Acetylcholine and Myasthenia Gravis

How does the neuromuscular junction work?

The neuromuscular junction is the connection between a motor nerve and muscle fiber.

The activated motor nerve triggers the release of acetylcholine (ACh), which then diffuses across the neuromuscular junction to the muscle (post-synaptic) membrane, binds to any available acetylcholine receptor (AChR), which then in turn  activates the muscle fiber, ultimately leading to a motor contractions and a volitional movement.

What happens in myasthenia?

Autoimmune (acquired) myasthenia gravis (MG) is caused by antibodies circulating in the blood stream which bind to AChRs and disrupt neuromuscular transmission in a variety of ways:

Some of these antibodies simply block the receptor’s binding sites so that ACh cannot activate the muscle membrane:

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Other antibodies link the receptors together:

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Which then leads to internalization of the receptors (endocytosis) and simplification of the post-synaptic membrane:

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The end result is that the post synaptic membrane becomes simplified and devoid of working AChr, so there are little or no available binding sites for the released ACh to bind to:

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Excess ACh is removed from the synaptic cleft by the enzyme acetylcholinesterase (AChE), which breaks it down into inactive constituents.

nmj achr

So, you can think of MG like a game of musical chairs, when some of the chairs have been taken away, and there some of the acetylcholine can’t find a place to sit down before it is gobbled up by the AChE.

musical chairs

You can tip the odds more in favor of facilitating neuromusucular transmission by inhibiting AChE, allowing ACh to stick around longer, making it more likely to find an available AChR to bond to, rather like waiting longer to remove the chairs in musical chairs.

Dr Mary Walker first uses physostigmine in MG

mg mwDr Walker was first to discover the benefits of using a acetylcholinesterase inhibitor (AChEI) in MG in 1934.  While still a house physician at St Alfege’s Hospital, Greenwich, she found herself taking care of a 56-year-old woman with severe MG.  She happened to review the case with visiting neurologist, Dr Denny Brown, who explained to Dr Walker that MG resembled the effect of curare poisoning. Dr Walker, reading that the effect of curare could be reversed by injecting physostigmine, tried this drug on her patient, with remarkable improvement. She then treated a second case, a 40-year-old woman, using prostigmine, marketed by Roche. This case was presented to the Royal Society of Medicine in December 1934, and became known as ‘The Miracle of St Alfege’s’.

The Tensilon Test

We do still (rarely) use injectable AChEIs  like prostigmine (neostigmine) for managing MG.

However, we now more often use them for diagnosing MG, and in particular the short acting drug edrophonium or Tensilon has become synonymous with the diagnosis of MG, the so-called Tensilon test.

Mestinon

The oral AChEI pyridostigmine or Mestinon is now widely prescribed for symptomatic treatment of MG

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Abraham Lincoln’s Ventriculostomy

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Ventriculostomy

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During ventriculostomy, the catheter is inserted through the brain and dura into the ventricular system via through a hole drilled into the skull.

Ventriculostomy, or external ventricular drainage, is surgical procedure to alleviate raised intracranial pressure by inserting a tube through the skull into the ventricles to remove cerebrospinal fluid.

Ventriculostomy was first used by Claude-Nicolas Le Cat for treatment of a newborn boy with hydrocephalus in 1744.

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Hydrocephalus before (A) and after (B) CSF drainage via ventriculostomy, showing significant reduction in ventricular size.

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Ventriculostomy for head trauma

Ventriculostomy is also used to measure (monitor) and treat raised intracranial pressure by draining CSF and blood to relieve increased pressure inside the skull from cerebral edema (brain swelling) after head trauma.

EVD trauma

Top row: CT scans after head trauma, showing bleeding and edema in the brain after head trauma, causing raised intracranial pressure.
Bottom row: Ventriculostomy (external ventricular drainage) used to monitor and treat raised intracranial pressure.

Untreated, raised intracranial pressure can result in “herniation” (downward compression of the brain stem), leading to dysfunction of vital centers that regulate breathing and heart function, and ultimately brain stem death.

herniation

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The Lincoln Assassination

Abraham-Lincoln-Shooting

Lincoln was shot in the head by Johns Wilkes Booth at Ford’s Theatre in Washington DC on April 14, 1865.

The mortally wounded Lincoln was carried out of the theatre, across the street to the Petersen House , where he was attended by three doctors from the theater’s audience including army surgeon Charles Leale, later joined by other doctors including Joseph Barnes (Surgeon General Of the US Army).

Lincoln was declared dead at 7.22am on April 15, 1865.

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The Abraham Lincoln Head Shot

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Illustrations depicting Abraham Lincoln’s head wound by David A. Peace MS from University of Florida’s Department of Neurosurgery. The track of the bullet passes through the lateral horn of the lateral ventricle.

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The Doctor’s Notes

Dr Leale, feeling around by hand, discovered the bullet hole in the back of Lincoln’s  head right next to his left ear.  Leale attempted to remove the bullet, but the bullet was too deep in his head,and instead Leale dislodged a clot of blood in the wound. Consequently, Lincoln’s breathing improved.  Leale learned that if he continued to release more blood clots at a specific time, Lincoln would still breathe.

Here are some exerts from Leale’s actual account of the event:

I quickly passed the separated fingers of both hands through his 
blood matted hair to examine his head, and I discovered his mortal 
wound. The President had been shot in the back part of the head, 
behind the left ear. I easily removed the obstructing clot of blood 
from the wound, and this relieved the pressure on the brain.

As the symptoms indicated renewed brain compression, I again 
cleared the opening of clotted blood and pushed forward the button of 
bone, which acted as a valve, permitted an oozing of blood and re- 
lieved pressure on the brain. I again saw good results from this action.

The Hospital Steward arrived with the Nelaton probe and an ex- 
amination was made by the Surgeon General and myself, who introduced 
the probe to a distance of about two and a half inches, where it came 
in contact with a foreign substance, which lay across the track of the 
ball ; this was easily passed and the probe was introduced several inches 
further where it again touched a hard substance at first supposed to 
be the ball, but as the white porcelain bulb of the probe on its with- 
drawal did not indicate the mark of lead it was generally thought to 
be another piece of loose bone. The probe was introduced the second 
time and the ball was supposed to be distinctly felt. After this second 
exploration nothing further was done with the wound except to keep 
the opening free from coagula, which, if allowed to form and remain 
for a short time, produced signs of increased compression, the breathing 
becoming profoundly stertorous and intermittent, the pulse more feeble 
and irregular. After I had resigned my charge all that was profes- 
sionally done for the President was to repeat occasionally my original 
expedient of relieving the brain pressure by freeing the opening to the 
wound and to count the pulse and respirations. The President's posi- 
tion on the bed remained exactly as I had first placed him with the 
assistance of Dr. Taft and Dr. King.

lincoln death bed

It is clear that the bullet track left an opening into the lateral ventricle, a ventriculostomy.

When this ventriculostomy track occluded with blood clot and tissue, the dying President developed raised intracranial pressure, with compression of the breathing center in the brain stem and more labored breathing.

When the clot was removed, and the ventriculostomy opened, the President would transiently improve.

Lincoln’s ventriculostomy.

Numb tingling hands, it’s probably carpal tunnel syndrome

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Numbness and tingling in the hands is most often from Carpal tunnel syndrome (CTS).

CTS is caused by compression of the median nerve as it travels across the wrist with the tendons between the carpal bones and the flexor retinaculum (also know as the transverse carpal ligament):

flexor retinaculum

CTS is caused by compression of the median nerve under the flexor retinaculum also known as transverse carpal ligament.

Compression an injury to the median nerve causes numbness and tingling mostly affecting the thumb, index finger, middle  finger, and half of the ring finger.

cts_numbness

CTS usually causes numbness and tingling mostly in the thumb, index and middle fingers

More severe cases also cause weakness and wasting of the muscle at the base of the thumb that abducts the thumb away from the fingers (abductor pollicis brevis or APB):

thumb abduction

Thumb abduction, the movement that is weak in more severe cases of CTS, where there is involvement of both motor and sensory median nerve fibers.

OLYMPUS DIGITAL CAMERA

Wasting of APB muscle belly (“thenar eminence”) in severe CTS

In severe cases, the numbness can seem to affect the whole hand, and can even radiate up the forearm and arm:

Carpal-Tunnel-foream

Symptoms are often worse typing, driving, and frequently wake the affected patient up at night:

cts night

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CTS can usually be diagnosed on clinical grounds.  A helpful physical finding is a tingling in the wrist and fingers caused by a tap over the carpal tunnel (Tinel’s sign):
http://www.youtube.com/watch?v=VtrC9dnVrrQ&start=37&rel=0

In some cases, an electrodiagnostic study may be necessary to confirm the diagnosis:

cts emg

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CTS is usually “idiopathic” (we don’t know why it happened), but some cases are caused by diabetes, pregnancy, thyroid disease, joint swelling from rheumatoid arthritis, heavy manual work and work with vibrating tools.

Treatment usually begins with conservative measures, like avoiding exacerbating activities, and wearing a neutral position night splint:

cts splint

Patients who do not improve with these conservative measures can undergo a surgical procedure to release the compressed median nerve:

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Want to find out more?

Click here to take an on-line quiz to see if you have CTS.

Watch this on-line video tutorial explaining the causes and treatment of CTS:
http://www.youtube.com/watch?v=_p799CIpRL0&start=13&rel=0

If you think you might have CTS, you should make an appointment to see a neurologist.

Click here to use our physician finder service.

MMC Free Education Event, May 1

125th-annv-logo-blue-and-gray

Join us for a FREE education event

WHEN – Wednesday May 1, 2013 1-2pm

WHERE – SCAN Adult Learning Center

Dr Neil Holland, Chief of Neurology and Medical Director of the Neuroscience Institute

strokeTIA RAPID EVALUATION CENTER

Essential-tremor-is-characterized-by-sporadic-and-postural-tremor-on-handsTREMOR

CALL 732 542 1326 To Register!

Click here for directions

Free Seminar – Warning signs of stroke, April 11

WARNING SIGNS OF A STROKE

WHAT ARE TIAS?

Thursday April 11, 2013 AT 1PM

Marlboro Recreation Center

1996 Recreation Center Dr Marlboro, NJ 07746

(732) 617-0100

Click here for directions.
Click here for more details.
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A stroke is a medical emergency that happens when blood flow to the brain stops and brain cells begin to die.

Join Neil Holland, MD, Medical Director, Neuroscience Institute at Monmouth Medical Center, to learn about the warning signs and symptoms of a stroke and how timing in getting medical treatment is crucial to saving lives.

“Mini-strokes” or transient ischemic attacks (TIAs) will also be explained.

This program, for ages 60 and older, will take place at Marlboro Recreation Center, located at 1996 Recreation Way in Marlboro.

Registration is required by calling 732-617-0100. Free.

2012-13 Neurology Student Research Presented at Drexel University College of Medicine

Monmouth neurology students presenting their posters during medical student research day at Drexel University College of Medicine in Philadelphia on March 20, 2013:

medical-student-research-day-2

1: Addressing blood glucose control in diabetic peripheral neuropathy:  A missed opportunity for neurologists?

Darsi Pitchon and Seun Ku Kim

IMG_20130320_143958 IMG_20130320_152931

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pichon1

Key points:

Most neurology visits for diabetic neuropathy did not include counseling about blood glucose levels, unless they were with a neuromuscular fellowship trained sub specialist.   Because neuropathy can be the presenting and/or predominant problem in diabetes, some of these patients may be primarily followed by their neurologist, so this is a missed treatment opportunity.

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2.  Acute myelopathy with normal CSF and imaging:

Denis Chang

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Chang

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Key Points:

Spinal cord infarction from fibrocartilaginous embolism can present with acute quadriparesis in young patients with normal CSF and MRI scans.  If this diagnosis is suspected, a follow-up MRI 2-3 days can be quite helpful.  This is not an inflammatory process, and will not improve with steroids or other immunosupressive medications, which can hurt more than they help.

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3. The benefits of an on-line neurology clinical course for 4th year clerkship students

Ilya Grinberg

IMG_20130320_144208

ginsberg2

Key points:

The on-line video course used by the Monmouth neurology clerkship led to improved test scores on an on-line clinical test compared to students who did their clerkship at other sites.  The on-line clinical test is a low cost but effective method of evaluating students’ clinical skills in neurology over multiple clerkship sites.

Updated – Concussion Management

NEW Updated Concussion Guidelines

from the American Academy of Neurology

Background information:

Concussion is a mild traumatic brain injury that occurs when a blow or jolt to the head disrupts the normal functioning of the brain.

Symptoms include persistent headache, problems with memory and communication, personality changes, and depression.

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Concussion can occur from a blow to the head/body, such as helmet to helmet contact, or contact with the ground or another object.

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More than a million Americans sustain a concussion each year.

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A concussion does not always “knock you out”.

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Symptoms of a concussion can last, hours, days, weeks, or even months.

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Why is this important?

Repeated concussion can lead to permanent brain damage, affecting academics, internships, social interactions, and athletics.

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Athletes who continue to play after sustaining a concussion, may take longer to recover and are at an increased risk for developing Second Impact Syndrome or a more prolonged Post-Concussion Syndrome.

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Numerous studies in professional boxers have shown that repeated brain injury can lead to permanent brain damage (dementia), sometimes referred to as “punch drunk” syndrome or dementia pugilistica.

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Autopsy studies have shown similar brain changes in former professional football players who experienced multiple concussions.

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Recent studies of college football players showed an association between multiple concussions and reduced cognitive performance.

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Guidelines for concussion evaluation and management

New American Academy of Neurology guidelines suggest the following management of concussion:

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Suspected Concussion:

Any athlete with suspected concussion should be closely observed and undergo repeated “side line assessments” for at least 30 minutes:

concussion screen

The presence of one or more of these symptoms and signs indicates concussion, that athlete should be removed from play, and referred to an emergency room or experienced concussion program for more detailed assessment.

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Brain Imaging Studies

six_types_TBI

Any athlete who sustains a head injury who has unconsciousness, persistently altered mentation, or progressive deterioration on the screening tool (above) over time should be sent to the emergency room for a brain imaging study to rule out a skull fracture or intracerberbral hemorrhage.

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Follow-up Care at a Concussion Center

All athletes with concussion, whether they did not need to go the emergency room, or whether seen in the emergency room and sent home, should be evaluated by a health care provider experienced in managing concussion or a concussion center.  They should be prohibited from return to play or practice (contact risk activity) until the concussion has resolved and they are asymptomatic off medications.

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The concussion center uses clinical assessment of symptoms, computerized cognitive testing and balance testing to follow an athlete’s concussion, and determine when it has resolved.

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Computerized testing:

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Immediate Post-Concussion Assessment and Cognitive Testing (or ImPACT ) is used at many centers to help assess the severity of concussive brain injury and determine when it safe for athletes to resume sporting activities.

The test is computerized and lasts approximately twenty minutes.

Ideally, athletes should take a baseline test at the beginning of the season.

The test should then be repeated within 24-72 hrs after a concussion. The scores are compared to that athlete’s baseline to identify any residual change in verbal and visual memory, processing speed, and reaction time.

ImPACT testing can then be repeated to look for improvement, once the symptoms have cleared, or 7-10 days after the first post-concussion test.

This information can assist with decisions regarding when a player may return to action.

It should be noted that the widespread application of ImPACT testing has been criticized by some authorities.

ImPACT testing can be helpful, but is only part of the neurologic evaluation of athletes with concussion, and should not be the only factor used to determine when that athlete can return to sporting activities.

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Balance Testing:

The Balance error scoring system (BESS) is a clinical assessment of postural stability that is administered in the concussion center and contributes to the diagnosis of concussion.

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Recovery from concussion

Most athletes recover fully from a concussion, but it can take weeks, months, and even years.

School attendance, student work load and other activities may need to be modified according to the individual’s symptoms.

The athlete’s symptoms should be closely monitored until they feel symptom free.

Once the athlete is symptom free, and they have been cleared through ImPACT, they may begin a progressive return to their sport.

A progressive return involves gradually increasing the level and intensity of the activity, while closely monitoring the athlete for any return of symptoms

Day 1: Walking or easy biking for 20-30 min.

Day 2: Jogging or moderate biking for 20-30 min.

Day 3: Running or heavy biking for 20-30 min.

Day 4: Sport specific drills/practice (non-contact)

Day 5: Return to contact sports

If symptoms return at any point during the progression the activity should be stopped. The athlete should return to rest and must be symptom free for at least 24 hrs before starting the progression again.

Recovery may take longer in those with a previous history of concussion, learning disability, or attention disorder.

It must be stressed to athletes, parents and athletic trainers that these guideline are important, and must be followed to minimize the risk of permanent brain injury.

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Retirement from play

Health care professionals in a concussion center may suggest that athletes who have experienced multiple concussions and have persistent neurobehavioral problems permanently retire from contact sports.

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Download the AAN Concussion App

Download a concussion quick check app specially developed for coaches and parents directly to your ipad or droid device.