Dr. Leshner: I would like to turn to a discussion of the clinical problem and introduce Sarah Spence, who will serve as the session chair.
I would like to point out that we are on time. So, don’t feel any pressure, Dr. Spence, or speakers in this session.
Dr. Spence is staff clinician at NIMH, where she works in the Pediatrics and Developmental Neuropsychiatry Branch. Thank you.
Dr. Spence: Thank you, Dr. Leshner.
I think we may have one of the most difficult sessions to do, which is to introduce the clinical problem and do it in an hour and 20 minutes and no more. So, I am not going to spend a lot of time on the introduction. I think the most important thing to keep in mind during this session is that it is about what we know and what we need. It is about introducing the main issues to set the stage for a productive discussion later on today and getting a diverse audience, kind of onto a level playing field about what the issues are.
So, to start with the clinical problem, I am going to introduce my boss, Dr. Susan Swedo, the chief of the branch that I work in at the NIMH.
CLINICAL OVERVIEW:
HOW CAN THE CLINICAL MANIFESTATIONS OF AUTISM SHED LIGHT ON POTENTIAL ENVIRONMENTAL
ETIOLOGIES?2 Dr. Susan Swedo
Dr. Swedo: Since I only have 15 minutes today to describe all of autism to you and why we believe that the environment plays such a crucial role in this disorder, I’m going to be using videos to show you in a few seconds what it would take me a very long time to try to explain.
2Throughout Dr. Swedo’s presentation, she may refer to slides that can be found online at http://www.iom.edu/?id=42456.
Autism is characterized by two areas of deficit, deficits in social interactions and communication deficits. It is also defined by an excess of repetitive behaviors or fixated interests. Now, these fixated interests and repetitive behaviors are not usually present during the very earliest stages of the illness and increase in time as the child becomes older.
As we know, autism is a developmental disorder. By definition, symptoms must appear before age 3 years and affect development. The crucial thing is that the development affects the symptom expression and the symptom expression also affects development. Since this is a disorder of social communication, which is essential to all development-al interactions, autism can quickly take you very far off of your expected trajectory. Autism is one of several pervasive developmental disorders (PDDs), which are now commonly called the autism spectrum disorders.
I think that expanding the continuum to include all pervasive developmental disorders as “autism” is a bit confusing and dilutes the meaning of the term, so I am asking that we keep our focus today on those children who meet full criteria for autism.
Rett disorder is caused by a genetic mutation, which leads to symptoms very similar to autism and, in fact, until we knew what the gene was, girls with Rett disorder were included in the autism group.
Since the gene has been identified for Rett disorder, it is now considered to be separate from other autistic disorders. Similarly, childhood disin- tergrative disorder presents with symptoms of autism, except that the children don’t begin to regress and lose their skills until after age 3.
Here is an example of the social deficits in autism. One of the crucial components of social interactions is joint attention—being able to pay attention to things that are of interest to others. (Video shown of a child performing a task of joint attention.) Here you see a normal volunteer from our lab. His reward is a bunny and he is very clearly excited and he tries to share that excitement with the examiner.
Here is a 4-year-old girl with autism performing the same task. The bunny is behind the examiner again. You see the examiner saying “Look!
Is it a bunny?” but the child is oblivious, preoccupied with other thoughts. I am going to replay that section of the video and ask you to also watch the repetitive behaviors that she exhibits. Notice that the child pulls her hands into her sides. Then when she gets excited, there is a repetitive motion.
Another common social interaction is shared enjoyment. (Video shown.) The young child with typical development says, “Wow! Look at that!” when shown the bubble gun. He invites his mother to share in his enjoyment of the new toy before asking if he can have a turn operating it.
It is easy to see how excited he is by the toy. He uses gestures to make his needs known, as well as his verbal comments.
(Next video is shown.) Here is XXXX,3 a little boy of about the same age, with fairly severe autistic symptoms, presented with the same bubble task. He clearly sees the bubbles, is interested in them. The examiner gives him every cue she can to get him to ask for more bubbles, but he doesn’t. He just seems terribly confused and somewhat upset.
(Video segment.) Here is an example of an autistic child’s perseverative behaviors. You probably have heard about the autistic children who spin the wheels of the bus, rather than playing with the bus as it is intended. Here the pop-up toy has become an instant area of fixated interest for him. He isn’t playing with it as intended, but rather, chooses to repetitively open and shut one of the doors. The examiner is trying to get him to look over at the bunny. But he is not willing to attend to anything but the pop-up toy. Even when she gently takes the toy away, he remains fixated on the spot where it was sitting. So, this child demonstrates both deficits in social communications and an excess of repetitive behaviors.
The causes of autism that are known are mainly genetic. About 10 percent of children diagnosed with autism have been found to have a genetic cause. Less than 1 percent have been attributed to teratogens, such as valproic acid or thalidomide. That leaves about 90 percent of the kids, or 9 out of 10, for whom the cause is idiopathic, meaning we just don’t know. That does not mean that there is no known cause. It just means that the cause is not known.
When autism is related to a genetic defect, the pathogenesis is relatively “simple.” Even then, there is a great deal that happens between the genetic mutation and the manifestation of neuronal dysfunction and/or damage. But when something in the environment is causing the symptoms, it is even harder to make a direct link. But the working model is that environmental factors, in a genetically susceptible population, lead to neuronal dysfunction and/or damage and the symptoms of autism.
The tricky thing about that pathogenic model is the fact that it has so
3Out of respect to privacy for the family, the name of this individual has been replaced with “XXXX.”
many stages, each of which is actually broken down into many, many more steps. So, for the purposes of the conference, you are going to be hearing a lot about genetic mechanisms that might create vulnerabilities, about the environmental factors that trigger the symptom onset, and even though we’ll be addressing individual parts of the diagram, we need to keep the larger picture in mind at all times.
Potential environmental triggers that have been suggested are numerous. They include the toxicants, which will be discussed by Isaac Pessah; the infectious agents, which Ian Lipkin will be speaking to in a later session; and household exposures, such as household chemicals and cleaning products. The household exposures are one of the areas of study for the NIEHS-sponsored CHARGE (Childhood Autism Risks from Genetics and the Environment) study and the CDC-sponsored CADDRE studies (Centers for Autism and Developmental Disabilities Research and Epidemiology).
Food, dietary supplements, and vitamins and minerals may also be involved in autism. If you think about how we eat today, compared to how we ate in the 1950s, it is mind boggling how many changes there have been. Of particular interest have been changes in folic acid supplements, and the utilization of aspartame, because both have been associated with other neurologic conditions.
Additional environmental factors include drugs, medications, and herbal remedies. For example, as a pediatrician, I know that there was a dramatic change in the treatment of children with fever following the Reye’s syndrome epidemic. And practice guidelines required a switch from giving children aspirin following vaccinations to prescribing Tylenol and/or ibuprofen. We don’t know what the effect of that might have been, but it is certainly an area for investigation.
Other medical interventions that might play an etiologic role include the use of ultrasounds during pregnancy, and the administration of vaccines—not just the contents of those vaccines, but also the increasing number and the immunologic challenges that are faced by our children today, in comparison with previous generations.
Technological advances include the ultrasounds, but also microwave ovens, cell phones, and everything else. So, you really end up with an overwhelming array of environmental factors to consider because in essence, everything encountered by the mom, the dad, and the child could be a potential environmental trigger.
There are some clinical clues that suggest that the environment is
playing a role in the etiology of autism: first, the association with the teratogenic agents is a direct cause-and-effect relationship; second, the reported prevalence of autism is increasing at dramatic rates; and third, the fact that the symptoms frequently have their onset between 12 and 18 months of age (not at birth). I think this is the thing that the parents see as the most compelling evidence that there must have been an environmental trigger. They tell us, “My child was healthy and then he wasn’t”—something must have happened in between.
The change from typical development to autism certainly may have been the result of an environmental exposure, but we have to keep in mind the fact that many disorders that are genetically based do not present in the first year or even 2 years of life. Sickle cell disease is a prime example. In addition, there are disorders like Rett syndrome in which the girls are developing normally until about 12 to 15 months of age and then have a regression and lose their skills. So, I think that the age at onset of symptoms in autism is an important clue, but it isn’t evidence on its own.
Medical comorbidities may also provide information about environmental factors in autism. For example, within the past few years, there has been increasing attention to the link between autism and immune dysfunction that suggests a common environmental exposure is increasing prevalence rates for both autism and autoimmune disorders.
We will hear more about that during this workshop as well.
A request has been made that we start paying attention to the response to treatments that are being given to these children in order to find clues to the original etiology of symptoms. Many parents and practitioners are finding that symptoms can be dramatically improved or eliminated by a variety of biological and dietary interventions. At the NIH, we are attempting to do systematic studies of some of the more commonly used treatments, because open-label trials and anecdotal reports of benefit can be very difficult to assess because the child is developing naturally during that same period of time.
The regressive subtype of autism is one of the most clinically compelling pieces of evidence for environmental triggers. The regressive subtype of autism is actually regressive “subtypes,” just as there are multiple autisms. For most children with regressive autism, they develop normally until about 12 to 30 months of age, when they begin to lose the language they have acquired and stop interacting socially. However, 12 to 30 months of age is a tremendous span in development, and suggests
that even within the regressive group, there is likely to be a significant amount of heterogeneity.
Fifteen to 50 percent of children with autism will have regressive features, depending on how narrowly you define “regression.” If you take the strictest definition, which requires that the child has at least 10 words and loses those, then the proportion is closer to 15 percent. To date, the prognosis for the regression group is reported to be particularly poor.
Of note is the fact that regression can be very acute. We have already seen children at the NIMH clinic who were developing normally, became ill, and within a few weeks had lost all of their verbal and social skills.
For most children, the process is slower and subtler; it is a painstaking process to find out how they were developing at each developmental phase and to begin to pinpoint the area at which the regression occurred.
The final caveat in consideration of the regressive autism subtype is work from Dr. Geraldine Dawson and her colleagues at the University of Washington which shows that for many of the children, development wasn’t completely normal before the regression occurred, but there is still a very obvious loss of acquired skills. Here is an example of a little girl who had a clear regression. She is the one that you saw with the self- stimulatory behaviors and the lack of attention. Here she is at 6 months of age. Her dad calls her name, and she gets a huge smile. Here she is at her 1-year birthday party. Again, her father calls her name, and see if you can tell when he says it. You can’t, can you? So, she had already lost attention to her name. By the time she is a year and a half, he is shouting her name repeatedly, and she is completely oblivious to his presence. She had also lost words during this period. As you can see in the videos, the regression is profound. The family describes it as having their daughter
“stolen” from them by the autism. I think that is a superb description to keep in mind of the regressive subtype. The child is developing on an expected trajectory and then falls off completely.
Certainly in regressive autism, the hunt for the environmental trigger should take prominence, but how do we trace back from the clinical picture to that environmental trigger? As I said earlier, it is complex.
Each of these cartoon boxes has multiple stages, multiple phases, and multiple levels to be investigated—it is a huge task, but it isn’t hopeless.
I was asked to tell you what I think we need to do to find these environmental factors. First, we need a standardized definition of autism and related disorders. We really need to be dealing with as clinically
homogeneous a group as possible, because within that homogeneous group, we are going to find biological heterogeneity. We already know this from all of the other medical disorders of childhood, and particularly from Type 1 diabetes and leukemia, where knowing exactly what the clinical picture looked like helped us to get to the pathophysiology.
We need brain pathology. As we had our planning conference calls, it became very clear that until we know what is happening in the brain, there is not much point in trying to figure out when or where the trigger occurred.
It would be helpful to have incidence data from populations with disparate risk factors. If we could look at developing nations and their rates of autism, we might be able to find clues to environmental triggers here in the United States and elsewhere in the industrial world. In order for such studies to be meaningful, however, we need to use the same diagnostic criteria for each time and place. It is very clear from work being done by international epidemiologists that if you change the diagnostic cut-off scores by just one point, the prevalence rates change dramatically. Obviously, the same thing would be true for the incidence data and would complicate any international comparisons.
We need systematic evaluation of anecdotal case reports as we already know from genetic disorders that it is the exception that ends up proving the rule. So, we need to start looking for those exceptions and studying them in depth. At the same time, we need to be doing randomized control led trials of novel therapeutics, using reliable, valid, developmentally appropriate and change-sensitive outcome measures—
such measures still need to be developed. And finally, we need identification of clinically meaningful subtypes, perhaps by identifying unique ages of onset, similarities of clinical presentations or associated symptoms, or by identifying a group with similar developmental or clinical trajectories.
Since I am out of time, I will stop and take questions.
Dr. Spence: So, the next 2 or 3 minutes we can use for questions directly related to Dr. Swedo’s talk or else we can move on.
Dr. Swedo: Since there don’t appear to be any questions, I am going to spend the next 3 minutes talking about PANDAS (Pediatric Autoim- mune Neuropsychiatric Disorders Associated with Streptococcal infect- ions) and how we at the NIMH were able to use clinically meaningful subtypes of obsessive-compulsive disorder (OCD) to go from the unique clinical presentation to the environmental trigger, and meaningful
treatment and prevention strategies in a relatively short period of time.
Our hope is that we will be able to find a similarly informative subgroup of children with autism.
The PANDAS subgroup differs from other children with OCD in that it has a very abrupt onset and an episodic course, in which there are periods of both relapse and remission. Boys predominate in this young population of children. When the children are acutely ill, they have developmental regression, social isolation and aggressiveness, emotional lability, sensory defensiveness, sleep difficulties, and choreiform movements. The symptoms are found in many children with autism, as well as in Sydenham’s chorea, which is the neurologic manifestation of rheumatic fever. The association between obsessive-compulsive disorder and Sydenham’s chorea is what led us to suspect that strep bacteria might be the environmental trigger for the abrupt-onset form of obsessive- compulsive disorder. A decade of research suggested that the presence of untreated strep bacteria in a genetically susceptible host could cause an abnormal immune response and lead to clinical manifestations of obsessive-compulsive disorders and tics. We already knew that only a few of the 120 strains of strep were capable of producing rheumatic fever, and that not all children were susceptible to the poststrep complications. In fact, only about 1 in 20 families was susceptible to rheumatic fever. It seemed like a difficult model to investigate—not all strep infections could cause symptoms and not all children would be affected, so there would be many false starts and dead ends.
However, by starting with this model, we were able to borrow from the experience with rheumatic fever eradication, and conducted a controlled trial of antibiotic prophylaxis that showed beautifully that preventing strep infections was capable of preventing neuropsychiatric symptom exacerbations. By giving antibiotics to prevent strep, we were preventing episodes of OCD and tics. The slide shows the results of the trial for the first 10 patients—on the left side of the red line is the year prior to study entry and on the right side is the year of antibiotic administration; just visually scanning the data, you can see that there are fewer symptomatic months (represented by the bars) during the year of antibiotics administration. The summary data showed that the children went from having two strep infections on average per year to zero strep infections, and that they went from having 2.4 to 0.7 neuropsychiatric exacerbations during that same period. What isn’t shown here are the follow-up data demonstrating that continued antibiotic prophylaxis has