Francisco J. Gomez, MD

You can tell it is the last day of a conference when most of the few people who remain are attending with their suitcase in tow. This morning, I attended the MRI in Multiple Sclerosis (MS) course, hosted by Robert Bermel, MD, from the Cleveland Clinic and Robert Naismith, MD, from Washington University in St Louis. These physicians provided a “hands-on” review of the current state of monitoring disease and treatment decision making in patients with MS.

The main topics included NEDA (no evidence of disease activity) and an approach to treatment given today’s multiple options.

In MS, NEDA can be defined in at least 2 different ways-clinically and radiologically. But why define NEDA radiologically? Because MS studies have shown that MRI is more sensitive to disease activity than to clinical symptoms and is a good objective measure of the patient’s response to treatment.

Is clinical improvement or stabilization in disease course sufficient? Unfortunately, MS studies have shown that the answer is no. A 2009 study by Prosperini and colleagues

of patients receiving interferon-beta (IFNB) therapy showed this. MRI done at 1 year after initiation of IFNB therapy was correlated to disability at 5 years. Clinical status of the patient did not matter during that first year, but if 

 additional T2 lesions were found, then there was a greater than 50% chance of increased disability. Disability was defined as persistent loss of more than 1 point on the Kurtzke EDSS (expanded disability status scale).

The MRI predicted the patient’s outcome. This is something to think about when reviewing follow up MRI studies on patients with MS.

confirmed and expanded this. He showed that if you look at the activity of disease at years 1 and 2 of treatment with IFNB, and then follow patients for 15 years, those with active disease at years 1 or 2 were more likely to be in the top quartile of patients with worst EDSS progression (ie, more disability). In his study, evidence of disease was defined as 2 or more new gadolinium-enhancing lesions at 1 or 2 years after starting IFNB, 3 or more new T2 lesions at 2 years after starting IFNB, or 2 or more clinical relapses in the first 2 years of treatment.

Although no data have been published for some of the other therapies in MS, I wouldn’t be surprised if the findings are similar.

This leads me into the topic of how to handle patients with continuing MS disease. Although we have a lot more alternative disease modifying therapy (DMT) today, it is still very possible that at some point you are going to feel like you’ve used up all your options.

What should you use to determine when treatment should be added or changed? Do you rely on the MRI? The patient? Both? The Bermel study can provide some guidance for those being treated with IFNB-but what if they are receiving other DMT? How often should the MRI be done? When do you decide that they have tried a DMT adequately to determine its effectiveness?

Although there are no hard and fast rules, suggestions were presented by the speakers. 

Dr Naismith, presented a scale that he has been working on that looks at a combination of demographics, disease characteristics, and imaging results to “rate” a patient’s disease severity as mild, moderate, or severe. He also divided DMT into 2 groups-“standard” or “enhanced”-based on their efficacy. The enhanced efficacy medications included natalizumab, fingolimod, and alemtuzumab. He presented 3 sample cases and rated them. An example of a severe case was that of a young African American man with active clinical disease, poor recovery from his prior symptoms, and active lesions on MRI. He would be a candidate for the enhanced-therapy group of DMT.

Although Dr Naismith still needs to confirm his scale, it provides a framework for looking at the disease and DMT therapy. He also presented Dr Freedman’s

2013 updated scale of “treatment optimization recommendations”

 model as another way to think about when should we change therapy in the MS patients.

Naismith and Bermel concluded by discussing how to monitor MS patients. The decision to change therapy should be influenced by several factors (as noted above): following a standard protocol of monitoring was recommended. After a DMT is started, a 3 month follow-up visit to review patient’s tolerance and initial response was suggested.

Obtaining a “re-baseline” MRI at 6 months was proposed-earlier if needed, or later if disease is milder or if the patient is taking a DMT that takes longer to be fully effective, such as glatiramer acetate. At 6 months, you would have a good idea of the effectiveness of most DMTs on individual patients. Surveillance MRI studies were recommended once a year for the first 2 to 4 years until you have a sense of the patient’s overall disease activity, at which time you would begin to extend the timing between studies if the patient is stable or you would change therapy and begin this process again.

1. Prosperini L, Gallo V, Petsas N, et al. One-year MRI scan predicts clinical response to interferon beta in multiple sclerosis.

2009;16:1202-1209.
2. Bermel RA, You X, Foulds P, et al. Predictors of long-term outcome in multiple sclerosis patients treated with interferon beta. 

 2013;73:95-103.
3. Freedman MS, Selchen D, Arnold DL, et al. Treatment optimization in MS: Canadian MS Working Group updated recommendations. 

Articles

Here's a handy synopsis of a “hands-on” review of the current state of monitoring disease and treatment decision making in patients with multiple sclerosis.

Update on Monitoring and Treating MS

When I walk around the poster sessions at any of our neurological meetings, it excites me that the state of neurological knowledge continues to improve. At AAN 2015 today, I saw 3 posters that especially intrigued me.

Poster #1. How useful is the EEG in predicting neurological outcomes in post-anoxic encephalopathy due to out-of-hospital cardiac arrest?

For treating a typical cardiac arrest patient who is older and who has multiple cardiac risk factors, the EEG can be helpful. Typically, a reactive EEG background is a good prognostic factor, and a non-reactive background-or the presence of a spontaneous burst-suppression pattern-are poor prognostic factors. 

Does this pattern hold true when the patient is younger and whose reason for cardiac arrest is drug overdose? Can we use the EEG to help prognosticate in these patients?

Dr Mantica presented her group’s retrospective review of 74 patients, collected from 2008 to 2014, who suffered out-of-hospital cardiac arrest attributed to recreational drug overdose. Median patient age was in the mid-30s; and they were admitted in a comatose state. Criteria for inclusion was survival beyond 6 hours, no repeat cardiac-arrest, and at least 24 hours of continuous EEG monitoring. The EEG patterns were correlated with overall neurological outcome as measured by the modified Rankin Scale. The EEGs were independently reviewed by 2 board certified neurophysiologists for what were considered “malignant” patterns, including burst-suppression, generalized suppression, and generalized periodic discharges (GPD).

The researchers found that contrary to the older cardiac arrest patients, a burst-suppression pattern on an EEG did not automatically portend a poor prognosis. In addition, other “malignant” patterns such as GPD were not predictive of a poor outcome, unless the patient had been seen after 48-72 hours of the cardiac arrest. Although stronger data are needed, these facts can be useful to neurologists who see comatose cardiac arrest patients of all ages and causes. Nevertheless, the physician should hesitate to extrapolate the data from the older patients to this younger age group.

Poster #2. Women, migraine, TIAs, and stroke. 

It is well known that younger women suffering from migraines have higher rates of stroke. If a young woman smokes or uses oral contraceptives, her risk of stroke is even higher. TIAs are a well known risk factor for stroke in both men and women.

What if you have a woman who suffers a TIA and has a past history of migraine: is she at even higher risk for stroke?

Dr Rahman presented his group’s review of the data from the observational study (OS) of the Women’s Health Initiative (WHI). They analyzed data collected from 93,676 women (median age mid-60’s) who had participated in the OS-WHI for about 12 years. During that time, a total of 153 women had TIA and stroke, but only 20 had a prior history of migraine.

My initial guess was that women with a history of migraine would have higher rates of stroke-with or without TIA. Instead, these women had a 

 risk of stroke. The reason isn’t clear. I wouldn’t consider migraines as “protective” against stroke given their negative impact in younger women. (I did not speak to the presenter and wondered what the rates of first stroke without TIA were in these women and how it correlated with their migraine status.)

Poster #3. The relationship of MS and vitamin D levels in minority populations

It has been established that lower vitamin D levels are correlated with higher risk of MS in caucasians.

The typical serum test for vitamin D levels, 25-hydroxyvitamin D (25-OH Vit D), measured the protein-bound portion of this vitamin. This bound portion was metabolically inactive, but correlated well with the active vitamin D molecule, 1,25-dihydroxyvitamin D, in caucasians and Asians. Lower rates of 25-OH Vit D in these two groups correlated with higher rates of bone fractures and osteoporosis. This correlation wasn’t found to be true for African-Americans (AA) and Hispanics, however. These groups were found to have lower rates, or to be “vitamin D deficient,” yet they had “better” rates of bone fractures and osteoporosis.

The reason for this turned out to be a lab artifact.

Since people in these racial and ethnic groups have only about 25%-35% of the vitamin D binding protein found in caucasians and Asians, and since this bound vitamin D is what was measured, their levels didn’t correlate with the active vitamin D.

With this in mind, how do the vitamin D levels correlate with MS rates in these minority populations? Dr Langer-Gould presented an interim analysis of a multi-ethnic case-control study, 

. Their data included almost 400 AA and hispanic patients and their matched controls. The researchers found no correlation between the 25-OH Vit D level and odds ratio for MS.

This result could not be easily explained and begged the question as to whether we should use the current 25-hydroxyvitamin D test or look for a more definitive measure of the active Vitamin D level.

I look forward to seeing more posters throughout this conference.

Can the EEG predict neurological outcomes in post-anoxic encephalopathy from out-of-hospital cardiac arrest? What effect does TIA have on stroke risk in women migraineurs? What's the relationship between MS and vitamin D levels in minority populations?

EEGs, Migraine, and MS: 3 Intriguing Findings From AAN2015

One of my favorite meetings to attend is the American Academy of Neurology’s Annual Meeting. It is a great way to gather information on all topics in neurology. Every time I register for this event, I feel like a child gaining entrance into an amusement park. Every ride seems thrilling, but time, cost, and my schedule force me to limit my choices.

This year, one of the first courses I attended was on epilepsy therapy, presented by Dr Erik St Louis from the Mayo Clinic in Rochester, MN.

Dr St Louis’s course on epilepsy therapy was a great way to receive updated information. There are alternative methods to get this information, however. For instance, I could meet with 10 to 15 pharmaceutical representatives, but that would be inefficient. It would also prove dangerous to my health-unless I provided my own healthy lunch or dinner. I’d also have to consider the inherent biases in using them as my only source of medical information.

Another possibility is reading in multiple journals about each of the medications. Or, I could wait for the triennial “Continuum” 

 update. Although I don’t like being “spoon-fed” my information, there is something about a combination of visual and aural information that works well for me.

Quick, how many of the following-eslicarbazepine, ezogabine, parampanel-do you recognize? Is this a list of the most recent cancer-causing food preservatives? No, these are just the latest 3 entries into the medical armamentarium available to neurologists treating epilepsy.

Dr St Louis gave thumbnail introductions to the medications. If you have seen the Blue Man Group, then you would recognize what I say when the “blue person syndrome” has been seen with ezogabine. Up to 6% of study patients taking this medication developed a bluish hue to their lips, fingernail beds, and sometimes even their retinas. Dr St Louis mentioned that this drug is considered “dead on arrival” similar to vigabatrin and felbamate due to this nontrivial side effect and like those 2 medications is reserved for intractable epilepsy cases.

Eslicarbazepine appears to be a useful and safe medication. Parampanel, although useful, carries a blackbox warning from the FDA due to possible neuropsychiatric adverse events, including aggression, hostility, irritability, and even homicidal thoughts. Unfortunately, there were no characteristics that pointed out which patient may have these significant adverse events.

I was hoping to get a cheat-sheet on the new-generation antiepileptic drugs (AEDs) that could help me get through the maze of these medications or at least help me find my new “best” medication for seizures. Eslicarbazepine only partially fits the bill. However, the information Dr St Louis provided helped me draw an “internal map” of how to use these medications.

Following the KISS (“keep it simple, stupid”) method, here is my “internal map” to the current use of AEDs in epilepsy:

• Most all AEDs are similar in efficacy.

• Initial treatment should be based on the seizure syndrome; if unknown, then seizure type.

• If seizures are mixed or generalized, consider lamotrigine, levetiracetam, topiramate, zonisamide, clobazam, or valproic acid. But with valproic acid, keep in mind its adverse effects on the unborn child in women who are of childbearing age and not using effective contraceptive therapy.

• If seizures are focal, consider eslicarbazepine, oxcarbazepine, gabapentin, carbamazepine, or phenytoin.

• The newer drugs are better tolerated.

• Save the “old drugs” for refractory cases.

• Don’t forget quality of life (QOL) for your patient.

These last 2 were emphasized in the latter half of Dr St Louis’s presentation: first, regarding the diagnosis and referral of refractory epilepsy; and second, covering the often-ignored interictal state.

The diagnosis of refractory epilepsy has undergone an evolution. For a long time, it was considered one of those items that “you’d know it when you see it.” In 2014, the AAN updated its Epilepsy Quality Measures and added “referral of treatment-resistant epilepsy to comprehensive epilepsy center every 2 years.”

Dr St Louis clarified that intractable epilepsy is now considered to be the failure of 2 AEDs (alone or in combination) that have been adequately chosen, trialed, and tolerated. He pointed out the dismal odds of getting seizure freedom after failing 2 AEDs as being as low as 4% to 5%.

A conference attendee asked whether Dr St Louis believed this statement, to which he answered “yes,” with caveats: Having intractable epilepsy does not mean you don’t keep trying other medications, it should act as a prompt to the neurologist to refer the patient to a comprehensive epilepsy center and it should also open the neurologist’s and patient’s options to nonpharmacological treatment, such as diet changes and nerve stimulators.

Dr St Louis also covered the interictal state, or the time period in between seizures, and measures of QOL for patients with epilepsy. Patients who have poorly controlled seizures consider their QOL as worse than do patients with most other neurological diseases. The predictor of QOL was the effect on cognition and coordination. Of utmost importance was avoiding adverse effects with medications by personalizing both the medication and the dose titration schedule based on the patient’s characteristics, comorbid conditions, and co-medications.

Dr St Louis’s talk touched on multiple other topics that would make this blog piece seem like a book. They included:

• An update on the definition of epilepsy.

• Epilepsy as a “network problem” rather than being only anatomic in nature.

• Drug pharmacotherapy and interactions as being absent, unidirectional (only the AED is affected), or bidirectional (both the AED and other co-medications are affected).

• Observational studies on autoimmune epilepsy and its treatment with steroids or immunoglobulins.

• Daytime sleepiness in patients with epilepsy and the significance of looking for obstructive sleep apnea and restless legs syndrome.

• And even when to consider discussing with the patient the sudden unexplained death in epilepsy syndrome, especially as you consider a patient with intractable epilepsy.

In the end, this was a true whirlwind review of the current status of therapy in epilepsy.

 is taking place April 18-25 in Washington, DC.

Quick, how many of the following-eslicarbazepine, ezogabine, parampanel-do you recognize? These new entries into the medical armamentarium were highlighted at the AAN 2015 Annual Meeting.

Epilepsy Therapy Update: A Whirlwind Review

There have been many times during my 20 years of practice that I have seen patients who were referred for evaluation of an abnormal brain MRI and the possibility that they had MS. The typical patient is a younger woman. The MRI was done for an unrelated reason-- typically a severe headache--and it revealed abnormalities that suggested MS.

For most patients like this, their level of distress and fear is palpable, and they envision a future surrounded by wheelchairs and walkers. Some patients adopt an “ignorance is bliss” stance. An even a smaller number come in with mountains of research they have done online.

I can reassure most-after reviewing their MRIs-that the findings are a false alarm, because the few white matter abnormalities seen on the images are located in areas not typical for MS and instead suggest a migrainous syndrome. Many patients remain concerned, but one or two additional clinical visits usually reassure them that their condition is benign.

For a small number, the MRI images will show a pattern that suggests MS. Once the patient’s history is thoroughly reviewed, highly suggestive transient symptom complexes are found that strengthen this diagnosis. The harder task then becomes confirming the diagnosis and setting up a treatment course. Interestingly, most patients feel relief that their symptoms are not just “all in their head.”

Most neurologists are aware of the “Clinically Isolated Syndrome” (CIS), such as optic neuritis. In the majority of these cases, CIS is the harbinger of MS. CIS in association with an abnormal MRI of the brain leads to a diagnosis of MS.

aware of the “Radiologically Isolated Syndrome” (RIS). RIS remains a controversial entity. I have come across a couple of instances in which abnormalities were found on a patient’s brain and/or spinal cord MRI that suggest MS, but the patient had not experienced any symptoms. Without symptoms, a diagnosis of MS cannot be made.

 have provided some baseline information about RIS. Last year, this group published a multinational retrospective review of RIS that showed that over a 5 year period, up to 34% of such patients go on to have their first clinical “MS attack” and receive a diagnosis of MS.

 These researchers also provided some characteristics in RIS that suggest a higher risk of future MS: these include lesions in the spinal cord; age younger than 37; and male gender. Stromillo and coworkers

 used MRI spectroscopy to show that there was neuronal damage in these lesions. However, independent confirmation of this and its significance to patient clinical outcome has not been determined.

I had a patient who experienced a similar situation. She had a history of occasional headaches that were rarely migrainous in nature. An unusually severe headache prompted an MRI study of the brain. This showed white matter abnormalities in the corpus callosum and in juxta-cortical and periventricular locations. Her MRI suggested she had MS. Yet, she did not have current symptoms of MS, nor had she had prior symptoms that suggested MS. Her neurological exam was normal. A lumbar puncture revealed clean cerebrospinal fluid. Visual evoked potential study was normal. Her spinal cord MRI was negative for lesions, and followup MRI studies remain unchanged. We discussed the diagnosis of RIS. She agreed that since the diagnosis of MS could not be made, treatment and its possible risks seemed unnecessary.

Does this patient have MS? I am not sure, but I continue to monitor her clinical and radiological condition and look forward to seeing more definitive information on this entity.

1. Okuda DT, Siva A, Kantarci O, et al. Radiologically isolated syndrome: 5-year risk for an initial clinical event. 

2. Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. 

3. Stromillo ML, Giorgio A, Rossi F, et al. Brain metabolic changes suggestive of axonal damage in radiologically isolated syndrome. 

Do you have a patient with "radiologically isolated syndrome" -- and, if so, what do you tell your patient?

Francisco J. Gomez, MD

Articles

Update on Monitoring and Treating MS

EEGs, Migraine, and MS: 3 Intriguing Findings From AAN2015

Epilepsy Therapy Update: A Whirlwind Review

Multiple Sclerosis and the Radiologically Isolated Syndrome

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