Down Syndrome Disintegrative Disorder: A Clinical Regression Syndrome of Increasing Importance

In 1946, Rollin⁶  described a cohort of 73 institutionalized adolescents and young adults with DS, 17 (23.3%) of whom were diagnosed with “catatonic psychosis.” These individuals had an appropriate developmental period followed by behavioral changes, including agitation and harm directed toward self and others, during early adolescence (ages 11–14) that led their families to seek institutional care. Afterward, they experienced a deterioration phase marked by incontinence, mutism, apathy, social withdrawal, occasional behavioral outbursts, and psychosis, eventually leading to catatonia.

In 2000, Kerbeshian and Burd⁷  provided a clinical description of autistic-like regression in a child with DS. In this study, the authors described an 8-year-old girl with DS who experienced autistic regression (loss of social and communication skills), loss of cognitive functions, and a rapid-onset insomnia, referring to this condition as autistic-like regression.⁷  Subsequently, in 2015, Worley et al⁴  presented similar case reports and characterized DSDD as a subacute onset of “autistic regression,” cognitive decline resulting in a dementia-like state, occurring at an older age typical for autistic regression, and no other established diagnosis to explain the condition (Table 1).⁸ 

The demographic profile of DSDD includes a postpubertal onset and an elevated female/male patient ratio of 2:1.^4,5  A defining feature of DSDD is regression of previously attained skills, notably in the domains of language, communication, and social skills. No formal criteria exist within the diagnosis of DSDD to define either regression or autistic-like behavioral regression; however, some groups have used the Diagnostic and Statistical Manual of Mental Disorders criteria of autism spectrum disorder to aid in standardization of phenotypic description for the latter phenomenon.^4,9  Diagnosis by using these guidelines involves new-onset impairments in social interaction; communication; stereotyped patterns of movement, behavior, and thought; and developmental delays.⁹  At baseline, autism can be present in roughly 15% of children with DS; however, a previous diagnosis of autism was not observed in any of the studies reviewed in this report.¹⁰  DSDD is an entity that is believed to be distinct and separate from autism spectrum disorder.

Beyond regression, symptoms of DSDD can be heterogenous and are reported with variability (Table 2). In 3 large studies, up to 87% of patients with DSDD were diagnosed with language regression, with symptoms ranging in severity from dysfluency to mutism.^5,11,12  Among patients in whom severity of language regression was quantified, 38% had partial language regression and 52% had mutism.^5,11,12  Mood symptoms are also reported and include depression (42%), social withdrawal (34%), and anxiety (16%).^5,12,13  In recent studies, catatonia was observed in 47% of cases labeled as DSDD, which is higher than rates originally reported by Rollin⁶  (38%).^5,11,12  New-onset insomnia was also described in 43% of cases.^4,5,7,11,12  Pooled estimates from 4 studies revealed a 14% rate of psychotic symptoms, including delusions and hallucinations, in persons with DSDD.^4,5,11,12  Aggressive behavior was reported in 42% of patients.^2,5,11,13  As was highlighted by Mircher et al,⁵  aggression in persons with DSDD may be directed toward self (auto-aggression) or others (hetero-aggression). A minority of patients with DSDD (12%) also had anorexia as part of their clinical presentation.^11,12 

Because there are no diagnostic criteria available, DSDD is best described as a clinical syndrome that should be considered in adolescents and young adults with DS and subacute-onset behavioral changes.¹³  It is also key to appreciate that persons with DS may experience adaptive, social, or cognitive regression for reasons other than DSDD, making a complete workup critical in the assessment of these patients (see Evaluation and Differential Diagnosis). Compared with the typical onset of autistic regression in persons with DS, DSDD takes place when patients are older, typically between the first and third decade.^4,13  The acute regression appears to last for ∼6 months and is followed by a chronic phase in which previous skills may not be completely recovered (Table 3). In 2 studies, it has been reported that 58% of persons with DSDD experience a partial or total recovery. Only 7.5% of patients experience additional worsening, whereas 35% of patients stabilize.^4,5  However, in patients with stabilizing DSDD, a complete recovery to the premorbid baseline condition appears to be infrequent.^2,4 

The imaging features of DSDD are heterogenous, and no defining characteristics have been identified. Across 5 studies, abnormal MRI findings were found in 26% of patients (n = 9 of 35).^4,5,11,12  The imaging findings were described to be dementia-like in 2 cohorts in which hippocampal atrophy was reported in 20% of patients (n = 4 of 20).^5,12  In other studies, there has been a failure to find any imaging findings associated with DSDD, which may reflect the significant heterogeneity of the study cohorts.^2,4,11 

Whereas the etiology of DSDD is not fully understood, 2 possible causes that have been proposed are immune dysregulation and psychological stress triggering neuropsychiatric presentations (analogous to Rollin’s⁶  original report). The demographic profile of DSDD includes a postpubertal onset and an elevated female/male patient ratio of 2:1 in the 2 largest studies to date.^4,5  This finding has raised the suspicion that inflammation may play a role in the etiology of DSDD because this demographic is mirrored in other inflammatory disorders such as multiple sclerosis and autoimmune encephalitis.^4,5,13,15  Additionally, recent research has revealed the presence of other autoantibodies, such as antinuclear antibodies, anti-microsomal antibodies, striational antibodies, thyroperoxidase antibodies, and anti-tissue transglutaminase antibodies, which have elevated levels in some individuals with DSDD.¹¹  These findings may be understood as a consequence of DS, which is generally associated with high serum levels of proinflammatory cytokines, high rates of complement protein consumption, and various other forms of immune dysregulation.¹⁶  As the autoimmune etiology of several psychiatric syndromes becomes increasingly accepted, researchers speculate that some cases of DSDD may be driven by autoimmunity.^17,18 

Elevated serum and cerebral spinal fluid levels of anti-thyroperoxidase antibodies found in some patients with DSDD have led some researchers to propose Hashimoto encephalopathy (HE) as an underlying etiology. Across 4 studies, 35% of persons with DSDD (n = 16 of 46) had high titers of anti-thyroperoxidase antibodies, although the agreement between these studies is considered poor because rates range from as low as 20% (Mircher et al,⁵  n = 15 tested) to as high as 82% (Worley et al,⁴  n = 11 tested).^11,13  Epidemiological studies have revealed that thyroid disease has a greater prevalence in patients with DSDD than in the general population.⁴  In addition, the rates of thyroid disease increase with time, as does the prevalence of thyroperoxidase antibodies, with rates up to 22% in asymptomatic patients.¹⁹  The significance of anti-thyroperoxidase antibodies is unclear because steroid therapy, the gold standard treatment of HE, has revealed no clinical benefit in DSDD.⁴  HE also differs from DSDD because it presents with seizures, headaches, hallucinations, and ataxia. Although HE can present as an isolated psychiatric illness, this presentation is rare in children.^20,21  Thus, additional studies are needed to fully elucidate the pathologic role of anti-thyroperoxidase antibodies in patients with both DS and DSDD (Table 4).

An alternative hypothesis proposes that psychological stress may act as a trigger of regression in DSDD (Fig 1). In their studies, Stein et al²²  and Mircher et al⁵  postulated that such behavioral changes may be a way for persons with DS to express distress in the context of their developmental delays. Across 3 studies, 86% of persons with DSDD (n = 30 of 35) reported identifiable life stressors preceding the onset of symptoms. In the largest study of 30 patients, Mircher et al⁵  described a new school environment as the most common life stressor preceding a diagnosis of DSDD (51%).^11,22  Other common stressors were awareness of disability triggered by the wedding or departure of a sibling (23%), assault (17%), illness of a close one (13%), and overstimulation (10%).⁵  Although notable, many children with DS experience similar stressful triggers and do not have similar neuropsychiatric changes, rendering stress-related triggers an incomplete explanation. Stein et al²²  also reported on the role of environmental changes as potential triggers for regression in DSDD. In their case study, the authors reported that a patient with DS developed reactive depression after moving to a new city and changing schools.²³  The authors postulated that the patient dealt with distress through complex behavioral and adaptive changes because she failed to express her distress with the usual verbal channels.²²  This description would exist on the spectrum of an acute stress reaction as opposed to a primary psychiatric disease and thus may explain the recovery noted in patients over time. Mircher et al⁵  put forth a hypothesis that explains the susceptibility in terms of widespread dysregulation of serotoninergic and cholinergic circuits. If this were the case, DSDD may be amenable to treatment with selective serotonin reuptake inhibitors (SSRIs), which have only been explored in a few studies thus far.^24,25 

An exact etiology of DSDD remains difficult to identify, although components of immune dysregulation, psychiatric symptoms in persons with intellectual disability, and dysregulated cholinergic and serotonergic circuits may be involved (Fig 1). Although the role of inflammation in neuropsychiatric disease continues to evolve, the combination of neuroinflammation, autoantibody generation, and/or cytokine dysregulation could interface with existing psychological capacities to cope with external stressors and the baseline circuity of these responses. For this reason, additional investigation into the cause of this potentially polyfactorial phenomenon is needed.

At this time, DSDD is best described as a constellation of symptoms without a distinct etiology. Thus, clinicians should pursue a comprehensive psychosocial and medical evaluation of potential secondary causes of behavioral change and regression. In their article, Jacobs et al¹³  provide a suggested diagnostic workup for such cases organized in 5 different tiers of testing (Table 5). The first 2 tiers are common causes of a new onset of psychiatric symptoms in young adults with DS, which include psychosocial stressors, depression, electrolyte disturbances, infections, liver disease, thyroid disorders, and immunologic disorders. Common co-occurring conditions associated with DS should also be considered such as sleep apnea, acid reflux, celiac disease, and constipation. Another diagnosis in tier 2 is pediatric acute-onset neuropsychiatric syndrome, which displays some overlap with DSDD. Persons with pediatric acute-onset neuropsychiatric syndrome may present with a subacute onset of abnormal motor movements, tics, and obsessive-compulsive symptoms, although caution should be exercised before making this diagnosis, as well, given the heterogenous diagnostic and clinical criteria.

Multiple genetic conditions can occur in the same patient, and because DS is one of the most common genetic disorders, evaluation for other genetic disorders should be considered. Two important diagnoses to evaluate for are Fragile X syndrome and Rett syndrome, which are 2 important genetic causes of regression in early childhood. By the same token, inborn errors of metabolism are possible causes of regression and behavioral abnormalities in children and young adults. These syndromes are characterized by an inability to process certain metabolites, including amino acids, fatty acids, or organic acid. A final differential diagnosis to be aware of is Lesch-Nyhan syndrome, the presentation of which may closely resemble DSDD, except that onset is typically in infancy or early childhood. Patients with Lesch-Nyhan syndrome present with a combination of a regression of intellectual skills, dystonic movements, and compulsive self-mutilation because of a failure of purine metabolism.²⁶  These genetic conditions typically present in early childhood rather than adolescence and young adulthood like DSDD, but delayed diagnosis is plausible.

Finally, it is important to note that DS is associated with several psychiatric conditions. As previously mentioned, DSDD differs from other forms of autistic regression in the later age at onset, high female/male patient ratio, and presence of additional symptoms such as insomnia and catatonia.^4,5  In the presence of stressful triggers, primary psychiatric disorders, such as major depressive disorder, bipolar disorder, and anxiety disorders, may have symptoms that mimic a regression.²⁷  These disorders should be evaluated thoroughly because they unify the presence of environmental triggers and associated neuropsychiatric disease, although diagnosis can be challenging in persons with intellectual disability.²⁸  A key point to consider is that the presence of mild baseline psychiatric disease and exposure to stressful triggers may yield regression-like symptoms, although this likely exists along a complex spectrum. One final important differential diagnosis to consider is early-onset Alzheimer disease (AD), which continues to be an important differential for patients with DSDD.¹¹  Early-onset AD is common in patients with DS owing to the 3 copies of chromosome 21 (and thus 3 copies of amyloid precursor protein genes) carried by these patients. Early-onset AD differs from DSDD because of the later onset between the ages of 40 and 60 years and its steady and irreversible decline, as opposed to the subacute and partially reversible decline observed in DSDD.²⁹  However, AD onset may occur earlier than age 40 and may be exacerbated by factors similar to those reported in DSDD.³⁰ 

Of note, the diagnosis of DSDD is based on clinical phenotype, and for this reason, it is important to realize that this syndrome may be produced by multiple causes. This is a necessary consideration regarding not only the need for a standardized workup but also the need for choosing the most appropriate intervention.

Several therapies have revealed some clinical benefit in patients with DSDD. Symptomatically, antipsychotics (eg, risperidone), SSRIs (eg, fluoxetine and sertraline), and anticholinergic drugs (eg, donepezil and rivastigmine) have been used to address many of the neuropsychiatric disturbances observed in DSDD.⁴  In 3 recent studies, 25% of patients showed a response to SSRIs, which seem to improve mood symptoms, motor symptoms, and sleep disturbance.^12,31  Tamasaki et al³¹  reported a case study of a 14-year-old boy with DSDD symptoms who was treated with donepezil, which led to a complete psychosocial recovery; however, the efficacy of cholinergic medications for cognitive impairment in individuals with DS is debatable, and they are not US Food and Drug Administration approved for children and adolescents.^32,33  Another therapeutic option for persons with DSDD is antipsychotic treatment. Across 4 studies, 70% of patients experienced at least some improvement in motor symptoms, sleep disturbance, and catatonia with antipsychotic therapy.^2,12,13 

Ghaziuddin et al²  reported that high-dose benzodiazepines, such as lorazepam, could benefit patients with DSDD and catatonia. Across 4 studies, 91% of patients with DSDD and catatonia demonstrated at least a partial response to benzodiazepines; however, catatonia was unresponsive to benzodiazepines in only 1 patient.^2,11–13  Electroconvulsive therapy (ECT) has also been shown as an effective therapy for DSDD with catatonia that warrants careful consideration by clinicians.²  However, ECT can have several complications, including the requirement of sedation, the potential for memory impairment and neurocognitive sequelae, and the need for repeated ECT sessions to maintain symptom remission; thus, it should be considered in conjunction with specialists experienced with its use in DS.³⁴  In a recent case report, administering high doses of the antipsychotic clozapine was the only effective treatment of catatonia and was started after other treatment options were exhausted.¹³  It is crucial to consider that catatonia may be a symptom of DSDD because it may be easily mistaken for schizophrenia or another psychiatric disorder (Table 6).² 

Newer therapies have been proposed that target the hypothesized autoimmunity etiology of DSDD. Cardinale et al¹¹  explored the use of various immunotherapeutic regimens in 4 patients with DSDD who had positive serum autoantibody screening results. Different regimens were attempted because of the side effects associated with many of these treatments, which required treatment discontinuation in many instances. The regimens included intravenous and/or oral steroids, mycophenolate mofetil, intravenous immunoglobulins, and rituximab. The clinical benefit in the domains of hallucinations, mood, autistic features, and insomnia was immediate in 3 of 4 patients, whereas 1 patient showed a clinical improvement in ∼3 months.¹¹  Catatonia was present in all patients who responded completely to immunotherapy. Approximately 50% of patients experienced an improvement in sleep disturbance and autistic behaviors. These results may lend more credence to the hypothesis of an immunologic component in the pathophysiology of DSDD for individuals with positive autoantibody screening results, but in this study, a limited cohort was analyzed, and additional studies with larger cohorts are needed.⁴  However, as noted above, the presumed etiology may differ between cases; thus, the choice of therapeutic intervention should mirror this because multiple causes could produce the same clinical phenotype.

DSDD is a recently redefined constellation of symptoms, including mood lability, socio-communicative regression, loss of activities of daily living, psychomotor changes, and insomnia, which may permanently alter the adaptive and social functions of persons with DS.^4–6  Both patients and families are impacted by this condition. Additional research is urgently needed with particular focus on identification of the pathophysiology of the syndrome and the interplay between DSDD and other chronic comorbidities seen in patients with DS.

Prospective studies are needed to identify the effective therapies for each of the symptoms in DSDD. Several classes of therapies have revealed some clinical benefit (ie, benzodiazepines and ECT for catatonia and SSRIs for mood symptoms), but a standardized treatment guideline should be developed. Future studies will also be needed to elucidate the role of immune dysregulation in DSDD and the effectiveness of immunotherapies in larger cohorts.

Molecular biomarkers and radiologic hallmarks also need to be identified that correlate with the clinical findings. Additionally, truly separating the symptoms of DSDD from chronic comorbidities associated with DS will be a necessary component of future analysis. Finally, prospective studies are needed to understand the long-term prognosis and the effectiveness of therapies for this unique and troubling condition.

AD

Alzheimer disease

DS

Down syndrome

DSDD

Down syndrome disintegrative disorder

ECT

electroconvulsive therapy

HE

Hashimoto encephalopathy

SSRI

selective serotonin reuptake inhibitor