MS, Tysabri and PML

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The disease:

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).

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The drug:

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.

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The problem:

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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,

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Large confluent areas of demyelination in PML.

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).

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I’m taking Tysabri, what’s my risk of PML?

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:

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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.

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So, what should I do?

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.

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Click here to find out more about Tysabri and PML from the MS society.

Correct clinical diagnosis of dizziness in the ER could save $$ billions

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We have already blogged about the danger of escalating health costs in the USA.

The cost of emergency room visits for severe dizziness has grown exponentially in recent years, topping $3.9 billion in 2011 and projected to reach $4.4 billion by 2015.

Investigators from Johns Hopkins estimate that half a billion a year could be saved immediately if emergency room physicians stopped the routine and excessive use of head CT scans to search for stroke in dizzy patients, and instead used simple bedside physical exams to identify the small group of patients that truly needs imaging.

Click here to find out more about the Johns Hopkins study.

Click here to find out more about the hidden dangers of unnecessary CT scans.

Once they understand how inner ear disease can cause vertigo and nystagmus, any physician can use our simple clinical scheme to distinguish inner ear problems from more serious and rarer central causes like stroke in dizzy patients.  Click here to find out how.

A ripping yarn – a tale of cervical artery dissection

Case Summary:
This 46-year-old woman was healthy except for a history of occasional migraine headaches and cigarette smoking. On the day of admission she had fallen down a short flight of steps carrying a heavy box. About 2 hrs later she complained of some neck pain.  Then later that evening developed abrupt onset left sided weakness. She arrived at the emergency room within 1.5 hrs of the onset of weakness. On examination, she was alert, but she had a right gaze deviation (she wouldn’t look to the left side) and the left side was completely paralyzed. She had a normal brain CT scan.

The stroke team was notified, and she was given intravenous thrombolytic (“clot busting”) drug therapy within 1/2 hr of her arrival at the hospital and 2 hrs since the onset of her symptoms.

Carotid ultrasound subsequently showed no flow in the right internal carotid artery, and carotid arteriography subsequently showed near occlusion of the artery from an arterial dissection (see image below, red arrow):

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What is cervical artery dissection?

Cervical artery dissection is caused by bleeding inside the wall one of the major arteries in the neck.

This process is thought to be triggered by local injury to the inside layer of the vessel wall.

Cervical artery dissections occur from blunt trauma:

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Cervical artery dissection can also occur after minor trauma, particularly in someone with a genetic predisposition:

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What diseases predispose to arterial dissection?

There are some specific syndromes such as Marfan syndrome, Pseudoxanthoma elasticum and Ehlers- Danlos syndrome type IV that are associated with a weakness in the arterial wall making an arterial dissection more likely:

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In other cases, the specific cause of arterial weakness is unknown, but there is ongoing research to try to identify genetic links.

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What happens after a cervical artery dissection?

Symptoms can be caused from the damaged arterial wall itself (local symptoms) and some affected patients will later develop strokes.

Local symptoms include neck pain, unusual headache and/or Horner’s syndrome.

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L Horner’s syndrome (small pupil and drooping eyelid) caused by damage to the sympathetic nerve fibers in the arterial wall from carotid dissection. Click here to find out more about Horner’s syndrome and other causes of unequal pupils.

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What about stroke?

Stroke symptoms only occur in 25-30% dissections and can occur several days after the neck trauma and/or onset of local symptoms.

The arterial dissection narrows the space inside the blood vessel (the lumen), so less blood flow gets to the brain:

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A carotid artery dissection with blood clot inside the arterial wall (left) leading to narrowing of the vessel lumen and less blood flow (right).

Cervical arterial dissections can also cause stroke when pieces of blood clot break off and move with the blood flow only to block small arteries further inside the brain (cerebral thromboembolism), or if the dissection tracks across (and blocks off) an arterial branch (see below):

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How is arterial dissection diagnosed?

Magnetic resonance imaging is probably the easiest way to make the diagnosis:

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MR angiogram (left) showing tapered occlusion of the left internal carotid (white arrow) from dissection. Fat suppressed T1 weighted MR axial image through the dissected cervical artery (right) showing bright blood within it’s wall (black arrow) from dissection.

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How is it treated?

In most cases the arterial dissection ultimately heals on its own without any surgical intervention.  There has been some controversy surrounding the use of anticoagulant vs anti-platelet drugs for stroke prevention after cervical artery dissection, but most current data favors the use of the anti-platelet drug aspirin:

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Of course, for patients presenting with symptoms of acute stroke, throbolytic therapy is also an option, and can improve outcome without increased risk in stroke from dissection:

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Click here to find out more about cervical artery and dissection and stroke.

Click here to find out what to do if you think your having a stroke.

Click here to find out more the certified stroke center at Monmouth Medical Center.

Lactic Acid gone to your head?

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D-Lactate Encephalopathy and Periodic Ataxia
Posted by Michael Twomey, Drexel MSIV, Class of 2014

Remember that pain in your side during a long hard workout? That’s the buildup of lactic acid or L-lactate which is a way for your body to burn energy when it there isn’t much oxygen around (like when you think it’s a good idea to run 5 miles). This feeling, although uncomfortable, won’t make you loopy–it’s twin brother, however, has no such qualms.

D-lactate is just like normal old lactic acid, only completely different. In fact, it is the mirror image of the molecule that causes us such grief. For those of us who have forgotten organic chemistry, or would rather walk on broken glass than take such a torturous class, think
of it like a pair of gloves. L-lactate would be your left hand glove and D-lactate the right. They look like the same darn thing from a distance (made out of the same leather and thread, and stuffing), but no matter how you rotate them, you could never get them to match up.

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Our bodies happen to be finicky. Like the 7 year old fussy eater we all know and (hopefully still) love, the human body can only make and break down L-lactate. Thus, under factory settings, we all have an undetectable level of D-lactate in our blood. Bacteria, however, are wired a bit differently (shocking, I know). Some can take the same sugars that we eat, turn them into D-lactate, and when those buggers are in your intestinal system–this form of lactic acid can enter our blood stream.

Lactobacilli (the bad guys)

It just so happens that high levels of D-lactate effects the brain just as much as it does the rest of our bodies. We aren’t exactly sure the why or how this compound acts on our central nervous system, but it can cause anything from making you unbalanced to putting a patient in a delirious state. Case reports show symptoms of sleepiness, hallucinations, clumsiness, blurred vision, disorientation, dizziness, lethargy, excessive irritability, and abusive behavior. All of which can last up to a few days! The gait can be very unsteady (ataxic) during each episode, and this syndrome is one of the causes of “periodic ataxia”.

To make the diagnosis these patients also had an elevated amount of acid in their blood (something normal Lactic Acid can do as well) and high levels of D-lactate.
So can you blame the next time you trip over the doormat on bacteria? Probably not.
Fortunately the only reports of this syndrome have been found in people with extensive small intestine surgery. It turns out that the bacteria who can make D-lactate tend to live in our large intestine where they almost never see large amounts of sugar. Normally our small intestine is long enough to absorb all of those nutrients and leaving them to digest your Mexican meal instead. People with short bowel syndrome, however, should be aware of this possibility and eat appropriately. Otherwise having meals high in simple sugars could cause you to end up in the hospital with some strange behaviors and a nice long course of antibiotics!

Foreign Accent Syndrome – Their “Problem” or Yours?

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Foreign accent syndrome (FAS) is a rare condition which causes affected patients to suddenly speak their native language in a foreign accent.

Cases of FAS were reported as early as 1900.  However, one of the best known historical cases is “Astrid L”, a Norwegian woman who suffered a traumatic brain injury from shrapnel during a WW2 air raid in 1941.  She survived, but found herself mispronouncing vowels in such a way that she seemed to have a German accent, leading to social isolation and stigmatization for the remainder of the war.

Since then, there have been about another 60 FAS cases reported in the literature and media, mostly in patients who have suffered acute neurologic events such as strokes, multiple sclerosis and head injury.

Unlike most neurologic syndromes, FAS has not been localized to a lesion in a particular brain area.

The only thing that can be said is that most affected patients have lesions affecting the dominant hemisphere in or around known language areas.

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Brain imaging studies from a FAS patient: The MRI (left) shows enlargement of the Sylvian fissure from atrophy of the left temporal lobe. The PET scan (right) shows focal hypometabolism in the left temporal lobe.

Many affected patients were initially mute, then developed FAS as they recovered from a non-fluent aphasia:

There are also some cases of FAS that have developed after minor neurologic events, or even without any clearly identifiable neurological cause at all.  Some of these patients have had normal brain imaging, suggesting that the problem can be functional or psychogenic.

This is all further complicated by the fact that different listeners can perceive different accents in a single speaker.

The video clip is a patent with FAS syndrome after brain injury from hemiplegic migraine.  She is said to have a Chinese accent.  Does it sound Chinese or just slurred to you?

The table below is from a FAS case report, where the affected patient’s “foreign accent” was obviously described very differently by observers.

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This suggests that FAS may not be a true syndrome after all, but simply a listener-bound epiphenomenon.

What does this mean?

Well, we have already explained that most FAS patients have some kind of speech or language problem that changed how they speak.  That explains the association with lesions in the dominant hemisphere.   However the “foreign accent” may actually just something perceived by the listener – the variability of perceived accents is explained by the fact that listeners have different experiences with languages other than their own.

In other words FAS may not be a true syndrome, but simply an epiphenomenon that exists only in the ears of the beholder.

Deep Brain Stimulation for Essential Tremor

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We have already blogged about “benign” essential tremor.

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Here is a recap of the patient featured in one of those previous posts. He has a long history of worsening essential tremor, which has not responded to oral medications, and has made it impossible for him to hold a cup or write with a pen:

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He decided to undergo deep brain stimulation, a procedure where tiny electrodes are placed into deep nuclei inside the brain. When these electrodes are activated, they cause an interruption in the brain circuits which cause tremor:

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Here he is, after surgery, with the electrodes switched off:

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Here he is with the electrodes to both sides of the brain switched on, see how much better his tremor is, particularly on the right side:

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He can write and hold a cup for the first time in >10 years.

These same pathways can be inactivated by gamma knife radiosurgery in tremor patients who cannot undergo deep brain stimulation because of blood thinners, dementia or some other medical problem.