Neuromuscular

Question 1

History of MG

Answer 1

Long known to physicians, perhaps back to the 17th century and Sir Thomas Willis
Called myasthenia gravis by Jolly (1895)
One of the first known “auto-immune” diseases
Still best defined as a “fatiguing WEAKNESS” but NOT fatigue alone
Predilection for muscles innervated by the cranial nerves, and less often the spinal nerves
Found in approximately 1 in 10,000 Americans
More common in women than in men before age 40, then about equal in men and women

Question 2

Immunological basis of myasthenia

Answer 2

THYMOMAS in about 10 - 15% of patients, and hyperplasia in 70% of patients’ thymuses
Disease could be transferred to animals with injection of a patient’s IgG
Electron microscopy showed deposition of immune complexes on the postsynaptic membrane, specifically the Ach receptors
Binding of antibodies may be at many different sites on the ACh receptor (AChR): the major pathology is immune-mediated DESTRUCTION of AChRs more than simple BLOCKING of AchRs

Question 3

MG Patient presentations

Answer 3

Generally increasing weakness over weeks or months, but may seem abrupt with diplopia or loss of speech or swallowing
At first presentation, about 40% of patients have EYE involvement; eventually over 90 % of patients have: ptosis, diplopia, or inability to close eyes completely
Usually extraocular muscles in both eyes are affected, in a way that cannot be explained only by disease of CNs 3, 4, 6 or 7

Also common is fatiguing weakness of speech and swallowing

1. Power of voice decreases quickly, restored by pausing
2. Chewing and swallowing become increasingly difficult; also restored by pausing or resting during meals

In severe cases, normally much later: weakness of limbs, difficulty with neck flexion and extension, and respiratory failure

Question 4

Who gets MG?

Answer 4

Seemingly young women, especially around pregnancy or childbirth, in 20s 30s OR
Older men, 50s, 60s, 70s
More common in patients with other autoimmune disorders including hyperthyroidism and perhaps Systemic Lupus Erythematosus
Patients often considered depressed or simply hysterical at first for complaining of weakness, yet the arms and legs are usually strong and reflexes are normal, and they always regain strength after a brief rest or nap

Question 5

Course of Myasthenia Gravis

Answer 5

Can be severely progressive in some patients
Prognosis often clear in the first two years
Some will only have ocular symptoms, and if the only symptoms are ocular after 2 years, unlikely to spread
Some patients have a slow decline, but others may have a MYASTHENIC CRISIS:
1. Severe impairment of swallowing, even their own secretions, and respiratory impairment, causing aspiration pneumonia, and may require intubation and mechanical ventilation

Question 6

Diagnosis of Myasthenia

Answer 6

Easy when there is a combination of bilateral ptosis, generally worse in one eye, with multiple extra-ocular palsies, or weakness of voice, swallowing or facial expression
More difficult when there is only ptosis of one eye, or only dysarthria, or only dysphagia
Typically patients are strongest in the morning, and then become weaker during the course of the day
Usually no changes in reflexes, and no sensory changes or cerebellar involvement, or ANS effects

Question 7

Diagnostic aids for myasthenia

Answer 7

Circulating antibodies to skeletal muscles in perhaps 80 – 90% of patients with generalized myasthenia, but only 60 - 70% of patients with strictly ocular involvement have these antibodies
Anti-striated muscle antibodies are more commonly positive in patients who have a thymoma than in patients who do not
Nerve conduction studies show a DECREMENTAL RESPONSE; at slow rates of repetitive stimulation (@3HZ) the size of the muscle electrical response keeps declining
CT or MRI of the chest to look for a thymoma; if present it should be removed if possible
Consider MRI of the brain if there is only ocular involvement: rarely tumors of the orbital region or brainstem may “mimic” myasthenia gravis
Laboratory tests for thyroid disease or auto-immune disorders

Question 8

The Tensilon (Edrophonium) Test

Answer 8

Tensilon (edrophonium) is a short-acting cholinesterase inhibitor, which allows acetylcholine to last longer at the NMJ (nicotinic as well as muscarinic), and therefore briefly overcome myasthenia gravis
Atropine, an anti-muscarinic, is first injected to limit bradycardia from muscarinic receptors
Then 1-2 mg of Tensilon is given IV as a test
If no problems, up to 10 mg of Tensilon is given; maximum effect is seen in 1 to 5 minutes

Question 9

Treatment of MG

Answer 9

Generally start with an oral cholinesterase inhibitor, such as pyridostigmine (Mestinon) 60mg, twice a day going slowly up to four or five times a day
Adverse effects: intestinal cramping, diarrhea, nausea, bradycardia, sweating

Long acting form of Mestinon, 180mg Timespan, can be given at bedtime to help patients the next morning

Question 10

steroids and MG

Answer 10

Many patients will also need corticosteroids, such as Prednisone
Patients may begin with high doses, 60 – 90mg/day, but consider hospitalization, since prednisone somehow can worsen myasthenia when first given
A. Eventually patients may do well on lower dosages of prednisone
B. Precautions for GERD, ulcers, diabetes, osteoporosis, cataracts, hypokalemia, etc
Other immunosuppressants sometimes: azathioprine, cyclophosphamide, mycophenolate (CellCept)

Question 11

Severe myasthenia

Answer 11

May respond to plasmapheresis, which removes many of the patient’s own immunoglobulins
May also respond to intravenous IgG (IVIG)
Cholinergic crisis: worsening from use of too much cholinesterase inhibitors
Steroid myopathy: weakness from prolonged use of steroids
Some drugs may worsen myasthenia gravis, including antibiotics (aminoglycosides), anticonvulsants, anesthetics

Question 12

Amyotrophic Lateral Sclerosis history

Answer 12

Discovered in the mid 1800s, mostly by the great French neurologist Jean Martin Charcot
Known in most of the world as Charcot Disease
Known to most Americans as Lou Gehrig’s Disease, of course
A loss of nearly motor function by the time of death, with both peripheral motor neuron and corticospinal tact disease in most patients

Question 13

Amyotrophic Lateral Sclerosis

Answer 13

Pathologically a disease of upper and lower motor neurons, so increasing weakness is what is one expects to find in patients, atrophy, fasciculations and usually HYPEREFLEXIA
However, asymmetric weakness often occurs
Some complaints of numbness and pain are expressed by patients early in the disease, somehow
Few patients notice diffuse weakness at first
Predilection for certain muscles: the forearms and hands, tongue, larynx, pharynx, muscles of facial expression, lower extremity, respiratory muscles at the end
Virtually NO INVOLVEMENT of extraocular muscles

Question 14

ALS: Early Features

Answer 14

Presenting symptoms:
Dysarthria 33%
Painless loss of hand function 20
Weak, wasted shoulder 14
Foot drop 12
Fasciculations/cramps 11
Exercise intolerance 4
Respiratory failure 4
Cognitive impairment 2

Question 15

Amyotrophic Lateral Sclerosis- what’s going on

Answer 15

Gradual cell death of both upper motor neurons and lower motor neurons
Weakness, fasciculations, atrophy, yet increased deep tendon reflexes
Prominent effects on lower brainstem and cervical spinal cord: speech may be impaired especially early in the course;
Upper motor neurons: motor (frontal) cortex, via corticospinal tracts, to all levels of the brain stem and spinal cord
Lower motor neurons: anterior horn of spinal cord to skeletal muscles

Question 16

Clues to diagnosis of ALS

Answer 16

Worsening weakness, over months at least; mean time to correct diagnosis is 12 months
Frequent fasciculations, in the tongue as well as involved limbs, and worsening atrophy of the involved muscles
Multiple lower brainstem findings without other known cause, especially loss of speech or inability to move the tongue; many patients will have obvious atrophy and fasciculations of the tongue
Split hand: the lateral side (abductor pollicis brevis, first dorsal interosseous muscles) is usually more impaired than the medial side (abductor digiti minimi)
No involvement of orbital or extraocular muscles
Little or no involvement of urinary or bowel sphincters

Question 17

ALS Diagnostic Criteria

Answer 17

El Escorial (meeting in Spain) Criteria:
Patients must have evidence of both upper and lower motor neuron function in at least two levels: brainstem, cervical cord, thoracic cord and lumbar-sacral cord
ALS diagnosis is confirmed by evidence of upper and lower motor neuron disease at three levels
UMN Signs: increased deep tendon reflexes, spasticity, Babinski signs
LMN Signs: weakness, atrophy, fasciculations

Question 18

ALS Cognitive Decline

Answer 18

Found in about 10 % of patients
Much more like frontotemporal dementia than Alzheimer’s Disease
Patients can be apathetic, impulsive, limiting in speech content as well as production, depressed, lacking in initiative
But generally have preserved memory
Moods can be labile: laughing one moment, crying the next; called “Pseduobulbar affect,” due to diffuse brainstem disease

Question 19

Possible Etiology of ALS (not important)

Answer 19

Progressive cell death in corticospinal tracts and anterior horn cells still not well-explained
SOD1: most patients have a mutation in this enzyme, Cu/Zn Superoxide Dismutase, but it may still be functional in ALS patients, clearing free radicals
Oxidative stress may occur, but not necessarily from a mutant form of SOD1
Many patients have a mutation in TD-43, which metabolizes RNA
Apoptosis, or cell death, is somehow triggered, possibly by release of glutamate, an excitatory neurotransmitter released in other neurologic diseases
May be familial in 5 – 10 % of patients, otherwise sporadic, without known environmental causes
More common on the island of Guam, where ALS patients may also have Parkinsonian features, and dementia

Question 20

ALS Diagnosis

Answer 20

Exclude other diagnoses:

Multiple Sclerosis
Stroke, especially brainstem stroke
Tumors of brainstem or spinal cord
Myasthenia gravis
Inflammatory myopathy (dermatomyositis, Inclusion Body Myositis)
Cervical Spondylosis
Myelopathies due to trauma, infections, discs

Question 21

ALS Diagnostic Aids

Answer 21

Electromyograms (EMGs)
1. Should show denervation in at least three limbs if evidence of lower motor neuron involvement

MRIs of brain and/or cervical spinal cord to exclude other causes of diffuse weakness

Blood tests: genetic testing for SOD1, TFTs, Lyme, B-12, ANA, Parathyroid hormone, West Nile, heavy metals, HIV, HTLV-1

Question 22

Treatment of ALS

Answer 22

Riluzole (Rilutek) is the only FDA-approved drug
Riluzole prolongs life, or time to respiratory failure, but only by approximately three months; possible hepatic damage, so serum ALT is monitored
Patients’ hope cannot be taken away, especially at first diagnosis
Plans need to be made for terminal care and decisions about feeding tubes, ventilators, tracheosotomy, etc.

Question 23

Peripheral neuropathy

Answer 23

Also commonly called Polyneuropathy
A common condition, in which multiple peripheral nerves are slowly damaged
They can be purely sensory nerves, motor nerves, or both, but most of the common ones are purely sensory
Patients usually give a history of months or even a few years as the time of onset
Symmetric loss of sensation, or less commonly only motor function, or both motor AND sensory function
Primarily affects the feet, and then the shins sometimes as high as the knees
Less of an effect on the fingers and hands, rarely in the forearms

Question 24

Peripheral sensory neuropathy

Answer 24

Patients note many symptoms, more often in the feet than the hands:

1. Numbness
2. Tingling
3. Burning (“My feet are too close to the camp fire”)
4. Stinging
5. Asleep
6. Cold

Question 25

peripheral neuropathy Clinical findings

Answer 25

Patients may still have full strengths unless there is a pure motor neuropathy (Guillain-Barre) or mixed neuropathy
Reflexes are diminished, especially in the Achilles (ankle) reflexes
Sensory loss is most obvious with testing of vibration, and less obvious with proprioception, fine touch, temperature and pin prick
Gait may be affected, with a high “steppage” gait sometimes
Falls are more common in patients with polyneuropathy
Autonomic deficiencies may also occur, affecting urinary, sexual, gastrointestinal or peripheral vascular function, especially orthostatic hypotension

Question 26

Sensory Peripheral Neuropathy Common etiologies:

Answer 26

1. Diabetes, whether type I or type II
2. Hypothyroidism
3. Alcoholism
4. Deficiency of vitamin B-12
5. Immune-mediated: multiple myeloma, monoclonal gammopathies, rheumatoid arthritis
6. Drugs, including agents for chemotherapy
7. Heavy metals such as lead, thallium, arsenic
8. Infections, such as Lyme disease, leprosy, shingles

Question 27

Treatment of sensory neuropathy

Answer 27

Improved control of serum glucose is the most important goal by far for diabetic neuropathy
Rapid replacement of vitamin B12, usually with weekly injections, or beginning oral thyroid supplements for patients with hypothyroidism
No effective treatment for the loss of sensation
Pain is usually controlled by amitriptyline (Elavil) or some but not all antidepressants: duloxetine (Cymbalta)
Antiseizure drugs: gabapentin (Neurontin) works well or pregabalin (Lyrica), less effective, sedating
If necessary, opioids, especially tramadol (Ultram)
Patients must look for infections or trauma to their feet which may not be readily felt

Question 28

Single Neuropathies

Answer 28

Almost any peripheral nerve can be damaged, from metabolic, infectious or traumatic causes
Entrapment neuropathy is very common
Overuse of the hands or elbows, crossing of the legs, tumors, hypertrophy of muscles, tendons, ligaments may damage one or more peripheral nerves
Median nerve entrapment, or CARPAL TUNNEL SYNDROME, is the most common

Question 29

Carpal Tunnel Syndrome

Answer 29

Very common problem, producing paresthesiae of one or both hands due to MEDIAN nerve compression
A. Patients should note sparing of the pinky, but many patients complain that the entire hand is numb
B. Paresthesiae may spread up the arm to the shoulder
C. Most (but not all) patients will develop thenar atrophy

Prominent symptoms during sleep, including NOCTURNAL AWAKENINGS;
Patients who shake or FLICK their wrists at night to relieve the numbness or pain will have carpal tunnel syndrome more than 90 % of the time

Question 30

Treatment of carpal tunnel syndrome

Answer 30

If caught early, without significant thenar atrophy or weakness, limit repetitive use of the hands, and have the patient wear cock-up splints
A. Cock-up splints allow more cross-sectional area of the wrist, and inevitably limit the patient’s use of the involved hand or hands
Certain activities must be limited:
Bending, squeezing, gripping, exposure to vibrations (machines, hair dryers, vacuum cleaners, steering wheels)

Question 31

Carpal tunnel release surgery

Answer 31

Indicated if persistent pain and weakness, especially if symptoms are not improved after one year
Symptoms over one year if not treated surgically, may cause permanent paresthesiae and muscle loss
Procedure done on an outpatient basis, with only the upper extremity anesthetized
Transverse carpal ligament (flexor retinaculum) is sectioned, allowing more room for the median nerve
Limited use of the hand for approximately one month

Question 32

Ulnar neuropathies

Answer 32

Much more common at the elbow, around the medial epicondyle, due to overuse, pressure on the medial elbow, fratures, etc, than at the wrist
Elbow: Cubital tunnel
Wrist: Guyon’s tunnel
Patients generally have forearm paresthesiae, pain and weakness, not upper arm symptoms
Often pain at the elbow

Question 33

Signs of ulnar neuropathy

Answer 33

Loss of sensation, particularly pinprick in the pinky and the lateral half of the ring finger, ON BOTH SIDES of the hand
Atrophy of ulnar-innervated muscles, including abductor digiti minimi, ADDUCTOR pollicis, and interosseous muscles
Ulnar clawing may occur: flexion of the pinky and ring finger

Question 34

Treatment of ulnar neuropathy

Answer 34

Site of injury or disease must be found: usually the elbow, occasionally the wrist
Distinguish from median neuropathy, radial neuropathy, cervical radiculopathy (@C7 or C8)
Nerve conduction studies and electromyograms are very helpful
Limit bending of the elbow, or pressure on the elbow when sitting or sleeping

Question 35

Ulnar surgery

Answer 35

Transposition of the ulnar nerve at the elbow: invasive, sometimes ineffective operation
Ulnar nerve is moved IN FRONT of the medial epicondyle, limiting the pressure on the nerve

Exploration of the wrist may be necessary if a lesion is diagnosed around Guyon’s tunnel
MRI scans can be done of the elbow or wrist, as well as plain xrays

Question 36

Radial neuropathy

Answer 36

Presents almost always as a WRIST DROP
Occasionally only pain in the arm or forearm, with paresthesiae over the back of the wrist
Often patients have no idea how it happened:
Falls, trauma to the spiral groove of the humerus, injury within the axilla, elbow or forearm trauma
Intravenous catheters over the dorsum of wrist
May be part of a progressive polyneuropathy, as in diabetics, alcoholics (Saturday night palsy)
Classically found in lead intoxication
Nearly all cases resolve in < 2 months, unless severe disease or trama; patients can also benefit from a cock-up splint

Question 37

MERALGIA PARESTHETICA

Answer 37

Pressure on the lateral femoral cutaneous nerve, whose roots are L2-L3
Often patients are misdiagnosed with “sciatica” which is nearly always L4, L5 and S1 in distribution
There is numbness, sometimes pain, in the LATERAL THIGH, occasionally both thighs
Patients are typically obese men, or pregnant women
Resolves with weight loss, gabapentin for the pain
Rarely corticosteroid injections or inguinal release surgery are necessary