Recent study links marijuana use to structural brain changes

 

 

Post  prepared by Amanda Baker, Drexel University College of Medicine Class of 2014

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A study recently published in the Journal of Neuroscience by Harvard researchers have linked casual marijuana use to structural changes in distinct areas of the brain.

These areas, the nucleus accumbens and amygdala, and are largely involved in recognition of reward, motivation, fear, and memory.  In this study, the brain scans of 20 young adult casual marijuana users were compared to those of 20 young adult non-users.

While the results clearly demonstrated significant structural differences between the two groups, the structural changes have not been correlated with consequences in mental or physical functioning.  In other words, researchers aren’t entirely sure of the impact of these brain changes.

 

Casual marijuana use may damage your brain

The debate regarding the use of marijuana medically and recreationally is ongoing in the United States.

Although the Drug Enforcement Administration(DEA) categorizes this drug as Schedule I, “with currently no accepted medical use and a high potential for abuse”, many argue that there is, in fact, much benefit to medical marijuana, especially in comparison to other sedating pain medications.

This is reflected in 21 state laws which have legalized medical marijuana to varying degrees.

Last summer, Dr. Sanjay Gupta completed a documentary “Weed” highlighting the benefit of medical marijuana:

However, some states such as Washington and Colorado, have gone one step further by legalizing marijuana for both recreational and medical use.

Given the ongoing research on the effects of marijuana, perhaps this new study will call into question continued legalization of the most widely used recreational drug in America.

 

Click here to find out more.

 

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STIFF PERSON SYNDROME: A misleadingly flippant name for a serious disease

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Posted by Jennifer Ding, MSIV Drexel University College of Medicine

What is Stiff Person Syndrome (SPS)?

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Exaggerated lumbar lordosis in SPS

Stiff Person Syndrome (yes, the official moniker) is a very rare autoimmune disease of the nervous system that affects maybe 1 in 1,000,000 people worldwide. Most patients experience fluctuating, involuntary muscle rigidity in the trunk and limbs, an exaggerated lumbar curve, and a heightened sensitivity to their environment.

Loud or unexpected noise, touch and emotional distress can actually set off muscle spasms or even falls in those afflicted.

Attacks of spasms are usually unpredictable, last for minutes and tend to recur over hours. These spasms can be so intense that they actually can cause.

The rigidity seen in SPS is characterized by a stiffness (hence the name) that begins over several months along the spine and spreads to the legs. In the lucky few, the fluctuating rigidity becomes fixed leading to difficulty walking, bending, and frequent falling.

Who gets SPS?

Moersch and Woltman first described SPS in 1956 based on 14 cases that were observed over 32 years. It was initially called “stiff man syndrome” before the disease was found in females and children as well.

Today, we see that SPS affects twice as many women as men and is frequently associated with other autoimmune diseases, such as Diabetes Mellitus Type 1, thyroiditis and vitiligo. Age of onset varies between 30 to 60 with it occurring most frequently in people in their 40s.

What causes SPS?

Now for the science behind SPS: like any autoimmune disease, the problem is thought to lie with antibodies that attack the body’s own cells or enzymes. Patients with SPS have antibodies against glutamic acid decarboxylase (GAD), an enzyme, that produces gamma-aminobutyric acid (GABA), a chief inhibitory neurotransmitter (a chemical) that plays a crucial role in regulating our central nervous systems. GABA is also directly involved in regulating muscle tone.
Mechanism

The exact details of the way GAD antibodies cause SPS remain unknown. Many people with GAD antibodies don’t develop SPS. But most patients with SPS have a high level of GAD antibodies in their blood as well as antibodies that inhibit GABA-receptor-associated-protein (GABARAP). Therefore, scientists hypothesize that the root cause of the muscle rigidity and spasms seen in SPS lie in a GABA impairment.

Think of it this way: muscles work in pairs. When one contracts, the other relaxes, and vice versa. GABA is key in regulating this relaxation and without it, both muscles end up contracting. When both muscles contract, they lose the ability to work together, leading to a stalemate, or stiffness that we see in patients with SPS.

How is SDS diagnosed?

The level of GAD antibodies can be measured in the blood and cerebrospinal fluid (CSF). As aforementioned, the mere presence of GAD antibodies in the blood does not directly correlate with a diagnosis of SPS. Instead, the higher the level of GAD antibodies in the blood, the more likely SPS is the diagnosis.

Electromyography (EMG) can also be used to demonstrate involuntary neuronal firing in muscles.

How is SPS treated?

While there is no cure for SPS to date, there are treatment options that are aimed at symptom relief. Benzodiazepines, such as Valium (diazapam) or Ativan (lorazepam), that act similarly to GABA are the primary treatment for symptom relief. These drugs have muscle relaxant and anticonvulsant effects. Baclofen, another type of GABA-agonist that is dispensed from an implanted pump, can be used as a muscle relaxant. Neurontin (gabapentin) is a seizure medication that has also been used for symptom relief. However, SPS tends to worsen over time, leading to patients requiring increased dosages of drugs.

Intravenous immunoglobulin (IVIG) that target the antibodies themselves are also used in patients with advanced disease. IVIG has been shown to decrease stiffness and the heightened startle reflex. Steroids, rituximab, and plasma exchange have also been used to target the immune system in SPS patients, but the benefit of these treatments remains unclear.

Additional reading material

Click here for more information on SPS, the most up-to-date research on the neurological disease, and social networking for those interested, afflicted, or who have family members who are afflicted.

Click here for an article about a patient with SPS.


News segment about a young dancer with SPS.

Plasma Exchange For Myasthenia Gravis

Posted by Christopher Orr,  Drexel University College of Medicine 2014

Ms. AB presented last week in the Neurology office with shortness of breath and weakness, and she knew it was from her myasthenia gravis.

She was already on an anticholinesterase inhibitor, but it was very apparent that she was suffering from a severe exacerbation of myasthenia gravis.

We sent her to the Emergency Room in order to be admitted so she could receive plasmapheresis in order to minimize the antibodies that were blocking the acetylcholine receptors at her neuromuscular junctions.

To give a brief history of Ms. AB’s myasthenia gravis, she was diagnosed in the Fall of 2013 when she presented with muscle weakness and difficulty breathing.  She was treated with plasmapheresis during that initial episode, and improved.

In the interim, she had also been given steroids to reduce the immune response of her autoantibodies towards her acetylcholine receptors, but this actually caused increased leg weakness, more likely from steroid myopathy than myasthenia gravis.

Unfortunately she experienced another exacerbation in December, and she was treated with intravenous immunoglobulin (IVIG).  What is interesting is that when she was treated with IVIG, her symptoms did not improve as they had done plasmapheresis.

There is limited research on the efficacy of IVIG in comparison to plasmapheresis in the literature.  A comparison study of IVIG vs. plasmapheresis waspublished by Mandaway et. al. in the Annals of Neurology in 2010 and included 1,606 patients – both therapies showed similar clinical outcomes in terms of both mortality and complications.  From a purely financial perspective, IVIG was more cost effective because of lowered length of stay and total inpatient charges.

However, a smaller study published by Stricker et. al. in JAMA in 1993 reported 4 patients who did not respond to initial IVIG treatment but later responded to plasmapheresis.  There were no definite prognostic factors mentioned that might explain why plasma exchange may be better than IVIG in certain patients.  The article stated further research was needed.

Ms. AB did present with myasthenia gravis at a later age of onset than is typically observed.  For future studies that compare IVIG to plasmapheresis, I would be highly interested in a subgroup analysis on a patient’s age and the efficacy of the 2 treatment modalities of IVIG and plasmapheresis.

When we saw Ms. AB in the hospital, she was already doing much better with plasmapheresis.  In addition, we were For the future, Ms. AB would likely be discharged to a rehabilitation facility and there are considerations to start her on CellCept (mycophenolate mofetil).  It would be preferential to start the patient on CellCept as an immunomodulatory drug to decrease the autoantibodies against her acetylcholine receptors and reduce her need for plasmapheresis.

I chose to write a reflection on Ms. AB for 2 reasons.  First, she and her husband are both very kind people, and it is a pleasure to see her improve.  Second, I love technology in medicine and healthcare.  When we saw Ms. AB’s plasmapheresis treatment, it was fascinating to see the apparatus that was using centrifugal force to spin her blood and separate her plasma from the WBCs, RBCs, and platelets.  The mechanism behind performing the plasmapheresis was to take off her plasma, which had the autoantibodies, and replace new plasma with albumin.  Please look below to see a picture of a plasmaphresis apparatus and an explanation of how it works.  After my experience seeing Ms. AB, it was a pleasure to treat her and learn from her condition.

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Pictured above is an apparatus that is used for the plasmapheresis treatments.  Although this machine may seem very intimidating, it operates on the basis of how spinning blood can separate the blood into different components, such as the plasma, RBCs, WBCs, and platelets. To explain in a simple manner, a central venous line is obtained from the patient so blood can be brought to the machine and spun.  After the plasma is removed by the centrifugal force, the remaining components (RBCs, WBCs, and platelets) is added with albumin and saline (a protein found in plasma) then reintroduced into the patient.

In many instances, diseases can be complicated to comprehend.  I wanted to give a better understanding of myasthenia gravis.  I hope this picture and caption that I included make the disease easier to digest.

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The above image shows the synapse of a neuromuscular junction.  In a healthy patient, the acetylcholine can bind the acetylcholine receptor and produce a response in the muscle.  In a patient with myasthenia gravis, the antibody (shown in green) is blocking the acetylcholine receptor and preventing the acetylcholine in the synapse from reaching the muscle.  This picture is a good educational tool because it also shows how the treatment of pyridostigmine (Mestinon) can improve a patient’s symptoms.  The acetylcholinesterase (AChE, the red pac-man figure) is what degrades the acetylcholine in the synapase.  Pyridostigmine is an anticholinesterase inhibitor and impedes the red pac-man figure in the picture from working.  Therefore, pyridostigmine increases the amount of acetylcholine in the synapse that can reach the receptor and will improve the symptoms in an episode of myasthenia gravis.

Duchenne Muscular Dystrophy

Posted by Elliot Dubowitch from Drexel University College of Medicine Class of 2014

Duchenne muscular dystrophy (DMD) is one of the four main groups  of muscular dystrophy, a muscle disorder that affects and weakens the musculoskeletal system.

Muscular dystrophies are genetically inherited and progressive.

DMD is inherited in an x-linked manner.  This means that the mother, who is unaffected, is a carrier for the disease and has a 50% chance of passing it on to her male children.

The disease is caused by a deficiency in the Dystrophin protein, a complex that anchors the muscle to surrounding tissue.

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This disease has a wide spectrum of symptom severity, depending on the type of genetic mutation, with Duchenne being very severe, and Becker’s muscular dystrophy being much more mild.

The symptoms in DMD are not usually present at birth.  As the child ages, however, they symptoms will gradually become worse and worse.  Most children are unable to walk by thirteen years of age and die in their twenties due to respiratory failure.

One of the earliest signs of DMD is called to as the “Gower Maneuver.”  Although not pathognomonic for DMD, this maneuver is a sign for proximal muscle weakness and is often correlated with DMD.  Below is a clip of a child performing to Gower’s maneuver to stand.  The patient must “walk” up his body using his hands from a sitting position due to weakness in his hip and thigh muscles.  Below is a video clip demonstrating this.

Another early sign is calf pseudohypertrophy.  Although the muscle looks bigger, it is not necessarily stronger, as the functional muscle is replaced by nonfunctional fibrous tissue.

Unfortunately, there is currently no cure for DMD.  However, there is symptomatic treatment available, such as respiratory support, cardiovascular monitoring and treatment and (if needed) surgery for scoliosis.

Steroids are the only current medication that has been shown to keep the boys walking longer.  A study was conducted in which one group of boys were given steroids daily, whereas the other group of boys were given steroids 10 days on and 10 days off.  The boys receiving daily steroids walked on average until the age of 14.5 year, while the boys receiving steroids intermittently walked to only 12 years of age.  The boys receiving continuous steroids also had more side effects including weight gain, mood swings, increase risk of infection, and other side effects of steroid usage.  If one is to consider steroid use, it is imperative to remember that it must be used at the time the child is still ambulating.  The boy will not regain lost function, however he may retain his current function longer.  In the future we hope that new drugs like VBP-15 will hopefully provide the benefits of corticosteroids without some of the side effects.

Genetic research is currently being done to hopefully find a cure for this disease.

Diagnosis of Myasthenia Gravis Confirmed with Tensilon Test

Post prepared by Dr Mrugesh Panchani, PGYIII Medicine Resident, Monmouth Medical Center.

For patients with clinical features and signs suggestive of myasthenia gravis, the Tensilon test can serve as an easy bedside confirmatory test.

Edrophonium (Tensilon) is an acetylcholinesterase inhibitor and we have already blogged about how these drugs can improve conduction across the neuromuscular junction in myasthenics.

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Tensilon is preferable for diagnostic testing because of the rapid onset (30 s) and short duration (5 min) of its effect.

However, an objective end-point must be selected to evaluate the therapeutic effect, such as improvement in eye movements, ptosis, impairment of speech, or the length of time that the patient can maintain the arms in forward abduction.

Here’s a real life example (we have a signed consent form on file):

The first video shows our patient at her baseline with R>L ptosis and facial weakness:

Then the patient is given a low dose (2mg) of iv Tensilon (with telemetry monitoring and bedside atropine at the ready) is given and we see a definite improvement in ptosis and a more expressionful face:

This test was considered positive and hence terminated.

Had there been no change, the patient would have been given an additional 8 mg of iv Tensilon.

We typically start with a low dose at first because some patients react to edrophonium with side effects such as nausea, diarrhea, salivation, fasciculation, and (rarely) bradycardia. Atropine (0.6 mg) should be drawn up in a syringe, ready for IV administration if these symptoms occur.

BYM338 (Bimagrumab) for Inclusion Body Myositis – New cure or next dud?

Posted by Jeffrey Schneider, MSIV, Drexel University College of Medicine

There has recently been a flurry of news articles about a new treatment in clinical trials for Inclusion Body Myositis. Novartis has announced that BYM338 (Bimagrumab) has recently received FDA breakthrough status for the treatment of inclusion body myositis. What does this mean and what are the implications? Is this a cure or sensationalist hype? What do we need to know about BYM338 other than a sorely needed name change. Before we get to that let’s talk a little about inclusion body myositis.

What is Inclusion Body Myositis?

Inclusion Body Myositis (IBM) is a progressive disease of muscle weakness. Myositis, derived from Greek as many of our beloved medical terms are, is aptly named as it is a disease characterized by inflammation of the muscle. This disease most commonly presents insidiously with weakness of the fingers and quadriceps (thigh). This leads to difficulty with everyday activities like walking or holding objects. Some may also develop dysphagia (difficulty swallowing). The disease may occur sporadically (sIBM) and rarely as Hereditary IBM. It is not a fatal disease but the progressive muscle weakness means that many will rely on assistance for walking and everyday activity within 5 years.  This condition can often be difficult to diagnosis and can be aided with the help of a muscle biopsy.

Epidimiology

IBM is an age related disease that typically affects those 50 and older. Men are more often affected It is the most common of the inflammatory myopathies but is still a relatively rare condition

Differential Diagnosis

A common laboratory finding of myositis is an elevated in Creatine Kinase (CK).  CK, however, is not specific for just Inclusion Body Myositis and many conditions may also have this abnormal laboratory finding. More commonly cholesterol lowering drugs like Statins and Fibrates may lead to myositis. IBM may be mistaken for the other inflammatory myopathies, polymyositis and dermatomyositis. Polymyositis and dermatomyositis are treated with steroids and other immunosuppressive drugs of which have little effect on IBM which can sometimes be the clue that you might be dealing with IBM.

Pathology

The cause of IBM is not fully understood. What is evident is that there is an element of muscle inflammation and an element of muscle degeneration. A muscle biopsy will show the architecture of muscle at the microscopic level. Some of the key features that help to identify IBM are of course the inclusion body itself which are abnormal clumps of protein and tubules. Another feature are rimmed vacuoles which are empty pockets found within the cells. They are found in other inflammatory myopathies but occur in greater numbers in IBM.

Here is another biopsy slide showing some of the characteristic vacuoles and also the inflammatory cells in the endomysium (the layer that surrounds each individual muscle fiber).

Current Treatment

Unlike dermatomyositis and polymyositis there is currently no effective treatment of IBM.  Studies have shown the failure of steroids and other immunosuppressive agents.  Therefore it is approached symptomatically with physical therapy and exercise.

Where does that leave us now?

Novartis’ recent announcement is quite an interesting one. BYM338 (Bimagrumab) is a monoclonal antibody targeted to a very specific receptor on muscles cells. Monoclonal antibody therapy is a very field based on the human body’s own immune system.  B cells, a type of white blood cell, produce millions of variations on a common antibody to target infection. When the right antibody is found to bind to an infectious particle that B cell will undergo a series of interactions leading to cloning of that cell. This is the monoclonal proliferation that leads to a highly specific response. Researchers  have taken advantage of this concept to create highly targeted drugs.

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In the case of BYM338 (Bimagrumab), it is targeted to Type II Activin receptors on muscle tissue. This receptor normally binds an enzyme called Myostatin which inhibits muscle growth. By blocking this receptor the drug is blocking the effect of Myostatin and in theory allowing muscle growth. It is a novel approach to muscle degeneration seen in IBM.An interesting side note is that there is a breed of cattle with a defect in the gene for myostatin. The Breed is called Belgian Blue, their mutation leads to non-functioning Myostatin. They also look like this…

So is this the cure to IBM that we have been looking for. Currently the data has not been published so it is impossible to say. What we do now is that the FDA has approved BYM338 for “breakthrough” status. What this means is that the FDA is going to expedite the review of BYM338 based on what it has seen so far. This does not mean that it is a new breakthrough therapy that has passed all of its tests but rather that the FDA is intrigued by its prospects. It is also important to know that BYM338 has only gone through Phase II of Clinical trials. Phase I assesses the safety of a drug. Phase II trials are compared against placebo with a relatively small sample size (100-300). Phase 3 trials and FDA review will most likely take several more years before we will find out whether BYM338, or rather endearingly BYM338, lives up to its expectations. Could this drug be expanded to treat muscle wasting in cancer patients or the elderly? That is something developers are probably interested in but we currently don’t have the published data to support it. Could this effectively treat IBM? Maybe. Could this be a dud? Possibly. Will it be expensive? Most definitely.

Diaphragmatic Pacing and ALS

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Amyotrophic lateral sclerosis (ALS), sometimes referred to as “Lou Gehrig’s Disease“, is a progressive neurodegenerative disease that affects motor nerve cells in the brain and the spinal cord ultimately leading to muscle paralysis.

The diaphragm is a large muscle that moves air across the lungs to facilitate gas exchange and oxygenation of the tissues:

In ALS degeneration of the motor nerve cells that innervate the innervate the diaphragm via the phrenic nerves ultimately leads to respiratory failure.

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The diaphragm (purple arrows) a large muscle innervated by the phrenic nerves (green arrows).

The diaphragmatic pacing (DP) system bypasses the degenerated phrenic nerves in ALS, and provides direct electrical stimulation to the diaphragm, facilitating enhanced ventilation.

So we know we can electrically stimulate the weak or paralyzed diaphragm and make it contract.

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However, the real question is does this make a difference in terms of life and survival?

We have already blogged about the symptoms of nocturnal hypoventilation and benefits of NIPPV.

Here is a link to a recent summary of studies that have looked at DP for hypoventilation in ALS:

Data presented to the FDA in 2011 included 106 ALS patients who had undergone the surgery.

DP patients lived 9 months longer than a historical cohort of ALS patients with respiratory difficulties treated with NIPPV.

Unlike NIPPV, DP patients do not have to use a mouthpiece or mask.

However, the serious surgical complication rate from the procedure was 3.5%, 26% patients report mild-moderate discomfort from the electrical stimulation, and there were many technical problems including broken electrodes.

In ALS, unlike in spinal cord injury, the denervated diaphragm muscle will ultimately become inexcitable, rendering the DP system ineffective.

DP surgery costs about $20,000, compared to <$1000 for a NIPPV system.

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So, the jury is still out.

But before you sign up for DP,

Consider these facts:

DP is FDA approved as a medical device not as a therapy.

Many neuromuscular physicians are calling for real outcome data before widespread adoption of this invasive and expensive interventional procedure.   In response to these concerns, the Muscular Dystrophy Association (MDA) and ALS Association (ALSA) have co-sponsored a prospective study to determine whether the DP system in effective or not.

Finally, we know that ALS patient care varies at different centers around the country.  However, we don’t know how many ALS patients are getting their FVC measured or being assessed for hypoventilation appropriately.  We hope that the new MDA sponsored clinical registry will answer this question.

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Find out more:

Click here to find out more about hypoventilation in neuromuscular diseases.

Click here to link to a podcast about DP in ALS.

Click here to find out more about the DP system from the device manufacturer.

Click here to find out more about the DP clinical trial.