Down Syndrome - 'Regression'

Often parents and other caregivers seek consultation from diagnosticians related to early onset dementia when an adult in his or her teens or 20s begins to show significant decline in function and behavior (such as mood changes), and cognition. The behavioral changes often manifest in changes in motor skills, unusual movements, changes in speech capabilities, and problems with oral intake.

As these symptoms often mimic those seen in adults with Down syndrome in their 50s or 60s, they are often misdiagnosed as related to Alzheimer's disease. 

 

Clinicians are now noting that this phenomenon in young adults with Down syndrome is not a form of early-onset Alzheimer's disease, but a heretofore previously undefined brain neuropathology. Generally, this condition has been termed a form of 'regression', but is now known clinically as 'Down syndrome disintegrative disorder' or DSDD -- among other terms. Core features include regression in adaptive function (such as changes in functional activities of daily living [ADLs], speech, and social skills), cognitive–executive function (such as functional skills, declarative memory, procedural memory, learning memory, planning/organizing, and attention), and motor control (such as stereotyped movements, extrapyramidal, initiation–motivation, and catatonia).

A working group of the American Down Syndrome Medical Interest Group (DSMIG-USA) was charged with examining the science and clinical aspects of this condition and in 2019 published an article in Genetics in Medicine. In its paper they refer to this condition via a clinically descriptive term -- “unexplained regression in Down syndrome” (URDS). Other groups have also explored this condition and some of their reports are noted below.

Resources
Unexplained regression in Down syndrome: 35 cases from an international Down syndrome database
Santoro, S.L., Cannon, S., Capone, G., Franklin, C., Hart, S.J., et al.
Genetics in Medicine, 2019, Apr;22(4):767-776. doi: 10.1038/s41436-019-0706-8. Epub 2019 Nov 26.

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Abstract: An entity of regression in Down syndrome (DS) exists that affects adolescents and young adults and differs from autism spectrum disorder and Alzheimer disease. Since 2017, an international consortium of DS clinics assembled a database of patients with unexplained regression and age- and sex-matched controls. Standardized data on clinical symptoms and tiered medical evaluations were collected. Elements of the proposed definition of unexplained regression in DS were analyzed by paired comparisons between regression cases and matched controls. We identified 35 patients with DS and unexplained regression, with a mean age at regression of 17.5 years. Diagnostic features differed substantially between regression cases and matched controls (p < 0.001 for all but externalizing behaviors). Patients with regression had four times as many mental health concerns (p < 0.001), six times as many stressors (p < 0.001), and seven times as many depressive symptoms (p < 0.001). Tiered medical evaluation most often identified abnormalities in vitamin D 25-OH levels, polysomnograms, thyroid peroxidase antibodies, and celiac screens. Analysis of the subset of patients with nondiagnostic medical evaluations reinforced the proposed definition. Our case-control evidence supports a proposed definition of unexplained regression in Down syndrome. Establishing this clinical definition supports future research and investigation of an underlying mechanism.

Down syndrome disintegrative disorder: A clinical regression syndrome of increasing importance
Mattia Rosso, Ellen Fremion, Stephanie L. Santoro, Nicolas M. Oreskovic, Tanuja Chitnis, Brian G. Skotko and Jonathan D. Santoro
Pediatrics, June 2020, 145 (6) e20192939; https://doi.org/10.1542/peds.2019-2939

Abstract: Down syndrome disintegrative disorder (DSDD), a developmental regression in persons with Down syndrome (DS), is a clinical entity that is characterized by a loss of previously acquired adaptive, cognitive, and social functioning in persons with DS usually in adolescence to early adulthood. Initially reported in 1946 as “catatonic psychosis,” there has been an increasing interest among the DS community, primary care, and subspecialty providers in this clinical area over the past decade. This condition has a subacute onset and can include symptoms of mood lability, decreased participation in activities of daily living, new-onset insomnia, social withdrawal, autistic-like regression, mutism, and catatonia. The acute phase is followed by a chronic phase in which baseline functioning may not return. No strict criteria or definitive testing is currently available to diagnose DSDD, although a comprehensive psychosocial and medical evaluation is warranted for individuals presenting with such symptoms. The etiology of DSDD is unknown, but in several hypotheses for regression in this population, psychological stress, primary psychiatric disease, and autoimmunity are proposed as potential causes of DSDD. Both psychiatric therapy and immunotherapies have been described as DSDD treatments, with both revealing potential benefit in limited cohorts. In this article, the authors review the current data regarding clinical phenotypes, differential diagnosis, neurodiagnostic workup, and potential therapeutic options for this unique, most disturbing, and infrequently reported disorder.

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Rapid clinical deterioration in an individual with Down syndrome
Julia Jacobs, Alison Schwartz, Christopher J. McDougle, and Brian Skotko
American Journal of Medical Genetics [Part A], 2016, Jul, 170(7), 1899-1902. doi:10.1002/ajmg.a.37674

Abstract:  A small percentage of adolescents and young adults with Down syndrome experience a rapid and unexplained deterioration in cognitive, adaptive, and behavioral functioning. Currently, there is no standardized work-up available to evaluate these patients or treat them. Their decline typically involves intellectual deterioration, a loss of skills of daily living, and prominent behavioral changes. Certain cases follow significant life events such as completion of secondary school with friends who proceed on to college or employment beyond the individual with DS. Others develop this condition seemingly unprovoked. Increased attention in the medical community to clinical deterioration in adolescents and young adults with Down syndrome could provide a framework for improved diagnosis, evaluation, and treatment. This report presents a young adult male with Down syndrome who experienced severe and unexplained clinical deterioration, highlighting specific challenges in the systematic evaluation and treatment of these patients

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Acute regression in young people with Down syndrome

Clotilde Mircher, Cécile Cieuta-Walti, Isabelle Marey Anne-Sophie Rebillat, Laura Cretu Eliane Milenko, Martine Conte, Franck Sturtz, Marie-Odile Rethore, and Aimé Ravel

Brain Science, 2017,May 27, 7(6), 57. doi:10.3390/brainsci7060057.

Abstract: Adolescents and young adults with Down syndrome (DS) can present a rapid regression with loss of independence and daily skills. Causes of regression are unknown and treatment is most of the time symptomatic. We did a retrospective cohort study of regression cases: patients were born between 1959 and 2000, and were followed from 1984 to now. We found 30 DS patients aged 11 to 30 years old with history of regression. Regression occurred regardless of the cognitive level (severe, moderate, or mild intellectual disability (ID)). Patients presented psychiatric symptoms (catatonia, depression, delusions, stereotypies, etc.), partial or total loss of independence in activities of daily living (dressing, toilet, meals, and continence), language impairment (silence, whispered voice, etc.), and loss of academic skills. All patients experienced severe emotional stress prior to regression, which may be considered the trigger. Partial or total recovery was observed for about 50% of them. In our cohort, girls were more frequently affected than boys (64%). Neurobiological hypotheses are discussed as well as preventative and therapeutic approaches

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Down syndrome disintegrative disorder: New-onset autistic regression, dementia, and insomnia in older children and adolescents with Down syndrome

Gordon Worley, Blythe G Crissman, Emily Cadogan, Christie Milleson, Deanna W Adkins, and Priya S Kishnani

Journal of Child Neurology, 2015, Aug, 30(9), 1147-1152.   doi: 10.1177/0883073814554654. Epub 2014 Nov 3.

Abstract: Over a 10-year period in a Down syndrome Clinic, 11 children and adolescents were encountered with a history of new-onset (8) or worsening (3) autistic characteristics. Ten of the 11 (91%) had cognitive decline to a dementia-like state and 9 of the 11 (82%) new-onset insomnia. The mean age at which symptoms developed was 11.4 years (standard deviation = 3.6 years; range 5-14 years), an older age than usual for autistic regression in Down syndrome. Ten of 11 cases (91%) had elevated ("positive") thyroperoxidase antibody titers compared to only 5 of 21 (23%) age-matched control subjects with Down syndrome (P < .001). At follow-up at a mean age of 20.7 years (standard deviation = 3.9 years), 8 of the 11 (73%) were at least somewhat better. Down syndrome disintegrative disorder seems an appropriate name for this newly recognized clinical association, which may be due to autoimmunity.

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Regression and loss of skills in adolescents and adults with Down syndrome

Brian Chicoine, MD, Adult Down Syndrome Center, Advocate Lutheran General Hospital, Park Ridge, Illinois

This video is of a recording of the Center's medical director, Brian Chicoine, MD, presentation on "Regression and Loss of Skills in Adolescents and Adults with Down Syndrome." He defines regression and loss of skills as well as describes possible causes and potential treatments. He also discusses strategies that can be used when supporting an individual with Down syndrome who is experiencing regression or loss of skills. This was a presentation at part of the Center's 2020 Health Education Series, held on February 17, 2020, in Park Ridge, IL.

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Regression in adolescents and adults with down syndrome

 

Brian Chicoine and George Capone

Regression in Adolescents and Adults with Down Syndrome. (2019) In: Prasher V., Janicki M. (eds) Physical Health of Adults with Intellectual and Developmental Disabilities. Springer, Cham. https://doi.org/10.1007/978-3-319-90083-4_7

Abstract: There has been a growing number of clinical case reports of regression in adolescents and adults with Down syndrome who have shown unexpected and severe regression in cognitive and adaptive functioning, motor function, communication skills, and behavior. In this chapter, we call this adult regression syndrome. It most commonly affects people with Down syndrome in their teens and twenties and is associated with cognitive-executive impairment, social withdrawal, loss of functional language and previously acquired adaptive skills, lasting greater than 3 months. The differential diagnosis is extensive suggesting that the brains of individuals with Down syndrome are vulnerable to further impairment from a variety of underlying causes. Several of the most important diagnoses are discussed further. Prognosis is highly dependent on both the cause and the certainty of the diagnosis. Further study is needed to improve our understanding of adult regression syndrome.

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Catatonia in Down Syndrome: Systematic Approach to Diagnosis, Treatment and Outcome Assessment Based on a Case Series of Seven Patients

Judith H Miles, Nicole Takahashi, Julie Muckerman, Kerri P Nowell, Muaid Ithman

Neuropsychiatric Disease and Treatment, 2019, Sep 20, 15, 2723-2741.

doi:10.2147/NDT.S210613. eCollection 2019.

Abstract: The goal is to expand our knowledge of catatonia occurring in adolescents and young adults with Down syndrome (DS) by describing the first prospective, consecutive, well-characterized cohort of seven young people with DS diagnosed with catatonia and treated between 2013 and 2018, and to assess each patient's treatment responses. Longitudinal assessment of each patient's response to treatment is intended to provide clinicians and psychiatrists a firm foundation from which assess treatment efficacy. Young adults with Down syndrome were consecutively enrolled in the study as they were diagnosed with catatonia. A comprehensive data set included medical, laboratory, developmental, demographic, family, social and genetic data, including query into disorders for which individuals with DS are at risk. Catatonia was diagnosed based on an unequivocal history of regression, positive Bush-Francis Catatonia Rating Scale and positive response to intravenous lorazepam. Patients' longitudinal progress was monitored using the Catatonia Impact Scale (CIS) developed for this purpose. Seven consecutive DS patients, who presented with unequivocal regression were diagnosed with catatonia and treated for 2.7-6 years using standard-of-care therapies; primarily GABA agonist, lorazepam, electroconvulsive therapy (ECT) and glutamate antagonists (dextromethorphan/quinidine, memantine, minocycline). Responses to each treatment modality were assessed at clinic visits and through weekly electronic CIS reports. Seven young adults with DS were diagnosed with catatonia; all responded to Lorazepam and/or ECT therapy with good to very good results. Though ECT most dramatically returned patients to baseline, symptoms often returned requiring additional ECT. Dextromethorphan/quinidine, not used until mid-2017, appeared to reduce the reoccurrence of symptoms following ECT. Though all seven patients improved significantly, each continues to require some form of treatment to maintain a good level of functioning. Findings of a significant number of autoimmune disorders and laboratory markers of immune activation in this population may guide new diagnostic and treatment opportunities.

Catatonia in Down Syndrome: A Treatable Cause of Regression

 

Neera Ghaziuddin, Armin Nassiri, Judith H Miles

Neuropsychiatric Disease and Treatment, 2015, Apr 2,11, 941-949. doi:10.2147/NDT.S77307. eCollection 2015.

Abstract: The main aim of this case series report is to alert physicians to the occurrence of catatonia in Down syndrome (DS). A second aim is to stimulate the study of regression in DS and of catatonia. A subset of individuals with DS is noted to experience unexplained regression in behavior, mood, activities of daily living, motor activities, and intellectual functioning during adolescence or young adulthood. Depression, early onset Alzheimer's, or just "the Down syndrome" are often blamed after general medical causes have been ruled out. Clinicians are generally unaware that catatonia, which can cause these symptoms, may occur in DS. Four DS adolescents who experienced regression are reported. Laboratory tests intended to rule out causes of motor and cognitive regression were within normal limits. Based on the presence of multiple motor disturbances (slowing and/or increased motor activity, grimacing, posturing), the individuals were diagnosed with unspecified catatonia and treated with anti-catatonic treatments (benzodiazepines and electroconvulsive therapy [ECT]). All four cases were treated with a benzodiazepine combined with ECT and recovered their baseline functioning. We suspect catatonia is a common cause of unexplained deterioration in adolescents and young adults with DS. Moreover, pediatricians and others who care for individuals with DS are generally unfamiliar with the catatonia diagnosis outside schizophrenia, resulting in misdiagnosis and years of morbidity. Alerting physicians to catatonia in DS is essential to prompt diagnosis, appropriate treatment, and identification of the frequency and course of this disorder.

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New definition of unexplained regression in Down syndrome proposed

American Journal of Medical Genetics, 12 February 2020, 182A(3), 421-422.  https://doi.org/10.1002/ajmg.a.61226

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