Catatonia in Down syndrome: systematic approach to diagnosis, treatment and outcome assessment based on a case series of seven patients

Abstract

Objective
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.

Study design
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.

Results
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.

Conclusion
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.

Full text

CASE SERIES
Catatonia in Down syndrome: systematic approach
to diagnosis, treatment and outcome assessment
based on a case series of seven patients
This article was published in the following Dove Press journal:
Neuropsychiatric Disease and Treatment
Judith H Miles
1,2
Nicole Takahashi
2
Julie Muckerman
2
Kerri P Nowell
2,3
Muaid Ithman
4
1
Department of Child Health, University
of Missouri Healthcare, Columbia, MO,
USA;
2
Thompson Center for Autism and
Neurodevelopmental Disorders,
University of Missouri, Columbia, MO,
USA;
3
Department of Health Psychology,
University of Missouri Healthcare,
Columbia, MO, USA;
4
Department of
Psychiatry, University of Missouri Health
Care, Columbia, MO, USA
Objective: 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.
Study design: Young adults with Down syndrome were consecutively enrolled in the study
as they were diagnosed with catatonia. A comprehensive data set included medical, labora-
tory, 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.
Results: 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 antago-
nists (dextromethorphan/quinidine, memantine, minocycline). Responses to each treatment
modality were assessed at clinic visits and through weekly electronic CIS reports.
Conclusion: 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 drama-
tically 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 con-
tinues 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.
Keywords: lorazepam, electroconvulsive therapy, dextromethorphan/quinidine, benzodiazepines,
Trisomy 21, Bush-Francis Catatonia Rating Scale
Introduction
Down syndrome (DS), occurs in around one in 800 live births, yielding a prevalence of
200,000–250,000 children and adults in the United States.
1–3
A free-standing extra
chromosome 21 (Trisomy 21) occurs in 95% of cases. Approximately 2% have a
mosaic karyotype with a mixture of normal and trisomy 21 cells. In 3% the trisomy
Correspondence: Judith H Miles
Thompson Center for Autism and
Neurodevelopmental Disorders, 205
Portland Street, Columbia, MO 65211, USA
Tel +1 573 884 6838
Fax +1 573 884 1151
Email milesjh@missouri.edu
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http://doi.org/10.2147/NDT.S210613

results from a chromosome translocation. Children with DS
are born most often to families with no previous DS history.
4
Recently the DS medical community has come
together around the fact that adolescents and young adults
with DS are at risk of significant functional regression as
adolescents or young adults.
5
When medical conditions,
common to DS, such as seizures, infections, celiac, meta-
bolic and cardiac diseases have been excluded, catatonia
has emerged as the common diagnosis.
6–11
Though the
three previous reports of catatonia occurring in DS indi-
cate it is eminently treatable, prospective studies have
been limited by the number of patients and the length of
medical follow-up.
6–8
This has led to unease by physicians
and families in the choice of treatments and even some
concern about the legitimacy of the catatonia diagnosis in
DS, autism and other neurodevelopmental disorders.
The purpose of this publication is to expand knowledge
of catatonia occurring in Down syndrome by describing a
prospective, consecutive, well-characterized cohort of
seven young people with DS who were diagnosed with
catatonia and treated at University of Missouri Health Care
between 2013 and 2018, including demographics, medical
status, laboratory and neurologic evaluations, responses to
standard-of-care therapeutic modalities and preliminary
outcomes. We hope this will demystify the diagnosis of
catatonia in DS, facilitate the diagnostic process, inform
treatment decisions and provide a basis for treatment
expectations. Finally, we hope to dispel any doubt that
catatonia in this population is the same disorder as catato-
nia encountered in patients with other medical, neurode-
velopmental and psychiatric disorders.
We present evidence that DS patients who have devel-
oped catatonia are relatively easy to diagnose utilizing the
Bush-Francis Catatonia Rating Scale (BFCRS) and respond
to acknowledged catatonia treatments.
9,12–22
Use of this
information by a medical team experienced in care of
patients with genetic disorders and psychiatry allowed us
to successfully treat seven young adults.
Materials and methods
Families were either self or physician referred to the
Thompson Center for evaluation of regression. Most had
found our previous paper online, through a friend or DS
organization.
6
The seven families live in Missouri. Out of
state families were assisted in locating appropriate care
closer to home. Each patient was evaluated following a
protocol, developed for patient #1 and updated as new
information has become available. Diagnosis of the
catatonia syndrome was based on an incontrovertible his-
tory of regression, identification of clinical catatonia
symptoms and a diagnostic trial of lorazepam.
The BFCRS, published in 1996, is considered the gold
standard diagnostic measure, based on good inter-rater relia-
bility and concordance, and a track record of use.
17,12,15
It is
easy to administer, especially when unfamiliar German
descriptors are converted to English. The 23 items each
query a specific catatonia symptom including changes in
motor activity (reduced movement, freezing or maintaining a
posture, alternating episodes of hyperactivity), unusual move-
ments (stereotypies, grimacing, blinking, motor or vocal tics,
posturing, ambitendency, automatic obedience), changes in
speech (mutism, reduced meaningful speech, echolalia),
changesinfoodorfluid intake (reduced appetite, slow food
intake), negativism (refusal to engage in previously enjoyed
activities) and a variety of autonomic abnormalities including
temperature, blood pressure, respiratory rate and sweating.
The Screening score is generated by summing the number of
positive responses to questions 1–14. The Severity score sums
the severity levels of all 23 symptoms.
17
The BFCRS is
considered positive when three or more of the 14 screening
symptoms are present, though the highest diagnostic confi-
dence is achieved with a screening score of four or more
symptoms.
12
Families completed a 23-page history form capturing
pregnancy, health, neurologic, regression, medication,
sleep, autonomic nervous system, behavioral, diet, fever,
GI, sensory and family history. Medical and neurologic
examinations were augmented by medical tests selected to
identify known causes of catatonia, medical problems
common to DS, and additional causes of regression that
may mimic catatonia. The standard laboratory testing pro-
tocol is provided in Supplementary materials, Protocol 1.
Once catatonia was clinically diagnosed and medical
evaluations had excluded most infectious, autoimmune,
metabolic and neurologic causes, a diagnosis of idiopathic
catatonia was stipulated and treatment initiated. Most
patients had previously been prescribed a variety of anti-
depressants, psychiatric, anti-epileptic and sleep medica-
tions which had not ameliorated their symptoms; all had
been discontinued prior to this study. Treatment was begun
with lorazepam, the acknowledged initial treatment for
catatonia.
6,9,20–25
Based on response, the lorazepam dose
was gradually increased until 2 mg increases failed to
provide improvement or the dose reached approximately
20 mg/day in divided doses. A number of other medica-
tions, previously reported as efficacious for some patients
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with catatonia including N-acetyl cysteine (NAC), mino-
cycline, and dextromethorphan + quinidine (Nuedexta
@
)
were used as clinically indicated.
26–30
Failure to achieve a
close to baseline recovery prompted recommendation for
bilateral electroconvulsive therapy (ECT). All except the
first patient continued to receive catatonia medications
during the course of ECT. Resurgence of symptoms often
prompted repeated courses of ECT, or maintenance
treatments.
Patient follow-up consisted of monthly clinic visits and
weekly symptom reports completed by families using the
electronic, email distributed, Catatonia Impact Scale (CIS)
(Supplementary materials; Protocol 2). The CIS adhered to
the format of the fully validated Autism Impact Measure
(AIM), developed by Kanne and Mazurek.
31,32
and quer-
ied symptoms enumerated in the BFCRS, DSM-5 and
current medical literature. Thirty questions provided a
longitudinal assessment of both symptom frequency and
impact on functioning, using a 5-point Likert scale.
Description of the CIS is in preparation.
33
University of Missouri Institutional Review Board
approval (Project # 1210315) was obtained to collect clin-
ical data with storage in the Thompson Center Database,
which can be analyzed and published in an effort to
increase knowledge of catatonia in DS. All parents/legal
guardians provided written, informed consent regarding
data collection, and storage on University of Missouri
servers, for presentation at medical and parents’meetings
and publication of anonymous results. In addition, all
parents/legal reviewed their Case Reports and provided
written informed consent for the case details to be pub-
lished. This study was conducted in accordance with the
Declaration of Helsinki. Weekly collection of data using
the Catatonia Impact Screen (CIS) from families via email
provides longitudinal records of each patient’s response to
therapies. Deidentified data can be made available to the
research community.
Case reports
Cases are presented in the order they were diagnosed
(numbered 1–7), such that the length of time each patient
has been treated is less with succeeding cases. Age is at
presentation for diagnosis.
Case: 1: BK –18 yo male (1
st
visit 3/13; lorazepam
initiation 6/13; follow-up 6 yrs)
BK is a Caucasian male with no previous psychiatric
problems, aged 18 years at presentation. His only medical
problem was alopecia areata treated since age 12 years.
Despite moderate-range intellectual disability (ID) based
on school testing prior to development of catatonia, he
demonstrated higher-than-expected adaptive functioning,
including playing the piano, reading and working part-
time. He pitched Special Olympics Softball and excelled
in team soccer. Family history was positive for adult-onset
hypothyroidism, Raynaud’s and anxiety. There were no
identifiable initiating stressors. Symptoms emerged at age
18 years, 4 months, with progressive psychomotor slow-
ing, episodic immobility, freezing, reduced speech and
eye-blink rate, loss of hedonic capacity, grimacing and
holding his tongue out, repeated shrugging and turning of
the shoulders, slow eating, and stereotyped movements of
the fingers. He became negativistic. There were no sleep
problems and minimal snoring. Neurological examination
revealed overall motor slowing with general but mild body
stiffness, anisocoria that was considered within normal
range by neuro-ophthalmology and a change from right
to left-handedness for eating. Neurologic studies were
unremarkable, including brain MRI and routine and 24 hr
EEGs. Extensive neurologic and medical evaluations, as
described in Methods, to identify conditions that may
cause or mimic catatonia failed to provide an alternative
diagnosis. The pretreatment BFCRS Screening score was 8
and the Severity score 25. Based on these findings, his
response to a diagnostic trial of lorazepam and lack of
evidence to suggest another underlying medical or neurop-
sychiatric disorder, BK was diagnosed with unspecified
catatonia.
35
Lorazepam was titrated to a maximum dose
of 20 mg/day over an 11-month period. Parental report,
based on their subjective symptom levels endorsed a 75%
return to baseline function. Other medications were tried
including minocycline, which was discontinued within a
week due to dizziness, and memantine, used for a short
period, appeared to exacerbate catatonia symptoms. Due to
failure to achieve baseline functions, bifrontal ECT treat-
ments were initiated after 15 months resulting in an
immediate and robust response, with more spontaneous
speech and fluidity of movement. He maintained this
response on no other catatonia specific treatments for
approximately 2 years. Gradual reemergence of symptoms
including loss of spontaneous speech, motor slowing and
freezing, and decreased interest in activities led to reinsti-
tution of medical treatment. Low dose lorazepam appeared
to stabilize symptoms; he has returned to playing the
piano, working part time and exercising. Parents did not
see a benefit of NAC or dextromethorphan/quinidine and
decided against repeat ECT, though he is not completely
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back to baseline. He is on 3.5 mg of lorazepam per day,
which parents increase to 4.5 mg if symptoms increase.
Current BFCRS Screening scale is 1 and Severity
scale 2.5.
Case 2: MS –19 yo female (1
st
visit 8/13; lorazepam
initiation 10/13; follow up 5.2 yrs)
MS was diagnosed with Trisomy 21 Down syndrome
shortly after birth. Patent Foramen Ovale closed sponta-
neously. Early milestones were delayed with walking at
22 months and toilet training at 8 years. She was described
as an easygoing baby with good eye contact, who reached
to be picked up, and was cuddly with immediate family.
During the second year, she plateaued and regressed in
many skills. She lost her previously obtained 10 words,
became aloof with poor social initiation, decreased eye
contact, fascination with lights, repetitive finger move-
ments, and inspection of objects with a sideways glance.
At 4 ½ years of age she was diagnosed with autism and a
16p13.11-p12.3 duplication. Duplications in this region
have occasionally been reported in subjects with autism,
neuropsychiatric and neurocognitive disorders including
one child with catatonia and Autism.
36–38
Because of the
commonality of small duplications in neurodevelopmental
disorders, its significance is unclear.
Despite ear infections requiring multiple pressure
equalizing tubes, adenoidectomy at age 4 years, strabismus
surgery was at age 6 years, celiac disease diagnosed at age
7 years and Hashimoto’s thyroiditis at age 15 years, MS is
considered medically healthy by her parents. She wears
glasses for myopia and astigmatism. In elementary school,
she was described as engaged and willing to participate in
activities. She was included in the regular classroom with
an aide, read at a first-grade level, told jokes and was
identified as having moderate to severe ID. The Cattell-
Binet given by the school at age 11 years provided a FSIQ
of 29. When, not actively engaged she preferred to sit on
the floor and repetitively shake her dolls.
Parents think regression started at age 13 years with
waxing and waning symptoms over the next 7 years. In
middle school, when placed in a special education class,
she began a new behavior whereby she had her dolls
scream, “I hate you”,“Get out of my face”, in a voice
that mimicked some aggressive classmates. Having a one-
on-one aide decreased the behavior but when support was
discontinued she became more distressed. At age 19
(March 2013) MS developed abrupt, severe regression
coincident with an incident at school when a fellow stu-
dent was restrained. She became withdrawn, off in her
own world. She stared without appearing to notice things,
sat all day with her head down repeating phrases and
slapping her legs, and become combative when given
directions. She lost self-help skills such as toileting, buck-
ling her seatbelt and self-feeding. She began using her left
hand for some tasks. Sleep was impaired, she refused
previously enjoyed activities, engaged in repetitive rock-
ing, echolalia and exhibited facial grimaces. Medications
prescribed by their local psychiatrist included aripiprazole,
risperidone, an SSRI and clonidine. With risperidone, she
developed a temperature of 104 and incontinence, which
resolved with medication discontinuation. Incipient neuro-
leptic malignant syndrome was suspected. In August 2013,
a diagnosis of catatonia was made based on history, exam-
ination, positive BFCRS Screening (12) and Severity (29)
scores and a positive response to 2 mg IV lorazepam.
Extensive neurologic and medical evaluations failed to
provide an alternative diagnosis. Brain MRI revealed
mild hypoplasia of the cerebellar vermis and the EEGs
consistently showed background slowing.
Oral lorazepam was gradually increased to 9 mg/day
with intermittent but unsustained periods of improvement.
Trials of minocycline, N-acetyl-cysteine, and folinic acid
did not provide appreciable improvement. Memantine was
discontinued when the family noted increased agitation.
ECT administered February through April 2014 reduced
symptoms. Its discontinuation led to gradual recurrence. A
second 12 treatment series was followed by maintenance
ECT which decreased symptoms during the treatment
week which waned by the next treatment. Because of the
failure to more completely control the symptoms intermit-
tent ECT was discontinued. Reintroduction of lorazepam
was recommended but rejected by her family, fearing MS
would revert to her severe impairment level at diagnosis.
Her symptom level remained stable with a scattering of
good and bad days. Dextromethorphan/quinidine, a gluta-
mate antagonist, was started in November 2016 at 1 tablet/
day, increased to bid dosing in January 2017. Her parents
reported she seemed happier, was sitting up straight and
looking others in the face, had lost body and facial stiff-
ness, was talking in short phrases without prompting, will-
ing to participate in activities with her therapists, and
sleeping well most nights, without enuresis. In July 2017,
parents noted a gradual return of symptoms with irritabil-
ity, poorer sleep and louder vocalizations. Reinstituting
ECT was discussed. Family elected to continue the dex-
tromethorphan/quinidine. Over the next two years she has
cycled between episodes of reduced and increased
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symptoms. Repeat ECT is being considered. Parents note
she does best when a therapist or family member helps her
maintain interactions and activities.
Case 3: BC –33 yo female, (1
st
visit 1/14; lorazepam
initiation 6/14; follow up 5 yrs)
BC was diagnosed with Down syndrome shortly after
birth. She did well as an infant and remained healthy
throughout childhood. Mother recalls she was social, talka-
tive and engaged. At age 25 yo, her father died unexpect-
edly, after which she began to regress with a decline in
speech, activity level and social interactions. Her family
was led to believe this was a typical course for DS. At
age 33 yrs, she was referred to the Thompson Center and
was diagnosed with unspecified catatonia, complicating DS,
based on ten Catatonia symptoms. She also developed
periods of incontinence, loss of daily living skills like
showering, and developed compulsive moving of objects
from room to room. Subsequent to lorazepam administra-
tion, she seemed more engaged and interactive and started
to read again. Despite increasing lorazepam gradually to
15 mg/day, improvement was not sustained. Trials of min-
ocycline, memantine and N-acetyl cysteine did not stimu-
late improvement. Sertraline caused significant side effects
(sleep, dizziness, anorexia) and was discontinued when
pharmacogenomic testing revealed reduced CYP2C19
enzyme function, which decreases the rate of clearance of
sertraline thereby causing side effects. Lorazepam was con-
tinued at 15 mg/day in 3 doses. BC received 17 ECT
treatments from 8/8/16 through 10/12/16, resulting in sig-
nificant improvement. Over the next 6 months, symptoms
gradually reoccurred. Treatment was augmented with dex-
tromethorphan/quinidine two tablets/day and a second
course of 16 ECT treatments. She responded well and her
mother estimated that she was back to 85% of baseline
functioning. Dextromethorphan/quinidine 20/10 was contin-
ued; remission lasted approximately 8 months. In August
2018 she received a third course of 14 ECT treatments. She
continues on monthly maintenance ECT, lorazepam and
dextromethorphan/quinidine. She is considered almost at
baseline with BFCRS scores of 2 and 3 (1-17-19).
Case 4: PL –25 yo female (1
st
visit 6/15; lorazepam
initiation 7/15; follow up 3.5 yrs)
PL was diagnosed with Trisomy 21 DS shortly after
birth. She did well as an infant; a small ASD closed sponta-
neously. She remained healthy throughout childhood.
Mother reports she was a social, talkative, interactive with
an excellent sense of humor. She read at a 5
th
grade level,
was independent with activities of daily living, and got
along well with classmates. At age 19 years, PL was hospi-
talized with an idiopathic left transverse and sigmoid sinus
thrombosis with tentorial hemorrhage. Hypercoagulability
evaluation was normal. She was treated with anticoagulants
for 6 months and is maintained on 81 mg aspirin daily.
Recent MRI (6/17) indicated recanalization of the left cere-
bral sinuses. At age 20 years she was diagnosed with
hypothyroidism, easily controlled with Synthroid.
Parents noticed in about ninth grade, she was moving
slower and was less interested in activities. By her junior
year she seemed slower but still planned to work and get
married. Following High School there was marked regres-
sion. She became inactive, sitting abnormally still and star-
ing for long periods. She was slow going up and down
stairs, paused/froze when reaching for things, and took at
least an hour to eat a meal. By the time she was evaluated
she had lost most spoken language, did not respond to most
questions, used repetitive phrases such as “Steve got mad
today”, and had developed facial grimacing with odd facial
expressions, stereotypic hand movements and a rigid tailor’s
sitting posture with a straight back. She would dwell on bad
events, made poor eye contact and was resistant to sugges-
tions and instructions. She angered easily and had crying
episodes. Affect was flat and she had lost interest in family
and friends. She needed help dressing. She was withdrawn
from the adult workshop as she could no longer participate
in piece work. Comprehensive medical and psychiatric eva-
luations led to diagnoses of celiac disease and moderate
obstructive sleep apnea, both were treated but did not ame-
liorate catatonia symptoms.
PL was diagnosed with catatonia, complicating DS,
with a BFCRS Screening score of 9 and Severity score
of 21 and started on lorazepam 2 mg/day. Initially she
seemed more engaged and interactive and started to read
again. Lorazepam doses up to 8 mg were observed to
improve symptoms quickly but by the end of two hours,
the effect would wear off. For about a year, the family
maintained behavioral equilibrium with 2 mg doses every
two hours. Trials of minocycline and N-acetyl cysteine did
not improve symptoms. She cycled good and bad days.
Dextromethorphan/quinidine, 1 tablet a day, improved
symptoms with better engagement, talking, telling stories
and enjoying outings. When improvement stalled, a course
of 19 ECT sessions was started in March 2017 and dex-
tromethorphan/quinidine was increased to twice a day.
Symptoms improved including resolution of previously
unexplained facial flushing. In September she moved into
a residential Independent Living Home, attends a day
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program and is doing well. She was considered almost at
baseline with BFCRS Screening and Severity scores of 3
and 2.5 (11-1-18). Recent reduction of lorazepam to 6 mg/
day led to significant symptoms, which resolved quickly as
lorazepam was restored to 13 mg/day.
Case 5: JT, 26 yo female, (1
st
visit 11/15; lorazepam
initiation 12/15; follow up 3.2 yrs)
Diagnosed with Trisomy 21 DS shortly after birth, JT was
considered healthy with spontaneous closures of a PDA at
6 months and ASD at 8 years. Hypothyroidism was diagnosed
at age 8 years. She wore glasses for myopia and esotropia. The
main health concern was early obesity, which was complicated
by hidradenitis treated with long-term minocycline.
Milestones were described as typical for Down syndrome
with walking independently at 30 months. There were no
episodes of regression below the age of 3 years, and no overt
autistic symptoms, though she had a number of stereotypic
behaviors, attachments to specific objects, and resistance to
changes in routines. JT did well in special education classes
where she preferred writing to talking which was in 3–4-word
phrases. She read at a 3
rd
grade level and loved to knit, using a
knitting form. As a child, JT was described as friendly and
eager to please. She took meticulous care of her room, not
wanting others to dust, as they put things in the wrong place.
She attended to all her self-care and made her own breakfast.
She liked feminine dresses, jewelry and often wore a tiara. As
an adult, she worked in a daily workshop. In September 2015,
JT missed a few days at work with non-specific complaints
andcryingjagsbutotherwiseseemedfine. In early October,
she developed an explosive diarrheal illness, refused to eat and
retreated to bed. In the Emergency Room, a head CT, abdom-
inal ultrasound, EKG and screening blood work were normal;
gastroenteritis was considered likely. Following discharge, she
continued to seem ill. She shook her hands in what was
described as a tic-like behavior, had arm posturing, refused
to eat or drink, and became mute and unresponsive to ques-
tions. She got stuck trying to move, had freezing episodes, and
trouble climbing up and down stairs. She spent the majority of
her time lying in bed staring at the ceiling, or sitting in a chair
and staring straight ahead. She also developed repetitive ton-
gue clicking, facial grimaces and repetitive finger movements
as well as remaining in a rigid position with resistance to
moving. She developed enuresis and required assistance with
self-care skills in which she had previously been independent.
When evaluated in Regression Clinic she had been
immobile for 6 weeks. Medical evaluations led to new
diagnoses of celiac disease and autoimmune liver disease.
The BFCRS Screening score was 9 and Severity score 26.
She responded to a test dose of 2 mg of IV lorazepam
becoming more active, looking at things and getting up to
walk around. She was diagnosed with unspecified catato-
nia and started on lorazepam 2 mg/day. Her family had
significant problems giving her daily medication due to
irregular sleep patterns. Her dose was gradually increased
to 14 mg/day, dextromethorphan/quinidine was added to
the lorazepam resulting a significant improvement in CIS
scores. She was talking more, amenable to getting dressed,
and more social. By Christmas 2018, family perceived her
to be at her baseline or possibly better, presumably reflect-
ing concurrent diagnosis and treatment of previously
unrecognized celiac disease.
She remained well, continuing on dextromethorphan/
quinidine BID and lorazepam 12 mg/day. In September, JS
developed abdominal pain and diarrhea and was diagnosed
with acute B cell precursor lymphoblastic leukemia. She
died following her third round of chemotherapy with liver
failure and septic shock at age 29 years.
Case 6: CN, 19 yo female (1
st
visit 3/16; lorazepam
initiation 5/16; follow up 2.8 years)
CN was diagnosed with mosaic Trisomy 21 DS shortly
after birth. An arterial-ventricular canal defect was success-
fully repaired at 6 months of age. Except for mild exotropia,
for which she had muscle revision, she remained healthy.
Early development was mildly delayed with independent
walking at 18 months. Parents reported her foremost impe-
diment had been severe aphasia and apraxia for which she
was in continuous speech therapy; prior to the regression
she spoke in four-word sentences. She read at the 2nd grade
level. Though there was never consideration of autism, her
mother described her as shy, with poor eye contact and
limited imaginative play. She had no echolalia or motor
stereotypies, loved parties and had friendships in school.
At 16–17 years of age, CN’s parents noted she was moving
slower, had lost much of her speech and answered questions
with just one word. She was evaluated by Child Neurology
and treated for anxiety, poor sleep, depression and possible
psychosis based on increasing self-talk. Medical treatments
included fluoxetine, sertraline, escitalopram, clonidine, zol-
pidem and trazodone without improvement. She was self-
referred to the University of Missouri in March 2016.
Symptoms included slow walking, mutism with some whis-
pering, weight loss, sitting still for long periods, and getting
stuck/freezing when trying to move, pick up a fork or open
a door. She remained in rigid positions, resisting efforts by
others to change her position. She had lost interest in
Special Olympics basketball and swinging which, she
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previously enjoyed. She lost self-help skills including bath-
ing, shaving her legs and making her bed. Her behavior and
mood were described as flat with staring and standing with-
out moving.
At diagnosis of unspecified catatonia complicating DS,
BFCRS Screening score was 9; Severity score was 18.
Lorazepam, started at 2 mg/day, was gradually increased
to 15 mg/day. Initially she seemed more engaged but
symptoms continued; minocycline and N-acetyl cystine
were added without improvement and were discontinued.
She was started on dextromethorphan/quinidine in
November 2016, resulting in improved interactions,
which gradually faded. ECT was started in April 2017
with excellent response, which also dissipated. She
remained stable but did not resume talking and was not
as engaged in everyday activities. A short course of 4 ECT
treatments returned CIS levels to near normal; stopping
ECT allowed symptoms to return. In April 2018, a longer
course of ECT returned symptoms to near normal, but
required maintenance ECT to maintain. Currently she is
treated with lorazepam 10 mg/day, dextromethorphan/qui-
nidine 40 mg/day and maintenance ECT, in clusters of
three sessions every 3 weeks. Parents report she is pretty
much back to baseline, enjoying her day program, listen-
ing to music, doing art work and word searches.
Case 7: BI, 26 yo female, (First visit 6/16; lorazepam
7/16; Follow up 2.5 yrs)
BI was diagnosed with Down syndrome shortly after
birth. Early motor development was within normal limits,
sitting independently at 8 months and walking at
24 months. There were no developmental losses during
childhood. She did well in school, read at a 4
th
grade level,
spelled well and engaged in basic conversations. She sang
in the choir, made friends, took Spanish in High School
and participated in Special Olympics. She independently
walked to school and to the store to buy groceries with her
debit card. She graduated from High School in both reg-
ular and special classes. At 19 years, parents noted she
stopped going to school events she had previously
enjoyed. After graduation at age 21, she moved into a
residential day service program. By 22 years, she stopped
communicating verbally and became non-compliant with
instructions. By the fall, she would just lie in bed or on the
couch. When first seen in June 2016, she had no language,
did not respond to questions or instruction and sat motion-
less for long periods. Her physical movements were slow,
she held her head down, and exhibited repetitive move-
ments including shoulder shrugging, facial grimacing, and
repetitive hand movements. Her mood was depressed and
she became combative and angry when pressed. She had
lost activities of daily living and when taken to the shower
would just stand.
BI was considered healthy. A possible seizure was
observed with shaking of arms and legs in October 2015.
She was hospitalized for 4 days with normal EEGs and
basic labs. Brain MRI revealed focal encephalomalacia
within the right caudate head reflective of a remote
ischemic or inflammatory insult. Neurology concluded
she did not have a seizure disorder and mother felt it
was stress induced. Recent review of that admission by
Psychiatry was deemed consistent with Catatonia
BI was diagnosed with unspecified catatonia in July
2016. She was begun on lorazepam 2 mg/day. Initial
response to low dose lorazepam was minimal, partially
due to medication refusal. As lorazepam dose increased
to 14 mg/day and dextromethorphan/quinidine was added,
she showed significant improvement with some talking,
improved sleeping and eating, cooperating with her mother
in showering, dressing and leaving the house. ECT started
in March 2017 provided immediate improvement with
some rebound symptoms which gradually diminished
over the next 6 months on dextromethorphan/quinidine
and lorazepam. When last seen in 2017, BFCRS
Screening =5, Severity =4. Mother considered her about
80% baseline. Recent phone visit indicates increased
symptoms; ECT is being considered.
Results
Each catatonia diagnosis was based on a history of sig-
nificant regression and symptoms enumerated by the
BFCRS. At diagnosis, all patients scored in the catatonia
diagnostic range with Screening scores ranging from 8–12
with mean of 9 (Table 1) and Severity scores from 16 to 29
with mean of 20. The nine most common symptoms were
mutism, immobility, getting stuck during motor activities,
involuntary movements, perseveration or obsessive symp-
toms, negativism, and social withdrawal. Loss of indepen-
dence in daily living skills and sleep disturbances were
also common. Though not considered part of catatonia,
emotional lability with episodes crying, sobbing, laughing
or giggling was reported by all families. The diagnosis of
catatonia was corroborated by detecting at least three core
symptoms specified by the more diagnostically conserva-
tive DSM-5 criteria.
35,39
Positive responses to customary
medical treatments of catatonia known to affect the
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GABA/Glutamate neurotransmitter systems confirmed the
diagnoses.
Each family provided comprehensive medical,
genetic and social histories and patients received thor-
ough medical and neurologic examinations (Table 2 ).
Previous genetic testing results confirmed complete tris-
omy 21 in 6 subjects and a mosaic karyotype in the
other. One patient also carried a 16p13.11–12.3 duplica-
tion. Ages at diagnosis ranged from 19 to 33 years, with
delays from symptom onset to diagnosis ranging from
3 months to 10 years. Six of the seven families
described gradual onset with fluctuation in symptoms
as their child became steadily more symptomatic.
Three families described one or more early episodes
resembling mild catatonia that appeared to resolve. The
shortest intervals to diagnosis were one and nine
months. Five families reported significant life stress
prior to symptom onset including death and serious ill-
ness of fathers, divorce, anxiety caused by classmates
and leaving high school. In most respects, these seven
individuals resembled other young adults with DS. The
only demographic outlier was the male to female ratio
of 1:6 which differed from the commonly reported ratio
of about 1.2:1. Medical histories were also consistent
with Down syndrome. Premorbid adaptive functioning
ranged from low to moderately high.
Neurologic symptoms and testing are tabulated in Tabl e 3.
None of the patients had evidence of seizures, encephalitis or
other brain infections. Patient MS (#3), who was the most
intellectually impaired, had background slowing on the EEG
andmildvermishypoplasiaonbrainMRI.Sixoftheseven
patients had cerebral spinal fluid (CSF) studies including cell
counts, glucose, pH, lactate and protein. Studies specifically
aimed at causes of catatonia, included the CSF Paraneoplastic
autoantibody Evaluation, which included antibodies to
NMDA (N-methyl-D-aspartate)-type glutamate receptors,
Glutamic acid decarboxylase (GAD), and others.
40
CSF was
also tested for Methyltetrahydrofolate, neurotransmitter meta-
bolites (5HIAA, HVA, 30MD) and Neopterin (a marker for
CNS immune system stimulation); all were within normal
ranges.
41
Plasma Paraneoplastic Autoantibody Evaluations
obtained for all 7 patients were normal. Six of the seven
patients were Vitamin D deficient or insufficient; oral
Vitamin D supplementation led to normalization of levels.
Three patients underwent overnight Polysomnography due to
snoring, day time sleepiness or restless sleep. All had positive
studies; two were treated and remain on CPAP; the milder
patient declined CPAP.
Table 1 Symptoms of catatonia in DS using the Bush-Francis Catatonia Rating Scale (BFCRS)
Notes: = symptom reported or observed at first visit. = symptom reported or observed in follow -up. *Wachtel et al, 2019.
34
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Table 2 Demographic, genetic, medical and psychiatric features in seven cases of DS and catatonia
1. BK 2. MS 3. BC 4. PL 5. JT 6. CN 7. BI Composite
Gender M F F F F F F 1M:6F
Age at diagnosis (yrs) 19 19 33 25 26 19 25 19–33 yrs
Age- symptom onset (yrs) 18 13 25 15–19 26 17 19 13 −25 yrs
Diagnosis delay 9 mo 6 yrs 8 yrs 10 years 1 mo 2 yrs 6 yrs 1mo - 10 yrs
Follow up period 6 yrs 5.2 yrs 5 yrs 3.5 yrs 3.2 yrs 2.8 yrs 2.7 yrs 2.7 −6 yrs
Current functioning
(% baseline)
90% 80% 90% 95% (100%)
b
90% 85% 80%-100%
Cytogenetic diagnosis T21 T21 T21 T21 T21 T21 mosaic T21 6=T21 1=mosaic
Premorbid Cognitive Testing Moderate ID FSIQ =29 ––– –––
Premorbid adaptive
functioning
High Low Medium High Medium Low to Medium High –
Premorbid reading level 7
th
grade none 4
th
grade 5
th
grade 5
th
grade 2
nd
grade 7
th
grade 0–7
th
grade
Potential precipitating
stressors
None Aggressive
classmates
Death of father Leaving HS None Father ill Parent
divorce
71%
Congenital heart disease - PDA –spontaneous
closure
ASD secundum ASD - spontaneous
closure
ASD, PDA-
spontaneous closure
AV canal surgery –
6mo
- 71%
Ophthalmic disorders; visual
impairment
myopia,
esotropia
myopia,
astigmatism
esotropia, s/p
surgery
astigmatism myopia, esotropia esotropia, s/p
surgery
esotropia s/
p surgery
100%
Allergies Hay fever Hay fever None Hay fever None None Hay fever 57%
Medical history - other Sleep apnea
a
–Sleep apnea
a
Osteopenia
(DEXA)
Sleep apnea
a
Cataplexy*
Morbid obesity Apraxia, Aphasia ––
Psychiatric history None Autism None None None None None 14%
Family history Anxiety (F) hypo-
thyroid (F)
Mild ASD
(Brother)
Hemochrom-atosis
(M)
Anxiety (M) Depression,
pancreatitis, Panic
(M)
Anxiety (M),
Nephro- pathy (F)
Depression
(M)
–
Notes:
a
Diagnosed during regression evaluation.
b
Deceased. See Table 4 for autoimmune disorders.
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Table 3 Medical and neurologic features and test results in seven case of DS and catatonia
1. BK 2. MS 3. BC 4. PL 5. JT 6. CN 7. BI
Electro-encephalogram Negative Background
slowing Negative Negative Negative Negative Negative
Brain MRI Negative Vermis
hypoplasia
Small
cerebellum
Post CVT,
recanalization
Cervical
spondylosis with
narrow right
neural foramina
Negative Focal
calcifications
Cerebral Spinal Fluid Negative Negative nd Negative Negative Negative Negative
Neopterin, MTHFR,
Dopamine metabolites (CSF)
Medical Neurogenetics
Laboratory (MNG)
Negative Negative nd Negative Negative Negative Negative
Neurologic signs
(not generally regarded as
catatonia symptoms)
Anisocoria,
dilated pupils,
Flushing b
(resolved with
catatonia), switch
right to left hand
Switch right
to left hand
for some
activities
None
Flushing b–
(resolved with
catatonia control)
None Sl dilated
pupils None
Medical diagnoses Obstructive Sleep
Apneaaon C-Pap None
Obstructive
Sleep
Apneaa
Osteopenia
Obstructive Sleep
Apneaaon C-Pap
CVT@ 20y,
Morbid obesity Apraxia &
aphasia none
Vitamin D level at diagnosis 27ng/ml a
(insufficient)
16 ng/ml a
(deficient)
21ng/ml a
(insufficient)
54ng/ml
(optimum)
29ng/ml a
(insufficient)
29ng/ml a
(insufficient)
16 ng/ml a
(deficient)
Notes:
a
Diagnosed during regression evaluation.
b
Reported in catatonia affecting ASD (Wachtel et al 2019).
34
Abbreviations: nd, not done; CVT, cerebral venous thrombosis; OSA, Obstructive Sleep Apnea; , positive symptom or out of range laboratory.
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Autoimmune disorders were diagnosed or confirmed in
four patients, including three with celiac disease (42%),
two of whom were diagnosed during the catatonia evalua-
tion, three with hypothyroidism (43%), one immune hepa-
tic disease (14%) and one alopecia areata (14%). (Table 4).
Four patients had two or more autoimmune disorders.
Only the four with recognized autoimmune disorders had
elevated FANAs or ESRs and the three without diagnosed
autoimmune disorders had no autoimmune markers other
than an elevated ASO titer in one and elevated DNase
antibody in the other. Paraneoplastic autoimmune panels
including serum (7 patients) and CSF (4 patients) revealed
no infectious or neoplastic markers, including GAD65,
NMDA receptor and GABA receptor antibodies.
40
On
the other hand, the Cunningham panel which detects
neural autoimmune antibodies associated with neuropsy-
chiatric disorders including PANS, PANDAS and
Sydenham’s chorea revealed high titers to one or more
neural proteins in six of the seven patients.
42–44
The
CaM Kinase II (Calcium-dependent Calmodulin Protein
Kinase II) activation, which is a measure of neural
immune stimulation was elevated in 3 cases.
Response to treatments
Each patient displayed a favorable reaction to the 2 mg IV
test dose of lorazepam given at the first clinic visit (Table 5).
Common observations were faster walking, and looking
around at people and the clinic environment rather than
looking down. For example, BC (#3), who had regressed
10 years earlier, sat in clinic without moving or acknowl-
edging us. About 20 mins after receiving lorazepam, she
began turning her head and looking around. She noticed a
book on sea animals. With some prompting she read the
descriptions under the pictures. She had not done that in
years. In all cases parents noticed small improvements in
symptoms ranging from faster walking or eating, looking
around during the ride home, relaxed posture and less
negativity lasting up to 24 hrs. Following medical evalua-
tions, patients started 2 mg oral lorazepam each morning.
As the doses were gradually increased, the amount of
improvement varied. The first two patients, BK (#1) and
MS (#2) started treatment before the CIS tracking measure
was developed, hampering our ability to track specific
symptoms. This was especially problematic for MS (#2)
whose combination of DS, autism and catatonia made it
problematic to accurately evaluate her response to low
lorazepam doses, which led to relatively early introduction
to ECT. All six patients who clearly responded to increasing
doses of lorazepam, continued to have some symptoms
including facial movements, shoulder shrugging, staring
and resisting previously enjoyed activities. All appeared to
reach a plateau where increasing lorazepam by 2 mg did not
improve symptoms. At that time ECT was recommended as
the next treatment. Unfortunately, Missouri’s requirement
for court approval for individuals with diminished capacity
to consent, often delayed ECT up to 6 months.
Three glutamate antagonists, memantine, N-acetyl
cysteine (NAC) and minocycline, were considered due to
their anti-inflammatory properties and reports of some effi-
cacy, and tried for limited periods. None provided sustained
improvement and were eventually discontinued. In
November 2014, positive outcomes with dextromethor-
phan/quinidine, another glutamate antagonist, were reported
in adult psychiatric patients with catatonia.
29
Subsequently,
six of our seven patients were treated with dextromethor-
phan/quinidine starting with the 20 mg dextromethorphan a
day, increasing to 40 mg after one week. Four appeared to
have symptom improvement maintained for a number of
months. In two cases, dextromethorphan/quinidine appeared
to sustain improvement derived from ECT. As noted by
others, response to glutamate antagonists was notably
slower than response to lorazepam.
45
Six patients received
from one to three courses of ECT, two remained on main-
tenance. One young woman had 3 ECT courses, and con-
tinues on maintenance ECT, which her family reports
maintains close to baseline functioning. The Catatonia
Impact Scale (CIS) proved to be sensitive to small symptom
changes providing a response trajectory which helped for-
mulate timelier treatment decisions (Figure 1).
33
Discussion
For generations, catatonia symptoms were interpreted as
signs of other named diagnoses, including schizophrenia,
autism, encephalitis, cataplexy and even hysteria. As
Shorter pointed out
recent revisions in the classification of psychiatric disease
has afforded the opportunity to rescue catatonia from the
swamp of competing diagnoses and establishing it as an
independent illness entity in adults and children.
49
Initially, this rested on recognition that catatonia was not
a subtype of Schizophrenia.
9,10,46
And more recently,
that catatonia was not a symptom of autism as had
been suggested.
47,48
Catatonia is now accepted, by
most psychiatrists, as a discrete syndrome, stemming
from a variety of psychiatric, neurologic or medical
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Table 4 Autoimmune diagnoses and testing in seven case of DS and catatonia
Notes:
a
Diagnosed during regression evaluation.
b
Unclear autoimmune etiology.
Abbreviation: , Autoimmune diagnoses and laboratory indicators.
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Table 5 Catatonia treatments and results in seven case of DS and catatonia
Mechanism Treatments 1. BK 2. MS 3. BC 4. PL 5. JT 6. CN 7. BI
GABA Agonists lorazepam –effect
of test dose 2 mg IV
(1–5 Likert score)
Positive –4 Positive −2 Positive - 4 Positive - 4 Positive −3 Positive −2 Positive −2
lorazepam –oral Rx
(% baseline achieved)
75% initially,
Maintained on low
dose
DC’d - parent
concerns
50% 50% 100% 60% & then
recurrence
70% Maintained after ECT
ECT
(% baseline achieved)
90% for 2 yrs, 90% >90% >95% na 90% 90%
Number ECT
Courses
1 course 1 course plus
maintenance
ECT
3 courses 1 course –3 courses plus
maintenance
ECT
1 course plus maintenance
ECT
Glutamate Antagonist dextromethorphan/
quinidine
Unclear. Short
course 3 years after
ECT
Maintained after
ECT
Maintained
after ECT
Maintained
after ECT
–With
Lorazepam &
ECT
Improved & maintained after
ECT
memantine DC’d-efficacy DC’d-efficacy ––DC’d -irritability ––
Anti-inflammatory minocycline DC’d–lethargy DC’d–efficacy DC’d–efficacy –DC -possible liver
risk
––
Multiple mechanisms N-acetylcysteine
(NAC)
Possibly improved –DC’d -efficacy –– – –
Medications prior to diagnosis that did not
reduce symptoms
divalproex sodium,
sertraline
aripiprazole,
sertraline,
fluoxetine
sertraline none none SSRI SSRIs x3, bupropion HCl,
diazepam, lorazepam 0.5 mg
Note: Likert scale: 1=none, 2=some, 3= good, 4= very good, 5=excellent. Per Parent & Physician; See Figure 1 for CIS longitudinal course examples.
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causes.
9,11,14,23,38,46,50–53
Adolescents and young adults
with neurodevelopmental disabilities are merely the
most recent group recognized at risk to develop
catatonia.
6,10,14,38,50,54
This overdue recognition should
not come as a surprise, since until the 1980s, physicians
did not believe individuals with DS were susceptible to
the same psychiatric disorders or would respond to the
same treatments as their typical peers.
55–57
The first signs of regression in our patients were
noted between 13 and 26 years, similar to published
experience for Down syndrome and Autism.
48,58,59
Most families described a gradual downhill course
over a few months to 6 years. Time from onset of
symptoms to diagnosis generally reflected the time it
took families to persuade physicians and/or schools
that the change was not behavioral or just part of DS.
Only JT (#5) presented abruptly over a 2-week period.
Our experience was similar to previous observations
that 75% of young people with developmental disorders
had more insidious onsets compared with abrupt onsets
in 77% of patients with medical disorders.
14
Stressful
events or situations temporally coinciding with func-
tional regression have been postulated as triggers or
causes.
60
In our patients, significant emotional trauma
rangingfromdeathorsignificant illness of a parent,
divorce, a stressful class room and leaving a supportive
high school environment were described. Moreover, all
but one family reported that highly stressful situations
continued to exacerbate catatonia symptoms. On the
other hand, each of the seven young people, especially
as they were responding to treatment, improved more
rapidly when they were able to interact with friends,
therapists and families. Removal from social situations
appeared to exacerbate withdrawal.
Once the possibility of catatonia is acknowledged, the
diagnostic process for individuals with Down syndrome is
identical to that for patients with primary psychiatric diag-
noses. The first step is to substantiate a history of unam-
biguous regression from baseline functioning. This may be
more difficult for the clinician to appreciate in a young
person with developmental and/or behavioral symptoms as
opposed to an otherwise functional adult who is more
easily identified as unwell even by those who had not
known him before. The catatonia diagnosis is established
by identifying specific clinical symptoms on the
BFCRS.
17,12,13,15
Patients with catatonia complicating psy-
chiatric or medical diagnoses present with similar catato-
nia symptom profiles.
12,14,61
As iterated by Francis (2010),
“catatonia caused by psychiatric disorders and that due to
medical conditions or toxicity shows similar structure and
severity”.
12
Waxy flexibility, excitement, automatic and
passive obedience, grasp reflex and combativeness which
were infrequently observed in our patients have also been
reported less commonly in psychiatric patients.
12,24
We
found that night and day time enuresis which often accom-
panied severe catatonia improved as the catatonia was
0
10
20
30
40
50
60
A
B
Case 4. PL. Time - 7/31/15 to 2/10/19
0
10
20
30
40
50
60
Case 6. CN. Time - 4/6/16 to 2/7/19
Key CIS Frequency; CIS Impact; BFCRS Severit y; BFCRS Screening ;
Lorazepam (mg); Dextromethorphan (mg); ECT (date); Minocycline (10mg); Folinic acid (mg); NAC (100mg)
Figure 1 Longitudinal progress measured by parent reports using the Catatonia Impact Scale (CIS) and BFCRS. (A) Case 4. PL. From 7/31/15 to 2/10/19. (B) Case 2. CN.
From 4/6/16 to 2/7/19.
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treated, implying a shared origin. Sleep problems with
insomnia, early wakening and restlessness were also com-
monly reported and again resolved or greatly improved
with resolution of the most severe catatonic symptoms,
without other medical intervention. Verification of a cata-
tonia diagnosis is based on the resolution of symptoms in
response to standard first line treatments. This was clear in
our patients, all of whom responded positively to a test
dose of lorazepam (2 mg IV) and ECT. Prior treatments
with antidepressants, antipsychotics, anxiolytics or sleep
medications had not resolved catatonia symptoms.
Benzodiazepines and electroconvulsive therapy (ECT)
remain the standard, first-line therapies for catatonia in
both children and adults regardless of underlying psychia-
tric or medical disorders and are also the most clinically
studied.
16,20,21,62,63
The preponderance of reports in DS,
Autism and other neurodevelopmental disorders affirms
their efficacy in these populations.
6–9,11,14,53,63
A recent
Cochrane report of 31 articles revealed lorazepam
response rates of 66–100% in Western countries; ECT
response rates varied 59–100%.
22
Though, excellent
response to ECT is generally acknowledged, including
endorsement from the American Academy of Child and
Adolescent Psychiatry, rigorous evidence including ran-
dom controlled trials and meta-analyses have not been
performed.
62–65
In addition, it is suggested a synergistic
effect may be obtained by providing lorazepam and ECT
simultaneously.
66–68
Catatonia also responds to glutamate antagonists, which
work through NMDA receptors, to raise GABA relative to
glutamate. A number N-methyl-D-aspartate (NMDA)
antagonists, including memantine, amantadine, N-acetyl
cysteine (NAC), minocycline, topiramate and dextromethor-
phan/quinidine have each had proponents.
26–29
In our
patients, NMDA antagonists were used to supplement lor-
azepam when increasing GABA agonist dosages failed to
elicit optimal improvement. In this limited clinical experi-
ence dextromethorphan/quinidine appeared the most effec-
tive controlling symptom rebound following ECT.
An unanticipated distinction between catatonia in our
Down syndrome cohort and catatonia reported in patients
with psychiatric and medical disorders is the chronicity of
symptoms and dependence on sustained treatment to main-
tain recovery (Tab le 5). Each of the patients, followed from
2.7 to 6 years, eventually responded to therapy and is cur-
rently functioning close to their baseline. However, each
remains on medications (Lorazepam - 3.5–16 mg/day, and/
or dextromethorphan/quinidine 40/20 mg/day) and/or
maintenance ECT. Response to ECT was clearly superior to
medications (Figure 1). Reasons for the protracted nature of
catatonia in DS is unclear. Consoli et al reported 75% of
patients with developmental disorders had a chronic course,
compared to only 17% of adolescents with a medical cause
and 7% with underlying psychiatric disorders.
14
Arecent
description of 22 patients with Autism and catatonia found
that ECT provided marked benefit in all patients, though
often required ongoing maintenance treatments.
34
One plau-
sible explanation for the catatonia’s chronicity in young
people with neurodevelopmental disorders may be delayed
diagnoses, which might render treatment more difficult.
Based on this experience, Pelzer and colleagues recommend
that patients with long term symptoms of catatonia be treated
expediently with ECT, a recommendation our experience
supports.
22
At this time, we feel comfortable advising
families that whereas we can’t promise recovery will be
rapid, experience supports optimism that with standard of
care treatments including lorazepam, ECT and possibly dex-
tromethorphan/quinidine a return to baseline or close to base-
line functioning is expected.
An additional objective of this study was to ascertain
any clinical or laboratory characteristics that might foretell
a risk of catatonia (Table 2,3,4). For the most part, our
patients displayed typical DS features, including cytoge-
netic variation; six with isolated Trisomy 21 and one
mosaic Trisomy 21. One (14%) was diagnosed with
Autism, consistent with the 13–18% concordance com-
monly reported.
69–72
That our patient MS (#2), who had
the most severe intellectual disability and problematic
behavior is consistent with previous reports that children
with DS plus ASD tend to have more severe cognitive
impairment, language deficits, stereotyped behavior, over
activity, impulsivity and self-injurious behavior
73–77
Likewise, medical diagnoses in our patients were com-
pared to DS norms (Tables 2 and 3). Congenital heart
diseases (71% vs 25–45% expected), ophthalmologic dis-
orders (100% vs 40% expected), speech delays (100% vs
almost 100% expected), autism spectrum disorders (14%
vs 12–18%), obstructive sleep apnea (57% vs 30–66%
expected) and osteoporosis (29% vs >50% expected)
were the most common.
78–82
Only, the incidence of con-
genital heart defects (71%) was appreciably higher than
expected (25–45%). Of the five cardiac diagnoses, three
resolved spontaneously and none of the five children had
on-going cardiac problems requiring medications, activity
limitations or close cardiac follow-up, making it unlikely
that congenital heart defects provoked catatonia. Each
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DovePress 2737

family considered their child medically vigorous with
expected growth parameters and general good health.
Based on this small sample, we found no evidence that
young people with DS who developed catatonia were less
healthy than their typical DS peers. IQ scores were not
consistently available for our patients, as parents had often
declined school testing; once catatonia developed valid
assessments were impossible. In lieu of psychometric
data, we used each person’s highest reading level, which
ranged from none to 7
th
grade, and found reading levels
roughly corresponded to functional levels as described by
parents and in school records.
83
Functional abilities ranged
from low to high functioning and roughly mirrored or
surpassed cognitive functioning reported in DS adults
(moderate-severe impairment in about 70%, mild-moder-
ate impairment in 20% and 8% in the mild range).
84
On the other hand, the DS+CAT patients appear to
have more of some autoimmune disorders (Table 4).
Hypothyroidism (Hashimoto’s thyroiditis and/or Graves’
disease) occurred in 57% vs 35% reported in DS alone,
celiac disease was found in 43% vs 5–10% in DS and
Alopecia areata in 14% vs 4–11% in DS.
85–91
This is
noteworthy in light of the elevated risk for catatonia in
typical patients with autoimmune disorders including
Celiac disease, Graves’s disease, Diabetes Type 1,
Alopecia Areata, Lupus, Cerebral Folate deficiency and
Paraneoplastic Autoimmune Encephalitis.,
52,53,92,93
raising
the question of a pathophysiologic relationship between
DS and catatonia.
Laboratory corroboration of autoimmune activation
occurred almost exclusively in our patients with autoim-
mune medical diagnoses. JT (#5), with four autoimmune
disorders, had the most salient results including a speckled
pattern FANA, elevated ESR and CRP plus borderline
serum and CSF Paraneoplastic Autoantibody Panels.
Since, autoimmune laboratory data have not been collected
from healthy, age matched DS populations it is not possi-
ble to speculate whether laboratory evidence of autoim-
mune activation might predict or correlate with
development of catatonia. Though none of our patients fit
clinical criteria for PANS (Pediatric Acute Neurologic
Syndrome), anecdotal reports of catatonia being misdiag-
nosed as PANS prompted us to obtain the Cunningham
Panel, which is used in diagnostic evaluations for PANS,
measuring levels of circulating antibodies directed against
brain antigens, and measuring their ability to increase the
activity of the CaMKII enzyme that upregulates neuro-
transmitters in the brain.
42–44
Of the seven DS+Cat
patients tested, six exhibited between 2 and 4 elevated
anti-neuronal protein titers and three exhibited a positive
neural immune stimulation assay. This suggests inclusion
of the Cunningham Panel may help identify whether in
DS, regression is related to autoimmunity.
An unexpected observation was the high (6:1) female
to male ratio in our DS+Cat population, which mirrored
the 6.5:1 ratio from three previous DS+Cat reports.
6–8
This
differs from sex ratios reported in unselected DS popula-
tions. One review of fifty-five publications found consis-
tent 1.31:1 male to female ratios in Trisomy 21.
94
Similar
ratios are reported in the US, Europe and China.
95,96
This
information, plus the increased propensity for females to
develop autoimmune disorders in the general population
raises the question whether females with DS are at a
higher risk for catatonia.
Young people with neurodevelopmental disorders pre-
sent an additional diagnostic challenge for many clini-
cians. To the inexperienced, the individual symptoms of
catatonia may be misconstrued as part of their neurodeve-
lopmental disorder. Furthermore, for the 15–20% of indi-
viduals with Down syndrome also diagnosed with autism,
their array of behavioral symptoms, some of which over-
lap with symptoms of catatonia, can steer clinicians away
from the catatonia diagnosis. These impediments will only
resolve through comprehensive descriptions in the medical
literature.
Conclusion
A comprehensive evaluation of catatonia in young adults
with Down syndrome confirmed that the diagnosis of
catatonia in DS is straightforward when based on a clear
history of functional regression, symptoms specified by the
BFCRS and positive responses to lorazepam and/or elec-
troconvulsive therapy. Furthermore, comparing catatonia
in DS patients to catatonia described in Autism, in various
psychiatric and medical disorders we observed no quanti-
fiable differences in either the catatonia diagnostic process
or catatonia symptoms. That is not to say that the under-
lying neurodevelopmental disorder may not influence the
severity or tenor of the symptoms or the ease in reaching
remission. For these reasons, further evaluation of catato-
nia in homogeneous patient groups is recommended.
Though our treatment protocols remained the same
throughout the five years, some modifications were made
based on increasing clinical experience. Significant
changes were 1) lorazepam was continued during ECT
after patient BK (#1); 2) lorazepam doses were increased
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Neuropsychiatric Disease and Treatment 2019:15
2738

more rapidly; 3) ancillary treatment modalities, including
NAC, minocycline, and memantine were tried less often
and for shorter periods before discontinuing; 4) dextro-
methorphan/quinidine was started earlier in the course and
continued for longer periods. These clinical judgements
developed in the course of patient care and can’t be con-
strued as clinical trials. In addition, each young person
presented with previously undetected health problems,
with symptoms apparently overshadowed by the catatonia.
Concurrent treatment of these health conditions undoubt-
edly optimized health and functioning, and also allowed us
to track responses to the catatonia specific treatments,
independently of symptoms related to specific medical
disorders.
Finally, following these seven patients with DS and
catatonia for three and a half to six years, provided a
number of fresh observations including a high prevalence
of autoimmune disorders (57%), laboratory evidence of
immune activation and an enhanced female gender ratio
(6 F:1 M), each of which raise the prospect of immunolo-
gical influences. Future investigations, following these
clues, may lead to a clearer understanding of catatonia
triggers in DS.
Acknowledgments
The authors thank the Leda Sears Foundation, the
Department of Child Health, and the Thompson Center
for the grant and in-kind support of this work. Especially
we thank the young people and their parents who partici-
pated fully in this endeavor including reviewing and refin-
ing the Catatonia Impact Scale.
Disclosure
The authors report no conflicts of interest in this work.
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