U-Turn: Down Syndrome Regression Disorder

An Interview with Dr. Jonathan Santoro and Dr. Eileen Quinn

Reprinted from 3.21: Canada’s Down Syndrome Magazine (Issue #18: Bridging the Knowledge Gap). Click here to download the full magazine.

This article is adapted from Season 6, Episode 2 of The LowDOWN: A Down Syndrome Podcast. Click here to listen to the full conversation and access related resources.

We don’t often have breaking news that causes a major stir in the Down syndrome research community, but Dr. Jonathan Santoro and Dr. Eileen Quinn have done just that with their cutting-edge research into Down syndrome regression disorder.

There has long been a recognized phenomenon in which some people with Down syndrome regress in certain areas, seemingly losing skills they had previously mastered. Reported incidences of regressive episodes, which happen at an earlier age than that at which early onset dementia typically becomes an issue, are on the rise, particularly since the COVID-19 pandemic.

As a result, regression in people with Down syndrome is currently receiving a great deal of attention in medical literature, and Drs. Santoro and Quinn are at the forefront of that work. Dr. Santoro is a pediatric neurologist with special training in inflammatory and demyelinating disorders of the brain, spinal cord, and peripheral nervous system. Dr. Quinn, whose younger brother Danny had Down syndrome, is a developmental pediatrician. She is also mom to a 25-year-old woman with Down syndrome.

Hina Mahmood and Marla Folden, hosts of The LowDOWN Podcast, recently sat down with Dr. Santoro and Dr. Quinn to learn more about Down syndrome regression disorder.

Hina: Can you please start by defining regression for us?

Dr. Quinn: Regression is just a loss of previously acquired skills. There are a number of different areas that people can have regression in. It can be in the activities of daily living; people’s ability to take care of themselves and wash and dress and that sort of thing. You can also have regression in language and communication, or in motor skills, memory, or behaviour.

Marla: Is regression inevitable in Down syndrome? Does everybody go through regression?

Dr. Santoro: Not necessarily. An important piece when it comes to regression is, when is it happening? In the first ten years of life, regression is often associated with autism spectrum disorder, whereas later on there seems to be this regressive phenomenon in the early teens in females, and right around the onset of puberty in our male patients. The term autistic regression has been used for a long time, but we know that autism doesn’t suddenly develop in the teen years. Meanwhile, regressions on the other end of the age spectrum are more related to Alzheimer’s disease. So, we are focused on this surprising phenomenon that cannot be attributed to either autism or Alzheimer’s.

Marla: When should a parent wonder if regression is happening?

Dr. Quinn: Any child can have good days and bad days. You think they’ve mastered something, and then suddenly they forget all the words that they used to be able to read. That kind of ebb and flow is pretty normal. I think the time to really be concerned is when there’s a substantial change that doesn’t get better in a week or two, especially if they start losing more skills and it really starts to affect their daily life and interfere with their ability to do the things that they used to do.

Dr. Santoro: I tell a lot of families, if your mom and dad radar is going off, that’s the time you should be contacting your doctor. There’s no set timeframe of ten days, seven days. You know when something’s off and those activities of daily living are just evaporating before your eyes.

Marla: We know that autism occurs more frequently in people with Down syndrome, but as you said, the signs of autism typically show up early in childhood (even if the actual diagnosis comes later). We don’t typically expect to see autism symptomology appearing for the first time in that 10-20 age range, so if you’re seeing a regression or a skill loss in this age group, it typically means something different. Is that what we call Down syndrome regression disorder?

Dr. Quinn: People with Down syndrome can have a milder degree of regression in many areas, and it’s important for families to be aware of the different medical conditions that can cause this. If people start to see a change in their child’s behaviour or their ability to do things, the first step is to make sure that they are up to date on all the recommended screenings, and consult with their physician about what might be causing the change. We know that things like hypothyroidism, sleep apnea, and other medical conditions that people with Down syndrome are predisposed to can cause changes.

People with Down syndrome, even if they’re verbal, may have difficulty expressing what’s going on. They might have trouble locating sources of pain or discomfort, and instead of telling you about it, you’ll notice a change in their behaviour or skill level. So, you want to screen for thyroid problems. Is he having symptoms of celiac disease? Is he up to date on his vision and hearing tests? You need to rule out these physical issues that can feed into changes in behaviour.

Dr. Santoro: Down syndrome regression disorder (DSRD) is really a diagnosis of exclusion. Our workup is not to diagnose DSRD; our workup is to rule out other explanations for it. What are the common things in persons with Down syndrome, and can we rule them out?

What makes DSRD unique is that symptom onset tends to be pretty quick. We go very quickly from high function to, oh boy, what’s going on? Why can’t you toilet independently? Why can’t you do all these other tasks that you’ve been able to do in the past? And it happens over the course of a few weeks. In our new consensus criteria that was just released last month, we used a 12-week guideline. It’s not the slow decline that we see in Alzheimer’s disease or autism spectrum disorder.

There are eight core features that we look at:

  1. Altered mental status or behavioural dysregulation: It can be things like confusion; it could be inappropriate laughter; it can be changes in eating habits: everything from anorexia and not wanting to eat and losing quite a bit of weight, to hyperphasia, just nonstop eating, and mom and dad have to lock the fridge.
  2. Cognitive decline: This can be things like apathy or an unwillingness to engage with family members and loved ones. A lot of patients will just kind of sit in their room and not do anything in the early stages of the condition. Often there can be either a memory impairment or decreased processing speed, where you’ll ask a question and you can tell the gears are turning, but there’s not really a response.
  3. Social withdrawal: This includes the inability to perform the activities of daily living, and increasing rigidity around routine. Having to leave the room may provoke tantrums or aggression. There may be a decrease in eye contact and engagement with others, and it may just seem like they’re not enjoying things. We’ve had many families say that their loved one is just kind of cruising through the motions, which is hard because so many of our young persons with Down syndrome are very animated, life-loving individuals. This is often the most dramatic change that brings people in for care.
  4. Focal neurologic issues: This could manifest as weakness, sensory changes, or seizures. If you see any of these things, you’ve got to take the express lane to get evaluated.
  5. Sleep problems: We see quite a bit of insomnia and circadian rhythm disruption. Insomnia often surfaces very early in the disease process; people will just stop sleeping or drop down to two hours of sleep a night.
  6. Language deficits: It can start as whispered speech, and then progress to decreased verbal output. In many situations, it will go on to full mutism and not being able to communicate at all, and it crosses domains: not just expressive language but also their ability to point, gesture, or sign.
  7. Psychiatric symptoms: We’ll see anxiety, depression, a lot of OCD. And not the type of OCD where they have to touch the doorknob 50 times before they leave the house, or hyper cleanliness. It’s really about rigidity and having thoughts that are just trapped in this circuit. Very often there’s a fixation. Sometimes it’ll be on a Disney movie or a particular show that they like, but because it’s such a repetitive loop, they’re almost in that other world, as opposed to the world that they’re actively surrounded by.
  8. Movement disorder: Often this will be catatonia; we see this in about three quarters of our patients. We’ll see slowed movement – it almost looks like somebody who has Parkinsons; they’ll just kind of shuffle along the hallway floor. We’ll see freezing behaviour: we’ll ask the person to take a turn, and they kind of clam up and they can’t actually initiate that.

That’s a lot of symptoms, but if you’re seeing more than two or three of them, that’s an indication that you should get your child in for evaluation.

Marla: That’s a hard list for families who are experiencing that. It must be very scary for families who are going through that.

Dr. Quinn: My daughter Sara had a full-blown regression 11 years ago. For us, and in my experience in speaking with other families I think this is common, the sum total of all those symptoms is that your child is gone. The child that I knew, who was the light of my life and made me laugh out loud every day, was just totally different. I even say it was like Sara died and I didn’t have time to mourn her because I had this belligerent stranger in my midst that I had to deal with. It can really be a very catastrophic thing to happen to families. I have families that say their life is divided into pre-regression and post-regression eras.

Hina: A lot of families first started noticing signs of regression during COVID. What are your thoughts on the impact that something like a pandemic can have in triggering regression?

Dr. Quinn: Well, we know people with Down syndrome like their routines. And the majority of them like to be social and they like to be out in the community. The pandemic was very difficult for many people, including those with Down syndrome. That type of stress on them might be the thing that kickstarts regression. As with many conditions, this could be a case where the person has a biological predisposition and then an environmental trigger makes it happen.

Dr. Santoro: To steal from psychiatry literature, the concept is called diathesis stress. You’re already predisposed to develop, let’s say this autoimmune disease or regression in general. And there’s just something that tips you over the edge. If you go into other neuroimmunology literature, this is quite frequently reported. So many patients, for instance, who have multiple sclerosis, their first attack will be preceded by some life stressor. And it’s not that the life stressor is causing their multiple sclerosis, it’s giving their body that final push off the cliff to actually develop the clinical symptoms.

Hina: How prevalent is Down syndrome regression disorder?

Dr. Santoro: I wish I could tell you. This is still the wild west. Historically, I think a lot of individuals with regression didn’t get the name. It was just labeled as early onset Alzheimer’s, or it was just seen as part of Down syndrome. Now that we’ve come up with formal terminology and developed an assessment tool to help physicians identify it, people are coming out of the woodwork saying they’ve had the symptoms for a long time and they just didn’t know what it was. It’s similar to what happened with autism in the early 2000’s: once we finally had a name for that condition, the rates of autism went up, so to speak. But in reality, we were only now able to actually capture these. I think that it’s still rare, but we really don’t know how many patients are out there with this.

Hina: Moving into treatment options, how can families help their loved ones?

Dr. Santoro: If all other causes are ruled out and the final diagnosis is DSRD, there are a variety of different therapeutics. It’s very symptom specific. As more patients have come over to our clinic, we have utilized all sorts of different treatment modalities. It’s often a matter of trying different things until we find something that works for the patient. It’s common for an individual to be on multiple different therapies at the same time to address various symptoms.

Hina: You’ve seen some very encouraging results. 50% of the people in your current cohort are regaining some of their lost skills. What are your thoughts on recovery?

Dr. Santoro: It’s variable. We’ve seen efficacy from as low as 10% improvement for some patients all the way to probably 95%. I think families are very hesitant to ever say one hundred percent, but we get many patients close. I would say our median is probably about 60-75% return to baseline. And that’s when we add on symptomatic treatments to see if we can push people a little bit closer to their prior functional statuses. The more research we do, the more these outcomes will improve.

Since this interview was conducted, an expert consensus paper on the now named Down Syndrome Regression Disorder has been published, along with another recent paper on the use of immunotherapy as a treatment option and related protocols. A multi-partner double blind study that is furthering the understanding of this disease and providing vital insights into treatments is currently in progress in the US. A closed Facebook group and public Facebook page (started and overseen by Dr. Quinn) provide support and information to families around the globe. If you are concerned that your loved one with Down syndrome is showing signs of regression, please speak with your physician.