Thursday, September 20, 2007

Does Cerebellar Injury in Premature Infants Contribute to the High Prevalence of Long-term Cognitive, Learning, and Behavioral Disability in Survivors

Published online August 31, 2007PEDIATRICS Vol. 120 No. 3 September 2007, pp. 584-593 (doi:10.1542/peds.2007-1041)

Does Cerebellar Injury in Premature Infants Contribute to the High Prevalence of Long-term Cognitive, Learning, and Behavioral Disability in Survivors?

Catherine Limperopoulos, PhDa,b, Haim Bassan, MDb, Kimberlee Gauvreau, ScDc, Richard L. Robertson, Jr, MDd, Nancy R. Sullivan, PhDe, Carol B. Benson, MDf, Lauren Avery, PhDg, Jane Stewart, MDh, Janet S. Soul MD, CM FRCPCb, Steven A. Ringer, MD, PhDi, Joseph J. Volpe, MDb and Adré J. duPlessis, MBChB, MPHb

OBJECTIVE. Although cerebellar hemorrhagic injury is increasingly diagnosed in infants who survive premature birth, its long-term neurodevelopmental impact is poorly defined. We sought to delineate the potential role of cerebellar hemorrhagic injury in the long-term disabilities of survivors of prematurity.

DESIGN. We compared neurodevelopmental outcome in 3 groups of premature infants (N = 86; 35 isolated cerebellar hemorrhagic injury, 35 age-matched controls, 16 cerebellar hemorrhagic injury plus supratentorial parenchymal injury). Subjects underwent formal neurologic examinations and a battery of standardized developmental, functional, and behavioral evaluations (mean age: 32.1 ± 11.1 months). Autism-screening questionnaires were completed.


RESULTS. Neurologic abnormalities were present in 66% of the isolated cerebellar hemorrhagic injury cases compared with 5% of the infants in the control group. Infants with isolated cerebellar hemorrhagic injury versus controls had significantly lower mean scores on all tested measures, including severe motor disabilities (48% vs 0%), expressive language (42% vs 0%), delayed receptive language (37% vs 0%), and cognitive deficits (40% vs 0%). Isolated cerebellar hemorrhagic injury was significantly associated with severe functional limitations in day-to-day activities. Significant differences were noted between cases of cerebellar hemorrhagic injury versus controls on autism screeners (37% vs 0%) and internalizing behavioral problems (34% vs 9%). Global developmental, functional, and social-behavioral deficits were more common and profound in preterm infants with injury to the vermis. Preterm infants with cerebellar hemorrhagic injury and supratentorial parenchymal injury were not at overall greater risk for neurodevelopmental disabilities, although neuromotor impairment was more severe.


CONCLUSIONS. Cerebellar hemorrhagic injury in preterm infants is associated with a high prevalence of long-term pervasive neurodevelopment disabilities and may play an important and underrecognized role in the cognitive, learning, and behavioral dysfunction known to affect survivors.

27 comments:

Anonymous said...

This would be one of those - "DUH" studies, right?

Anonymous said...

what's the point of this? so, if your preemie has a bleed in the first few days of life you are supposed to...
A) discontinue life support
B) become depressed b/c studies show you *might* be raising a special needs child
C) nothing

I'll go with C.

About Time said...

It's about time studies like this were done and published. They help back up what many preemie parents have been noticing for a long time, yet were often dismissed by some medical and educational professionals. As for what to do about it, these studies should help improve NICU treatments as well as future long-term treatments and education. They can also help prevent "frustration" and "depression" of parents who now may have closure about what caused their preemie to be so different. Duh! It isn't parental uptightness after all! It isn't genetic! It isn't caused by something the mom did or didn't due during pregnancy, giving her long-term "my-fault" feelings. It's a preemie thing after all!

Helen Harrison said...

It *sure* is about time!

Anyone who has spent any time at all on "preemie-list" and "preemie-child" can testify to the constant stream of new autism diagnoses.

Meanwhile, doctors and the public have been expressing alarm at the "mysterious" new epidemic of autism! (an increase that has occurred exactly in tandem with increased preemie survival)

Some of us put "two and two together" long ago -- a cursory review of the large, long-standing psychiatric literature on prematurity and schizophrenia/autism should have been sufficient...But now even the *neonatologists* cannot claim ignorance.

More importantly, the public should be informed.

There is an autism cover story, I am told, on the most recent "People" magazine. Apparently one of the children featured is a twin (a preemie?)

Those of us with autistic preemies should be writing in to publications like these, citing the _Pediatrics_ article (among many, many others!) to help the world understand where a huge part of the new autism epidemic is coming from.

I have been writing such letters since the mid-1990s. Sometimes they even get published.

If you are on autism boards or lists, write to them about this -- get the word out!!!!

Write to the CDC (I have). They'll be happy to hear from you!

[And if your child was born at term after a high-risk pregnancy in which you received prenatal steroids and/or tocolytics you might also want to write in...]

daedalus2u said...

What bleeds do is put hemoglobin in the CSF, where is lowers NO levels.

I was just at a nitrite conference at NIH, where nitrite was talked about as treatments for many things,

http://www.strategicresults.com/nitrite2/agenda.html

including preventing vasospasm from cerebral hemorrhage.

http://jama.ama-assn.org/cgi/content/full/293/12/1477

Anonymous said...

How exactly do they determine if there has been cerebellar injury? Is it automatically assumed that it occurs with a certain level of IVH? Is it something they routinely scan for? My child had Grade III bleeds, and enlarged ventricles, but has never had any diagnostics beyond NICU cranial US.

Kassie

Helen Harrison said...

To Kassie who aked:

"How exactly do they determine if there has been cerebellar injury? Is it automatically assumed that it occurs with a certain level of IVH? Is it something they routinely scan for? My child had Grade III bleeds, and enlarged ventricles, but has never had any diagnostics beyond NICU cranial US. "
***
Ultrasounds in the NICU were used to see damage in the cerebellum in this study, but they were later confirmed with MRI.

From my understanding, almost any child who has had an IVH has probably had something similar happen to the cerebellum.

To do an ultrasound of the cerebellum, the scanners need to look at "the "mastoid view of the posterior fossa."

The scans in the study were done this way, but this is probably not routine in NICUs.

Also, it is probably the case (as it is with ultrasound-dxed periventricular bleeds and PVL), that only the very worst damage is being doumented by ultrasound.

The authors of this study discuss the strong possibility that "smaller cerebellar lesions were missed by ultrasound."

I think this study, as important as it is, may only be looking at the tip of the iceberg of cerebellar damage/autism.

Careful MRIs, focused on the cerebellum, are needed.

Helen Harrison said...

To daedalus who said:

What bleeds do is put hemoglobin in the CSF, where is lowers NO levels.

I was just at a nitrite conference at NIH, where nitrite was talked about as treatments for many things,

http://www.strategicresults.com/nitrite2/agenda.html

including preventing vasospasm from cerebral hemorrhage.

http://jama.ama-assn.org/cgi/content/full/293/12/1477
***

If neonatology can figure out how to control vasospasm, hemoglobin where it shouldn't be, and the other results of inappropriate bleeding (something that worries me personally, as a golden ager)...then a medical golden age will be upon us...

I truly hope your microbes offer a clue/cure for all of this! More about this later...

Nancy Brown said...

I guess I wanted to say.. DUH.. of course it's going to happen. I think because of my degree I knew I was facing defecits. I also saw that shunting him made him a little better off than others. I realize when school starts we are in for a whole new ball game. Thanks for the article.

And to the first anonymous.. It is up to the parents. We who have done the severe brain bleeds were given much hope and much discouragement. Who knows what will actually happen... and you know ... some will chose all of those at some point. Let us make that choice for our lives.

Long Term Listener said...

When we see these outcomes and we can see the road ahead, honestly and truly, we really need to be sorting out decreasing the amount of premature births, hitting hard the major of causes of prem births where ever it is possible. We need to get mums good ante natal care that keeps them as well as possible for as long as possible.

There will always be prem births- nature always wins but I am saddened to see, not in this post , but in general that people really are accepting it as almost usual.

It is utter madness sometimes.

daedalus2u said...

I think that vasospasm occurs when the normal control system for vascular tension gets out of range, or rather in a different control range. Normally that system is controlled by NO. When you get bleeding in "the wild", vasospasm and constriction of blood vessels where there is extravascular hemoglobin is a "feature", that slows additional bleeding. A very important survival feature in "the wild", where there is no source of replacement blood, and stopping blood loss is more important than preventing cellular damage where there is extravascular hemoglobin.

I very much agree with Long Term Listener. I think that the problem of premature birth is primarily a low NO problem. I see it as a normal physiological response to low NO. Low NO mimics the physiology of metabolic stress, mimicking the metabolic stress of starvation. Under sufficient metabolic stress, a woman can't sustain her pregnancy, nurse her infant and provide sufficient food until that infant is self-sustaining. If the chain of infant support breaks before the child becomes self-sustaining the child will die. Under such circumstances, the evolved response is to break the chain as soon as possible and start over when times are better. I discuss this at length in my blog on postpartum psychosis, which I see as an evolved "feature" to deal with metabolic stress.

terri w/2 said...

Long Time Listener said: "It is utter madness sometimes" -

YES, it is!

I find the utter madness in that fact that we have a generation of micro preemies now - a GENERATION of children who were born at 23 weeks and higher who are struggling and suffering as a result of their preterm births, and STILL there has to be these studies that say - gosh, preemies with IVH's may have some on-going neuro damage that affects their life? C'mon. Do neos really have their heads buried in the sand THAT far? It's a stroke people!

The Preemie Experiment said...

Anonymous (8:17am) wrote: "what's the point of this? so, if your preemie has a bleed in the first few days of life you are supposed to...
A) discontinue life support
B) become depressed b/c studies show you *might* be raising a special needs child
C) nothing"

Anonymous, keeping information from parents because they *may* become depressed? I'd rather know it all. He/she is MY baby. I deserve, in order to give the best care possible, to know ALL of the facts.

If a parent does not want to know, they can ignore what they have heard.

There is also another option.

D) Tuck the info away in my mind so I may better understand my child in the future.

The Preemie Experiment said...

about time said: "They (the studies) can also help prevent "frustration" and "depression" of parents who now may have closure about what caused their preemie to be so different."

Absolutely!

The Preemie Experiment said...

Helen Harrison said...
It *sure* is about time!

Anyone who has spent any time at all on "preemie-list" and "preemie-child" can testify to the constant stream of new autism diagnoses."

You are so right Helen. We see it all of the time on the preemie boards, especially the ones for older preemies. People join, state the reasons they feel their child is different and then the parents of older preemies chime in about autism and how the new parent should investigate. A few weeks later comes the update from the new parent about their new autism diagnosis!

Over and over again. Year after year.

The Preemie Experiment said...

daedalus2u... nice to see you again. Thanks for the links. I will be checking them out as soon as I have a free moment.

Since I am sure some of it will be over my head, maybe you could elaborate on your blog??

The Preemie Experiment said...

long term listener wrote: "There will always be prem births- nature always wins but I am saddened to see, not in this post , but in general that people really are accepting it as almost usual."

This has been true for quite a long time now. The misconception that preemies are just tiny versions of full term babies, and the willingness of the media to promote the misconception has led to such wide acceptance by the public.

I want to scream everytime I hear someone say, "Oh, my cousins neighbor has a friend who was one pound at birth. He's 40 now and he's fine."

Long Term Listener said...

I think what adds to the madness is the number of eggs implanted in assisted reproduction. Do women who are planning assisted repro get to see the possibility of what may be? What might lie ahead for their lives?

Helen Harrison said...

Anyone who would like to see the entire Pediatrics article on cerebellar damage and autism can contact me at Helen1144@aol.com.

I have been going through the references cited in the study and found several of great interest, one of which appears to be avialable for free.

It is "Messerschimdt A et al, Disruption of cerebellar development: potential complication of extreme prematurity" AJNR Am J Neuroradiol 2005;26:1659-1667.

According to these researchers who have been studying patterns of brain development in preemies <30 weeks g.a. at birth, cerebellar abnormality is common in preemies and is not necessarily directly attributable to cerebellar hemorrhage alone.

In other words, you don't need a a bleed in the cerebellum to get cerebellar damage/abnormality, or, perhaps, autism.

Instead, it seems that bleeding elsewhere in the brain (like IVH)may lead to hemosiderin deposits (a breakdown product of blood)on the cerebellum that can interfere with neuronal development at a crucial time.

Also exposure to pain seems capable of causing such damage.

The damage may not begin to be visible until months after birth, suggesting these and other facets of prematurity and its treatments set up conditions for later abnormal development.

Here are some quotes from this article:

"Because cerebellar pathologies similar to what we found are not observed in children born after the 32nd gestational week, the disruption may be related to developmental steps that take place in the growing cerebellum at 24 - 32 weeks gestational weeks...Disruption of these fundamental steps of cerebellar developmental has devastating consequences.

During this period, selective vulnerability to damage is also due to regulatory alterations of excitotoxic and apoptopic[cell self-destruction] mechanisms, with high susceptibility to any disturbance. Inordinate activation of afferent pain pathways and hemosiderin deposits may ... affect immature neurons with preexisting apoptotic tendency [presumably causing these neurons to die]."

C & V said...

I like the question about what are we supposed to do with this information. Four options were mentioned, 3 by anonymous and 1 by Stacy. Helen names another option, getting the word out, writing to the Journals and the MOD and the newspapers that carry the stories. Terri w2 embraces a similar activism.

I think you do many things with this information over time: you use it to understand and accomodate your child, as Stacy has said. You refer back to it so that you can understand your own grief or guilt. You tell teachers and therapists about this information so that they can understand what areas of the brain, so that they can make their diagnoses faster and fine-tune their therapeutic efforts with our kids.

We can use this information to call medicine (and more specifically, neonatology) into accountability. If we teach ourselves to understand the brain structures, the cellular effects of NO, the diagnoistic tools, and learn the medicalese, we can talk back directly to the docs. . . . telling them to stop the madness.

We can decide what we would do if there was ever a next-time, antoher preemie birth for ourselves or for our nieces, or daughters.

We can live relatively at peace with our kids and their issues. It is not their fault and it is not our fault.

Hopefully, having this information teaches tolerance.

Chris and Vic

Anonymous said...

I've also read many studies that say that simply being born via vaginal delivery can cause brain bleeding. This was the norm until recently.

Personally I take information like this and tuck it away. I get sad for a moment and then realize that despite that my child WILL go on to do great things... just like millions of others that have suffered brain bleeds.

Being 'disabled' is not the end of the world - as a matter of fact it can be the door to a whole other world that can be even more enriching... you just have to be open to learning.

Helen Harrison said...

To anonymous who said "I've also read many studies that say that simply being born via vaginal delivery can cause brain bleeding. This was the norm until recently.

Personally I take information like this and tuck it away. I get sad for a moment and then realize that despite that my child WILL go on to do great things... just like millions of others that have suffered brain bleeds."
***

Clearly normal bleeding from normal vaginal delivery (which has occurred from time immemorial) hasn't been a part of the recent dramatic upsurge in autism.

What is happening to preemies (below 32 weeks, at a point of huge cerebellar vulnerability) might be.

At any rate, for a new parent of a preemie, this information is of little immediate benefit. Just tuck it away.

But for those of us further down the line, it explains a lot, and may give us access to diagnoses, acknowledgement, and, perhaps,even to help, that we haven't had before.

The Preemie Experiment said...

Chris,

So very well said!

Stacy

The Preemie Experiment said...

Helen Harrison wrote: "According to these researchers who have been studying patterns of brain development in preemies <30 weeks g.a. at birth, cerebellar abnormality is common in preemies and is not necessarily directly attributable to cerebellar hemorrhage alone.

In other words, you don't need a a bleed in the cerebellum to get cerebellar damage/abnormality, or, perhaps, autism."

Very interesting Helen. I've always suspected that something was being missed. Paige did not have any bleeds (has had many MRI's over the years) yet has issues common among kids with bleeds. She is not alone either. I've heard from other parents on preemie child in the same situation.

Helen Harrison said...

To TPE:

I think when the autism puzzle is unraveled it will turn out to be much more than "bleeds" and will involve more than just the cerebellum, although abnormalities of the cerebellum, particularly the vermix, are pretty clearly involved with severe autism.

I think the basic cause, however, is simply the exposure of the developing brain (before 30-32 weeks) to a variety of painful stimuli, drugs, infections, and blood pressure/chemical shifts) that derail the proper formation of the brain throughout, permanently interfering with proper myelination, neuronal migration, etc.

I previously mentioned on your blog a study by Skranes et al. "Clinical findings and white matter abnormalities seen on diffusion tensor imaging in adolescents with very low birth weight." _Brain_2007;130:654-666.

In this study, adolescents who had been born prematurely (before 32 weeks) were scanned with MRI and compared to term-born peers. The MRI findings were then correlated with scores on, among other things, tests for autism. Damage to white matter tracts in the external capsule and superior fasciculus was common among the preemies and was correlated with high autism spectrum scores.

(MRIs of non-preemie autistic adolescents in other studies show similar findings.)

Hannah's Mum said...

I was so pleased (as much as one can be about these things) when I got a hold of thi study.

As a Mum with an aspie daughter I have been searching for information linking her autism to her prematuirty. This study validated some of my concerns, and raised a few more questions. I'm going to push for some more in-depth neurological scans to see the extent of any damage that may have been done (PVL etc).

I think the valute of this study is enormous. Not so that we can discontinue life suport or become depressed, but so that parents are more aware of what may lie ahead.
If these studies continue to be published, and are taken seriously, eventually the neo's who tell us "she'll be caught up by 2" won't be able to say that anymore. Parents won't be living with the false hope that so many of us were given and were crushed by when our kids didn't turn out to be what society considers 'normal'.

One of my friends just gave birth to a 25 weeker. He's just come home from hospital and is a beautiful baby. He'll be caught up by 2, they've been told, maybe 3 at the latest. Without solid studies to back me up, how can I tell them that it probably won't happen. How can I tell them that their new baby will most likely have a learning disability, or a behavioural disorder, or autism, or a mental illness? The odds are more for than against at 25 weeks...

Parents need to be more informed, and these studies are providing answers and will hopefully, eventually, bring change.

Anonymous said...

Hannah's Mum wrote:

One of my friends just gave birth to a 25 weeker. He's just come home from hospital and is a beautiful baby. He'll be caught up by 2, they've been told, maybe 3 at the latest. Without solid studies to back me up, how can I tell them that it probably won't happen. How can I tell them that their new baby will most likely have a learning disability, or a behavioural disorder, or autism, or a mental illness? The odds are more for than against at 25 weeks...

Why "tell" them? Rejoice with them on their beautiful baby, give them time to breath, time to heal. Be there for them - both now in their happiness and relief, and later if indeed the child does begin to show long term effects. You are in a perfect position to provide support. You have been there, and you know all too well what *might* still be ahead of them. Just as all full term infants are not garunteed smooth sailing, ALL preemies are not garunteed a lifetime of disability.