Pathology Student

Q. My 28 year old friend was just diagnosed with multiple sclerosis. What can he expect regarding prognosis?

A. MS is a demyelinating disease that is thought to be autoimmune in nature. It is not easy to predict an exact prognosis for an individual patient, but I think you can boil it down to the fact that while a small number of people with MS become unable to write, speak, or walk, the vast majority of patients are mildly affected by their disease. Let’s look at this in a little more detail.

Subtypes

There are several subtypes of MS, each with different symptoms and prognoses. Note that the frequencies of the different subtypes listed in different sources may not be comparable, because some sources refer to the frequency at diagnosis, while others refer to an overall frequency. It would be useful to know which subtype your friend fits into, because that may help determine his prognosis.

1. Benign MS
People with this type of MS have only rare attacks, and are minimally disabled 10 years after their diagnosis (therefore, you can’t make this diagnosis until 10 years have elapsed!).

2. Relapsing-Remitting
People with this type of MS attacks followed by partial or complete recovery periods free of disease progression. This is the most common type at diagnosis – but some patients move into one of the other types later on.

2. Primary-Progressive
People with this type of MS experience a slow but nearly continuous worsening of their disease from the onset, with no distinct relapses or remissions. This is an uncommon subtype.

3. Secondary-Progressive
People with this type of MS experience an initial period of relapsing-remitting MS, followed by a steadily worsening disease course. Many people with relapsing-remitting MS developed this form later on – but that was before new drugs for MS were introduced. This subtype may be less frequent now.

4. Progressive-Relapsing
People with this type of MS experience a steadily worsening disease from the onset but also have relapses, with or without recovery. In contrast to relapsing-remitting MS, the periods between relapses are characterized by continuing disease progression. This is an uncommon subtype.

Factors influencing prognosis

1. Factors associated with a better prognosis:

• female gender
• age of disease onset earlier than 40 years
• a first attack consisting of optic neuritis or other sensory symptoms
• lack of significant disability 5 years after onset
• minor abnormalities on brain MRI scan at the time of diagnosis.

2. Factors associated with a less favorable prognosis:

• male gender
• age of onset at age 40 or later
• a first attack consisting only of motor symptoms
• difficulty walking or sustained impairment in coordination after resolution of first attack
• large number of MRI lesions

All that being said…

It’s going to be hard to tell with a lot of certainty at this point what your friend’s prognosis is, because the diagnosis is new. Once he has had the disease a few years, then it will be important to see how it has progressed (or not progressed), because one of the more important predictors of one’s future MS course is one’s past MS course.

Here are some good web resources for learning more about MS:

1. The NIH
http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm

2. The National Multiple Sclerosis Society
http://www.nationalmssociety.org/index.aspx

3. The University of California – San Francisco Multiple Sclerosis Center
http://www.ucsf.edu/msc/faq.htm#beyond

4. The Multiple Sclerosis International Federation
http://www.msif.org/en/about_ms/types_of_ms.html

The illustration above is from Joseph Babinski’s 1885 thesis, “Etude anatomique et clinique de la sclérose en plaques.”

Here’s a nice boards – type question that requires you to put together some clinical and laboratory data to form a diagnosis, and then describe what the blood smear would look like.

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A previously-healthy 32-year-old woman presents with recurrent headaches. She develops nausea, vomiting, weakness, and easy bruisability. Her laboratory values are as follows:

Hgb = 6.9
MCV = 80
Plt = 30,000
WBC=15,000

She is immediately admitted to the hospital. Over a two day period, she becomes lethargic, and lapses into a coma. A peripheral blood smear is most likely to show which of the following?

A. Macrocytes
B. Spherocytes
C. Schistocytes
D. Sickle cells
E. Target cells

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This question describes a patient with marked anemia and thrombocytopenia (but the WBC is normal – even above normal – so you can rule out the causes of pancytopenia). Her clinical symptoms include various non-specific findings, like nausea and vomiting, but also the specific finding of neurologic deficits.

Her symptoms and laboratory values are consistent with TTP (thrombotic thrombocytopenic purpura), which is a disorder that’s part of a group of disorders called “thrombotic microangiopathies.” Thrombotic microangiopathies are a group of syndromes, including TTP and HUS, in which something triggers platelet activation, and the patient ends up with thrombi all over the place – with resultant thrombocytopenia (the patient is using the platelets up in making the thrombi) and microangiopathic hemolytic anemia (red cells are getting snagged on the fibrin strands as they go through the thrombi-laden vessels).

In TTP, the “something” that triggers platelet activation is abnormal von Willebrand factor. It turns out that normally, when von Willebrand factor is released into the circulation, it’s in a big, long multimer (called “unusually large vWF.” In this state, it causes platelet aggregation! But we have an enzyme called ADAMTS13 that cleaves unusually large vWF into smaller, less active pieces, which work well (but not too well).

Patients with TTP lack this enzyme (either they’re making antibodies to it, or they are missing it from birth) – so they have this unusually large vWF floating around, which traps platelets and causes thrombi.

The symptoms in TTP are usually described as a pentad: 1) hematuria and jaundice (from the microangiopathic hemolytic anemia), 2) bleeding and bruising (from the thrombocytopenia), 3) fever (who knows why), 4) bizarre behavior or neurologic deficits (from thrombi in the brain), and 5) decreased urine output (from thrombi in the kidneys leading to kidney failure). In reality, not all patients have all of the symptoms – so you don’t need to have all 5 by any means to diagnose it. Treatment depends on whether it’s acquired or hereditary. Acquired cases tend to be more severe for some reason, and the treatment involves daily plasmapheresis (to get rid of the antibodies to ADAMTS13). The hereditary cases are usually treated with plasma infusions every three weeks or so (to replace the missing enzyme).

So: the answer to the question is C, schistocytes. Schistocytes are a special type of fragmented red cells (they are small, with pointy outlines, and no central pallor) that are characteristic of microangiopathic hemolytic anemia (you can see a whole bunch of these in the image above!). Sometimes you can see things that look sort of similar to schistocytes in other anemias – such as the bite cells you see in glucose 6 phosphate dehydrogenase deficiency. But any time you see something you even think might be a schistocyte, you need to explore the possibility of a microangiopathic hemolytic process, because some of the things that cause microangiopathic hemolytic anemia are very dangerous (like TTP!), and you would not want to miss them.

Note: the very nice image of a microangiopathic hemolytic anemia (see all the schistocytes?) was taken by Ed Uthman and can be found at http://commons.wikimedia.org/wiki/File:DIC_With_Microangiopathic_Hemolytic_Anemia_(301920983).jpg.