Tuesday, July 20, 2010

Maybe it WAS just chance ...

So after obsessing for a couple of weeks whether some fairly remarkable developments were due to fever or prednisone or chance, I must report that one of the 3 events has been at least partially duplicated without fever (I don't think) or prednisone. A couple of days ago, T began asking "What is that [sound]?" There's still something odd about the way he asks it, and it's really not clear that he is always really trying to find out the answer, but I'll take it. I'll take it.

As for the other 2 incidents, though, I have not seen either again. The one of course that stands out so clearly in my mind is him standing there, catching my eye and turning his head to direct my gaze to the object he was pointing out. Not once, but twice. In a row. It was simply breathtaking.

Although he points out objects a lot, I have never seen this before or since. Before Autism, it would never have even occurred to me that there was such a thing as joint attention, that it can be lacking. What a simple thing it seems to do, to meet eyes, to turn the head ... And even when it is missing, how subtle it is at first. You know something is not quite right, but you don't know what. And then you know, and it is so puzzling that someone can lack in this most basic of abilities. How can it be?

And it is so beautiful when you see it at last, after so long. And it is so painful to think that you might never see it again. It's kind of a cruel hope, maybe.

But clearly, there is no giving up now, because I have seen it. It is THERE, waiting to be unlocked. If only I could find the key.

Monday, July 12, 2010

PS about prednisone

T's regular pediatrician had something very interesting to say about my prednisone incident, which I don't think I've mentioned here yet. My husband is actually the one who spoke with her, but I think I've gotten all the major details correct.

According to my husband, when he brought up "the incident" with her (discussed previously in these posts), she was completely unsurprised. In fact, she told him that she had had another patient some time back who tried prednisone, and that it had worked marvels. However, there had been side effects, and she did not necessarily think it was worth it. She said that due to the side effects, they wouldn't use the prednisone at Emory, but she thought her patient had traveled somewhere else.

I'm a little unclear as to whether this patient was forced to discontinue due to the side effects, but the pediatrician says that the patient did retain some of the gains after stopping the prednisone.

I wish I knew more, but I'm not sure if our pediatrician really knows much more than that. If it's true, of course, I'm wondering why she never mentioned it before??

Also, what is it that might make it work, if it does? The folks at Johns Hopkins I thought were very certain that it wouldn't affect the inflammation that they saw in the tissue samples, although maybe I need to go back and read that more closely. I find it so striking, though, that elsewhere I read that prednisone is supposedly helpful for the kind of inflammation involved in asthma because it actually turns off the genes that trigger the release of the inflammatory chemicals.

My friend the infectious diseases doc also thought for that reason that it makes perfect sense that prednisone could have an immediate beneficial effect of this sort (not that she had any idea whether it did or not, you understand -- she is an HIV specialist, this is not her area) -- so it is hard for me to let go of this idea.

But still, assuming it's not that .... could prednisone have a hormonal effect rather than an anti-inflammatory effect (if those are even separate things)? Somehow, prednisone mimics cortisol in some sort of way. And I have read that autistic individuals appear to not experience the cortisol spike in the morning that others do.

I also read somewhere that cortisol has some sort of effect on calcium channels, which have also been implicated in autism, maybe that is relevant?

I think there's a lot of other stuff about cortisol and autism out there, and I just can't remember it all. But could there be some connection there?

I wish I understood all of these things so I could see how they all fit together ....

Sunday, July 11, 2010

A follow up on febrile seizures

Anonymous pointed out in response to my last post that pediatricians by and large think febrile seizures are not a big deal, and that is certainly true. If you visit the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, you will find this fact sheet on febrile seizures.

It is clearly designed to reassure the worried parent. Here's what it says:

"Are febrile seizures harmful?

Although they can be frightening to parents, the vast majority of febrile seizures are harmless. During a seizure, there is a small chance that the child may be injured by falling or may choke from food or saliva in the mouth. Using proper first aid for seizures can help avoid these hazards (see section entitled "What should be done for a child having a febrile seizure?").

There is no evidence that febrile seizures cause brain damage. Large studies have found that children with febrile seizures have normal school achievement and perform as well on intellectual tests as their siblings who don't have seizures. Even in the rare instances of very prolonged seizures (more than 1 hour), most children recover completely.

Between 95 and 98 percent of children who have experienced febrile seizures do not go on to develop epilepsy. However, although the absolute risk remains very small, certain children who have febrile seizures face an increased risk of developing epilepsy. These children include those who have febrile seizures that are lengthy, that affect only part of the body, or that recur within 24 hours, and children with cerebral palsy, delayed development, or other neurological abnormalities. Among children who don't have any of these risk factors, only one in 100 develops epilepsy after a febrile seizure."

Does this sound reassuring to you? I can see why it might. After all it prominently says that "the vast majority of febrile seizures are harmless." That would explain of course why a pediatrician will always be dismissive if your child has one. That's because doctors play by statistics. If they have seen 80 patients with X, and they all turned out fine, you can bet that when your child shows up with it they will not think there is a problem.

I, however, am not reassured by this discussion. You know why? 2 reasons: 1) I review and edit corporate disclosures for a living, and for that reason, I am less influenced by "spin" than other people. 2) My son has autism, which means 2 things: a) I have already learned that when there is a 1% chance of something, that means it really can happen to my child. b) my child is in the group that is clearly described in the last paragraph as being at increased risk of epilepsy.

So, just for fun, I have re-written the last paragraph in a way that highlights rather than downplays the risk. I feel pretty confident that I have not altered the actual content. See what you think:

"Between 2 and 5 percent of children who have experienced febrile seizures go on to develop epilepsy. Some children who have febrile seizures face an increased risk of developing epilepsy, althouh the risk is small. Children who are more likely to develop epilepsy include those who have febrile seizures that are lengthy, that affect only part of the body, or that recur within 24 hours. In addition, children with cerebral palsy, delayed development, or other neurological abnormalities are also more likely to develop epilepsy. Other children, who don't have any of the risk factors listed above -- have a one in 100 chance of developing epilepsy after a febrile seizure."

Still think that they're not a big deal? Then you might ask yourself why they are still researching ways to treat and prevent them:

The National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health (NIH), sponsors research on all forms of febrile seizures in medical centers throughout the country. NINDS-supported scientists are exploring what environmental and genetic risk factors make children susceptible to febrile seizures. Some studies suggest that women who smoke or drink alcohol during their pregnancies are more likely to have children with febrile seizures, but more research needs to be done before this link can be clearly established. Scientists are also working to pinpoint factors that can help predict which children are likely to have recurrent or long-lasting febrile seizures.

Investigators continue to monitor the long-term impact that febrile seizures might have on intelligence, behavior, school achievement, and the development of epilepsy. For example, scientists conducting studies in animals are assessing the effects of seizures and anticonvulsant drugs on brain development.

Investigators also continue to explore which drugs can effectively treat or prevent febrile seizures and to check for side effects of these medicines."

Now, of course this correlation between febrile seizures and epilepsy does not mean that the seizures "caused" epilepsy. It could be, I suppose, that these children already "have" epilepsy.

But I don't personally find this very reassuring, because as far as I can tell, all seizures are caused by a disturbance to the balance between excitatory and inhibitory neurons. See this discussion, for example, which states:

The Neurobiology of Seizures
Seizures can be caused by multiple mechanisms, and often they appear so diverse that one would suspect that no common theme applies. However, one principle that is often discussed is that seizures arise when there is a disruption of mechanisms that normally create a balance between excitation and inhibition. Thus, normally there are controls that keep neurons from excessive action potential discharge, but there are also mechanisms that facilitate neuronal firing so the nervous system can function appropriately. Disrupting the mechanisms that inhibit firing or promoting the mechanisms that facilitate excitation can lead to seizures. Conversely, disrupting the mechanisms that bring neurons close to their firing threshold, or enhancing the ways neurons are inhibited, usually prevents seizure activity.

And I think I have pretty good reason to find this disturbing, since there is material all over the place about how autism is also caused by a disturbance in this same balance. For example, this review from the Simons Foundation describes a couple of recent studies from last year:

"Together, the papers add heft to the hypothesis that an imbalance between excitatory and inhibitory neurons underpins autism. The high prevalence of seizures in individuals with autism is seen an indicator that the balance between excitatory and inhibitory circuits has gone awry in people with the disorder.

"The possibility is emerging that subtle changes in the numbers and proportions of this category of interneurons may result in a range of neurodevelopmental disorders, including schizophrenia, bipolar disorder and autism," says Anthony-Samuel LaMantia, lead investigator on the PNAS study and a neuroscientist at the University of North Carolina at Chapel Hill.

The studies also emphasize the essential role inhibitory interneurons play in the development of proper circuitry in the cortex. Restoring circuit balance may therefore be a plausible way to reverse autism, suggests Hensch, a neurobiologist at Harvard."

Now, again, let me point out that what this suggests is that autistic individuals are more likely to have seizures. It doesn't mean that a febrile seizure made them autistic.

But it is a rather far leap from there to conclude that febrile seizures do not harm an autistic person, either.

And how many studies have been done to ascertain the impact of a febrile seizure on an autistic person? I haven't seen anyone mention any. How would you design such a thing, I wonder? Who is your control group? Autistic children who didn't have one? How would you even know for sure who had had a seizure, since so many of them are undetectable? And how would you match them, given that autistic children have so many different levels of functioning, comorbid conditions, etc.?

So for me, I am back to common sense. I already have some pretty good reason to think that there is something wrong in my son's brain. And it is clear that he is at increased risk for febrile seizures.

And I dig deeper, and I find this from the CDC (emphasis added):

The 5%-7% of children who have either a personal history of convulsions or a parent or sibling with history of convulsions may be at increased risk for febrile convulsions after MMR vaccination (184). The precise risk has not been measured, but appears to be minimal. On the other hand, febrile seizures occur commonly among children in whom measles disease develops, and the risk for acquiring measles is substantial. Therefore, the benefits of administering MMR vaccine to children with a personal or family history of convulsions substantially outweigh the risks and these children should be vaccinated following the recommendations for children who have no contraindications.

This doesn't sound unreasonable to me. But this is NOT the same thing as saying there are no risks to the vaccine, or that it is perfectly safe.

I just can't see leaving this decision up to some stranger in Washington DC, or group of strangers, no matter how many degrees they have. I just can't understand how anyone could take this stuff lightly, I really don't.

MMR causes seizures??

It is kind of weird how no matter what I am actually trying to research, it always seems to lead me to something new and disturbing about vaccinations. I have to date stayed completely agnostic about vaccines, but I have to say I have really read some disturbing things. While trying to research more about fever and metabolism issues, I wound up at this CDC FAQs about the MMRV.

What is really creepy is this:

Does the MMR vaccine cause febrile seizures?

Children who receive the MMR vaccine are more likely to have febrile seizures 8-14 days after vaccination than children who are not vaccinated at all. 1 During the 8-10 days after vaccination, about one additional febrile seizure occurs among every 3,000-4,000 children who receive MMR vaccine, compared with children who do not receive any vaccines.


How serious is a febrile seizure?

Although febrile seizures can be frightening for the child's caregivers, most are harmless. The majority of children who have febrile seizures recover quickly and have no lasting effects. Up to half of children who have one febrile seizure will have at least one other febrile seizure. But children with simple febrile seizures--the most common form--have no greater chance of getting epilepsy or brain damage than children who do not have febrile seizures. A study 1 showed that children who have febrile seizures after receiving an MMR vaccine are no more likely to have more seizures, epilepsy, or learning or developmental problems than children who have febrile seizures that are not associated with a vaccine.

Good Lord! I do not recall hearing anyone say this before, although I do have a brain like swiss cheese, so maybe I have already been here before. I don't know.

But ... seizures?? Really? And somebody is actually doing studies to try to prove that having seizures is not harmful? You have got to be kidding me.

Wow, how impressive has modern science become! Now they can prove that really, seizures are no big deal.

Only a real ignoramus would dare to worry that her child had seizures.

Thursday, July 8, 2010

2005 neuroinflammation article

As Laura pointed out, my link to the neuroinflammation article is only to an abstract. The full publication is protected by copyright, and I don't think it is (legally) available for free anywhere on the internet. However, thanks to the Eide's blog, I found a copy of a second publication by the same authors that discuss the same findings. You can get your copy here.

Laura wondered whether the patients in the study included Hannah Poling. I can't really tell that, but the paper does tell us the following:

1) the brain tissues came from several different Brain Banks: Harvard, the University of Miami and University of Maryland.

2) There were tissue samples from 15 autistic individuals and 12 controls. 6 of the autistic individuals also had epilepsy. 3 of them had experienced regression, and it was unknown whether an additional 4 had or not; this states that 8 of them had not experienced regression. Their ages are really spread out. there's one 5 year old and one 44 year old. there are 7 tissue samples from children aged 7 to 10, one 14 year old, and 5 samples from individuals in their 20s.

3) An overwhelming majority of the autistic individuals had some mental retardation. Only one of them is listed as not having it, plus 2 that they weren't sure about. So that is certainly an important factor.

4) There were differences in the preservation of the different samples, and this affected which samples they performed some of the tests on.

5) It says "All autistic cases fit the diagnostic
criteria established in the Diagnostic and Statistical Manual–
IV and confirmed by the Autism Diagnostic Interview–
Revised (ADI-R).23,24 The ADI-R was administered previously
by researchers at the Autism Tissue Program (ATP) as
a criterion for inclusion in the repository. Additional clinical
and neurological information also was obtained from the

So although I'm not sure about this, it seems that they perhaps all had classic autism. Most of them were mentally retarded, which tells us something, perhaps, but since they didn't all have regression, I don't think they were all Hannah Poling cases, since I thought that regression was a key piece of her case.

Most of this is very difficult for me to read, but one section was a little easier to slog through, so I'll provide my summary here for any who are interested. In this section they are looking for pro-inflammatory cytokines. They only had 7 frozen samples from autistic individuals, so this portion of the study only involved those 7 and were compared to 7 controls. 3 of the 7 autistic individuals had regression, 3 hadn't, and one it was unknown. all of them had retardation, except for one, as to whom it was unknown. 4 had epilepsy and the other 3 did not.

They do not really come out and say that the cytokines were really elevated in all 7 of the individuals, although in several places it sounds like they are saying that. For example, they say: "A statistical analysis of the relative expression of cytokines in autistic and control tissues showed a consistent and significantly higher level of subsets of cytokines in the brains of autistic patients." But this could just mean that the average level in the autistic group was higher than the average level in the control group. There is one other statement that makes it sound as though they found higher levels of inflammation in all of the autistic samples. It says: "We found that in the three regions studied, the antiinflammatory
cytokine TGF- 1 was consistently and significantly higher in the autistic group than in the controls."

At any rate, unless I am misreading something, I think they do make it clearer in the Johns Hopkins FAQs that they found inflammation in all of the samples: "However, the presence of microscopic and immunological findings showing neuroimmune reactions in all of our autistic patients and the cytokine findings in the cerebrospinal fluid (CSF) support a potential role for neuroglia and neuroinflammation in the CNS effects in a number of individuals with autism."

The FAQs point out that some of the samples had epilepsy and mental retardation, and that therefore neuroinflammation is not necessarily ALWAYS present in the brain of an autistic individual. However, I was really surprised to see that they failed to point out that by far MOST of their samples had mental retardation, rather than just "some." In fact, only one of the samples was definitely not mentally retarded.

The Eides blogged about this at the time and included pictures from the study that showed the cell destruction. You can see them here.

The study also reports that they found evidence of Purkinje cell loss in every sample but one 8-year-old. Previous studies had seen reduced Purkinje cell numbers, but this study is suggesting that the cell loss is due to the inflammation. I was able to figure out that the 8 year old without signs of Purkinje cell loss did not have epilepsy or regression, but he did have retardation. But it would appear that all of the other individuals without regression also had Purkinje cell degeneration, including the one individual who is listed as definitely not having retardation.

I have seen a lot of things suggesting that the reduction in Purkinje cells is congenital, but I think what this study is to strongly suggest that the damage is ongoing. I don't doubt that it started prenatally, but I think it's still going on. The study also found evidence of anti-inflammatory chemicals that are used to restore and repair, in the same area where the degeneration was going on, suggesting to me this sort of eternal battle going on, of cell destruction and rebuilding. This would explain a lot in terms of my personal experience. So often it seems like we have two steps forward, one step back. I have never thought of T as "regressive" exactly, but he does exhibit abilities one day that are just gone the next day. And it takes SO LONG for him to learn something, so many repetitions. Could this be because this horrible destruction and rebuilding is going on in there?

I don't want to believe it, but my instinct tells me it is. I really think it is.

Wednesday, July 7, 2010

then again, maybe it was the fever?

So my continuing efforts to figure out what caused T's startling "good communication days" last week has led me back to somewhere I've been before ... fever. I had temporarily forgotten that T had a fever, although when I first speculated that maybe the steroid was responsible, my husband suggested maybe it was the fever. I can't remember if I have blogged about this before or not, but there are some startling studies out there which seem fairly conclusive that a subset of autistic children, mostly high functioning, improve (sometimes substantially) when they have a fever. The Simons Foundation has a summary of a recent workshop (this year) in which various experts from across the country convened to discuss this phenomenon and brainstorm about what it could mean.

This report says that Dr. Zimmerman et al. at Kennedy Krieger (the same folks who found the neuroinflammation) found, in a study of 30 children with autism, that symptoms like irritability, stereotypy, hyperactivity and inappropriate speech improved during fever.

One of the most fascinating (out of many) things in this report is some discussion about pupil responses. Previously it has been found that the pupils of autistic individuals don't respond as much or as rapidly as those of other people. According to this report, it appears that the children who show improvements with fever are not only generally more high functioning, but they have less impairment in their pupil response. Although the developmental pediatrician described T as moderately functioning the county people seems to think he is high functioning. I don't know. But I wonder about his pupil response. Of course the pediatrician is supposed to check this during well baby visits, isn't she? but of course every regular pediatrician I saw was always very quick to assure me how "fine" T is/was.

Interestingly, I was so sure when he was an infant that he was cross-eyed, but the doctor kept insisting he was fine. And yeah, I did take him to an ophthamologist. Another waste of time and money. This fellow also assured me how "fine" T was. Well, he was a nice guy. Really all the doctors have been pretty nice. Just not exactly helpful.

But there are a lot of things in this article, too many for me to figure out and blog about right now. But among them was a discussion about the relationship between fever and prostaglandins and neural function in general. this caught my eye because, interestingly, prednisone suppresses prostaglandins.

this one report could take me days to try to parse through!

oh, to go back in time and study some biology and chemistry.

Tuesday, July 6, 2010

more on prednisone, inflammation

I actually just discovered some FAQs on the website of the Johns Hopkins Neuroimmunopathology website about inflammation in autistic individuals and it was VERY informative! I wish I had found it first! Here's my Cliff Notes version:

1) There is inflammation in the brains of autistic individuals, and it is chronic. Maybe not all of them, but many of them.

2) Inflammation can be both good and bad, because it is a way to repair. It could be that the inflammation is in response to something else that is bad.

3) Most of the inflammation is in the cerebellum, predominantly in the Purkinje cell layer and the granular cell layer.

4) They characterize their findings as "consistent with an active and ongoing postnatal process of neurodegeneration and neuroinflammation" -- i.e., they don't know for sure that is what is going on, but that is what they suspect.

5) Prednisone and other steroids would not have any impact on the particular kind of inflammation that they found. Their study did not find evidence of the kind of inflammation that prednisone and other steroids addresses.

So this would seem to suggest that if the Prednisone was responsible for the astonishing things I saw in T last week, it is not due to an anti-inflammatory effect.

However, I am nonetheless extremely troubled by these findings. It is extremely upsetting. These FAQs are making comparisons to horrible conditions like HIV dementia, multiple sclerosis, ALS and stroke. The idea that this could be going on in my child's brain is, I will admit, making me feel rather panicky.

It is so hard for me to believe that this is coincidental when my son has also been having breathing problems that are also apparently caused by excessive inflammation.

And now I am wondering about something else: migraines. He has for as long as he's been able to communicate at all indicated pain in his nose/facial mask area. I have repeatedly raised it with the pediatrician but she either blew it off or blamed it on a head cold. When I took him to the ENT for what was supposed to be a swallow study (a story for another day), the ENT also dismissed it, and said his nose looked fine. He keeps telling me "it's hurting," but when I ask him where, he puts his hands over his face. What does that mean?

Well, while trying to research asthma(!) I came across an article in Web MD suggesting that asthma may be linked to migraines. What I was really surprised by was a statement that migraines are also caused by inflammation. I haven't really dug into this, but the article says:

Asthma and migraine share many inflammatory chemicals that are released during an attack, Cady says. “There’s a host of common neurotransmitters that are shared here,” he says, including calcitonin gene-related peptide, histamines and cytokines. “Those are names for inflammatory chemicals that get activated both during asthma and during migraine,” he says.

I don't know anything about Cady except this says he's an MD with some sort of practice specializing in headeaches, but this is really interesting. I had assumed that T's pain was coming from sinuses/allergies, but this article says that this is an assumption many people mistakenly make, and that asthma can in fact be responsible for these kinds of headaches.

Could T be having an asthma headache?? How would I know? He has decreased sensitivity to pain ... might this make him even less communicative than he is already inclined to be about such a problem? Again, how can I know?

I have had such demoralizing experiences with the pediatrician, the ENT, the developmental pediatrician, the ER doctor. Oh,yeah, and the orthopedic surgeon. They either are not interested in the whole picture, too impatient to listen to the whole story, not entirely up to date on everything, or in too big a hurry to impart what I consider to be full information. In short, I have to date found consulting MDs is a good thing to do when your kid is threatened with immediate physical danger, but not terribly helpful toward trying to actually achieve something more. Now that I am paying it all out of pocket, I am having a hard time bring myself to make the appointement with the pulmonologist and/or the allergist.

Monday, July 5, 2010

Prednisone and inflammation and ... vaccines???

Well, my efforts to research whether prednisone really caused some remarkable improvement in my son and if so why have led me down a very strange and twisty path. I can't even remember how I got here, exactly. But I somehow found myself reading a very short article rather forcefully urging that vaccines do not cause autism by authors Jeffrey Gerber and Paul Offit. I guess everyone knows who Dr. Offit is by now, but if you don't, Wikipedia has a bio for him. The short version is he's a prominent pediatrician and vaccine expert at the Children's Hospital of Philadelphia, he's done work for the CDC, and he's quoted OFTEN about the whole vaccine issue. He definitely does NOT think there's any link between vaccines and autism.

Anyhow, this article, Vaccines and Autism: A Tale of Shifting Hypotheses, was fairly unremarkable to me, until I got to this:

Autism is not an immune-mediated disease. Unlike autoimmune
diseases such as multiple sclerosis, there is no
evidence of immune activation or inflammatory lesions
in the CNS of people with autism [38]. In fact, current
data suggest that genetic variation in neuronal circuitry
that affects synaptic development might in part account
for autistic behavior [39]. Thus, speculation that an exaggerated
or inappropriate immune response to vaccination
precipitates autism is at variance with current scientific
data that address the pathogenesis of autism.

This is the part where I started tearing my hair out, because I just got done learning all about how autism is an immune mediated disease with an autoimmune component. Or at least I thought I had.

Frustrated by electronic searching, I had finally checked out what seemed like some "real" medical texts from the Emory University Health Sciences Library. One of them is called Autism: Current Theories and Evidence, and it was published in 2008. It's edited by Dr. Andrew Zimmerman, who as far as I can tell is an extremely well-published, -credentialed, and -respected neurologist at Johns Hopkins and the Kennedy Krieger Institute. This text is part of a series called "Current Clinical Neurology," edited by another impressive sounding individual at the Harvard Medical School. Not exactly sketchy people.

Part IV is called Immunology, Maternal-Fetal Interaction, and Neuroinflammation. There are four different pieces in here on the immune system in autism and neuroinflammation! And on page 329, Dr. Pardo-Villamizar, a colleague of Dr. Zimmerman at Johns Hopkins, writes:

"Several studies showing peripheral immune abnormalities support immune hypotheses; however, until recently there has been no demonstration of immune abnormalities within the [central nervous system]. Recently, our laboratory demonstrated the presence of neuroglial and innate neuroimmune system activation in brain tissue and cerebrospinal fluid of patients with autism ...."

Wow, could there be a more direct conflict here? So I check the dates. The vaccine article by Drs. Gerber and Offit was received by the journal on August 25, 2008. But the research of Dr. Pardo (and Dr. Zimmerman) was published well before then. I found it in a 2005 article called "immunity, neuroglia and neuroinflammation in autism."

So I continue trying to puzzle this out: who's right, who's wrong, can these 2 things be reconciled? I pull footnote 38 from Dr. Offitt's article, the one that supports his statement that "there is no evidence of immune activation or inflammatory lesions in the CNS of people with autism." And discover that Dr. Offitt's support is a 2004 report from the Instute of Health called "Immunization safety review: vaccines and autism." The first thing that went through my mind: really? The most recent citation you can find on this topic is from 2004? And not even a "but see" or "compare"? There's absolutely no suggestion here that maybe somebody else thinks there IS evidence of immune activation in the CNS of people with autism. It's just shocking to me, since I'm staring at it.

I pull the 2004 report. One of the first things that I notice about it and am a little disturbed by is that apparently, this was written by a committee, and it met only once to discuss this topic. At least, it appears that way. When I turned to page v to see who was on the committee I see this: "The following individuals are members of the Immunization Safety Review Committee but were unable to attend the meeting on the topic of this report." That certainly makes it sound like there was only one meeting, doesn't it?

I also notice that they had a large number of additional people review and comment on the report before publication, and interestingly one of those people is Dr. Zimmerman. However, the report expressly states that they didn't necessarily take all the comments from everyone, so it's possible Dr. Zimmerman didn't agree with the report. I can't tell.

But the real important part is what I found when looked at the report itself. There is an entire section on immune dysregulation, beginning on page 128. I found this shocking, because this section is full of citations to study after study after study showing weird things about the immune systems of autistic children. The committee doesn't seem to actually dispute these findings. And here, I will readily admit this material was over my head. But as far as I can tell, what the committee has actually done is this:

1) they critique the various theories and hypotheses that researchers have tried to come up with to explain the obvious immune anomalies that have been observed (without suggesting any of their own); and
2) state that it is irrelevant that autistic children have these immune anomalies, partly because they can't figure out how it could be relevant, and partly because (supposedly) autistic children don't seem to be more prone to allergies.

They start with the sentence: "A large number of studies have suggested that immune dysregulation occurs in autism." The first few weird findings they cite in this report:

* Decreased lymphocyte responsiveness in the lymphocyte blastogenesis assay to PHA, ConA, and Pokeweed mitogen
* significantly reduced natural killer (NK) cell activity (Warren et al., 1987);
* decreased proportion of IFN-gamma- and IL-2 (Th1 cytokine)-staining CD4+ T cells in the serum;
* significant increase in IL-4-(Th2 cytokine)-staining CD4+ T cells

I don't claim to know what all this stuff is, except that it all relates to the immune system. Interestingly, the IFN-gamma jumped out at me, because the medical textbook I picked up on asthma says that asthmatic children had reduced IFN-gamma, but that's not relevant here.

Anyway, there's more, some of which does seem to contradict the above:

*increased levels of plasma IFN-gamma and IL-2 (Th1 cytokines)
* Increased production of serum IL-12, IL-6, tumor necrosis factor-alpha and IFN-gamma, and increased urinary neopterin
* PBMCs (peripheral blood mononuclear cells) from patients with autism, both at baseline and after stimulation with LPS (lipopolysaccharide) and PHA (phytohemagluttinin), secreted significantly more pro-inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) than those from healthy controls and normal siblings

Basically, they go on to review this bewildering array of findings after which I get the distinct impression that:

1) something is really weird about the immune system in autistic people; and
2) no one really knows why or what it means.

In other words, there is a problem and we are deeply ignorant about it. Their conclusion about these things is: "In summary, although several studies have reported abnormalities of components of the immune systems, they have often had contradictory results, making it difficult to achieve a consensus on any specific immune abnormality that might characterize autism. More fundamentally, it is not clear how these abnormalities might explain the CNS defects in autism or whether they could be secondary to GI or other complications of developmental disability."

But wait, there's more, because then I read:

"A large number of serum autoantibodies have been detected at a higher frequency in children with autism compared to controls. The antigens against which these autoantibodies are directed include a number of CNS antigens, such as myelin basic protein and neuron-axon filament protein, but they also include a whole host of other proteins, such as nerve growth factor, serotonin receptor, alpha-2-adrenergic receptor, tubulin, heat shock protein 90, and chondroitin sulfate."

Now, I've read some of this stuff before, but not in a government report. I am pretty astonished. I never really imagined there was anything like this in here. Especially since Dr. Offitt's report makes it sound as though there is no evidence of anything wrong with autistic individuals' immune systems, although perhaps I misread what he said. But wait,there is just so much more in here, I can't stop quoting it.

The report says: "This suggests that rather than there being a specific antibody response to [central nervous system] antigens, generalized hypergammaglobulinemia resulting from polyclonal B cell activation occurs in autism." I really don't know what they are talking about here, but doesn't it sound a lot like they are suggesting that somebody this "generalized hypergammaglobulinemia" is something to be unconcerned about? Doesn't it seem like it might be relevant to vaccinations? Ok, I'll grant you that maybe it's not. But they are just a little too dismissive for my tastes. They are dismissive of EVERYTHING, and that doesn't sound ... balanced and neutral.

Perhaps my favorite sentence is this one: "Of note in the abovementioned studies, these antibodies were all also found in the serum of healthy controls, albeit at lower levels—i.e., they were not specific to autism, making their pathogenic significance questionable." Well, I don't know about "pathogenic significance," but being just another stupid layperson, I am wondering why they seem to think that it doesn't matter that my son has antibodies at higher levels than everybody else. How can this be irrelevant?

it continued to cite all sorts of evidence of weird things involving the immune system in autistic kids, but they always managed to dismiss them in some way or another. There is an intersting reference to Wakefield, too, btw, but I am trying not to get too off-topic here, so I won't detail that, but you may want to read it for yourself.

I realize that they were focused on addressing one specific question, but in general, it felt a little rude and frankly insensitive to have them lay out all of these horrible sounding findings and then just sort of brush them aside as though they just didn't matter.

Some of their logic is hard for me to follow. Like: "As mentioned, autoantibodies to cerebral antigens, including MBP, have been found at higher titers in children with autism compared to controls. It is important to note, however, that these studies all evaluated serum and not CSF or brain tissue." Okay, so I'm not a doctor, and maybe this would make sense to me if I were, but why would there be autoantibodies to CEREBRAL antigens in your body but yet not in your brain? Am I the only one who thinks this sounds as though they are saying: "Well, sure, they have antibodies in their blood that are designed to attack brain tissue, but hey, no one has ever proven that any of these antibodies actually made it to the brain, so relax. they probably didn't."

And then I hit this: "Some investigators have tried immunotherapies, such as corticosteroids ...." THAT'S prednisone!! They go on to cite anecdotal evidence of both success and failure with this treatment. It is ironic that is what I am REALLY trying to research, but now I don't have time to read the references cited yet. It will have to wait to tomorrow.

I must say I am deeply troubled by this report. Whatever the Truth is about vaccines, there is clearly something up with the immune systems of autistic children, and it has been known for some time. I sort of knew this already, but it was only in a dim and hazy way. Not like this.

This report does not deny that something is up with the immune systems of autistic children. It concludes this section with the anticlimactic:

"By analogy to Rett’s syndrome, similar epigenetic mechanisms may be operating in autism that simultaneously lead to abnormal development in the immune and central nervous systems (Zimmerman, 2000). However, the deviations from expected levels in various in vitro laboratory assays in both these conditions may represent only a secondary effect of the developmental or behavioral abnormalities."

[Note the reference to Zimmerman? I assume that's the same Dr. Zimmerman who edited the book I've checked out, the one full of articles about neuroinflammation and immune dysfunction (among other things).]

So I am left with 2 questions:

1) Why does Dr. Offitt say "Autism is not an immune-mediated disease. Unlike autoimmune diseases such as multiple sclerosis, there is no evidence of immune activation ... in the CNS of people with autism," and why does he think that this report substantiates such a bold assertion? I grant you that the immune problems may go hand in hand with autism without "mediating" autism, but I do not get the impression that anyone understands enough to know for sure whether this is true or not.

2) Why didn't one of my son's doctors tell me ANY of this stuff??

OK, obviously I have more than 2 questions, and those are actually the least important ones. what I really want to know is:

1) what is wrong with my son's immune system?

2) how do I fix it?

Sunday, July 4, 2010

Prednisone and language?

I haven't posted in a while, but I had to post about this, in case anyone is reading this. I had to take T to the ER last weekend for respiratory distress and they put him on prednisone. Within a day or 2, I had 3 remarkable experiences:

1) he asked me a question: "What is that?"
2) he commented to me: "That tickles!"
3) he exhibited true total joint attention: he pointed and said: "there's a mouse!" then looked at me, caught my eye and looked back to the mouse. then back to my eyes again, then back to the mouse.

At first I thought, wow he really is making progress. And to be clear, he HAS been making a lot of progress.

But then I thought, this is really dramatic, all at once. Could it be the prednisone (a sort of artificial cortisol)? I looked it up, and do you know that there ARE a lot of people out there who claim miraculous improvement in language when they put their autistic kid on prednisone? I don't really know whether this is real or not, but I am planning to find out.

I have been doing some reading about both autism and asthma lately, and there are some pretty striking links. It appears (to me) that it really is very clear that autism involves chronic inflammation, and so does asthma. So it kind of makes sense that prednisone, which is anti-inflammatory, might be beneficial also for someone with autism.

fyi, the prednisone was only for 4 or 5 days, so we're not on it anymore. but I am planning to find out more.