Take a tour of a new eLearning format we’re working on, and learn the basics of neurologic localization:
The drug is typically started between ages 4-6 at a dose of 0.75 mg/Kg. However, steroid cause may side effects to Duchenne boys, including weight gain and behavioral problems.
How does it work? We’re not sure, but we think the medication stabilizes muscle membranes and inhibiting cytotoxic T-cells.
Side effects are mediated by binding sites in the cell nucleus which lead to initiation of metabolic pathways :
The new drug VBP-15 is molecularity very similar to Prednisone, but lacks the 11 beta hydroxy arm, which reduces the metabolic side effects, without affecting the beneficial membrane stabilizing effects:
VBP-15 has been shown to improve muscle strength and function in an animal model of DMD without the metabolic side effects of Prednisone:
Clinical trials in humans are expected to begin in 2013-14.
Watch this space for more information.
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.
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
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.
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).
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.
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.
Each lung is composed of >300 million tiny membrane bound sacs of air sacs (alveoli) which if spread out would cover a piece of ground roughly the size of a tennis court. The purpose of this giant membrane is to exchange oxygen from the air for carbon dioxide from the blood stream.
Treatment includes adding extra oxygen to the air to make this process more efficient.
However, gas exchange across the alveoli can only occur if fresh air is brought into the lungs, and stale air is moved out, a process known as ventilation. The diaphragm and muscles of the chest wall act like a giant bellows to make this happen:
Patients with this type of ventilatory failure do not need extra oxygen, their lungs can extract oxygen from air normally, they need mechanical assistance moving air across their lungs:
Early neuromuscular respiratory muscle weakness causes nocturnal hypoventilation. This is because the weakened diaphragm is even more inefficient when laying supine in bed with the stomach contents pressing up on it.
Nocturnal hypoventilation presents with daytime sleepiness, early morning headaches, fatigue, and impaired cognition.
Click here to take an on-line test, and find out how sleepy you are during the day. If you score 10 or higher, you might have a problem!
Nocturnal hypoventilation is best treated using a non-invasive respirator at night, either with a face or nose mask:
Other patients use a negative pressure respirator vest, or cuirass, which requires the patient to wear an upper body shell attached to a pump which actively controls the respiratory cycle:
Neuromuscular respiratory failure also leads to an ineffective cough, which in turn predisposes patients to aspiration, retention of secretions, or pneumonia. Affected patients need to learn to use the cough assist machine when they get a minor respiratory tract infection to help them clear their secretions and prevent pneumonia:
More severe neuromuscular ventilatory failure leads to rapid shallow breathing, accessory respiratory muscle use, thoracoabdominal paradox (inward motion of the abdomen during inspiration), and ultimately high blood levels of carbon dioxide.
In these cases, respiratory support is needed day and night.
Some patients can continue to use non invasive respiratory support, sleeping with a face or nose mask, and using a mouth piece intermittently during the day:
Others cannot tolerate noninvasive ventilation or have anatomic abnormalities that preclude fitting of noninvasive ventilators. Some disease, such as advanced ALS and Duchenne muscular dystrophy, affect the upper airway muscles as well as the diaphragm, impairing swallowing and compromising airway protection from aspiration. These patients can chose to be managed with invasive respiratory support using a tracheotomy and conventional ventilator.
Ptosis can be congenital (you are born with it), or acquired (it develops during life).
When ptosis is caused by an oculomotor nerve lesion, there is generally also some degree of eye movement abnormality (ophthalmoparesis). Oculomotor nerve palsy can be caused by something as simple as diabetes, but if the nerve fibers to the pupil are involved (causing a dilated pupil in addition to the ptosis and ophthalmoparesis), that is very suggestive of a compressive lesion such as an aneurysm (see below) and warrants immediate evaluation.
Horner’s syndrome causes mild ptosis associated with a small pupil (miosis) sometimes associated with lack of sweating (anhidrosis) on the face, and can be caused by trauma to the carotid artery, lung tumors, or strokes.
Myasthenia gravis is an autoimmune disease that affects the neuromuscular junction, and frequently presents with fatiguable ptosis often associated with double vision and limb weakness. The ptosis will usually get worse when the patients is tired at the end of the day (diurnal variation):
However, acquired ptosis is most commonly caused by dehiscence or disinsertion of the levator aponeurosis, causing a disconnection between the eye lid and the elevating muscles.
This usually occurs in elderly patients, but can sometimes affect younger contact lens users.
Patients who notice a drooping eyelid, unequal pupils, or double vision should consult with a neurologist in order to establish the correct diagnosis.