Down Syndrome Disintegrative Disorder: A Clinical Regression Syndrome of Increasing Importance Mattia Rosso, MD,a Ellen Fremion, MD,b Stephanie L. Santoro, MD,c,d Nicolas M. Oreskovic, MD, MPH,c Tanuja Chitnis, MD,a Brian G. Skotko, MD, MPP,c,d Jonathan D. Santoro, MDe,f

Down syndrome disintegrative disorder (DSDD), a developmental regression abstract in children 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 aAnn Romney Center for Neurologic Diseases, Harvard the DS community, primary care, and subspecialty providers in this clinical Medical School, Harvard University and Brigham and area over the past decade. This condition has a subacute onset and can Women’s Hospital, Boston, Massachusetts; bInternal Medicine-Pediatrics Program, Baylor College of Medicine, include symptoms of mood lability, decreased participation in activities of Houston, Texas; cDivision of Medical Genetics and daily living, new-onset insomnia, social withdrawal, autistic-like regression, Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts; dDepartment of mutism, and catatonia. The acute phase is followed by a chronic phase in Pediatrics, Harvard Medical School, Harvard University, which baseline functioning may not return. No strict criteria or definitive Boston, Massachusetts; eDepartment of Neurology, Children’s Hospital Los Angeles, Los Angeles, California; and testing is currently available to diagnose DSDD, although a comprehensive fKeck School of Medicine, University of Southern California, psychosocial and medical evaluation is warranted for individuals presenting Los Angeles, California with such symptoms. The etiology of DSDD is unknown, but in several Drs Rosso and J.D. Santoro conceptualized and hypotheses for regression in this population, psychological stress, primary designed the structure of the review, drafted the psychiatric disease, and autoimmunity are proposed as potential causes of manuscript, and revised the manuscript; Drs Fremion, S.L. Santoro, and Skotko drafted the DSDD. Both psychiatric therapy and immunotherapies have been described as manuscript and revised the manuscript for DSDD treatments, with both revealing potential benefit in limited cohorts. In intellectual content; Drs Oreskovic and Chitnis this article, we review the current data regarding clinical phenotypes, critically reviewed and revised the manuscript for differential diagnosis, neurodiagnostic workup, and potential therapeutic important intellectual content; and all authors approved the final manuscript as submitted and options for this unique, most disturbing, and infrequently reported disorder. agree to be accountable for all aspects of the work. DOI: https://doi.org/10.1542/peds.2019-2939 Accepted for publication Nov 13, 2019 Down syndrome (DS) is the most implications on both quality of life Address correspondence to Jonathan D. Santoro, ’ common cause of intellectual disability and the autonomy of persons with MD, Department of Neurology, Childrens Hospital Los Angeles, 4650 Sunset Blvd, Mail Stop 82, Los Angeles, ∼ 4 worldwide and occurs in 1 in 800 DS. It is, therefore, key for all CA 90027. E-mail: [email protected] live births; it is most frequently caused providers to be aware of DSDD to PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, by trisomy of chromosome 21 due to evaluate and potentially treat this 1098-4275). nondisjunction or translocation condition. The etiology, Copyright © 2020 by the American Academy of 1–3 events. In recent years, multiple pathophysiology, and therapeutic Pediatrics fi centers have reported a speci c options for DSDD are currently unclear, FINANCIAL DISCLOSURE: The authors have indicated pattern of developmental regression although clinical data are rapidly they have no financial relationships relevant to this in individuals with DS, wherein emerging. Our focus for this review is article to disclose. patients lose language, behavioral, to summarize the current knowledge of FUNDING: No external funding. and cognitive skills that they previously clinical features, potential etiologies, 4,5 acquired. This condition has been neurodiagnostic workup, and To cite: Rosso M, Fremion E, Santoro SL, et al. more recently referred to as Down therapeutic options and to identify Down Syndrome Disintegrative Disorder: A syndrome disintegrative disorder future areas of focus and research in Clinical Regression Syndrome of Increasing Importance. Pediatrics. 2019;145(6):e20192939 (DSDD). DSDD can be severe, with this field.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 145, number 6, June 2019:e20192939 STATE-OF-THE-ART REVIEW ARTICLE HISTORICAL REPORTS TABLE 1 Characteristics of DSDD In 1946, Rollin6 described a cohort of Criterion Features 73 institutionalized adolescents and I Autistic regression young adults with DS, 17 (23.3%) of II Cognitive decline resulting in a dementia-like state whom were diagnosed with III Older age at onset than at autistic regression IV No other diagnosis that may explain the condition “catatonic psychosis.” These individuals had an appropriate Adapted from Worley G, Crissman BG, Cadogan E, Milleson C, Adkins DW, Kishnani PS. Down syndrome disintegrative disorder: new-onset autistic regression, dementia, and insomnia in older children and adolescents with Down syndrome. developmental period followed by J Child Neurol. 2015;30(9):1147–1152. behavioral changes, including agitation and harm directed toward self and others, during early Statistical Manual of Mental Disorders also reported and include depression adolescence (ages 11–14) that led criteria of autism spectrum disorder (42%), social withdrawal (34%), and 5,12,13 their families to seek institutional to aid in standardization of anxiety (16%). In recent phenotypic description for the latter studies, catatonia was observed in care. Afterward, they experienced 4,9 a deterioration phase marked by phenomenon. Diagnosis by using 47% of cases labeled as DSDD, which incontinence, mutism, apathy, social these guidelines involves new-onset is higher than rates originally 6 5,11,12 withdrawal, occasional behavioral impairments in social interaction; reported by Rollin (38%). outbursts, and psychosis, eventually communication; stereotyped patterns New-onset insomnia was also 4,5,7,11,12 leading to catatonia. of movement, behavior, and thought; described in 43% of cases. and developmental delays.9 At Pooled estimates from 4 studies In 2000, Kerbeshian and Burd7 baseline, autism can be present in revealed a 14% rate of psychotic provided a clinical description of roughly 15% of children with DS; symptoms, including delusions and autistic-like regression in a child with however, a previous diagnosis of hallucinations, in persons with DS. In this study, the authors autism was not observed in any of the DSDD.4,5,11,12 Aggressive behavior described an 8-year-old girl with DS studies reviewed in this report.10 was reported in 42% of who experienced autistic regression DSDD is an entity that is believed to patients.2,5,11,13 As was highlighted by (loss of social and communication be distinct and separate from autism Mircher et al,5 aggression in persons skills), loss of cognitive functions, and spectrum disorder. with DSDD may be directed toward a rapid-onset insomnia, referring to self (auto-aggression) or others this condition as autistic-like Beyond regression, symptoms of (hetero-aggression). A minority of regression.7 Subsequently, in 2015, DSDD can be heterogenous and are patients with DSDD (12%) also had 4 Worley et al presented similar case reported with variability (Table 2). In anorexia as part of their clinical reports and characterized DSDD as 3 large studies, up to 87% of patients presentation.11,12 a subacute onset of “autistic with DSDD were diagnosed with regression,” cognitive decline language regression, with symptoms Because there are no diagnostic resulting in a dementia-like state, ranging in severity from dysfluency to criteria available, DSDD is best occurring at an older age typical for mutism.5,11,12 Among patients in described as a clinical syndrome that autistic regression, and no other whom severity of language regression should be considered in adolescents established diagnosis to explain the was quantified, 38% had partial and young adults with DS and condition (Table 1).8 language regression and 52% had subacute-onset behavioral mutism.5,11,12 Mood symptoms are changes.13 It is also key to appreciate CLINICAL MANIFESTATIONS TABLE 2 Clinical Features Reported in DSDD fi The demographic pro le of DSDD Clinical Feature %(n/N) includes a postpubertal onset and an Language regression5,11,12 87 (42/48) elevated female/male patient ratio of Partial 38 (18/48) 4,5 2:1. Adefining feature of DSDD is Mutism 52 (25/48) regression of previously attained Catatonia2,5,11,12 47 (25/53) skills, notably in the domains of Mood symptoms2,5,12,13 language, communication, and social Depression 42 (21/50) Social withdrawal 34 (15/44) skills. No formal criteria exist within Anxiety 16 (8/50) the diagnosis of DSDD to define either Insomnia4,5,11,12 43 (25/58) regression or autistic-like behavioral Aggression2,5,11,13 42 (17/40) regression; however, some groups Delusions or hallucinations4,5,11 14 (8/56) 11,12 have used the Diagnostic and Anorexia 12 (5/43)

Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 ROSSO et al that persons with DS may experience The imaging features of DSDD are a postpubertal onset and an elevated adaptive, social, or cognitive heterogenous, and no defining female/male patient ratio of 2:1 in regression for reasons other than characteristics have been identified. the 2 largest studies to date.4,5 This DSDD, making a complete workup Across 5 studies, abnormal MRI finding has raised the suspicion that critical in the assessment of these findings were found in 26% of inflammation may play a role in the patients (see Evaluation and patients (n = 9 of 35).4,5,11,12 The etiology of DSDD because this Differential Diagnosis). Compared imaging findings were described to be demographic is mirrored in other with the typical onset of autistic dementia-like in 2 cohorts in which inflammatory disorders such as regression in persons with DS, DSDD hippocampal atrophy was reported in multiple sclerosis and autoimmune takes place when patients are older, 20% of patients (n = 4 of 20).5,12 In encephalitis.4,5,13,15 Additionally, typically between the first and third other studies, there has been a failure recent research has revealed the decade.4,13 The acute regression to find any imaging findings presence of other autoantibodies, appears to last for ∼6monthsandis associated with DSDD, which may such as antinuclear antibodies, anti- followed by a chronic phase in which reflect the significant heterogeneity of microsomal antibodies, striational previous skills may not be the study cohorts.2,4,11 antibodies, thyroperoxidase completely recovered (Table 3). In 2 antibodies, and anti-tissue studies, it has been reported that transglutaminase antibodies, which THEORIES ON ETIOLOGY 58% of persons with DSDD have elevated levels in some experience a partial or total recovery. Whereas the etiology of DSDD is not individuals with DSDD.11 These Only 7.5% of patients experience fully understood, 2 possible causes findings may be understood as additional worsening, whereas 35% that have been proposed are immune a consequence of DS, which is of patients stabilize.4,5 However, in dysregulation and psychological generally associated with high serum patients with stabilizing DSDD, stress triggering neuropsychiatric levels of proinflammatory cytokines, acompleterecoverytothe presentations (analogous to Rollin’s6 high rates of complement protein premorbid baseline condition original report). The demographic consumption, and various other appears to be infrequent.2,4 profile of DSDD includes forms of immune dysregulation.16 As

TABLE 3 Studies of Patients With Clinical Phenotypes Similar to DSDD Authors, Year Design Patient Population Summary of Results Rollin,6 1946 Case series 17 cases of DS with catatonic psychotic living in Description of a period of behavioral agitation followed by decompensation an institution characterized by incontinence, mutism, apathy, social withdrawal, occasional behavioral outbursts, and psychosis eventually leading to catatonia Kerbeshian and Case series 5 cases of DS and Tourette’s syndrome, 1 case Description of new-onset insomnia, autism, and loss of cognitive skills in Burd,7 2000 of childhood disintegrative disorder and DS a patient with DS Prasher,8 2002 Case series 357 patients with DS DSDD regression is severe and gradual, lasting 2 y and followed by a chronic plateau; regression affected language, social, and cognitive domains Castillo et al,14 Case- 24 patients with DS and autism 50% (12 of 24) of patients with DS and autism lost previously acquired 2008 control language, social skills, and communicative abilities; language loss study occurred later in DS with autistic regression than in isolated autistic regression (62 vs 20 mo) Akahoshi et al,12 Case series 13 young adults with DS with acute Patients with DS presented with depression, obsessive-compulsive 2012 neuropsychiatric symptoms behaviors, delusions, and hallucinations Worley et al,4 2015 Case series 11 patients with DSDD Late mean age of onset of DSDD (mean = 11.4 y); autism was new in onset in 8 of 11 patients and worsened in 3 of 11 patients; 91% (10 of 11) patients had cognitive decline; s82% (9 of 11) patients had new-onset insomnia Ghaziuddin et al,2 Case series 4 patients with DS and regression Regression was accompanied by motor symptoms, including catatonia; 2015 recovery after a therapy with benzodiazepines and ECT Jacobs et al,13 Case report Young adult male with DS 19-y-old patient presents with severe clinical deterioration; the patient 2016 presented with low mood, difficulty concentrating, anxiety, and motor symptoms Mircher et al,5 Case series 30 patients with DS and regression Regression was seen at all levels of cognitive functions; regression was 2017 characterized by partial or total loss of activities of daily living; regression was associated with other psychiatric symptoms, which included catatonia, depression, delusions, and stereotypical behaviors; regression was preceded by severe emotional stress in all patients

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 145, number 6, June 2019 3 the autoimmune etiology of several TABLE 4 Autoimmune Characteristics of DSDD psychiatric syndromes becomes Authors, Year Patient Population Summary of Results increasingly accepted, researchers Worley et al,4 11 patients with Anti-thyroperoxidase antibody levels were elevated in 91% of speculate that some cases of DSDD 2015 DSDD patients with DSDD (10 of 11) vs 23% of patients with DS (5 of may be driven by autoimmunity.17,18 21) (P , .001) Jacobs et al,13 Young adult male Negative results on autoimmune panel Elevated serum and cerebral spinal 2016 with DS fluid levels of anti-thyroperoxidase Cardinale et al,11 4 patients with Anti-thyroperoxidase antibodies (n = 3 of 4), anti-TSH antibodies antibodies found in some patients 2019 DSDD (n = 2 of 4), anti-microsomal antibodies (n = 2 of 4), anti-tTg with DSDD have led some researchers antibodies (n = 1 of 4), antinuclear antigen antibodies (n =1 of 4), anti-striational antibodies (n = 1 of 4) to propose Hashimoto encephalopathy – (HE) as an underlying etiology. Across anti-TSH, anti thyroid-stimulating hormone antibodies; anti-tTg, anti-tissue transglutaminase. 4 studies, 35% of persons with DSDD (n = 16 of 46) had high titers of anti- the largest study of 30 patients, An exact etiology of DSDD remains thyroperoxidase antibodies, although Mircher et al5 described a new school difficult to identify, although the agreement between these studies environment as the most common life components of immune is considered poor because rates range stressor preceding a diagnosis of dysregulation, psychiatric symptoms from as low as 20% (Mircher et al,5 DSDD (51%).11,22 Other common in persons with intellectual disability, n = 15 tested) to as high as 82% stressors were awareness of disability and dysregulated cholinergic and (Worley et al,4 n = 11 tested).11,13 triggered by the wedding or departure serotonergic circuits may be involved Epidemiological studies have revealed of a sibling (23%), assault (17%), (Fig 1). Although the role of that thyroid disease has a greater illness of a close one (13%), and inflammation in neuropsychiatric prevalence in patients with DSDD than overstimulation (10%).5 Although disease continues to evolve, the in the general population.4 In addition, notable, many children with DS combination of neuroinflammation, the rates of thyroid disease increase experience similar stressful triggers autoantibody generation, and/or with time, as does the prevalence of and do not have similar cytokine dysregulation could thyroperoxidase antibodies, with rates neuropsychiatric changes, rendering interface with existing psychological up to 22% in asymptomatic patients.19 stress-related triggers an incomplete capacities to cope with external The significance of anti- explanation. Stein et al22 also reported stressors and the baseline circuity of thyroperoxidase antibodies is unclear on the role of environmental changes these responses. For this reason, because steroid therapy, the gold as potential triggers for regression in additional investigation into the cause standard treatment of HE, has DSDD. In their case study, the authors of this potentially polyfactorial revealed no clinical benefitinDSDD.4 reported that a patient with DS phenomenon is needed. HE also differs from DSDD because it developed reactive depression after presents with seizures, headaches, moving to a new city and changing hallucinations, and ataxia. Although EVALUATION AND DIFFERENTIAL schools.23 The authors postulated that HE can present as an isolated DIAGNOSIS the patient dealt with distress through psychiatric illness, this presentation is complex behavioral and adaptive At this time, DSDD is best described rare in children.20,21 Thus, additional changes because she failed to express as a constellation of symptoms studies are needed to fully elucidate her distress with the usual verbal without a distinct etiology. Thus, thepathologicroleofanti- channels.22 This description would clinicians should pursue thyroperoxidase antibodies in patients exist on the spectrum of an acute a comprehensive psychosocial and with both DS and DSDD (Table 4). stress reaction as opposed to medical evaluation of potential An alternative hypothesis proposes a primary psychiatric disease and thus secondary causes of behavioral that psychological stress may act as may explain the recovery noted in change and regression. In their a trigger of regression in DSDD (Fig 1). patients over time. Mircher et al5 put article, Jacobs et al13 provide In their studies, Stein et al22 and forth a hypothesis that explains the a suggested diagnostic workup for Mircher et al5 postulated that such susceptibility in terms of widespread such cases organized in 5 different behavioral changes may be a way for dysregulation of serotoninergic and tiers of testing (Table 5). The first 2 persons with DS to express distress in cholinergic circuits. If this were the tiers are common causes of a new the context of their developmental case, DSDD may be amenable to onset of psychiatric symptoms in delays. Across 3 studies, 86% of treatment with selective serotonin young adults with DS, which include persons with DSDD (n =30of35) reuptake inhibitors (SSRIs), which psychosocial stressors, depression, reported identifiable life stressors have only been explored in a few electrolyte disturbances, infections, preceding the onset of symptoms. In studies thus far.24,25 liver disease, thyroid disorders, and

Downloaded from www.aappublications.org/news by guest on September 30, 2021 4 ROSSO et al FIGURE 1 Diagram of proposed DSDD pathophysiology. immunologic disorders. Common adults. These syndromes are disorder, and anxiety disorders, may co-occurring conditions associated characterized by an inability to have symptoms that mimic with DS should also be considered process certain metabolites, including a regression.27 These disorders should such as sleep apnea, acid reflux, celiac amino acids, fatty acids, or organic be evaluated thoroughly because they disease, and constipation. Another acid. A final differential diagnosis to unify the presence of environmental diagnosis in tier 2 is pediatric acute- be aware of is Lesch-Nyhan triggers and associated onset neuropsychiatric syndrome, syndrome, the presentation of which neuropsychiatric disease, although which displays some overlap with may closely resemble DSDD, except diagnosis can be challenging in DSDD. Persons with pediatric acute- that onset is typically in infancy or persons with intellectual disability.28 A onset neuropsychiatric syndrome early childhood. Patients with Lesch- key point to consider is that the may present with a subacute onset of Nyhan syndrome present with presence of mild baseline psychiatric abnormal motor movements, tics, and a combination of a regression of disease and exposure to stressful obsessive-compulsive symptoms, intellectual skills, dystonic triggers may yield regression-like although caution should be exercised movements, and compulsive self- symptoms, although this likely exists before making this diagnosis, as well, mutilation because of a failure of along a complex spectrum. One final given the heterogenous diagnostic purine metabolism.26 These genetic important differential diagnosis to and clinical criteria. conditions typically present in early consider is early-onset Alzheimer childhood rather than adolescence disease (AD), which continues to be an Multiple genetic conditions can occur and young adulthood like DSDD, but in the same patient, and because DS is important differential for patients with delayed diagnosis is plausible. 11 one of the most common genetic DSDD. Early-onset AD is common in disorders, evaluation for other Finally, it is important to note that DS patients with DS owing to the 3 copies genetic disorders should be is associated with several psychiatric of chromosome 21 (and thus 3 copies considered. Two important diagnoses conditions. As previously mentioned, of amyloid precursor protein genes) to evaluate for are Fragile X DSDD differs from other forms of carried by these patients. Early-onset syndrome and Rett syndrome, which autistic regression in the later age at AD differs from DSDD because of the are 2 important genetic causes of onset, high female/male patient ratio, later onset between the ages of 40 regression in early childhood. By the and presence of additional symptoms and 60 years and its steady and same token, inborn errors of such as insomnia and catatonia.4,5 In irreversible decline, as opposed to metabolism are possible causes of the presence of stressful triggers, the subacute and partially reversible regression and behavioral primary psychiatric disorders, such as decline observed in DSDD.29 However, abnormalities in children and young major depressive disorder, bipolar AD onset may occur earlier than age

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 145, number 6, June 2019 5 TABLE 5 Proposed Diagnostic Workup for Regression in Patients With DS sertraline), and anticholinergic drugs Tier Diagnosis Evaluation (eg, donepezil and rivastigmine) have Tier Thyroid disorders: hypothyroidism, TSH, fT4, thyroperoxidase antibodies, thyroglobulin been used to address many of the 1 hyperthyroidism, HE antibodies neuropsychiatric disturbances Electrolyte disturbance, infections, Electrolytes, CBC, LFTs observed in DSDD.4 In 3 recent liver disease studies, 25% of patients showed fi Vitamin de ciency Folate, vitamin B12, 25-OH vitamin D a response to SSRIs, which seem to Celiac disease Anti-tTg, total IgA Obstructive sleep apnea Polysomnography improve mood symptoms, motor Hearing loss Hearing test symptoms, and sleep Vision loss (cataracts, ulcers, etc) Vision screen disturbance.12,31 Tamasaki et al31 Constipation Abdominal radiograph reported a case study of a 14-year-old Depression Depression screen boy with DSDD symptoms who was Stress and anxiety Screen for stressors Other psychiatric disorders Psychiatric referral treated with donepezil, which led to Other neurologic disorders Brain MRI a complete psychosocial recovery; Tier Lyme disease Serological testing however, the efficacy of cholinergic 2 medications for cognitive impairment PANDAS Antistreptolysin O in individuals with DS is debatable, Seizure disorder EEG Other immunologic disorders Antinuclear antibodies, ESR, CRP and they are not US Food and Drug Syphilis, HIV RPR, HIV serology Administration approved for children Tier Fragile X syndrome Fragile X syndrome testing and adolescents.32,33 Another 3 therapeutic option for persons with Rett syndrome Methyl CpG binding protein 2 DSDD is antipsychotic treatment. Heavy metal toxicity Serum levels of lead, manganese, mercury, zinc, nickel, thallium Across 4 studies, 70% of patients NMDA receptor encephalitis Anti-NMDA receptor autoantibodies experienced at least some Microdeletion or microduplication Chromosomal microarray improvement in motor symptoms, syndrome sleep disturbance, and catatonia with Tier Aminoacidopathies Plasma amino acids antipsychotic therapy.2,12,13 4

Organic acidurias Urine organic acids, urine acylglycines 2 Fatty acid oxidation disorders Plasma acylcarnitines Ghaziuddin et al reported that high- Mitochondrial disorders Pyruvate, lactates dose benzodiazepines, such as Urea cycle disorders Ammonia lorazepam, could benefit patients Ovarian teratoma (limbic encephalitis) Ovarian ultrasound with DSDD and catatonia. Across 4 Tier Lesch-Nyhan syndrome Hypoxanthine-guanine phosphoribosyl transferase studies, 91% of patients with DSDD 5 gene mutation Porphyria Aminolevulinic acid, porphobilinogen, and catatonia demonstrated at least hydroxymethylbilane synthase gene mutation a partial response to Congenital disorders of glycosylation Carbohydrate deficient transferrin benzodiazepines; however, catatonia Peroxisomal storage disorders Very long chain fatty acids, phytanic acid, was unresponsive to benzodiazepines plasmalogens 2,11–13 Lysosomal storage disorders Urine glycosaminoglycans, urine oligosaccharides, in only 1 patient. urine sialic acid Electroconvulsive therapy (ECT) has Other genetic disorders Whole exome sequencing also been shown as an effective anti-tTg, anti-tissue transglutaminase; CBC, complete blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedi- therapy for DSDD with catatonia that mentation rate; fT4, free thyroxine; IgA, immunoglobulin A; LFT, liver function test; NMDA, N-methyl D-aspartate; PANDAS, warrants careful consideration by pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; RPR, rapid plasma regain; clinicians.2 However, ECT can have TSH, thyroid-stimulating hormone; 25-OH, 25-hydroxycholecalciferol. several complications, including the requirement of sedation, the potential 40 and may be exacerbated by factors also the need for choosing the most for memory impairment and similar to those reported in DSDD.30 appropriate intervention. neurocognitive sequelae, and the need for repeated ECT sessions to Of note, the diagnosis of DSDD is maintain symptom remission; thus, it THERAPEUTIC INTERVENTIONS FOR based on clinical phenotype, and for should be considered in conjunction DSDD this reason, it is important to realize with specialists experienced with its that this syndrome may be produced Several therapies have revealed some use in DS.34 In a recent case report, by multiple causes. This is a necessary clinical benefit in patients with DSDD. administering high doses of the consideration regarding not only the Symptomatically, antipsychotics (eg, antipsychotic clozapine was the only need for a standardized workup but risperidone), SSRIs (eg, fluoxetine and effective treatment of catatonia and

Downloaded from www.aappublications.org/news by guest on September 30, 2021 6 ROSSO et al TABLE 6 Previously Reported Experimental Therapies in DSDD Authors, Year Design Patient Population Summary of Results Akahoshi et al,12 Case 13 young adults with DS with acute A total of 10 of 11 patients responded to pharmacotherapy, and marked improvements 2012 series neuropsychiatric symptoms were seen in 3 of 11; attempted pharmacotherapy included fluvoxamine, amantadine, haloperidol, and benzodiazepines Ghaziuddin Case 4 patients with DS and regression High-dose lorazepam and ECT were associated with the improvement of catatonia; SSRIs, et al,2 2015 series mood stabilizers, antipsychotics, and antiepileptic drugs resulted in no change or worsening of symptoms Jacobs et al,13 Case Young adult male with DS Antipsychotics exacerbated the patient’s catatonia; trazodone and high-dose 2016 report benzodiazepines had no therapeutic benefit; the patient benefited from clozapine, which brought him back to 85% of his baseline status (as reported by the patient’s mother) Tamasaki et al,31 Case Male teenager with DS Initiated escitalopram after immune therapy with IV methylprednisolone and 2016 report anticatatonia therapies; improvement over 4-wk period, although continued autistic features; initiated donepezil, with improvement in autistic features over an additional 4wk Cardinale et al,11 Case 4 patients with DSDD Immunotherapy improved catatonia, insomnia, autism severity, cognitive decline, and 2019 series psychosis in DSDD; regimens included IV and oral steroids, IV immunoglobulins, mycophenolate, and rituximab IV, intravenous. was started after other treatment hypothesis of an immunologic classes of therapies have revealed options were exhausted.13 It is crucial component in the pathophysiology of some clinical benefit(ie, to consider that catatonia may be DSDD for individuals with positive benzodiazepines and ECT for catatonia a symptom of DSDD because it may be autoantibody screening results, but in and SSRIs for mood symptoms), but easily mistaken for schizophrenia or this study, a limited cohort was a standardized treatment guideline another psychiatric disorder (Table 6).2 analyzed, and additional studies with should be developed. Future studies larger cohorts are needed.4 However, will also be needed to elucidate the Newer therapies have been proposed as noted above, the presumed role of immune dysregulation in DSDD that target the hypothesized etiology may differ between cases; and the effectiveness of autoimmunity etiology of DSDD. thus, the choice of therapeutic immunotherapies in larger cohorts. 11 Cardinale et al explored the use of intervention should mirror this various immunotherapeutic regimens Molecular biomarkers and radiologic because multiple causes could hallmarks also need to be identified in 4 patients with DSDD who had produce the same clinical phenotype. positive serum autoantibody that correlate with the clinical fi screening results. Different regimens ndings. Additionally, truly were attempted because of the side FUTURE DIRECTIONS separating the symptoms of DSDD effects associated with many of these from chronic comorbidities DSDD is a recently redefined treatments, which required treatment associated with DS will be constellation of symptoms, including discontinuation in many instances. a necessary component of future mood lability, socio-communicative The regimens included intravenous analysis. Finally, prospective studies regression, loss of activities of daily and/or oral steroids, mycophenolate are needed to understand the long- living, psychomotor changes, and mofetil, intravenous term prognosis and the effectiveness insomnia, which may permanently immunoglobulins, and rituximab. The of therapies for this unique and alter the adaptive and social functions troubling condition. clinical benefit in the domains of 4–6 of persons with DS. Both patients hallucinations, mood, autistic and families are impacted by this features, and insomnia was condition. Additional research is ABBREVIATIONS immediate in 3 of 4 patients, whereas urgently needed with particular focus 1 patient showed a clinical on identification of the AD: Alzheimer disease improvement in ∼3 months.11 pathophysiology of the syndrome and DS: Down syndrome Catatonia was present in all patients the interplay between DSDD and DSDD: Down syndrome who responded completely to other chronic comorbidities seen in disintegrative disorder immunotherapy. Approximately 50% patients with DS. ECT: electroconvulsive therapy of patients experienced an HE: Hashimoto encephalopathy improvement in sleep disturbance Prospective studies are needed to SSRI: selective serotonin reuptake and autistic behaviors. These results identify the effective therapies for each inhibitor may lend more credence to the of the symptoms in DSDD. Several

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 145, number 6, June 2019 7 POTENTIAL CONFLICT OF INTEREST: Dr Skotko has received payment for expert witness testimony related to Down syndrome (but not Down syndrome disintegrative disorder); the other authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 30, 2021 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 originally published online May 29, 2020;

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