Dr. William Graf was watching an on-line discussion at the CLS discussion group, and added his commentary to the conversation on medication for drop attacks.—MCH

As a child neurologist, I am very interested in CLS and in the problem of sudden falling that I have witnessed in Mary Hoffman's son, Davis. I am also committed to telling parents exactly about what is known and not known--because of a) the concern about any potential to do harm through misdiagnosis or misdirected treatment, and b) the importance of understanding the biological basis of the problem for targeted therapy in the future. (It is also important that physicians only be involved in the management of an individual's medical problem where the "doctor-patient" relationship is established--that means the physician must respect confidentiality in individual patients and refrain from commenting on any child's care where this relationship does not exist). With that caution in mind, I'll make some general comments:

One way of thinking about this "sudden falling" problem is to divide up the issues as follows:

1) The "what" (i.e. diagnosis);
2) The "why" (i.e. biological mechanism); and
3) The "so what" (i.e. what is the usefulness [utility] of accurately knowing the "what" and "why")

I could go on to give numerous examples of neurological conditions where there is either "good" or "not-so-good" knowledge of the "what" and the "why". However it is most important to know that even in some human conditions where the diagnosis is clear and the mechanism is fairly well understood (e.g. Duchenne muscular dystrophy from a dysfunctional dystrophin protein in the muscle membrane)--there is still NO GOOD TREATMENT for the condition (i.e. the "so what” [usefulness] of the current knowledge today is about the same as it was before we knew the gene and its product [e.g. dystrophin in Duchenne dystrophy]). In the case of CLS, we suspect [Rsk-2] on chromosome Xp22.2 in most persons but the biological mechanisms are still fairly vague.

1) Diagnosis. In CLS and this "falling problem" we remained at the level of not even knowing exactly what to call it for a long time. Some researchers called it "cataplexy" and others called it "hyperekplexia". I thought the latter term was better because the phenomena seemed to be "startle-sensitive falling". This level of diagnosis is descriptive only.

2) Biological mechanism. Indeed, we developed a reasonable hypothesis that this startle-sensitive falling (hyperekplexia) was related to a defect in a receptor on the brain's nerve cell endings (because other genetic forms of hyperekplexia had a documented receptor dysfunction and also clinically responded to clorazepate and/or clonazepam.
Specifically, Dr. Sarah Cheyette and I hypothesized that the children with both CLS and hyperekplexia may have a “contiguous gene syndrome" involving both the Rsk-2 and the glycine receptor alpha-2 subunit (GlyR a2) genes (because the GlyR a2 gene is contiguous with the [Rsk-2] Xp22.2 locus of CLS). To study this possibility, we worked fairly hard (mostly on our weekends) by "hunting for gene mutations" (sequencing) of BOTH the glycine receptor alpha-1 (GlyR alpha 1) gene and alpha-2 subunits (GlyR a2) in seven or eight patients with CLS and startle-sensitive falling. We are very thankful for the families and the physicians who contributed time and DNA
for this study.

However, we found no evidence of a "contiguous gene syndrome" or mutations in the glycine receptor alpha genes. Thus, our preliminary hypothesis could not be substantiated and ours was a "negative study" (i.e. using the baseball metaphor, we "struck out at the plate"). It is more difficult to publish negative studies--that is to say, it is the "positive" studies that get headlines (analogous to "hitting a home run")--and we did not submit our study results to a medical journal for publication.

3) Utility. We often judge the brain based on its performance and subjective symptoms rather than more detailed analysis (because the brain tissue is generally "off limits"). Other studies such as MRI and EEG have not been too helpful in studying this complex problem of falling in CLS. If the severity of the problem is high enough, then empiric medication trials can be justified. We have learned from these trials about what seems to work and what doesn't--but this "clinical experience" is difficult at times because anecdotally one medication may seem to help for one person and not the other. There a multiple potential reasons for this.

I agree that clonazepam and clorazepate seem to be the most effective medications in this condition to date--and I would assume it is because of the effect it has on certain neuron receptors (rather than the anti-anxiety hypothesis). Lamictal (lamotrigine) is a very good medication for epilepsy--and its mechanism is completely different. The good news is that both of these medications are very safe if used correctly.

In summary, since the biological mechanism is still NOT well understood, we are left with empiricism and our experience. Any individual with CLS and falling may or may not respond to these treatment trials--but sharing of information can be helpful if the collective experience is carefully analyzed.

However, this type of clinical methodological approach never seems to end because there is always a new medication coming out that "might work". For this reason, please allow me to advise parents about the "top ten" principles of medication treatment trials (in my opinion):

1. Only consider medication if the severity of disability resulting from the condition is considerable;

2. Pick established treatments beginning with the treatment most likely to be successful and least likely to be negative;

3. Define goals, minimum of success, and endpoint before the treatment trial begins;

4. Start low (in dose), go slow;

5. Be cautious-consider stopping the trial if the child shows signs of an unexpected negative response;

6. Be systematic-make one change at a time (i.e. do not make two changes at once-with the possible exception of tapering previous med while starting new med);

7. Begin medication trials and make medication changes during stable periods (e.g. avoid med trials during the first two weeks of the new school year, during the typically busy weeks of the Winter/New Year holidays or when the family is traveling or experiencing major life changes);

8. Discuss the placebo effect candidly (i.e. be objective and skeptical);

9. Make use of objective before/after rating scales (if available) during the medication trials-and strongly consider involving the schoolteachers as a part of the trial.

10. Avoid multiple medication "cocktails" (mainly because of increased chances of drug metabolism interactions).

And lastly, for these types of problems it is essential that parents work closely with a clinician near their home who is experienced with very complex developmental disorder like CLS.


William Graf, MD
Child Neurologist and Neurodevelopmental Pediatrician
Seattle WA

Hi Mary -
   Hope this finds you and Davis doing well. Just wanted to update you on Charlie's spinal fusion. Also, I don't remember if I gave you my new e-mail address: cgarrett63@aol.com.
   We finally had it done on January 6th after having it cancelled in October last year. The surgery was successful and he is now 4 1/2 inches taller and lost about 15 lbs.!! The doctors were able to take the hunch out of his upper back and straighten his spine. It's amazing to see him so straight and tall. The surgery lasted about 13 hours, what a long day that was for all of us. My parents were here (and still are to help out) from Arizona and my ex in-laws were with us also, along with my ex-husband, Charlie's father. He was in the hospital for about 10 days with no complications. His pain tolerance is very high so he was on minimal morphine, which I was thankful for. On the other hand, because his pain tolerance is so high, he has been very active (after the first month) and the doctor won't release him to go back to school yet. He's afraid he will do too much and pull loose the pins, etc. that are holding the rods in place. We took him for his first check-up last month and the x-rays looked good, so the doctor was relieved that nothing had come loose. How long was Davis at home before he could go back to school? Charlie's teacher comes to the house to do home schooling every day, which helps, but Charlie still misses all the kids, etc.

Take care,

Carol Garrett

Dear Mary,

   We have seen recent messages between yourself and Theresa Moxley regarding the medications for drop attacks. Katrina (5yrs old, one of twins) our grand daughter began these attacks at around 3 yrs, they have progressed a good deal to where they are now a regular occurence, particularly if she is tired. They are usually in response to unexpected noise or touch but recently we have seen her drop even when she was aware that a noise would occur, or that she was about to be touched. She seems unconcerned at present but she is still small and is not hurting herself in these falls. Our GP, the Paediatrician, the Geneticist, and ourselves are looking in to medication and we would appreciate any information or history of treatment encouraging or otherwise. There was a reference to a book "Hyperekplexia in Coffin-Lowry Syndrome" by Sarah Cheyette in the CLS newsletter some time ago, do you know of a source (if it is still available). Thank You, we`ll pass on any progress we make.

From Monica and Bob Mitchell.

Dear Mary

   Hi, This is Kathy Stewart (BJ’s) mom. I don't know if I had told you that we moved back to PA, from Texas. I am writing to just let you know what is happening with BJ. Mentally he is improving and learning everyday. I am so pleased with the progress he has made. He is reconizing words and loves learning from his leap pad. Physically he is deteriorating. His left side is so weak that he can not walk or even use the bathroom by himself any more. His drop attacks are 98 controlled. Ortho said his inability to walk has nothing to do with his bones. So he is going through Neurology now, so far nothing. He is scheduled for a muscle Biopsopy on the 28th of this month They also found white spots on his brain in the MRI he had. He is going for another of those also. I know a lot of the children cannot walk due to the seizures, but BJ could up until 10 months ago. And the weakness is getting worse. I can tell when I have to help him into the bath tub or to go to the rest room. Has any other parents told you of there child weakening for any reason. Is there anything in the syndrome that I am not aware of or new discoveries. If I just knew what was wrong it would not be so frustrating. You may put me on the list for Parent contacts.

Thank you,

Kathy

Hi Mary,

   Just wanted to send you a note because I wasn’t sure if you are familiar with a site: http://www.adaptivemall.com? I just bought a stroller there for Jacob & they were so helpful and great to work with, you can go into a menu & complete measurements for your child & they will assist you in finding the right stroller, car seat, etc. NO shipping charge if you spend $100 -- the one I bought him was $450 but it arrived today & looks great!!

   We are having a heck of a time finding the right helmet for him -- he's knocked out 2 teeth (baby teeth, thank goodness!) but his head gets so hot I hate these plastic foam "seizure" helmets. The drop attacks have not stopped completely, however the Tranzene seems to be helping. We are going thru a trial of Strattera currently, and are on the waiting list for a sleep study. Did your son fight the C-PAP (or is it B-pap??) or does he put it on willingly?

Thanks!

Lissa Walter

Mary,

   Sorry it's been so long since I last got hold of you. I've written many letters and just never got them in the mail. I have read all the newsletters you have sent. To let you know about how the boys are. Joel is 10 now and in 4th grade and Sean is 51/2 and in kindergarten. The baby [Erin] is now 2. She seems to be fine, a little small for her age but otherwise up with others her age. Mark and I are not sure how to handle her because she's doing things now that the boys didn't do until they were older or still don't do. She goes to KU Med. in April to see the doctor about her body size, I'll try to get back to you on that. The boys' health is fine. Just regular colds because Kansas weather is so crazy right now. I have an IEP for Sean next month too. He's my wild child, Paxal has helped lots. I have lots of questions. I don't stand the disorder at all and why the boys don't have all the same traits. I thought they would with the same parents. When I get my thoughts together or the questions in order I write back. Your doing a great job Mary! Thank You!

God Bless,

Barbara Bishoff

Dear Mary,

   I have been receiving your newsletter for quite awhile now, but never spoke up, now is my chance. Our son Joseph is 19 yrs old, with CLS. It was very overwhelming when we saw pictures sent in, how the resemblence is there. He has for the most part been the greatest happy go lucky kid, maturing with some difficulties, needing scoliosis surgery in 1999, seizures are controlled, has GERD, and naturally with puberty came behavioral problems, major ones. Today his medications include Dilantin, Risperdal, Cogentin, Concerta, Nexium, Miralax, prn Albertol Neb. treatments, and also Zyrtec.

   What I am looking for is another parent, or information of medication used others for behaviors. Possibly a calming agent. Joseph has had lashing out at others years ago, with only occasional outbursts, but now spring fever must have occurred, behaviors are out of hand once again. Joseph is essentially non-verbal, he uses a dynamo (an assistive techonology device) we majorly program so he can converse. He is in a multi-disability support classroom in our high school level. Everyone knows Joe! He's the greatest, except when he goes "off" and we never know when this is going to happen. CAT of head was normal (as
can be) and EEG didn't show anything new. We seen a neurologist this past week, and he and the psychiatrist increased the Risperdal morning dose (8 mg.) and his bedtime dose is (4). However, he hates anyone mentioning "work", school", for even having to go anywhere. As you can see, I'm looking for some answers or if anyone else has experienced similar situations with their child.

   Keep up the good work with the newsletter, I love reading them, I've shared them with many different physicians we have gone to.

Eliminate any physical cause, I.e., chronic pain.

Look for patterns to the outbursts. See if you can tell what is setting him off. Give him advance warning of what you want him to do. “In 5 minutes, we need to put on your shoes so we can leave.”

Prozac was mentioned as helping kids make transitions.

Give choices. Most people support decisions better if they have some say in them. “Would you like to wear the green pants or the blue ones?” We must remember that they are usually told what to do all the time by everyone, and we must allow them some sense of independence, dignity and pride.

Thanks for Caring!

Send your donations to:

Coffin-Lowry Syndrome Foundation

c/o Mary Hoffman

3045 255th Ave SE

Sammamish, WA 98075 

(U.S. Funds, please)