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Opinion / Q&A

Questions for Eric London: Alternative diagnoses for autism

by  /  2 January 2015
The Expert:
Expert

Deep dive: Listing detailed symptoms rather than assigning a single diagnostic label may be a better way to understand neurodevelopmental disorders. ImageZoo Illustration/Veer

The long process of diagnosing a disorder culminates in a name — a single word, or perhaps a few, that sum up a person’s particular set of symptoms. This name suggests that doctors know what’s wrong and may have treatments that could help.

But in the case of neurodevelopmental disorders, a name may be a distraction, says Eric London, head of the Autism Treatment Research Laboratory at the New York State Institute for Basic Research in Developmental Disabilities.

In an editorial published in December in Trends in Neuroscience, London argues that names such as autism, schizophrenia and intellectual disability are ‘umbrella’ terms that muddy the search for the true causes of various symptoms1. He calls for researchers to come up with an alternative.

Giving loosely linked disorders different names negates their similarities and ignores important symptoms that may not be part of the ‘core’ diagnosis, London says. Instead, he proposes that researchers note only whether or not a person has a neurodevelopmental disorder and proceed to carefully document their symptoms, or phenotype.

This idea has precedent. In 2013, the National Institute of Mental Health proposed an alternative to the widely used Diagnostic and Statistical Manual of Mental Disorders. Dubbed RDoC for ‘Research Domain Criteria,’ the new system encourages researchers to study domains of function, such as language, that may vary across all neurodevelopmental disorders.

Some researchers have also suggested that children younger than 6 with developmental symptoms be grouped into one large diagnostic category until their trajectory becomes clearer with age.

We spoke with London to learn more about his vision for the diagnosis of autism and how he hopes to make it a reality.


SFARI.org: How is autism diagnosed now?

Eric London: It’s diagnosed according to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The DSM is very good for reliability, so I’m sure that it’s being diagnosed very reliably around the world. My problem is that I don’t think this system is valid.

It would be great if categorical diagnosis worked, but it doesn’t. For the first 20 to 30 years of my career I was very hopeful, but I can’t continue to justify it now. I was at a meeting in 1995 with Francis Collins, director of the National Institutes of Health, and he said if you get 200 individuals with autism and their unaffected siblings, we’ll crack the genetics of autism. It hasn’t panned out. Maybe it’s not panning out because we’re not handling the phenotype correctly.


S: When you say we’re not handling the phenotype correctly, do you mean we’re missing some symptoms?

E.L.: Yes.Take motor deficits, for example. Because the categorical diagnosis of autism doesn’t include motor deficits — except, of course, for repetitive behaviors — investigators tend not to look for them. It’s a rather small literature, but it’s a rather positive literature in the sense that people are finding very, very interesting findings. Yet on some level it’s been problematic. You almost have to disguise your research as ‘not autism’ because motor deficits are not part of the description of autism.

Eric London

When someone wants to study the motor issues in autism, they still have to use autism as an inclusion or exclusion for the study. This knocks out all other motor issues that are not strictly autism, which may in fact be very important to understanding what these motor deficits are.

For example, it’s likely that motor symptoms are significant in the development of language. There are lots and lots of people who are not considered autistic but who have severe language difficulties. The mechanisms for their language deficit may be similar to what we’re interested in for autism, but we cut it off artificially.


S: What do you suggest as a solution?

E.L.: I believe that we should be looking at brain development as the problem. Developmental brain disorder would be the diagnosis. People would use different words for this, of course. And then we would endeavor, without prejudice and without a theory behind it, to describe what their symptoms are.

I would like to create a multi-tiered medical record. Underneath the same general diagnosis would be a level of description that would be appropriate to primary care. The primary care person might document that a person has intellectual disability or problems with fine-motor coordination. But then the medical record would link to a more sophisticated level where people could look at any one of these symptoms and try to further subdivide it.


S: Can you give an example of these subdivisions?

E.L.: Take social difficulties as an example. Where in development might social difficulties originate? There could be multiple etiologies for it: It could be genetic, it could be environmental or a combination of the two. And there may be multiple pathways leading to social deficits.

Saying that ‘social deficits’ is the symptom is a problem. We’re actually including many different symptoms under this same big umbrella. For example, we have social anxiety, we have lack of social cognition, we have a lack of social interest — all of these may have different origins, but they all lead to the same endpoint.

We need to subdivide autism symptoms into their components. It’s not that people aren’t doing this now, but by revising our overall concept we’ll actually encourage people to do it. Now people almost have to do it in spite of themselves.


S: Do you then recommend treatments tailored for a symptom, rather than for autism as a whole? And do you think the U.S. Food and Drug Administration (FDA) would allow that in clinical trials?

E.L.: Absolutely. I once held a meeting and invited a couple of representatives from the FDA. This question  — would you entertain treatment for components — came up. Their answer was, “Yes, we would, but it has to be the consensus of the field.” The FDA doesn’t want to create the science. They want the field to create the science for them and they’ll enforce whether we’re conforming to best practices. So we’re the ones who have to tell the FDA.


S: How can this vision become a reality?

E.L.: I think the first step is to write articles like the one I wrote to get the dialogue going. I’ve been happily surprised by how many people have contacted me saying, “I agree with you.” I do believe that a significant number of people agree with what I wrote, including people from the National Institute of Mental Health.

But it’s also a sad fact that orthodoxies die slowly, and science — which should be evidence-driven — tends to be as conservative as anything else. I think we need this dialogue to come front and center.

The next thing we need to do is to come up with a substitute for the DSM. Researchers have created an alternative diagnostic schema for personality disorders, for example. Enough prominent people in that field were in such violent disagreement with the DSM’s conclusions that they came up with an alternative.

What I’m hoping to do over the next couple of years is to come up with an alternative schema for developmental disabilities. I’d like to convene people who are interested, say, in motor functioning and developmental disabilities, to create a template — one for primary care and one for more sophisticated analysis.

I welcome people who may want to work on this to contact me. I’d be really happy just to be a catalyst for this to happen.


S: What’s your next step?

E.L.: I would want to write a similar article, but from a clinical point of view. This is not just a research issue. If a diagnosis is not a valid representation of nature, it’s also not helpful clinically. We have classes and clinics that specialize in autism. But autism is so broad that it would be more appropriate to focus treatment programs on the problems and not on the diagnosis.

Also, the diagnosis has tended to make people feel that we know what’s going on, and it has discouraged people from doing an appropriate amount of assessment. Diagnosis is a very special thing; it actually reduces the amount of information physicians need and gives them a shorthand for what they’re dealing with. It was never supposed to be used as an in-depth sophisticated phenotype, but I think we’ve lost this understanding: Don’t use the diagnosis when you’re doing neuroscience work.

References:

1: London E.B. Trends Neurosci. 37, 683-686 (2014) PubMed


  • Seth Bittker

    I completely agree with Dr. London that “umbrella” terms like autism can be used to over-simplify and I commend him for initiating a dialog on this. Relatedly once a diagnosis of autism is made, it is typically not seen as an opportunity for further investigation of cause. This is a tragedy in my view. Dr. London’s proposed solution of further categorizations based on the details of types of deficits or behaviors is only marginally better than the current coarser categorization based on behavior alone.
    The question should be what will lead to a better understanding of cause and treatment for each person affected? Take the example of motor deficits. If we say two people have severe motor deficits and group them together eventually somebody will think to try a common treatment on them. However, the dysfunction in the two may have very different causes and as such each may need a very different treatment. One may have a severe functional deficit of carnitine due to mitochondrial disorder and the other may have a functional deficit of cobalamin due to an issue with absorption.
    What should we do instead? I propose that the labels we use should be more objective and they should be based on biochemistry where possible. Specifically every child with autism of an unknown cause should be given an organic acid test and we should categorize based on the biochemistry as revealed by such a test. We know from past studies that the majority of those with autism have biochemistry that is quite different from controls. See http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0112445. In addition in some cases organic acid tests on those with autism have revealed avenues for obvious treatments such as biotin, a ketogenic diet, or carnitine. For the first two see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871708/.
    So for example, here are some categorizations one might use:
    1) Autism associated with valeric acid elevations with some amelioration with a ketogenic diet.
    2) Autism associated with beta-hydroxybutyrate with some amelioration with a ketogenic diet.
    3) Autism associated with elevations in 8-Hydroxy-2’-deoxyguanosine with some amelioration with vitamin C.
    4) Autism associated with elevations in methylmalonate with no amelioration in dysfunction with cobalamin.
    5) Autism associated with elevations in the lactate to pyruvate ratio with no amelioration with carnitine.
    6) Autism associated with an elevation in 3-(3-hydroxyphenyl)-3-
    hydroxypropionic acid with no amelioration with probiotics.
    Some may object that there are those that fit the behavioral definition of autism who do not have unusual results on their organic acid tests. This is undoubtedly the case but existing evidence suggests that such individuals are a minority of those with autism, and in such a case additional tests should be run to look at what biochemistry is driving the dysfunction, which can also be used for categorization and treatment.
    I suggest if such an approach were taken we could come up with truly meaningful categories and more importantly better treatment options for those affected. In short we have been using a behavioral definition of autism which has led to behavioral treatments. Instead we should use biochemical definitions of autism to get to biochemical treatments.

    • Alain Couvier

      “This is a tragedy in my view. Dr. London’s proposed solution of further categorizations based on the details of types of deficits or behaviors is only marginally better than the current coarser categorization based on behavior alone.”

      I agree – in autism we have a whole person that brings to the table everything that person is and more. Key medical information as above will help us personalize clinical diagnosis, treatment and add to our knowledge base.

      There’s to much siloing or sand castle building in Autism research and it needs
      to change.

      The message is clear as an ASD parent and member of the ASD community get some multidisciplined teams working together for each other and for us

  • Stunned parent

    What a great interview! This is the first time in a very, very long time that I am hearing from an ‘expert in autism’ and thinking WOW this person really gets it. Come to think of it probably the first time ever 🙂

    I have long stopped paying attention to what ‘experts’ are saying about ‘autism’, as none of it basically made much sense, for reasons outlined above. I realised long ago that research and clinical practice that handles ‘autism’ as a single entity doesn’t hold much relevance for my particular child. I also realised that treatment trials that recruit subjects on the basis of their diagnosis of autism alone do not tell me anything, regardless of their outcome, about particular treatment being suitable or not for my son. I have found detailed case studies and reports (yes, including the dreaded ‘anecdotal’ ones) that list child’s history and individual symptoms much more helpful when deciding on specific treatments and therapies.

    THANK YOU Eric London for making so much sense. What a breath of fresh air!!

    Here is to hoping that researchers, clinicians, funders and regulators take up your challenge! (If they don’t, ‘autism’ science will spend the next 100 years chasing its tail, as it has been done so far)

  • Alain Couvier

    One of the most viable biological hypotheses that incorporates environment, maternal health and Autism is Maternal Immune Activation which was at the heart of many elegant research papers by the late and great Paul Patterson (CalTech).

    The simple version is that Professor Patterson and his team clearly evidenced that a bacterial or viral infection during key windows in pregnancy and thus a unborn child’s development resulted in atypical neurological and physiological pathways that down the track are eventually diagnosed as Autism.

    Patterson thought that MIA could be the driver of some 24% of ASD cases and other researchers both prior to and after Patterson’s work have applied this to a range of disorders including anxiety, depression, schizophrenia and Parkinson’s and Alzheimer’s.

    It raises to my mind some very interesting questions about a new axis of maternal health, fever /inflammation and outcome. It also underpins once again that we need to really look at the patient, understand their risk factors, their physiology, neurology and genetics and what co-occurring disorders they bring.

    Issac Kohane (Harvard) showed that ASD could be characterized by specific medical co-occurring disorders – most notably epilepsy, multisystem disorders (gastrointestinal diseases / infections) and psychiatric disorders.

    For instance if a child presented with a psychological profile of ASD and Intellectual Disability then there is a large body of evidence that suggests this may be seizure / epilepsy related and that’s what Kohane found – ASD (Epilepsy)Seizures present in 77.5% of individuals, Lowest proportion of Boys, High Rate of Intellectual Disability 60%.

    If you want to read more

    doi: 10.1002/dneu.22024. Epub 2012 Aug 23.
    Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism.

    doi: 10.1038/tp.2012.24.
    Effects of maternal immune activation on gene expression patterns in the fetal brain.

    doi: 10.1542/peds.2013-0819
    Comorbidity Clusters in Autism Spectrum Disorders: An Electronic Health Record Time-Series Analysis

  • Amanda

    I admire London’s candor.
    It is true to say that genetic research into ASD causation and prevention has been overall disappointing.
    I do not think we will find answers in genetic phenotyping either, however.
    Patterson, James and Herbert have laid the most promising groundwork re the enviro/ genetic causation context.
    That is the way forward.

  • usethebrainsgodgiveyou

    Dr. Dorothy Bishop wrote a post that addressed this somewhat.( http://deevybee.blogspot.co.uk/2010/12/whats-in-name.html ) I’ve never forgotten it, especially the table which was SO descriptive. Something on that order might have picked up my child’s severe learning disability. Gifted in all things but math…we ended up homeschooling rather than having him flunk out of high school because of it. It would be intensive testing, but it was educational testing (WIAT-III) that picked it up at age 18…a little too late for accommodation/specific teaching. We do our kids no favors by trying to shove them all into the autism box.

  • Jose A. Jarimba

    Dr. London, amazing work.

  • Martyn Matthews

    I’m with Eric London, we are barking up the wrong tree with lots of our autism research. Wouldn’t it be great if we spent even 50% of the money currently vested in researching causes of autism (which research has already found to be certainly not one disorder and as such cannot possibly ever have one cause)and re-focused it on finding efective treatments for the individual components. My PhD research for the last seven years (Don’t ask, have been doing it part time on top of manageing an ASD intervention service for 800 children a year!!) has been on the mental health of adults with ASD diagnoses and what has become increasingly evident to me over that time is the neurobiology of each individual has been compromised, with clusters of similarity, but still individual variations. Take problems with attention and concentration for example, in my research, those with severe ‘autism symptoms’ and severe ID all have major difficulties in this area. I’ve been looking at this from a symptom severity point of veiw, but neurobiological research would indicate that this is likely to have been caused by abnormalities in the orbitofrontal–amygdala circuit, meaning the individual in almost constanly in a fight or flight stat of arousal. We could diagnose this a comorbid ADHD under the DSM system, but that doesn’t really help the affected individuals. What could help is a treatment for orbitofrontal–amygdala circuit dysfunction, not a treatyment for ‘autism’ per se.Current psychiatric drugs or behavioural interventions are no where near being this targetted and as a result this group often ends up on large doses of anti-psychotics and SSRIs with little benefit other than some genereal reduction in agitation, but with side effects that can be worse than the original problem.

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