy of calf muscles and muscle biopsy is seen below. What is causing the hypertrophy if his calf muscles?
This is DMD. Note the varying fiber size, internalized nuclei, degenerate fibers and proliferation of endomysial connective tissue. Calf hypertrophy is due to initial overcompensation of calf muscles due to pelvic girdle weakness. As the disease progresses, the muscles atrophy and fat/CT make the calf pseudohypertrophic.
You see an 8 year old female with a family history of progressive muscle weakness in the proximal limb and girdle muscles. What protein is likely mutated in this patient?
This sounds like an AD limb girdle muscular dystrophy. These tend to have mutations in sarcoglycan and caveolin
A mother brings her 12 year old boy to your clinic complaining of cataracts, abnormal gait and weakness in his hands and wrist extensors. She has a similar condition. Physical exam shows weakness in dorsiflexion of the foot. Biopsy shows splitting of the tissue indicated by the arrow. Based on your diagnosis, would this boy have a more or less sever condition than his mother?
The pathologic change in the intrafusal fibers of the muscle spindle is typical of myotonic dystrophy. This is an AD disease that gets worse with each generation because nucleotide repeats increase.
A patient's temperature begins to increase rapidly upon administration of local anesthetic. What is the molecular basis behind this reaction?
This is malignant hyperthermia caused by uncontrolled opening of the ryanodine receptor, leading to tetany and increased muscle metabolism.
A mother brings her child in to see you with onset generalized muscle weakness. Muscle biopsy is shown below. What is your diagnosis?
Those are nemaline rods typical in the congenital myopathy, nemaline myopathy.
By what different mechanisms are mitochondrial myopathies caused?
mtDNA point mutation (MERRF), DNA mutation (Leigh's) and deletions/duplications of mtDNA (ophthalmoplegia)
A patient comes to see you complaining of muscle weakness when getting out of a chair and combing his hair. He has a heliotrope rash on his eyelids and Grotton lesions on his knuckles. What histological finding is sufficient to confirm your diagnosis?
Perifascicular atrophy and CD4 inflammation in muscle confirms dermatomyositis.
How do polymyositis and inclusion body myositis differ from dermatomyositis?
DM is due to CD4 cells where PM and inclusion body myositis are due to CD8 infiltrate and destruction. Inclusion body myositis may also yield vacuolation and stain red with Congo Red due to amyloid deposition.
What are the toxic myopathies?
Thyroid, Ethanol, Drug-Induced (Steroids, Chloramphenicol, and Statins)
A 30 year old male comes to see you with drooping eyelids, double vision and generalized muscle weakness. The weakness comes and goes by the day and gets better with AChE inhibitor. What would electronmicrograph look like in the NMJ of this patient? How do you treat this patient?
This is Myasthenia Gravis. You would see a decrease in AChRs on the membrane and immune complexes along the postsynaptic membrane. You could treat with a thymectomy, AChE inhibitors, prednisone and plasmapheresis.
A 64 year old male with a 20 year history of smoking presents with proximal muscle weakness and autonomic dysfunction. Studies show enhanced neurotransmission with repetitive stimulation and no improvement with AChE inhibitors. What is the site that is affected in the NMJs of this patient?
This patient has Lambert-Eaton Myasthenic Syndrome. It is often a paraneoplastic syndrome from small-cell lung carcinoma that affects Ca2+ channels and limits the amount of vesicles released in a synapse.
What muscle fibers are particularly susceptible to atrophy when someone is taking glucocorticoids?
Type II muscle fibers
What type of nerve degeneration do you expect to see in someone who had their femoral nerve lacerated in their thigh?