Wilhelm Uhthoff (1853-1927) a German neuro-ophthalmologist described an optic neuritis patient in 1890 who would develop episodes of temporary vision loss during physical exercise.
This condition, subsequently known as Uhthoff’s phenomenon, was later found to be caused by a rise in body temperature.
More than half of all multiple sclerosis (MS) patients spontaneously report being sensitive to environmental heat.
When specifically asked, as many as 70% MS patients report that high temperatures worsened their MS.
Increased temperature blocks action potentials in compromised (demyelinated) neurons resulting in slower conduction velocities and/or temporary failure of conduction altogether (conduction block).
This explains the temporary exacerbations in neurologic dysfunction that underlie Uhthoff’s phenomenon.
So what can you do?
Drugs like Ampyra (dalfampridine or 4-aminopyridine) improve conduction across demyelinated neurons, and can improve Uhthoff’s phenomenon, but these drugs are not currently FDA approved for this indication, and used off label can cost as much as $1200/month. It might be cheaper to move to Alaska or buy a window box AC unit?
Multiple sclerosis (MS) is an auto-immune disease characterized by episodes of multi-focal inflammation and demyelination of the brain and spinal cord, leading to recurrent and unpredictable neurologic compromise (relapses or exacerbations), usually alternating with periods of disease inactivity (remissions).
Tysabri (natalizumab) is a monoclonal antibody that binds to the cell adhesion molecules involved in the white blood cell movement from the blood stream into the central nervous system across the “blood-brain barrier”.
Keeping these cells out of the brain and spinal cord can help prevent the immune-mediated inflammation and demyelination that leads to clinical relapses in multiple sclerosis.
Studies have shown that patients taking Tysabri have a 64% reduced risk of disability progression and >80% fewer exacerbations (relapses) compared to placebo. More than 1/3 patient who take the drug are clinically free of disease activity.
Tysabri is administered by iv infusion once a month.
More than 50% of people have been infected with the JC or John Cunningham) virus (JCV), most during childhood or adolescence, often with no symptoms at all or just a minor febrile illness.
Once infected, the virus then lies dormant in the central nervous system, like a Tojan horse, totally inactive and innocuous.
However, if the infected person becomes immune suppressed, for example from HIV infection (AIDS) or from taking a immune presupposing medication, the virus can become reactivated and lead to a very serious brain infection known as Progressive multifocal leukoencephalopathy (PML). PML leads to large confluent areas of brain infection and demyelination (below), causing disability and death,
When a few Tysabri patients developed PML during the initial clinical trials, the FDA temporarily pulled the drug, but then re-introduced it with more careful monitoring (the TOUCH porgram).
There have now been >350 cases of PML in MS patients taking Tysabri, and this constitutes an overall risk of about 1.5 cases per 1000 (or 0.15%) of those taking the drug.
The risk is higher for patients who have already been been exposed to (and test positive for) JCV, have taken other immunosupressive drugs, or have taken Tysabri for longer times:
So, if you take Tysabri but test -ve for JCV, your PML risk is 0.07 per 1000, or 0.007% or 1 in 14,000.
Even if you test positive for JCV but haven’t taken prior immunosupressive meds (like azathioprine, methotrexate or mycophenolate) your PML risk is only 0.6 per 1000 or 0.06% or 1 in 1,700.
If you take Tysabri, you should know your JCV status. If your negative, you should get re-tested every 6-months since there are false negative results and some people do seroconvert every year.
If (or once) you test positive, you don’t need any further blood tests, but you should carefully weigh the risk benefits of continuing to take Tysabri beyond 2 years, particularly if you have had prior exposure to other immunosupressive drugs.
Multiple sclerosis comes in different varieties:
Many patients with MS have discrete relapses, which then resolve either partially or completely resolve, and are separated by periods of disease inactivity. We call this relapsing-remitting (a) or progressive-relapsing (b) disease.
Most of the “disease modifying” drugs currently used in MS work by preventing discrete relapses (and by preventing relapses) they will prevent the progressive acquisition of disability which can accompany each relapse in these types of MS.
However, there are other MS patients develop progressive disability without discrete relapses. This can occur after a relapsing remitting phase, so-called secondary progressive MS (c). Or patients can start right out with progressive disease without any history of discrete relapses, so-called primary progressive MS (d).
The chemotherapy drug mitoxantrone was found to have some efficacy for treating secondary progressive MS, but the duration of therapy is limited to 2 years because of toxicity.
New data presented at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis this week suggests that the chemotherapeutic agent rituximab may also stabilize or even reverse disability in secondary progressive MS.
Posted by Ilya Shnaydman, Drexel University College of Medicine Class of 2013:
Spasticity is defined as a ‘stiffness’ or ‘tightness’ of muscle due to spasms, or increased muscular tone. It is usually due to a lack of inhibition, as seen in an upper motor neuron lesion affecting the brain or spinal cord. Examples of upper motor neuron lesions include stroke (cerebrovascular infarct), multiple sclerosis, traumatic brain injury and cerebral palsy.
Although the exact cause of spasticity is not know, it is theorized to be due to an imbalance between the excitatory and inhibitory input to a muscle group. Increased excitability leads to spasticity, whereas increased inhibition leads to a flaccid muscle.
This can be better understood by illustrating the popular ‘knee jerk reflex’. During this test, the examiner strikes the patellar ligament with a reflex hammer which stretches specialized sensory fibers called the muscle spindle. This produces a signal which travels to the spinal cord (specifically at the L4 level). From the spinal cord, another specialized nerve complex called the ‘alpha-motor neuron’ conducts an impulse back to the quadriceps femoris muscle which triggers the contraction (knee jerk).
One of the patients treated at Monmouth Medical Center by the Neurology Specialists of Monmouth County, TM (the patient’s name is hidden to preserve anonymity) is a 65 year old male who suffers from a spinal cord infarct 15 years ago, which resulted in spasticity of his lower extremities (legs) just as described above. The right side has been affected more than the left. He has difficulty walking, as his gait is very rigid, but does manage to get around using a cane.
For spasticity, medical treatment consists primarily of physical therapy and muscle relaxants such as baclofen, benzodiazepines, and even botulinum injections. When these methods have been exhausted and either do not work to the patient’s satisfaction or cause side effects, patient’s must turn to experts in the treatment of spasticity.
The patient’s multidisciplinary neuroscience physicians at Monmouth Medical center urged the patient to consider intrathecal baclofen to help the patient improve his gait and overall quality of life. By injecting baclofen directly into the spinal canal (where the spinal cord lays), his neurologists are able to give significantly lower doses of the medication (as it directly contacts the spinal cord) and prevent unwanted side effects.
Baclofen is infused into the spinal canal via a programmable pump that is implanted beneath the skin (similar to a pacemaker). The pump’s batteries last about 10 years and most patients do not notice any discomfort from having the pump implanted. The baclofen is replenished by injecting it into the pump’s port (yellow arrow) with a small needle.
Before undergoing surgery for placement of the baclofen pump, patients typically undergo a trial to see if the intrathecal baclofen will be beneficial to them. During this ‘trial’, baclofen is injected directly into the spinal canal during a spinal tap (lumbar puncture, or needle placed through the skin into the spinal canal). The patient is then observed over a few hours to see if they are a good candidate for the permanent intrathecal baclofen pump. During the trial, only a small dose of baclofen is used, so once the pump is placed and programmed, the patient can expect to see even more benefit from the therapy. After the pump has been placed it can be adjusted non-invasively using a magnet (similar to a pacemaker) and should be followed by a neurologist to adjust the dosage as needed.
Below you can see the effect of the baclofen trial (again with just a small dose) for our patient, TM
In the past disease modifying treatments for relapsing-remitting MS all needed to be delivered by injection, and many patients went untreated because of fear of needles, or because of injection site reactions or other side effects with each dose of the mediction, sometimes felt to be worse than symptoms from the underlying disease.
Fingolimod was approved by the FDA in Sept 2010, based studies showing less brain lesions on serial imaging studies, and reduced rates of clinical relapses and progression of disability in patients treated with the drug compared to those on placebo and interferon beta. Patients starting fingolomid do need heart rate monitoring after their first dose, eye exams at basele and after 3 months to detect macular edema (a rare side effect of the drug), and zoster vaccination for those who are not already immune.
Teriflunomide showed less brain lesions on serial imaging studies and reduced clinical relapse rates compared to placebo in clinical trials. The most common side effects were diarrhea, abnormal liver tests, nausea, and hair loss. Treated patients need liver function tests at basleine and periodically during treatment.
Unoftunately, we don’t have head-to-head trials directly comparing the efficacy of these two drugs.
So which drug would I choose? Well, I might be more inclined to recommend teriflunomide for patients with a history of cardiac arythmia or for those taking blood pressure medications such as propranolol or verapamil which can also lower the heart rate. I might be more inclined to use fingolimod in patients who taking other drugs that can affect the liver.
Neither drug is approved for use during pregnancy, although teriflunomide has a stronger warning (category X) of teratogenicity from the FDA.
In sum, we now have two oral medications available for MS patients who have previously been unable or too afraid to get treated with an injectable medication, and this can only continue to improve the long term prognosis for this disease.