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https://doi.org/10.1007/s00415-020-10179-w
REVIEW
Abstract
Down syndrome (DS) is one of the most well-recognized genetic disorders. Persons with DS are known to have a variety
of co-morbid medical problems, affecting nearly all organ systems. Improved healthcare interventions and research have
allowed for increased life span of persons with DS, although disorders of the neurologic system remain underexplored. The
purpose of this systematic review is to provide clinically pertinent information on the neurological phenotypes of frequently
occurring or clinically relevant conditions. A retrospective review of MEDLINE, Scopus, and Pubmed were used to identify
sources among seventeen, clinically relevant, search categories. MeSH terms all contained the phrase “Down Syndrome”
in conjunction with the topic of interest. ‘Frequently-occurring’ was defined as prevalent in more than 10% of persons with
DS across their lifespan, whereas ‘clinically-relevant’ was defined as a disease condition where early diagnosis or interven-
tion can augment the disease course. In total, 4896 sources were identified with 159 sources meeting criteria for inclusion.
Seventeen clinical conditions were grouped under the following subjects: hypotonia, intellectual and learning disability,
cervical instability, autism spectrum disorder, epilepsy, cerebrovascular disease, Alzheimer’s disease and neuropsychiatric
disease. The results of this review provide a blueprint for the clinical neurologist taking care of persons with DS across the
age spectrum and indicate that there are many underrecognized and misdiagnosed co-occurring conditions in DS, highlight-
ing the need for further research.
Keywords Down syndrome · Trisomy 21 · Neurologic disorders · Epilepsy · Hypotonia · Cerebrovascular
Introduction
* Jonathan D. Santoro
santoroj@usc.edu Down syndrome (DS) is one of the most common genetic
disorders and the most common genetic cause of intellec-
1
Keck School of Medicine at the University of Southern tual disability overall [1]. DS affects 1 in every 700 infants
California, Los Angeles, CA, USA born in the United States [2]. Initially described by Dr. John
2
Division of Neurology, Department of Pediatrics, Children’s Langdon Down in 1866, the genetic cause of DS was identi-
Hospital Los Angeles, Los Angeles, CA, USA fied in 1950 as a third copy of chromosome 21 due to non-
3
Department of Neurology, Keck School of Medicine, disjunction, mosaicism, or in rare cases, translocation [1].
University of Southern California, Los Angeles, CA, USA The presence trisomy of chromosome 21 accounts for exces-
4
Faculty of Medicine, Queen’s University, Kingston, ON, sive production of specific proteins, resulting in comorbidi-
Canada ties such as acute lymphocytic leukemia (ALL) and Alzhei-
5
Department of Neurology, Medical University of South mer’s disease (AD). DS presents with the hallmark physical
Carolina, Charleston, SC, USA traits of a flat nasal bridge, up-slanting palpebral fissures,
6
Department of Pediatrics and Program in Developmental brachycephaly, low-set ears, and a single palmar crease [3].
Neuroscience and Developmental Neurogenetics, The Saban Other associated congenital malformations include atrioven-
Research Institute, Children’s Hospital Los Angeles, Keck
School of Medicine, University of Southern California,
tricular septal defects, Hirschsprung’s disease, and atlanto-
Los Angeles, CA, USA axial joint instability [4].
7
Alzheimer’s Therapeutic Research Institute (ATRI), Keck
In the last few decades, the lifespan of persons with DS
School of Medicine, University of Southern California, (PwDS) has increased from just 10 years in 1960 to 47 years
Los Angeles, CA, USA
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Journal of Neurology
in 2013 [5]. As such, PwDS now present with new chronic Inclusion criteria
comorbidities that could not previously be diagnosed.
Among these, several neurologic comorbidities have now (1) The study must specifically include PwDS, (2) data
come to light ranging from intellectual disability to cerebro- included > 2 patients (no case reports), (3) study was pub-
vascular disorders [6]. lished after 1980, (4) study was published in the English
The purpose of this systematic review is to provide high- language.
level, clinically relevant, information on the neurologic con-
ditions observed across the lifespan in PwDS. Early diag-
Exclusion criteria
nosis of these neurological presentations is crucial to foster
the necessary care and improve prognosis and quality of
(1) Data reported previously published in another study,
life in PwDS.
(2) data reported did not address the neurologic disorder
searched, (3) data reported were unable to be analyzed for
PwDS specifically (e.g. only persons with intellectual dis-
Methods ability reported), (4) review articles that did not include
primary literature. Data that did not address the neurologic
Topic selection disorder searched were moved to other sub-categories/diag-
noses when appropriate. Systematic reviews and meta-anal-
Seventeen neurologic conditions were identified as fre- yses were included.
quently occurring or clinically relevant by the authors. ‘Fre-
quently-occurring’ was defined as prevalent in more than
10% of PwDS across their lifespan, whereas ‘clinically-rel-
evant’ was defined as a disease condition where early diag- Results
nosis or intervention can augment the disease course. All
topics were then grouped under disease area headings (e.g. In total, 4896 sources were identified across 17 search areas.
“epilepsy” or “cerebrovascular disease”) when appropriate. Of these, 1800 (36.8%) were reviewed beyond the abstract
level and 272 (5.56%) were reviewed in full. The most fre-
quent reasons for exclusion were titles being unrelated to the
Literature search topic (43.3%), abstracts demonstrating information unrelated
to the topic (27.7%), full review revealing the source was
A search of MEDLINE, Scopus, and Pubmed was conducted unrelated to the topic (2.5%), sources were published in a
for English language articles published between 1980 and language other than English (9%), were published before
2020. The authors used Medical Subject Headings [(MeSH); 1980 (7%), were case reports (4%), were referring to intel-
the NLM controlled vocabulary thesaurus for indexing] to lectual disability rather than DS specifically (0.65%), or
capture related entry terminology in our searches. All MeSH were duplicates of another source (0.45%). Table 1 reports
terms searched included the term “Down syndrome.” MeSH articles reviewed for each topic in this manuscript.
search terms are detailed in Appendix A. Of note, utilization
of the MeSH term Down syndrome also included 13 other
entry terms including but not limited to trisomy 21 (Appen-
dix A). The search, while broad, was not without limitation Hypotonia
as it was possible that certain manuscripts not utilizing these
terms may have been missed with such a screen, although Hypotonia, defined as low resting muscle tone, has been
this was felt to be the most systematic approach possible for reported in nearly 80% of newborns with DS [7–10]. Chil-
this type of review. dren with DS have previously been reported to have lower
resting tone than neurotypical children and have further been
found to have diminished strength, patellar reflexes, muscle
Literature review
girth, and grip strength [11–14].
The impact of hypotonia is far-reaching—it is the chief
All search results were reviewed at the title level by two
cause of gross motor delay, failure-to-thrive, and vari-
authors (DP and JDS.) Duplicate studies were removed.
ous musculoskeletal abnormalities in this population. For
Studies that were consistent with the topic searched were
instance, hypotonia in infants with DS is one of the causes
subsequently reviewed at the abstract level. Studies meet-
for the high incidence of feeding issues and subsequent
ing inclusion criteria were then reviewed in full by the same
failure-to-thrive, seen in as many as 60% of infants with
authors. Discrepancies in evaluations were arbitrated by
DS [15–17]. Hypotonia of tongue muscles and weakness
another author (KP) when required.
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of jaw muscles results in weak suck and a lack of coordina- Hearing and visual impairment
tion in the suck/swallow/breathe sequence during feeding
[18]. Feeding difficulties tend to improve by age 3 months Some of the behavioral and cognitive phenotypes of DS
and resolve by 8 months of age [19]. The early identifica- can be attributed to comorbidities like visual and auditory
tion and initiation of physical and speech/oral therapy are impairments [26]. Between 47.4 and 85% of PwDS are
warranted for PwDS to reach the appropriate fine and gross reported to have some form of hearing impairment, with
motor milestones. middle ear effusion or other types of conductive hearing loss
as the most common etiology and sensorineural hearing loss
accounting for 2.7–4.5% [27–30]. The prevalence increases
Intellectual and learning disability with age and higher frequencies are the most affected [31].
Hearing loss in PwDS has been associated with poorer
Intellectual disability speech and language development [32]. Vision impairments
are also common, with one study finding a prevalence of
DS is the most common genetic cause of intellectual dis- 43.3% of moderate-to-severe impairment among 91 PwDS
ability, which can be seen in nearly all PwDS [12]. However, [33]. Refractive errors, strabismus, epiphora, and nystagmus
the degree of intellectual disability exists on a spectrum. In are the most common ocular findings [34–36]. In a clini-
one study of intelligence quotients in PwDS (n = 121), 19% cal setting, these impairments may potentially complicate
had an IQ of 50–69, 30% had an IQ of 35–49, 33% had an a neurological exam and should be screened for with very
IQ of 20–34, and 18% had an IQ less than 20 [20, 21]. A low threshold.
Norwegian observational study similarly reported that the
severity of ID in PwDS was 25% mild, 56% moderate and
21% severe, although this was by parent report [22]. PwDS Atlantoaxial instability
exhibit a specific pattern of ID where nonverbal skills appear
to develop normally, whereas language skills become defi- Cervical or atlantoaxial instability is defined as excessive
cient and never fully recover. Limited diction and difficulties movement/ligamentous laxity between the C1 and C2 verte-
with syntax are prominent areas of impairment [23]. The brae. Its prevalence in PwDS ranges between 9.5 and 14.6%,
verbal skills of PwDS are greater in the expressive domain with 1.5–3.8% of these cases becoming symptomatic, typically
of language than in language comprehension (receptive lan- in the pre-teen and teen years [37–39]. Symptoms are usually
guage) [24]. PwDS are also found to have a shorter atten- caused by compressive myelopathy, which can present as a
tion span and diminished short-term and working memory decrease in muscle strength and tone, hyperreflexia, and gait
[23]. Due to these impairments, several interventions are instability [37, 38]. Bowel and bladder symptoms are only
needed for PwDS to thrive from a neurocognitive standpoint. present in severe cases of cervical myelopathy secondary to
These school-based interventions start in early childhood atlantoaxial instability [40, 41]. In terms of screening guide-
and require skilled therapists. During school enrollment, the lines for PwDS, the American Academy of Pediatrics (AAP)
focus shifts toward individualized programs that allow the no longer recommends routine X-rays in children with DS and
child to be educated without excessive restrictions, optimiz- PwDS who participate in high-risk contact sports [42]. Their
ing self-directed activities and decision-making. Finally, the rationale is related to the low prevalence of symptomatic cases,
transition to adulthood and, for some, working life is also a low reliability of X-rays, and an inability to predict the risk of
crucial [25]. spinal myelopathy on radiographs [42–45]. Current guidelines
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recommend obtaining comprehensive histories and assessing distribution: the onset is prior to age one in 40% of subjects
for symptoms such as neck pain, gastrointestinal complica- and over age 30 in another 40% [64]. Among infants with
tions, and neurological signs like changes in gait, muscle PwDS, the predominant cause of seizures is infantile spasms
strength and tone, and hyperreflexia before pursuing imaging (IS), while in older PwDS, late-onset myoclonic seizures
[21]. appear to be the chief cause of epilepsy. The most common
types of seizures in PwDS include partial seizures (47%),
Down syndrome and autism spectrum IS (32%), and generalized tonic–clonic seizures (21%) [63,
disorders 65, 66].
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therapies for children with DS and IS, a retrospective study Cerebrovascular disease
has identified that ACTH may be superior to other therapies
like oral steroids or vigabatrin [75]. Cerebrovascular disease in PwDS has been increasingly
recognized over the last 2 decades, prompting earlier iden-
tification and therapy. The two most commonly identified
Lennox‑Gastaut syndrome conditions are Moyamoya syndrome (MMS) and cerebral
amyloid angiopathy (CAA).
Lennox-Gastaut syndrome (LGS) is an epileptic encepha-
lopathy characterized by recurring seizures of multiple Moyamoya syndrome
semiologies that appears in early childhood and may impair
cognitive and behavioral development. There is a possibil- MMS is a rare cerebrovascular disease wherein arterial ves-
ity of IS preceding and inducing the onset of LGS, but as of sels, specifically the internal carotid, become stenotic lead-
now, this has only been postulated among individuals with- ing to intracranial collateral vessel formation. As a result,
out DS [76–78]. LGS has a prevalence between 0.4 and 7.7% patients with MMS are at risk for both ischemic and hem-
in PwDS [79, 80]. It has a mean age of onset of 9.1 years, orrhagic strokes (Fig. 1). The prevalence of MMS is 3.8%
has a notably high incidence of reflex seizures, and is drug in PwDS and as high as 9.5% in PwDS under 15 years of
resistant, requiring multiple anti-convulsant therapeutics to age [96]. While a bimodal distribution in the age of onset
effectively reduce seizure activity [70, 81]. has been established in the idiopathic MMS population,
this has not been reported in PwDS [97]. Patients present
with a bilateral infarction at onset, with 87% presenting with
Epilepsy later in life strokes and with a minority classified as transient ischemic
attacks (TIAs). The majority of strokes were ischemic (77%
The most common types of seizures in PwDS after age 30 in one study) with hemorrhagic strokes being rare [98].
are partial seizures and generalized tonic–clonic seizures Acute onset hemiplegia has been reported as the most com-
[63, 65, 82]. PwDS commonly present with slowed back- mon presentation, with aphasia being another common
ground activity and sharp and slow waves in the frontal leads
on EEGs [83].
A unique form of epilepsy in PwDS is late-onset myo-
clonic epilepsy in DS (LOMEDS). Often diagnosed after
40 years of age, it is also known as senile myoclonic epi-
lepsy and is considered as a subtype of progressive myo-
clonic epilepsy [84, 85]. This syndrome is characterized by
its clinical hallmarks and EEG features: patients present with
myoclonus and generalized tonic–clonic seizures with poly-
spike waves amidst slow background activity on EEG [83,
85–89]. Seizures classically manifest upon awakening [86].
A few recent studies indicate that LOMEDS may be under-
reported [90]. In terms of therapeutic options, levetiracetam
appears to be the most effective therapy, although further
research is required [86–88, 91].
The prevalence of seizures later in life in persons with
DS may be greater in the presence of AD, where 45–84% of
PwDS with AD also experience seizures, most commonly
generalized tonic–clonic seizures [66, 92–94]. The underly-
ing nature of this association is unclear but may be related to
an accelerated cognitive decline due to seizure activity [91,
93]. A recent study explored this mechanism and showed
that seizure activity may augment the production and release
of Aβ in hyperexcitable neurons, in addition to physically
and chemically damaging the hippocampus. The combined Fig. 1 Preoperative frontal view of the right internal carotid artery
mechanism establishes a vicious circle where seizures pre- angiogram demonstrates occlusion of the internal carotid artery dis-
tal to the posterior communicating artery and extensive parenchymal
dispose to additional neurologic insults and further cognitive (moyamoya “puff of smoke”) collaterals, Suzuki stage III. Published
decline [95]. with permission from Wolters Kluwer Health, Inc [100]
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clinical sign. These localizing findings are not unexpected diagnosed after age 50, signs of microbleeds possibly asso-
given that vessels of the middle cerebral artery are most ciated with CAA have been reported in PwDS as young
commonly affected. The largest study on children with DS as 30 [102, 103]. Moreover, another study found evidence
and MMS identified hypertension as a critical predictor of of microbleeds in the context of CAA in pediatric patients
future strokes. This study showed that PwDS with MMS with a mean age of just 5 years [104]. The reason for these
presented with hypertension up to 12 months prior to presen- earlier presentations in PwDS may be the additional chro-
tation, which can be explained as a dramatic auto-regulatory mosome 21 which contains the gene responsible for the
phenomenon of blood pressure in severe disease [98]. The production of amyloid precursor protein (APP). The clini-
prognosis in PwDS with MMS appears fairly good, where cal neuroimaging spectrum of CAA is wide, ranging from
almost all patients recover from their neurological, motor, intraparenchymal and subarachnoid hemorrhage to cortical
or language deficits. A minority of patients experienced one microbleeds and grey matter inflammation (Fig. 2). This
or more seizures, headaches or incomplete motor recovery, wide neuroimaging variability mirrors heterogenous clini-
and imaging tended to exhibit successful revascularization cal presentation in PwDS with CAA. These patients may
[99–101]. Given the permanent neurologic disability asso- experience seizures, focal weakness, progressive neuro-
ciated with stroke, early identification and intervention is cognitive decline, or a combination of the three.
critical in persons with DS and MMS. There are no definitive interventions for any person
with CAA and current research is focused on finding a
Cerebral amyloid angiopathy therapeutic target [102]. Thus far, amyloid appeared to
be a poor target, as shown in the recent clinical trial of
CAA is characterized by an accumulation of amyloid immunotherapy with ponezumab [105]. At present, the
proteins in the cerebral vessels. While CAA is frequently main focus of research on CAA is on finding biomarkers
for therapeutic targeting [102].
Fig. 2 Schematic representation of the neuroimaging spectrum of a Computerized tomography scan. e Inflammatory reaction in FLAIR
manifestations of cerebral amyloid angiopathy. a Convexal suba- sequence. f Dilated perivascular spaces in T2-weighted sequence. g
rachnoid atraumatic hemorrhage in a FLIAR sequence. b Microin- White matter hyperintensities in FLAIR sequence. h Cortico-subcor-
farcts in diffusion weighted imaging. c Cortical superficial siderosis tical microbleeds in susceptibility weighted imaging. Published with
in T2*gradient echo sequence. d Lobar intracerebral hemorrhage in permission from John Wiley and Sons [129]
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specifically amitriptyline, and electroconvulsive therapy as The exact etiology of DSDD is unknown. Studies have
well, although further research is needed [140, 147–149]. noted that many patients experienced an emotional stressor
prior to the onset of DSDD, with the most common events
Catatonia being changing schools or separation from parents [156,
157]. Although stressors are commonly reported, neuro-
Catatonia is characterized by aberrant movement, posture, inflammation has been proposed as a possible underlying
and behavior associated with an altered mental state (Fig. 3) pathobiological cause. Given that data are emerging on this
and is reported as early as 1946 in persons with DS [150]. potential disease entity, early identification and referrals
The age of onset of catatonia in individuals with DS is vari- to specialists who are familiar with DSDD is encouraged.
able, ranging from 8 to 33 years. PwDS with catatonia are Proposed therapies for this condition include antipsychotics
likely to suffer from other comorbid conditions, including such as aripiprazole and risperidone, antidepressants such as
ASD, autoimmune hypothyroidism, and exposure to adverse paroxetine, and IV immunoglobulins [157, 158].
life events [151–153]. Catatonia can be successfully treated
with pharmacological drugs such as benzodiazepines (e.g.
lorazepam), dextromethorphan, quinidine, and electrocon- Conclusion
vulsive therapy [151–155].
As the lifespan of PwDS expands, PwDS are bound to pre-
Down syndrome regression or Down syndrome sent with previously unseen conditions, including several
disintegrative disorder neurological disorders. As such, it is essential that neurolo-
gists and primary care physicians be familiar with these
Down syndrome regression disorder or Down syndrome presentations. Finally, it is fundamental to be cognizant of
disintegrative disorder (DSDD) is characterized by rapid underreported neurological presentations that may affect
regression with symptoms like mutism, a loss in the ability PwDS and severely impact their quality of life.
to complete activities of daily living, psychiatric symptoms
Author contribution Not applicable.
including catatonia, insomnia and other sleep disturbances,
and cognitive decline [156–158]. Cognitive decline with
Funding Not applicable.
autistic regression was reported as one of the most common
symptoms [156]. Although the first report of DSDD may be Data availability Not applicable.
traced back to 1946, literature on this entity has increased
dramatically in the last decade [150]. Code availability Not applicable.
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Conflicts of interest The authors report no disclosures. Search Phrase Using MeSH Terms: (“Autism Spectrum
Disorder”[Mesh]) AND “Down Syndrome”[Mesh].
Ethical approval Not applicable.
Search Phrase Using MeSH Terms: (“Vision, Low”[Mesh]) Cerebral amyloid angiopathy
AND “Down Syndrome”[Mesh].
Search Phrase Using MeSH Terms: (“Hearing Search Phrase Using MeSH Terms: (“Cerebral Amyloid
Loss”[Mesh]) AND “Down Syndrome”[Mesh]. Angiopathy”[Mesh]) AND “Down Syndrome”[Mesh].
Cervical instability
S e a r ch P h r a s e U s i n g M e S H Te r m s : ( “ J o i n t
Instability”[Mesh]) AND “Down Syndrome”[Mesh].
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