Neurologic Illness with Limb Weakness in Children

Coordinator:
Welcome and thank you for standing by. At this time all participants are in a listen only mode. During our question and answer session, you can ask a question by pressing star 1, on your touchtone phone and recording your name when prompted. Today’s conference is being recorded. If you have any objections you may now disconnect. And now, I’d like to turn today’s meeting over to Ms. Leticia Davila. You may begin.

Leticia Davila:
Thank you Kevin. Good afternoon. I’m Leticia Davila. And I am representing the Clinician Outreach and Communication Activity, COCA, with the Healthcare Preparedness Activity at the Centers for Disease Control and Prevention. I am delighted to welcome you to today’s COCA Call, Neurologic Illness with Limb Weakness in Children.

We are pleased to have with us today Drs. Feikin and Oberste here to provide information on the latest situation, surveillance, and CDC clinical guidance for testing, patient evaluation and case reporting.

There is no continuing education or slides provided for this call. Additional resources for clinicians are available on our COCA web site at emergency.cdc.gov/coca. Look under the Neurologic Illness Call web page.

Our first presenter, Dr. Feikin is Chief of the Epidemiology Branch in the Division of Viral Diseases, National Center for Immunization and Respiratory Diseases at CDC. He has a broad infectious disease experience in bacterial and viral infectious diseases including vaccine preventable diseases.

Dr. Feikin obtained his MD at Harvard Medical School and an MCPH from University of Colorado Health Sciences Center. He completed his residencies in both internal medicine and preventive medicine and training with CDC’s Epidemic Intelligence Service. He is Board Certified with the American Board of Internal Medicine and the Board of Preventive Medicine.

Our second presenter is Dr. Steve Oberste. He is Chief of the Polio and Picornavirus Laboratory Branch in the Division of Viral Diseases, National Center for Immunization and Respiratory Diseases at CDC. He has over 21 years of experience in molecular biology and biochemistry of enteroviruses. Through his leadership, his team developed molecular assays to detect, differentiate and identify picornaviruses.

In addition to today’s presenters, CDC subject matter experts as well as representatives from the state of Colorado and California will be available to answer questions during the Q&A section of today’s COCA Call.

At the end of the presentation you will have the opportunity to ask the presenters questions. On the phone dialing star 1 will put you in the queue for questions. Questions will be limited to clinicians who would like information on clinical guidance related to neurologic illness with limb weakness in children. For those who have media questions please contact CDC Media Relations at 404-639-3286 or send an email to media@cdc.gov. At this time, please welcome Dr. Feikin.

Daniel Feikin:
Good afternoon everyone. I’m going to describe briefly the two clusters of acute neurologic illness of unknown etiology in California and Colorado, both who were reported in an early release of the MMWR this morning. Then I will briefly discuss enterovirus D68 and then I will end by explaining what CDC is doing to investigate this situation and what you can do to help.

Before I start, I really want to acknowledge the work that was done in California and Colorado. It was really the people there that identified and characterized these clusters. In California, it was the Department of Public Health, Stanford, UCSF, Lucile Packard Children’s Hospital and in Colorado, the Colorado Children’s Hospital and Colorado Department of Public Health and Environment. And we have representatives on the line from those institutions who in the Q&A session will be able to field more detailed questions.

So first let me start with California. In August of 2012, the Department of Health was notified about a 29 year-old person with acute flaccid paralysis with anterior myelitis, and the request was to rule out polio.

Within a couple weeks there had been two other similar reports to the Department of Public Health and although an extensive workup showed no causative agent the Health Department was intrigued enough by the similarity and rarity of these cases that they put out an alert within the state to report other similar cases. In over a year and a half period they put out three alerts to the state to report more cases.

So what the case definition that was used in California was an acute flaccid paralysis with either radiologic or nerve conduction evidenced consistent with anterior myelitis.

And over a two and a half year period from January 2012 to June of 2014 they identified 23 cases who met their case definition. The median age of the cases was 10 years although they range from 1 to 73 years.

There was a diverse geography to where the patients came from and nor was there any particular clustering in time. The majority of cases had a preceding respiratory or gastrointestinal illness.

Of the patients, about one-third had cranial nerve involvement and 43% had altered mental status. The majority of them, 83%, had pleocytosis in the CSF. Five of the patients were ventilated and one of the patients died. Of the 13 that had follow-up information available all of them had some evidence of a prolonged paralysis.

An extensive laboratory workup was done in the laboratories of the California Department of Health and the cerebral spinal fluid was negative for all pathogens that they tested for.

There were two patients who had positive IgM for mycoplasma in the sera and then from the nasopharyngeal swab there was one patient who was positive for rhinovirus and two patients were positive for Enterovirus D68.

It was felt that poliovirus was unlikely. Most of the patients had been vaccinated against polio, nine of them who had stool tested negative and none of them had any recent travel. However - it is worth remembering that the guidelines for ruling out polio from WHO and CDC require two stools that are collected 24 hours apart within 14 days of onset. And even though we don’t see - even though we don’t have poliovirus in this country it is still worth remembering the algorithm for ruling out polio.

Now let me move to the Colorado cluster. This is a much more recent cluster. It occurred in August and September of this year. And there were nine children who were initially identified in one hospital in suburban Denver. The median age of these children was 8 years and they ranged from 1 year to 18 years of age.

All of these nine had a preceding respiratory or febrile illness that occurred 3 to 16 days before the neurologic onset. Eight of the nine had focal limb weakness and some of the children also had cranial nerve involvement. Unlike California, there were no mental status changes that were noted in the Colorado cases.

MRI of the spine revealed a multilevel gray matter involvement in seven of the eight that had an MRI of the spine. And seven of nine had evidence of brain stem non-enhancing lesions mostly in the pons.

Like in California, most of the CSF had a pleocytosis and again an extensive workup of the CSF revealed no organisms. Rectal swabs were negative in all of the patients.

From the nasopharyngeal swabs that were done on eight of the patients, four of them had evidence for enterovirus D68. One had rhinovirus. One had another enterovirus and two were negative.

So let me talk a little bit about enterovirus D68. I’m going to be much more brief than the previous COCA Call that was done by Sue Gerber a couple weeks ago that talked about respiratory disease related to enterovirus D68.

Enterovirus D68 is 1 of over 100 different types of enterovirus. This particular type was first identified in 1962 in California.

Unlike other enteroviruses, this one does have a tropism for the respiratory tract and tends to cause respiratory illness and in many ways is more similar to a rhinovirus in its clinical presentation. It’s known to cause infection in both children and adults although children tend to have the more severe disease.

There have been clusters that have been noted of respiratory illness from EV-D68. The largest one was in Japan, which was 120 cases.

In the U.S., we have a passive reporting system to CDC for enterovirus strains, and we usually find enterovirus. But not - we don’t get that many reports that the highest year was in 2009 when we had 47 enterovirus D68s that were reported and that was until this year when things changed.

You may have seen an MMWR that came out in early September that described a cluster of respiratory illness due to enterovirus D68 in Kansas City and Chicago among PICU patients. Many of these patients had asthma and history of asthma and many of them had wheezing on presentation.

Since that MMWR, enterovirus D68 seems to have spread to much of the United States. As of this morning, 538 cases have been confirmed in respiratory illness patients in 43 states although many of the - there are many specimens that are still pending testing.

The median age for these respiratory cases is six years but it ranges from 0 to 92. And about half the specimens sent to CDC for testing have been positive for EV-D68.

I should say that in Colorado there was a clear increase in respiratory illness coincident with the neurologic cases. And of a sample of specimens that was sent for typing here about three-quarters of them were positive for EV-D68.

In California, however, the California series predated this year’s increase in respiratory disease due to EV-D68. As they - as I mentioned their case series went through June of this year and we didn’t see the upswing in respiratory illness until August.

So, you know, one question is, are these neurologic cases related to EV-D68? I don’t think we can say that they are at this point. We’re really not sure what is causing this neurologic cluster.

We do know that enteroviruses can cause an anterior myelitis. Poliovirus obviously is the first. Enterovirus 71 can also cause anterior myelitis but so can other infectious causes such as West Nile Virus and Saint Louis encephalitis.

Enteroviruses are notoriously difficult to find in the CSF, so the fact that we haven’t found anything in the CSF doesn’t rule them out necessarily.

But the EV-D68 positives that we do have among the neurologic cases are all from upper respiratory tract specimens which are non-sterile sites. It is possible that it is a coincidental finding and - in these patients and may not be related to their neurologic illness.

And it’s for this reason that we need to further investigate these neurologic clusters. Try to determine if they have the same etiology both within the site and across both sites. I mean there are some notable differences between the California series and the Colorado ones. There’s a difference in the age distribution, in the timing of the cases and the incidence clearly is different which - with a much tighter cluster in Colorado.

So let me tell you a little bit about what CDC is doing to further investigate the situation. A health alert was issued on September 26th that described the Colorado cases.

And it went onto ask clinicians to report similar cases to their health department. And we laid out four criteria for reporting. The first is that the patient should be 21 years of age or younger. They need to have an acute onset of a focal limb weakness, and they need to have an MRI that shows spinal - a spinal cord lesion largely restricted to the gray matter. And the onset of illness needs to have been after August 1, 2014.

So if any patient meets these four criterias, we ask that they be reported to their departments of health and then report onto CDC. We do realize that this case definition is specific but not necessarily sensitive in the sense that if this is a neurologic syndrome it is possible that some of the cases would not meet this case definition.

But as far as case reporting on a national level, we chose to - we chose specificity over sensitivity so that we could have a tighter case definition.

You can find a Case Report Form for reporting on the CDC NCIRD web site under Investigation. And we also have set up an email box and the address to that is limbweakness@cdc.gov that you can send in any queries or questions about cases.

The goal of this investigation nationally is first of all to describe the epidemiology of this neurologic syndrome, what is the burden of it, what is the geographic distribution, how long will we be detecting such cases.

Part of the difficulty here is that we don’t have a baseline of this specific syndrome. We do not have a required national reporting of acute flaccid paralysis or of enterovirus. So we don’t have a real good sense of what the baseline rates of this syndrome would be.

The second goal is to describe the etiology of the syndrome. And we’re asking that on patients, specimens are collected from the CSF, stool, upper respiratory tract, NP, OP, and from sera for extensive testing including enterovirus testing.

Dr. Oberste will talk a little bit more about the testing. But our lab at CDC is able to do typing for enterovirus to determine if it’s EV-D68 on any suspect cases. And the last goal would be to define - try to define risk factors for this particular neurologic illness.

So in conclusion, I think these two clusters represent a good example of how clinicians and the public health community can work together to describe unusual clusters of illness and potentially new diseases.

So at this point I’m going to pass the mic over to Dr. Oberste to describe some of the laboratory aspects.

Steve Oberste:
Thank you. I’m going to speak very briefly about some of the laboratory testing that’s been done to date and what’s going to be happening from here on.

As Dr. Feikin said a few of the or a subset of these samples from cases described in California and Colorado have tested positive for EV-D68, but those were only in respiratory samples making it difficult to ascribe an etiology which is the reason why we would like to collect CSF despite the fact that enteroviruses may sometimes be difficult to find in that sample. Of course if you find it in a sterile site that’s a good link with etiology.

The standard polio investigation worldwide is with stool sample and stool is preferred to rectal swab simply because of the increased sensitivity by having a larger sample. And as Dr. Feikin described those should be collected within 14 days of onset. That will be used specifically for polio rule out using both cell culture and molecular methods.

And again NP swabs and serum can also be quite valuable, serum especially for arboviruses and some of the other etiologies.

For the EV-D68 testing we are in the process of developing a specific real time assay. The current assay is a generic enterovirus PCR followed by sequencing which yields a serotype. It’s very labor intensive and involved and takes a number of days and therefore, we have a bit of a backlog.

However, once we have an assay developed we will use that to clear our own backlog as well as make that assay available to the state Public Health Labs for testing. The validation of the assay is in progress and we hope to have that available very soon.

In addition to the enteroviruses as Dr. Feikin mentioned, the other agents that are high on the differential are the arboviruses as well as the herpes viruses. There are also a few other viruses that can be used and we will coordinate with other CDC laboratories as needed to investigate some of these other causes.

At this point, some of the laboratory testing is rather preliminary because we’ve only tested a limited number of specimens so far from a small number of cases. The investigation however is ongoing and will continue as new cases are identified.

And at that I think we’re finished for now.

Leticia Davila:
Thank you Dr. Feikin and Dr. Oberste for providing our COCA audience with such a wealth of information.

As a reminder CDC subject matter experts as well as representatives from the State of Colorado and California are available during the question and answer portion of today’s COCA call. Questions are limited to clinicians who would like information on clinical guidance related to neurologic illness with limb weakness in children.

For those who have media questions, please contact CDC Media Relations at 404-639-3286 or send an email to media@cdc.gov. We will now open up the lines for the question and answer session, Operator.

Coordinator:
Thank you. If you would like to ask a question please press star then 1. You will be prompted to record your first and last name clearly to ask your question. To withdraw your question you may press star then 2. Once again if you’d like to ask a question, please press star then 1. Record your first and last name; one moment for your first question. Your first question comes from (Geoff) Weinberg in Rochester. You may ask your question.

Geoff Weinberg:
Thank you. Hi Steve, this is Geoff Weinberg at University of Rochester. I have one simple and one more complex question. One simple question I think I had - have a patient with the neurologic acute flaccid weakness. And we’re in the process of getting D68 testing with New York State.

Before the updated 5-page Neurologic Illness Form came online, I had downloaded an EV-D68 Patient Summary Form. Do you want both of those forms or do you just want the neurologic one? Because this girl started with a respiratory illness and then of course developed her neurologic illness so the simple question is do you want both, these forms or just the neurologic one to report?

Steve Oberste:
I think the simple answer is we would like both if you can.

Geoffrey Weinberg:
Okay, that’s fine. The more complex answer is in the California cluster or clusters from before, I noted that there was actually a fairly high percentage of persistent paralysis or at least significant paresis whereas historically we’ve thought of enteroviral flaccid paresis or paralysis as being fairly brief and not as long-lasting certainly as polio.

Has there been any early experience in Colorado or in the - or was there further experience than what’s been written up in California (unintelligible)?

((Crosstalk))

Daniel Feikin:
I think we’d defer that answer to California and Colorado.

Geoffrey Weinberg:
Okay.

Carol Glaser:
Hi. This is Dr. Glaser in California. So we’ve actually done fairly extensive follow-up on a number of our cases and they are having prolonged paresis and paralysis six months out. There are a handful of cases however, that actually had a remarkable good recovery and maybe even as much as a year later. So it’s very mixed. It’s not consistent. And but it’s very prolonged in almost all cases. You know at least several months.

Dr. Messacar:
And this is Dr. Messacar from Children’s Hospital of Colorado. I think our cluster is a bit more recent so it’s too early to say outcomes in our patients. But the majority of our cluster has shown minimal improvement at this point.

Geoff Weinberg:
Thanks.

Coordinator:
Your next question comes from Dr. (Sukota). You may ask your question.

Dr. (Sukota):
Yes. Hi. This is Dr. (Sukota) from Seattle. Thank you very much for the information. I just had a couple of questions. Number one, is any treatment protocols that are available or treatments, clinical treatment guidelines that you can provide for our providers? That would be great. And also in light of that is recently it was posted on our PVM listserv a report about enterovirus H71 in China that it seemed to be related to poor outcomes with the use of steroids. So I just wondered if it was any relation to D68 or if you have seen treatment with steroids causing good outcomes versus otherwise.

James Sejvar)
Yes. This is Jim Sejvar. I’m a neuroepidemiologist here at CDC.

The issue with respect to treatment guidelines or guidance is an excellent point. And currently we are in the process of trying to provide a set of management and treatment guidelines for clinicians. We hope to have that available within, you know, the next week or so hopefully.

With respect to the use of steroids, you know, as you’ve noted, you know, in certain enteroviral infections really it’s been demonstrated to in fact complicate or in fact lead to a poor outcome.

Experience with other forms of infectious flaccid paralysis or anterior myelitis really essentially demonstrates the same thing. Often times there’s, you know, a natural desire to, you know, try anything, interferon, steroids, intravenous immunoglobulin however in enteroviral infections as well as other infectious forms of anterior myelitis none of these therapeutic modalities have been demonstrated to have any efficacy.

And really one needs to sort of weigh the sort of the risks of the immunocompromisation that these modalities result in in the face of perhaps, you know, an ongoing infection and...

Dr. (Sukota):
Yes.

James Sejvar:
...so, you know, again, you know, the - a set of management guidelines is on the way very shortly. And again I think we would caution against using these immune mediated therapies.

Dr. (Sukota):
My concern is especially from the pediatric and I’d be interested to see what Colorado has to say as well is that most of these kids with the respiratory D68 are acutely wheezing and, you know, having difficulty with bronchospasm. And of course steroids is a mainstay treatment for that.

So I’m just wondering is there’s any sort of link or concern that we’re getting these kids lots of high dose steroids to treat their respiratory component of D68 and could that be contributing or participating or precipitating some of the limb weakness that we’re also seeing especially in the Colorado cases, maybe not so much in California.

James Sejvar:
That’s a good question. I mean I don’t know that we really can definitively answer that but, you know...

Jane Seward:
Colorado may want...

Daniel Feikin:
Yes. Dr. Messacar.

James Sejvar:
...it’s difficult.

Daniel Feikin:
Do you know how many of your nine patients were treated with steroids for a preceding respiratory illness?

Dr. Messacar:
Yes. So there were two patients who received steroids, one for an asthma exacerbation about a week prior to onset of neurologic disease. The second was actually treated for what was thought to be a swollen pharynx so it was actually paresis in the bulbar area. So likely has onset of neurologic symptoms prior to receiving steroids so two patients received steroids out of our cohort.

Steve Oberste:
This is Steve Oberste. While we’re on the topic of treatment let me add as I’m sure you’re all aware, there is currently no antiviral drug available to treat enterovirus infections. There have been a number in the pipeline over a number of years.

There are three that we have tested specifically against the strains of EV-D68 that are currently circulating, Pleconaril which has been developed for enteroviruses and rhinoviruses and is actually currently not available at all; Pocapavir which is a drug that’s been through Phase II Trials and is being used or advanced for poliovirus infections; and Vapendavir which is another compound that is - has been through Phase II and is being advanced for rhinovirus infections. All three of these have the same mechanism of action.

And none of those has shown any kind of efficacy at physiologically attainable concentrations so unfortunately there’s nothing available right now. We continue to look at other compounds or other drugs that may be available or that have shown some promise and we’ll continue to screen and look and see if there’s anything that may have some effect.

Dr. (Sukota):
Okay, thank you very much.

Coordinator:
Your next question comes from (Ghazi Agha), MD. You may ask your question.

(Ghazi Agha):
Hi. I’m calling from New York. I just had a question. Do you think this is acute infectious or post-infectious complications of enterovirus because that may determine the treatment that it would benefit from?

James Sejvar:
This is Jim Sejvar again. You know from the standpoint of, you know, at least what has been observed in Colorado, you know, the clinical signs and symptoms, the radiologic findings all would point more to a sort of an acute infectious process.

Generally when we think of sort of para or post-infectious processes these generally tend to result in demyelinating illness although that’s not always the case.

And the - you know so these sort of para or post-infectious phenomenon will generally manifest as Guillain-Barré Syndrome or transverse myelitis. And that is not what we’re seeing in these cases in Colorado.

(Ghazi Agha):
Okay, thank you.

Coordinator:
Your next question comes from Dr. (Judith Hipple). You may ask your question.

(Judith Hipple):
Yes. I’m calling from Lancaster, Pennsylvania. And I just wanted to know how long after the acute illness will it be effective to actually test for the EV-D68?

And the reason being is I have a patient who may fall in that criteria with an acute onset of neurological symptoms but is obviously post-infectious and with a history of a viral illness. But it wasn’t - it was - you know everyone was sick at the time and so whether or not she really had - you know so I didn’t know how long they can test for it. And that was my question.

Steve Oberste:
Yes. This is Steve Oberste. As we mentioned earlier for stool sample testing for polio the standard is samples within 14 days.

(Judith Hipple):
Yes.

Steve Oberste:
Although the virus can be excreted longer. In CSF the virus is rarely there more than about three days. In an NP swab 7, maybe 14.

So and of course over time you’re less and less likely to detect it, so clearly as early as possible. One issue though is with serum especially for arbovirus testing that can be of course taken a little bit later.

(Judith Hipple):
Are you doing MRIs of the full spine and as well as the brain?

Steve Oberste:
Again that’s a question for Colorado or California.

Dr. Messacar:
This is Dr. Messacar in Colorado. The extent of the MRIs has been based on the symptoms that the children are presenting with. Some are presenting with only cranial nerve palsies and have gotten brain...

(Judith Hipple):
Okay.

Dr. Messacar:
...and brain stem imaging and those with limb weakness have gotten more of the full spine imaging.

(Judith Hipple):
Okay, great. Thank you so much.

Carol Glaser:
This is Carol (unintelligible). And I just want to add that almost all of our patients had both brain and spinal MRIs. But if you - it’s really important to realize in your own facility what - how strong your MRI machine is. We’ve had a handful of cases that only had a 1.5 Tesla MRI machine. When they were transferred to another facility for second opinion and it was done on a higher grade MRI sort of speak it was picked up. So this is something I as an infectious disease physician I never even heard of this Tesla. But you want to ask your Radiology Department how strong their machines are.

(Judith Hipple):
It’s going to be done at a Pediatric Hospital because...

Carol Glaser:
Perfect.

(Judith Hipple):
Yes.

Carol Glaser:
Okay. Thank you.

(Judith Hipple):
Perfect. Thank you so much.

Daniel Feikin:
Just one other comment, this is Daniel Feikin. You know if you do have a child who has cranial nerve involvement but might not have acute focal limb weakness I think and Dr. Messacar can correct me if I’m wrong, and that there was at least one case in Colorado that did not have focal limb weakness but they did do an MRI of the spine. And they did find gray matter involvement.

(Judith Hipple):
Okay.

Daniel Feikin:
It just hadn’t manifested clinically yet. So it does seem like sometimes the gray matter involvement of the spinal cord, it is possible that it would not match the clinical findings.

Dr. Messacar:
This is Dr. Messacar and that child actually eventually did develop upper extremity weakness which was not present on initial exam although it was present on his imaging when he presented.

Coordinator:
Your next question comes from (Cody Meister). You may ask your question.

(Cody Meister):
Thank you. And like to thank everyone for very interesting presentation. And Dan you and I spoke earlier this week. I’m calling from Tufts in Boston.

The question I have is I believe you said there was one death. And are there any pathology results that might be helpful from that child in terms of separating out whether we’re dealing with a post-infectious process or if this is a direct invasion by the virus as has been asked previously because in particular we have a young child who’s - was admitted and after 24 hours is continuing to have progressive paralysis. And it’s very difficult to watch that as you can imagine.

And then the second question I have is can you comment on the frequency of respiratory involvement? I think people from California said 5 of 23 patients required a ventilator. Did other patients have deteriorating respiratory involvement and how much of a concern is that?

Daniel Feikin:
Well maybe I’ll ask Dr. Glaser to comment on the death and her experience with respiratory involvement and then Dr. Messacar can respond about Colorado.

Carol Glaser:
Hi. Thanks. This is Dr. Glaser. So in our death that we had here it was an older adult. We have not had any deaths in the pediatric population. And he did not have an autopsy. We don’t even have a clear understanding of all the causes of death despite trying. We suspect it actually was a result or a complication of this condition.

The second question I just want to answer as far as the ventilator so about half of our cases actually were on a ventilator at some point. But it was five that were still on a ventilator at the time of discharge.

So again half needed a ventilator during their acute hospitalization and in five of them it was so prolonged they were still on a ventilator at the time of discharge to either a rehab or to a rehab site.

Dr. Messacar:
And this is Dr. Messacar in Colorado. We’ve had three patients who’ve required respiratory support in the Intensive Care Unit, two of which have been managed by noninvasive positive pressure ventilation and the other has required ventilation.

(Cody Meister):
Thank you. So that’s three out of nine?

Dr. Messacar:
That’s correct.

(Cody Meister):
Thanks.

Coordinator:
Your next question comes from (Don) from the University of Tennessee. You may ask your question. Excuse me (Don) you’re...

(John Devenchenzo):
Yes. I’m - yes, this is (John Devenchenzo). My question really is about the diagnostics. And are there sequences that are going to be released soon and for potentially development of home brew assays or protocols that you can share and if so when are they going to be shared?

Steve Oberste:
Yes. We have complete genome sequences now for seven isolates representing all of the circulating strains. And those should be released or put into GenBank today.

And then whatever time it takes GenBank processing which is usually fairly quick. So those will be available quite quickly.

And we will release our protocol as we develop an assay as well. So that should be available quite soon. Again we’re finalizing the validation right now so as soon as that’s done that’s going to be made available.

(John Devenchenzo):
Okay, thanks Steve. And what’s your timeline on the release of the real time PCR protocol you said?

Steve Oberste:
We hope to have it ready to use by the end of next week or beginning of the following week. Of course it’s always hard to predict these things. But that’s the timeline we’re looking at right at the moment.

(John Devenchenzo):
Yes, thanks Steve. Now that’s released to the state labs or released to the public for incorporation into current molecular diagnostic commercial laboratories?

Steve Oberste:
Yes. I think we’ll release a protocol more widely. What we do for the state labs is actually distribute reagents which is of course is a little bit more complicated because of regulatory issues. But that’s - both of those will be done.

(John Devenchenzo):
Okay, great.

Coordinator:
Your next question comes from Dr. (Marie Lozon). You may ask your question.

(Marie Lozon):
Hi. Good afternoon. I’m from Ann Arbor, Michigan. I’m a pediatric emergency medicine physician. We seem to be having a bit of a cluster here in Ann Arbor. We have about, I - as of this morning I believe seven children currently under care that presented in a very short period of about a week and a half.

And one of the - I would like to ask the clinicians in the group. Do the children you are caring for sometimes present with just a lot of pain that’s difficult to characterize? Because we’ve noticed two or three of the children aren’t - don’t have the obvious acute paralysis right away but they present with very difficult to characterize pain syndrome, refusal to sit, refusal to move - they’ll still walk but they walk slowly. They don’t have an obvious paralyzed or weak limb. And they’re usually toddlers.

And so and the - our physical therapists have been mentioning the high levels of pain in the acute paralysis kids and they are needing - some of them are on Gabapentin now to try to manage their pain so they can get their physical therapy started right away.

Could the clinicians comment on their cases?

Dr. Messacar:
This is Dr. Messacar in Colorado. And anecdotally we’ve seen several kids who have had preceding either calf pain or lower back pain prior to the onset of their neurologic deficit. So we’ve seen that same kind of clinical syndrome in several of our kids. But it seems to have gone away as they progressed in their disease course.

Carol Glaser:
This is Dr. Glaser in California. And what you describe is absolutely consistent with what we’ve been seeing as well, pains in various region including sometimes neck pain, sometimes calf pain, sometimes back pain so extremely consistent.

(Marie Lozon):
Thank you. The parents are coming earlier and earlier for care and so we’re not seeing the flaccid paralysis often until they’re admitted and have to have their MRI. And so that’s why it was concerning because some of the pediatricians in town are not sure what they’re dealing with and are sending the children in with mystery cases. And I think at least a few of our clusters have progressed to flaccid paralysis after these pain syndromes. So I appreciate that feedback.

Coordinator:
Your next question comes from (Anna Maria). You may ask your question.

(Anna Maria):
Hi. So I’m calling from the Children’s Hospital of Philadelphia. Steve, I have a question for you mostly concerning kind of how to guide our clinicians as to what would be the indications to ask the CDCs to send specimens.

So would it be kind of the overall consensus is if they have the mentioned less than 21 years of age, onset of focal limb on or after August 1st and an MRI showing a spinal cord lesion largely restricted to gray matter, then we move forward to contacting the CDC and getting CSF, stool, NP, OP and serum sent to the CDC?

In all other cases if they don’t comply with these then we should not contact the CDC? My question is because we have a patient currently that has this but it’s from July. And the CDC has asked us to send these specimens.

So I was kind of confused as to, is there a set cutoff of August 1st and then how we should proceed.

Steve Oberste:
Yes. Our highest priority right now is the neurologic cases with the, you know, meeting the criteria you’ve mentioned.

And however, of course in the context of the ongoing EV-D68 outbreak we are still accepting specimens for, you know, that have slightly different clinical pictures. We just have to prioritize and triage a little bit in the testing algorithm.

We always accept specimens from severe cases. And so that’s a little bit of clinical judgment. And we’re happy to discuss individual cases by email or by phone.

Carol Glaser:
So this is Dr. Glaser in California. I just want to add that in a number of our cases, some of ours had a negative MRI but we - the clinicians did an EMG.

So that may be a nice complementary assay to - not assay but a test to run. I know those are - can be painful and they’re difficult in children. But, you know, as many of you know MRI, spinal MRIs are not always that sensitive to pick this up particularly early. So an EMG may be very helpful.

(Anna Maria):
Great, thank you.

Leticia Davila:
Operator how many questions do we have in the queue?

Coordinator:
We have four.

Leticia Davila:
Thank you. We’ll take the next question.

Coordinator:
The next question comes from (Melanie Wellington). You may ask your question.

(Melanie Wellington):
Hi. I was just wondering. We’ve had a patient who had what sounds like now reasonably mild disease.

But there was a lot of discussion with our neurologist about whether or not she had more of a Guillain-Barré Syndrome or more of the focal paralysis. She really did have focal left leg disease but had some sort of spillover with some trunk weakness and some right leg weakness. And I think that’s sort of where some of the controversy was coming up.

Has anybody had any sort of patients present like that or perhaps our patient actually had Guillain-Barré?

Daniel Feikin:
Did you have MRI findings on that patient?

(Melanie Wellington):
Yes, we did.

Daniel Feikin:
And consistent with gray matter disease?

(Melanie Wellington):
Yes. So the strongest of the findings were the enhancement of the ventral nerve roots or the extension into the femoral nerve.

And there’s a bit of a debate amongst our readings of the MRI as well as to how much gray matter disease there was.

James Sejvar:
So this is Jim Sejvar again. And it really - you know as several people have kind of brought up, often times the sort of the main clinical question is, you know, is this due to acute, you know, sort of neuro invasive disease or neuro invasive infection or is it a post-infectious neurologic phenomenon.

Certainly with Guillain-Barré Syndrome you can see nerve root enhancement. I think, you know, in terms of neuro radiologic findings, it would really be, you know, distinct involvement of the sort of the gray matter of the spinal cord that would differentiate that.

In terms of differentiating Guillain-Barré Syndrome from, you know, this, you know, poliomyelitis or anterior myelitis, typically Guillain-Barré Syndrome is relatively symmetric. In other words affecting, you know, both size of the body fairly (unintelligible) although, you know, that there can be deviations from that.

The diagnostic modalities that can help differentiate Guillain-Barré Syndrome from the illness that we’re talking about are primarily the CSF findings. In Guillain-Barré Syndrome you’ll generally find what’s called cytoalbumin and neurologic disassociation in other words a protein, CSF protein elevation in the absence of a pleocytosis.

And then the second test that’s very helpful in the diagnosis of Guillain-Barré Syndrome is, as Dr. Glaser had brought up, electrodiagnostics, EMG and nerve conduction studies.

Those would generally, you know, be able to differentiate Guillain-Barré Syndrome from, you know, this sort of anterior myelitis. It’s important to keep in mind that if EMG is performed ideally those studies should be performed seven to ten days after the onset of the limb weakness. If they’re performed before that time often times they’ll be surreptitiously negative or unrevealing.

So hopefully that, you know, helps give a bit of guidance as to differentiating Guillain-Barré Syndrome or post-infectious flaccid paralysis from the illness that we’re talking about.

(Melanie Wellington):
Yes. That’s actually quite helpful. Our patient definitely has the CSF findings more consistent with the flaccid paralysis. The protein was right 23 or something like that. And but her EMG was normal. So it is interesting to think that that might have been an early EMG.

James Sejvar:
Yes. I mean if, you know, if the electrodiagnostics are done, you know, two or three days after the onset of limb weakness in general the - sort of the pathology hasn’t had time to sort of catch up with the electrodiagnostic findings.

So in your particular case, you know, if that EMG was done, you know, shortly after the onset of illness it might be worth considering repeating that EMG at the appropriate time.

(Melanie Wellington):
Great. Thanks very much.

Coordinator:
Your next question comes from (Ada Haas). You may ask your question.

(Ada Haas):
Hi. I’m a private pediatrician in New York with an infectious disease background. I just wanted to make everyone aware that while in the newspaper they report there are 20 cases on Long Island, we have been seeing many in the office who I think have this virus, although it’s not definite.

Some of them have wheezing. Some of them just have colds but they all have severe myalgia. Some of them in the ER did have rhinovirus/enterovirus positive testing. But they didn’t send it onwards to the D68 test. We haven’t seen any paralysis but we’re following because we heard some of them present two weeks later.

My question is these kids - we do not want to waste the resources by testing them because I don’t think it’ll help us in any - other than epidemiological way. Would you recommend that we do test these kids? They were flu negative.

Steve Oberste:
I think the state health department may be in interested in the epidemiologic question, so I would consult with them and see if they’re interested in further testing. They are using the same assay that we’ve developed and use here at CDC. So they can identify the EV-D68.

(Ada Haas):
Okay. So I just wanted people to know that there are cases of severe myalgia that usually we see only with flu that are presenting but are negative for A and B which is probably I think this virus. But we don’t know for sure yet. Thank you.

Coordinator:
The next question comes from (Nicole Alexander-Scott). You may ask your question.

(Nicole Alexander-Scott):
Hello. I’m adult and pediatric infectious diseases in Providence, Rhode Island with Brown and the department of health. My question is twofold. We have a case here in Rhode Island. We know there are a number in Boston. It sounds like seven in Michigan and then California and Colorado. Is there a sense of how many cases or clusters there are throughout the country or are what has been mentioned on the phone already about it in terms of the cases of neurological illness?

And the second component is based on these cases are we interpreting this to be a normal or an expected number of cases that are complicated with neurological illness in a setting of increased respiratory illness throughout the country or do we think that this is out of proportion to what’s anticipated or expected for seeing these neurological illnesses?

Daniel Feikin:
Well to answer the first part of your question, this is Daniel Feikin, I mean that - you know we’ve seen also media reports from different parts of the country. I mean what we’re trying to do here is take a systematic approach by having a case definition and asking for Case Report Forms to be filled out so we can systematically quantify how many cases might be out there.

We have had - we’re getting reports in right now. We’re under the process - we’re in the process of evaluating them. We just started this earlier this week so we don’t have any definitive numbers yet. But we are getting reports in from other places as well.

As I mentioned, we - you know part of our black hole here is that we don’t do surveillance for this syndrome and on a regular basis. So we don’t have a real baseline that we can compare to that we know that enteroviruses do circulate at this time of year and that they can result in neurologic disease. And but we don’t have a good baseline to compare to.

I mean anecdotally there - the neurologists and infectious disease docs in areas where they’re seeing this say we just don’t see that many of this presentation. It’s a very specific presentation. And in a normal year we don’t even see a case of this or maybe one case.

So, you know, there is an impression out there that there is an increase in this presentation at least in certain areas. But without a good baseline it’s really hard to define that and hopefully one of the things we can do this year and in at least some places is try to define an incidence of this presentation.

(Nicole Alexander-Scott):
Excellent. Thank you very much.

Jane Seward:
It’s Jane Seward here. Does Colorado want to comment? I believe they look back a year at their MRI findings. That was just one thing they were able to do for (unintelligible).

Dr. Messacar:
Yes. We’re in the process of going through the data to see how many cases would meet this case definition and so far we’ve gone back about four years. And this is about three times the incidence that we would expect to see of this case presentation or this case definition that we put together.

Jane Seward:
Thank you.

Dr. Messacar:
Certainly.

Leticia Davila:
Operator we’ll take one more question please.

Coordinator:
Okay. Your last question comes from (Ahmad). You may ask your question.

(Ahmad Tread):
Yes. Hi. This is (Ahmad Tread), Oakland, California. And this actually goes back to the MRI question. I think one of the questions as neurologists we are concerned about is in any of the anterior myelitis is this fairly rare syndrome of neuromyelitis optica which also can have longitudinally extensive disease and the presentation can overlap. Carol or the Colorado Group could you comment? How many segments are you guys typically seeing involved on the MRI and how extensive is the cord disease?

Dr. Messacar:
So this is Dr. Messacar in Colorado. We’re seeing confluent longitudinally extensive segments. We actually just kind of calculated number of vertebral level...

(Ahmad Tread):
Yes.

Dr. Messacar:
...at a median of about 18 so this is...

(Ahmad Tread):
Okay.

Dr. Messacar:
...long segments in the cord (unintelligible).

(Ahmad Tread):
Okay. Have you guys tested NMO antibodies in those patients also? I mean this would be a ridiculously large spike but are those (unintelligible) reacting?

Dr. Messacar:
Yes, all but three or four of our patients have been tested and were negative.

(Ahmad Tread):
Okay. Yes, okay.

Carol Glaser:
So this is Carol Glaser in California. So ours as far as the MRI imaging it’s been incredibly variable. It can be a couple - just two to three versus even longer as far as its involvement. As far as the NMO question almost all of our cases had an NMO testing. And it was negative.

(Ahmad Tread):
Yes. Thank you guys very much. Appreciate that.

Leticia Davila:
On behalf of COCA, I would like to thank everyone for joining us today with a special thank you to our presenters, Dr. Feikin and Dr. Oberste. We invite you to communicate to our presenters after the call.

If you have additional questions for today’s presenters please email us at coca@cdc.gov. Put October 3rd COCA Call in the subject line of your email, and we will ensure that your question is forwarded to them for a response. Again that email address is C-O-C-A @ C-D-C.G-O-V.

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END