VINCENT FOUNDATION
Case #1
Expert Panel Case Evaluation
Hypoxic-ischemic brain injury
occurring at age 5 years in a male child
with underlying mild autism spectrum disorder
Draft dated 14 November 2014 (JYS)
CONTENTS
About the Vincent Foundation .................................................................................................. 3
About the Expert Panel................................................................................................................ 4
Section 1
1.1
Clinical History ...................................................................................................................... 7
1.1.1
Summary Statement ............................................................................................. 7
1.1.2
Medical and Surgical History ............................................................................... 7
1.1.3
Birth History ........................................................................................................... 11
1.1.4
Family History ....................................................................................................... 12
Section 2
2.1
2.2
Clinical Data and Analyses
Supplemental Information and Appendices
Radiological Assessments ................................................................................................. 17
2.1.1
CT Scan Reports .................................................................................................. 17
2.1.2
MRI Scan Reports ................................................................................................ 17
2.1.3
PET Scan Reports ................................................................................................. 17
Metabolic and Neurometabolic Testing ........................................................................ 18
2.2.1
EEG Report 20.06.2012........................................................................................ 18
2.2.2
EEG Reports (21.6.2012, 22.6.2012, 23.6.2012, 19.7.12) ................................... 18
2.3
Medications and Timelines ............................................................................................... 21
2.4
Genetic Analyses............................................................................................................... 22
2.4.1
Amniocentesis - karyotype ................................................................................ 22
2.4.2
Amniocentesis - FISH ........................................................................................... 23
2.4.3
Microarray and Sequencing ............................................................................. 23
2.5
Physical Growth ................................................................................................................. 24
2.6
Neurology and Neuromuscular Evaluations .................................................................. 26
2.6.1
Neurological Status as of 30.08.2012 ................................................................ 26
2.6.2
Neurological Status as of 13.09.2012 ................................................................ 27
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2.6.3
Physical and Occupational Therapy Status as of 12.9.2012 ......................... 29
2.6.4
Speech and Language Evaluation as of 2.1.2013 ......................................... 34
Section 3
Evaluations and Guideline Recommendations .............................................. 36
3.1
Pharmacological Interventions ....................................................................................... 36
3.2
Nutrition and Nutritional Supplements ............................................................................ 37
3.3
Rehabilitation Interventions and Strategies ................................................................... 38
3.4
3.5
3.3.1
Physical Therapy.................................................................................................. 38
3.3.2
Occupational Therapy....................................................................................... 38
3.3.3
Speech and Language Therapies.................................................................... 38
3.3.4
Education ............................................................................................................. 38
Complimentary and Alternative Medicine Treatments ............................................... 38
3.4.1
Acupuncture ....................................................................................................... 38
3.4.2
Eastern Herbal treatment................................................................................... 38
Additional Interventions of Interest ................................................................................. 38
3.5.1
Intrathecal Baclofen........................................................................................... 38
3.5.2
Deep Brain Stimulation ....................................................................................... 38
3.5.3
Botulinum Toxin .................................................................................................... 38
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ABOUT THE VINCENT FOUNDATION
The Vincent Foundation (www.vincentfoundation.org) is a non-profit organization whose
primary mission is to promote translational research and novel treatments for children with
brain injury.
The Foundation’s multidisciplinary expert panel conducts in-depth clinical case
evaluations of prevalent types of childhood brain injuries. These in-depth case studies
serve as the basis for expert opinions about integrated and/or leading edge treatment
interventions. The opinions are integrated into problem-based “personalized” reports that
can provide clinical practitioners around the globe access to world-class medical
opinions about optimizing treatment for these children.
Patients seeking Foundation services must agree to provide detailed clinical data. The
records will be de-identified before submission to our Expert Panel for a comprehensive
review that results in a Foundation Expert Clinical Report. To be accepted for evaluation,
the Foundation must be provided with complete medical records, including clinical notes
and consultant reports, test results, details of prior treatments, copies of all radiological
images, and have had a recent status re-evaluation by their clinical care team. In
addition to the value of the Foundation’s Expert Clinical Report as an instructional tool,
the document can provide patients with a more intensive, personalized assessment of
clinical management than they would otherwise receive in a standard clinical setting,
particularly in medical resource-poor regions.
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ABOUT THE EXPERT PANEL
Dr Ralf Clauss
Dr Ralf Clauss is a Consultant Physician in Nuclear Medicine at the Royal Surrey County
Hospital, UK. He completed his MBChB at the University of Pretoria and his MMed in
Nuclear Medicine at the Medical University of Southern Africa. He completed his MD at
the University of Düsseldorf in Germany and is a fellow of the Royal College of Physicians
in London. In 1999, together with Dr Wally Nel, he described a patient in the Vegetative
State who regained consciousness on the medication Zolpidem, the first ever patient in
the world to do so. Dr Clauss completed a 99mTc HMPAO SPECT brain scan on this patient
and discovered the effect of Zolpidem on cerebral perfusion after brain damage.
Together with Dr Nel and other colleagues, he continues to research the effect of
Zolpidem on brain damage and also the role of neurotransmitter homeostasis after brain
damage particularly that of oxygen based amino acids such glutamate and GABA, and
monoamines such as dopamine, noradrenaline and serotonin.
[Dr X X]
[Dr X X]
[Dr X X]
Medical editor: Dr. Glenn H. Bock
Dr. Bock’s medical career has spanned more than 30 years. In addition to his medical
practice, his professional activities included university hospital teaching positions, having
served as Director of both Paediatric residency and Paediatric Nephrology fellowship
programs at the Inova Fairfax Hospital for Children and Children’s Hospital National
Medical Center, respectively. He also was a clinical and laboratory investigator
throughout his career, and has published or presented nearly 100 peer-reviewed papers
and textbook contributions. He has written or edited many medical manuscripts,
research proposals, and public medical education media. Dr. Bock has recently retired
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from clinical medicine. With a very broad knowledge base and a passion for life-long
learning, he is now devoting his time to editing and writing on numerous medical topics.
Dr. Bock received his medical degree from the University of Missouri – Columbia in 1975.
He then served as a Paediatric resident at the State University of New York – Upstate
Medical University, and completed a clinical and research fellowship in Paediatric
Nephrology at the University of Minnesota Hospitals in Minneapolis.
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SECTION 1: CASE 1
Clinical Data
and Analyses
CLINICAL DATA AND ANALYSES
1.1
CLINICAL HISTORY
1.1.1
Summary Statement
This is a case of severe hypoxic-ischemic brain injury occurring at age 5 years in
a male child with underlying mild autism spectrum disorder. The injury occurred
in the immediate postoperative period following administration of several doses
of ketamine and subsequent cardiopulmonary arrest. The total duration of the
episode, from initial recognition to successful resuscitation, was 10 to 15 minutes.
Thereafter he had severe dystonia/spasticity with radiographic confirmation of
permanent cerebral hypoxic-ischemic injury. His global physical disabilities and
inability to communicate verbally have made the evaluation of residual
cognitive function and realistic expectations of cognitive potential difficult.
1.1.2
Medical and Surgical History
This male child is currently 7 years old (DOB 15 June 2007). His diagnoses include
congenital cleft lip and palate, developmental delay whose evaluation at age
4 years suggested mild autism spectrum disorder, and chronic severe ischemic
brain injury following elective cosmetic nose surgery at age 5 years.
Cleft Lip and Palate
An uncomplicated amniocentesis was done at approximately 20 weeks
gestation prompted by findings on fetal ultrasonography that suggested an
orofacial abnormality. Karyotype was 46 XY, and no chromosomal abnormalities
were identified. FISH showed normal copy numbers for chromosomes 13, 18, and
21 with a threshold of detection of mosaicism of 20% and a test sensitivity of 95%.
He successfully underwent an initial cleft lip repair in the neonatal period. A
partial cleft palate repair was done at age 3 years, and the subsequent cosmetic
revision at age 5 years. His medical records do not suggest any chronic infectious
illnesses associated with his cleft palate.
Neurodevelopmental Delay
Early gross motor development was normal; crawled at age 6-9 months, walked
at 1 year. His first words were at 2.0 years. At age 3 years and 10 months he
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underwent developmental assessment due to parent and teacher concerns
about poor social skills and peer interactions, and observed speech and
language difficulties. The Early Autism Project subsequently evaluated him at age
4 years and 5 months. The findings from these evaluations included:
both expressive and receptive language delays with no structural
oropharyngeal abnormalities,
articulation difficult to understand,
inconsistent eye contact,
avoidance of peer interactions with a tendency to play by himself,
short attention span and easily distractibility,
use of nonverbal communication strategies
He also was noted to enjoy music, could count and knew his alphabet, and
understood familiar commands at home (with assistance of situational
understanding and visual clues).
The evaluations concluded that he had characteristics of mild autism, scoring 27
on the Childhood Autism Rating Scale (range for “minimal symptoms of autism”
15 - 29.5). Treatment recommendations from these evaluations included:
Placing emphasis on the use of one language at home (multi-lingual
family). The family followed through using English as primary language.
Enhancing language development skills through exposure to children of his
own language age, require use of language instead of acquiescing to nonverbal communication, implementing PECS (Picture Exchange
Communication System) in school,
Speech therapy
Intensified behavioural therapy
Assistance from a full-time shadow for socialization, limit setting, and
assimilation
He has not yet undergone a systematic re-evaluation of interventions and the
domains of developmental progress.
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Acute Hypoxic-Ischemic Brain Injury
On 20 June 2012 (age 5 years), the child was admitted to the hospital for cosmetic
nose revision and repair of extensive dental caries under general (inhaled)
anaesthesia. There was no pre-medication, nor notation of problems with
induction or intubation. No intraoperative problems or events are noted. In the
recovery room he was agitated and 5 mg ketamine was administered IV by the
anaesthesiologist. The solution was prepared as a 1:10 dilution of 1 mL ketamine
(50 mg/mL) in a 10 mL syringe. A short time later in the recovery room the child
was described as groggy, “making noise”, and touching his surgical dressing. A
recovery room nurse administered an additional ketamine dose from the same
syringe for “pain and agitation”. Although the narrative records state that the
dose was an additional 5 mg, the amount given was not clearly documented.
Very soon thereafter, the child’s father noted shallow breathing followed by
cyanosis. He alerted the nursing staff and a code blue was called. The child
appeared to have had a full cardiopulmonary arrest with an estimated duration
of 10 to 15 minutes until successful resuscitation. He remained intubated and
ventilated and BP was in acceptable range. Several hours’ later, vital signs were
still in acceptable ranges, pupils were stated to be 2 mm but reactive, although
no spontaneous movement was seen and the Glasgow Coma (GCS) scale was
3/15. He received several daily doses of intravenous dexamethasone, 4 mg, and
mannitol 75 mL over 1 hour. His initial magnetic resonance imaging study,
including an MRV, was done about 5 hours following his hypoxic event and was
essentially normal (see Section 2.1.2. for sequential MR findings). Initial and serial
laboratory studies are listed in Section 2.2.3. None of the initial test results obtained
was sufficiently abnormal to explain the arrest. Additional studies done during this
hospitalization included evaluation for possible Velo-Cardio-Facial Syndrome;
ECG and echocardiogram were normal, and genetic testing by whole genome
exome sequencing and microarray analyses were not consistent with the
diagnosis (see full summary of findings in Section 2.4.). Plasma amino and organic
acid analyses were normal as were serum lactate and pyruvate and, later, blood
ammonia.
The sequences of clinical events and findings during the hospitalization, lasting
approximately 3 months (discharged 22 September 2012), are described below,
and in Sections 2.2.3.(serial laboratory results) and 2.3. (medications).
Stable VS with GCS remaining 3/5 for first 2 days, followed by improvement
to 7/15 by day 2 to 3.
Probable seizures early in course, received barbiturates.
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EEG initially showed diffuse slow waveform cerebral rhythms that are noted
to have improved over subsequent days although “slowing” persisted with
diminished alpha component on repetitive studies.
On day 10, GCS still noted to be 7/15. By day 22 the GCS was 11/15.
Slow improvement of spontaneous activity, eye opening, not cognitively
interactive for first 2 weeks. During that time, developed significant dystonia
and spasticity.
Slowly improving environmental and family/staff interactivity, smiling
responsively by approximately week 4.
Hospital interventions included intensive PT, OT, and speech therapy.
Upper gastrointestinal dysfunction resulted in nasogastric tube feeding
dependency in the hospital.
Medications during latter part of hospitalization included baclofen 7.5 mg
QID, artane 2 mg QID, Valium (changing/tapering doses), and lanzoprazole
15 mg QD.
Rehabilitation Status Prior to Hospital Discharge
Findings from comprehensive rehabilitation
September 2012) and PT/OT reports:
medicine
re-evaluation
(3
Tardieu Scale assessment performed and compared to initial assessment on
2 July 2014 ((Section 2.6.3.).
Severe extensor posture, global dyskinetic movements including tongue.
Poor head control, feet in equinovarus position.
Inability to stand without support
Ability to make sounds but no comprehensible vocalization
Hearing appeared intact.
Ability to fix eyes on people, interacted by laughing and smiling when
spoken to. Responded to music, story-telling, visual stimulation in a similar
fashion
Inability to ascertain severity of present and potential cognitive impairment.
Recommendations for management included:
• Initial rehabilitation management “as an inpatient in a paediatric
rehabilitation centre specializing in neurological rehabilitation”.
• Use of botulinum toxin for management of dystonia/spasticity.
• Use of dopaminergic drugs (levodopa mentioned specifically)
• Consideration of intrathecal baclofen
Oromotor function evaluation and videofluoroscopy were done 9
September 2012. The assessment concluded: “severe Oro-Pharyngeal
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Dysphagia characterised by poor lip seal and bolus preparation, persistent
tongue thrusting resulting in premature spillage and delayed trigger of the
swallow reflex preceded by bolus filling in valleculae and pyrifom sinuses.
Although nil aspiration was noted in this study, it cannot assumed that the
patient is not at risk of aspiration, in view of significant base of tongue
residue and delayed swallow reflex trigger.”
Course of Chronic Hypoxic-Ischemic Brain Injury
Principal observations
Treatment since hospital discharge included PT, OT, and oromotor therapy
on a regular basis. According to nursing and therapists’ notes, he appears
to have made some modest progress in motor function, spasticity, and
contractures but no recent formal evaluations have been done. By daily
descriptions, his receptive language skills appear to be significantly better
than verbal expressive language, and non-verbal communication
strategies are used.
Oromotor function improved such that nasogastric feeds were discontinued
on 4 November 2012. At present he appears to do well with both solids and
liquids orally.
An autologous stem cell infusion was done in August 2013. This was followed
by epoetin alfa treatment. The stem cell blood type was A(-); volume 71.5
mL, total nucleated cells 4.7 x 108 with 99.9% viability. No other details about
the procedure and follow up are available at this time.
In May – June 2014, he received short trials of Stilnox (zolpidem) and Ritalin
(methylphenidate). The doses and times are noted in Section 2.3. These
brief treatments were given both individually and in combination. On higher
doses of Stilnox no sedative effect was noted; in fact his baseline level of
activity appeared to increase, as did his heart rate. By contrast, Ritalin
appeared to have a calming effect that lasted as much as 24-48 hours.
Ritalin also appeared to be associated with a sad demeanour and
insomnia. With a combination of both drugs, the Stilnox effect described
above was dominant.
1.1.3
Birth History
31-year-old mother of Asian (Siamese) descent. G1P1
Amniocentesis done at approximately 20 weeks gestation (see findings in
Medical and Surgical History). Full-term gestation without documentation of
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complications except as related to abnormal fetal ultrasonography and
subsequent amniocentesis.
Delivered by Cesarean section. Birth weight 3.4 kg.
1.1.4
Family History
Both parents in good health.
Male sibling born (approximately) May 2008 in good health.
Female sibling (cousin, now adopted) approximately 9 years old in good
health.
Nephews: 2 male children of paternal uncle with alkaptonuria.
1.2
CLINICAL PROBLEMS FOR EXPERT PANEL ASSESSMENTS
In your assessments, please include those following clinical issues that are
relevant to your area of expertise and feel free to add others.
1.2.1
Acute Brain Injury Event
The degree of brain injury that resulted from this patient’s hypoxic event was
severe although concurrent injury to other organs based on the available data
was modest: elevations of liver transaminases were minimal, there was no
evidence of acute kidney injury, and echocardiography demonstrated good
myocardial function. However, noted is a significant elevation of CPK, which may
occur in rhabdomyolysis. The fact that the AST was elevated, albeit mildly, while
ALT elevations were minimal, further support consideration of concurrent
rhabdomyolysis.
Questions:
Was the possible co-existence of transient rhabdomyolysis a significant
finding in this setting?
Given the clinical findings and studies performed, are there other potential
underlying conditions to consider?
1.2.2
Neuromotor Dysfunction and Spasticity
Previous treatment recommendations have included drug therapy to ameliorate
muscle spasticity and to modulate CNS neurotransmitter balance. He has
undergone a brief trial of zolpidem and methylphenidate treatment. The possible
use of botulinum toxin and intrathecal baclofen has been raised and he has
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received an autologous stem cell infusion. The patient’s cerebral palsy-like motor
dysfunction, as well as consequent physical disabilities from muscle spasticity and
contractures, doubtlessly affect physical rehabilitation, skills development,
cognitive development, and health in general. His records indicate on-going
physical and occupational therapy efforts, which include speech and language.
Questions:
Was the trial of zolpidem and methylphenidate sufficient to determine
benefit?
Is there a potentially beneficial drug regimen and, if so, with what goal(s)?
What would constitute a protocol for a proposed drug regimen, how should
this be coordinated with other efforts, how can side effects be addressed,
and what metrics could be used to guide ongoing treatment?
Regarding the autologous stem cell infusion, are there subsequent tests to
be done and is there recent new stem cell or related research observations
of potential benefit?
How can the treatments provided by physical, occupational, and speech
therapists be better coordinated and synergistic? In the hospital, the
patient had several assessments with a Tardieu Scale (Section 2.6.3.). What
roles should this, or other assessment tools, play in long-term treatment
planning? Is there the need for reassessment of the therapies provided by
home health caretakers; how can treatment coordination between all
players best be implemented?
Are there potential roles for other therapies such as non-invasive
transcranial therapies (i.e. magnetic stimulation or ultrasound),
acupuncture, Chinese herbal medicine, or other alternative medicine
interventions?
1.2.3
Language, Communication, and Cognition
The impression is that the patient vocalizes but has very limited recognizable
speech. Records indicate comprehensible nonverbal communication, raising
the issue of the degree to which language and other forms of expression are
limiting communication and cognitive performance. There have been numerous
previous recommendations about enabling the patient’s ability to
communicate. For understandable reasons, most of these have focused on nonverbal means of communication.
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Questions:
Is the patient’s vocal language disability a fait accompli, or are there verbal
and non-verbal communication tools and technology that currently exist or
are in development to be explored?
Would any other concomitant or novel treatments (such as for muscle
spasticity and hypertonicity) be of any benefit?
Is it likely that the patient’s pre-existing speech and language difficulties
play any role in rehabilitation efforts?
1.2.4
Anthropometric Growth
The patient’s weight and height have increased modestly over the intervening
time since hospitalization. Upon closer examination (see Section 2.5.), statural
growth (height) percentiles and z-scores have progressively diminished to zscores of less than -1.0. Although body weight has increased about 3 kg over this
same interval, this increase reflects sustained but very poor weight percentile
ranks and z-scores. Weight percentile has been consistently less than the 2nd
percentile with z-scores in the -2.0 to -2.5 range.
Questions:
Does he have undernutrition/malnutrition (despite current caloric intake)? Is
this having an adverse impact on recovery?
Are there reasons to consider underlying malabsorptive or hormonal
perturbations?
Is there a practical need for a metabolic/nutrition evaluation of energy
intake and needs (taking into account his energy consumption). If so, what
baseline and subsequent anthropometric or other measures of nutritional
status would be useful and what parameters should be used.
1.2.5
Hydration
According to the patient’s recent intake records, there is good daily fluid intake,
with an average in excess of 2,000 mL per m2 per day. Under usual circumstances
this would be considered more than adequate to maintain hydration. However,
central nervous system diabetes insipidus leading to excessive urine production
may occur in patients with CNS injury. Physical and/or cognitive limitations may
affect a handicapped child’s ad lib access to water in order to compensate for
the urine losses. Also, his unmeasured losses may be increased in his tropical
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environment. No documentation of urinary concentrating capacity or daily urine
volumes is identified.
Questions:
Is chronic under-hydration a significant contributing factor in this patient’s
growth impairment?
If so, how can this best be evaluated and treated?
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SECTION 2: CASE 1
Supplemental
Information
and Appendices
SUPPLEMENTAL INFORMATION AND
APPENDICES
2.1
RADIOLOGICAL ASSESSMENTS
2.1.1
CT Scan Reports
2.1.2
MRI Scan Reports
Time after event
Axial images in FLAIR, diffusion, Coronal T2, and Sagittal T1 weighted
sequences.
Essentially normal study. Specifically:
5 hours
2.1.3
●
●
●
●
No cerebral thrombosis or acute infarct
Normal grey-white differentiation
Normal basal ganglia
No AVM
2 days
Axial images in T1, T2, diffusion, and GRE sequences; Coronal in T2
sequence and Sagittal in T1.
Acute hypoxic-ischemic injury posterior parts of (right > left lentiform nuclei
indicating areas of acute hypoxic-ischemic injury in basal ganglia
21 days
Axial images in T2 FLAIR, T1 diffusion, Coronal images in T2, Sagittal images
in T1.
New areas of hypoxic-ischemic injury in globus pallidi substantia nigra, and
periventricular white matter, all bilaterally.
Prior ischemic foci in putamina now in subactute phase
Cerebral atrophy
45 days
Axial images in FLAIR, T2, T1, and diffusion, Coronal images in T2, Sagittal
images in T1.
No new abnormalities or foci of injury seen
Degree of cerebral atrophy unchanged
Sizes of ventricles and cortical sulci same as previous study
Normal MRS study
PET Scan Reports
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2.2
METABOLIC AND NEUROMETABOLIC TESTING
2.2.1
EEG Report 20.06.2012
An inpatient routine EEG recording was performed on 20.06.2012 with the patient
in ICU. Activation procedure of photic stimulation was done.
Background Activity & interictal EEG
The overall cerebral rhythms are slow and consists of diffuse polymorphic delta
activity (2.0-3.5 Hz, 20-200uv) and some theta activity (5- 6 Hz. 20-40 uv) and low
voltage beta. Sleep spindles are not evident.
Photic driving was poor. There is no significant response to deep noxious stimulus,
Impression; This EEG of 20.06.2012 shows diffuse slow wave cerebral rhythms
indicating diffuse cortical dysfunction or drug effect (encephalopathy).
Suggest to repeat later.
2.2.2
EEG Reports (21.6.2012, 22.6.2012, 23.6.2012, 19.7.12)
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2.2.3. Laboratory studies during early hospitalization
(abnormal values indicated in red)
Days after injury
20-Jun
20-Jun
21-Jun
21-Jun
21-Jun
22-Jun
22-Jun
22-Jun
23-Jun
23-Jun
24-Jun
27-Jun
30-Jun
9-Jul
9.1
12.1
13.4
13.5
13.2
12.8
Hb (g/dL)
11.9
10.9
9.5
WBC (x103)
21.7
14.6
14.4
18.6
19
19.4
16.8
13.3
% Neutrophils
83
86
68
64
69
66
71
71
Platelets (x103)
323
286
295
279
362
458
615
576
Sodium (mmol/L)
130
132
137
137
136
133
133
129
134
137
134
138
132
133
Chloride (mmol/L)
95
96
103
103
104
100
99
101
101
102
97
102
100
97
Potassium (mmol/L)
3.7
3.1
3.5
3.8
3.8
4.2
3.9
3.0
3.6
5.1
4.3
4.2
Urea (mmol/L)
4.6
2.6
1.8
2.5
2.7
2.3
3.2
3.7
3.2
4.3
3.3
1.9
2.9
3.2
Creatinine (mmol/L)
59
31
40
29
31
32
35
34
31
39
39
29
1.93
2.12
Calcium (mmol/L)
1.98
Magnesium (mmol/L)
0.85
2.17
2.06
2.16
2.46
0.77
Phosphorus (mmol/L)
1.17
Uric acid (mmol/L)
0.09
0.92
1.99
ALT (IU/L)
36
34
32
63
49
50
AST (IU/L)
65
52
45
87
82
94
GGT (IU/L)
25
19
20
31
37
73
Urinalysis
Glucose
56
Negative
RBC/heme/myoglobin
4+
Negative
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Days after injury
20-Jun
Micro RBC (/uL)
20-Jun
21-Jun
21-Jun
21-Jun
22-Jun
22-Jun
23-Jun
23-Jun
24-Jun
27-Jun
400
8.9
845
10.5
Free T4 (pmol/L)
9-Jul
369
30.3
8.1
0.9
3574
450
194
LDH (IU/L)
TSH (mIU/L)
30-Jun
Nil
CRP (mg/L)
CPK (IU/L)
22-Jun
702
0.167
12.6
Ammonia (umol/L)
Lactate (mmol/L)
44
34
0.7
Plasma Amino Acids
Normal
Urine Organic Acids
see
note*
Urine Orotic acid/creat
0.65
Plasma carnitine
Normal
Acyl carnitine
Normal
* “Marked increase 3-OH bulyrate (?butyrate) and acetoacetate. Possibilities: succinyl CoA3 ketoacid transferase deficiency or severe ketoacidosis
See Fukao T. Succinyl CoA3 ketoacid transferase (SCOT) deficiency. Orphanet encyclopedia, September 2004.
https://www.orpha.net/data/patho/GB/uk-scot.pdf
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2.3
MEDICATIONS AND TIMELINES
Vincent's Meds and Doses up to March 2013
35
Prevacid
30
Artane
Dose (mg)
25
Valium
20
Baclofen
15
Nootropil (mL)
10
5
0
9/8/12
10/18/12
11/27/12
1/6/13
2/15/13
3/27/13
Date
16
4
Zolpidem
14
3.5
Methylphenidate
12
3
10
2.5
8
2
6
1.5
4
1
2
0.5
0
4/21/14
Oxytocin (mL)
Dose (mL)
Dose (mg)
Vincent's Meds and Doses after May 2013
0
6/10/14
7/30/14
9/18/14
Date
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2.4
GENETIC ANALYSES
2.4.1
Amniocentesis - karyotype
RECEIVED DATE/TIME: 13/02/07 1200
COMMENTS: CULTURE #: 071049 AF
GA: 20 WKS G1P0
LMP: UNK EDD: 26/06/07
CLINICAL DIAGNOSIS: ABNORMAL ULTRASOUND FINDINGS
AMOUNT OF AF RECEIVED: 20 ML
FLUID APPEARANCE: CLEAR
PELLET SIZE / APPEARANCE: LARGE / CLEAR
DATE OF COLLECTION: 12/02/2007
CHROMO
KARY AF
GTG-banded cells/colonies scored : 16/16
GTG-banded cells analysed/karyotyped: 5/5
Cultures analysed : 3
Estimated band level: 500 BPHS
Karyotype : 46,XY
Cultures indicate a male karyotype with no apparent chromosomal
abnormalities.
The result confirms earlier normal FISH findings.
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2.4.2
Amniocentesis - FISH
RECEIVED DATE/TIME: 13/02/07 1200
SOURCE: UNCULTURED CELLS FROM AMNIOTIC FLUID
CLINICAL INDICATION: ABNORMAL ULTRASOUND
DATE OF COLLECTION : 12/02/2007
FISH PROBES: AneuVysion Multicolor DNA Probe Kit (Vysis) (CEP 18/X/Y-alpha
satellite, LSI 13 and 21)
No. of cells/probe examined: 50
FISH nomenclature:
nuc ish(DXZl,DYZ3)xl,(RBl,D18Zl,D21S259,D21S341,
021S342)x2
FISH indicates a male fetus with normal copy numbers of chromosomes 13,
18 and 21. However, the assay is unable to detect mosaicism occuring
below 20% at the established analytical sensitivity of 95%. This test is not
meant to be a standalone test. Please correlate FISH findings with
karyotype results.
This test was developed and its performance characteristics determined by
the Cytogenetics Laboratory, Department of Pathology, SGH. The above
probes have been cleared and approved by the FDA for clinical use.
2.4.3
Microarray and Sequencing
Studies performed for further evaluation of possible velo-cardio-facial syndrome.
Results reviewed by Dr. Shprintzen.
A whole genome exome sequencing analysis was done in conjunction with
microarray analysis. The exome sequencing found mutations in the following
genes:
1
2
A clinically significant known deleterious mutation was found in the CHD8
gene (c436G>A Val/Met) (OMIM*610528) which is altered in patients with
Autism Spectrum Disorder (ASD). CHD8 is located on chromosome 14q11.2
and the occurrences of the condition are de novo.
A clinically significant known deleterious mutation was found in the TBX1
gene (c1178C>T–aa Thr/Met) (OMIM*602054) which is altered in patients
with velo-cardio-facial syndrome (VCFS, OMIM#192430). TBX is located on
chromosome 22q11.21 and the inheritance pattern of the condition is
autosomal dominant or sporadic.
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3
4
5
A homozygous mutation in both copies of MTRR, at 5p15.31, a gene
associated with homocystinuria.
A mutation in BRCA1, a gene associated with breast cancer.
A mutation in COL2A1, the gene associated with Stickler syndrome.
The CGH microarray analysis showed three copy number variants (CNVs), all of
the duplications. Two of these CNVs were on the X chromosome and are known
to be normal variants. The third was on chromosome 18 at the q21.1 band and is
in a noncoding portion of DNA (intronic). Dr. Shprintzen did not believe that the
findings supported a diagnosis of velo-cardio-facial syndrome.
2.5
PHYSICAL GROWTH
40%
0
Height Percentile
35%
-0.2
Height z-score
30%
-0.4
25%
-0.6
20%
-0.8
15%
z-score
Percentile
Case 1 Height (percentiles and z-scores)
-1
10%
-1.2
5%
-1.4
0%
60
70
80
90
Age (months)
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Case 1 Weight (percentiles and z-scores)
0
-0.5
Percentile
8%
-1
-1.5
6%
-2
4%
-2.5
-3
2%
Weight Percentile
Weight z-score
Weight z-score
10%
-3.5
0%
-4
60
70
80
90
Age (months)
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Case 1 Weight and Height values
19
117
Height (cm)
115
17
114
16
113
15
111
112
110
14
Height (cm)
Weight (Kg)
18
109
13
108
9/18/14
6/10/14
3/2/14
11/22/13
8/14/13
5/6/13
1/26/13
10/18/12
107
7/10/12
12
2.6
Weight (Kg)
116
Date
NEUROLOGY AND NEUROMUSCULAR EVALUATIONS
(See full rehab evaluation in hospital record)
2.6.1
Neurological Status as of 30.08.2012
At 5 + years his general condition is satisfactory. He is alert, looks around and
makes sounds. He is non-verbal and non-ambulatory. There is fairly good eye
contact and he enjoys watching television. There is asymmetrical dystonic
spastic quadriparesis (left > right) with some athetoid posturing and tongue thrust
especially when he is upset. There is dystonic torticollis with intermittent head tilt
to the left and postural scoliosis. On stance (on the standing frame), his knees are
straight and he can plantigrade his feet. The neck needs support. There is thumbln-palm deformity on the left side. He can cross-sit well, although he has a
stooped posture (poor trunk control) and the head control is intermittent. The
overall spasticity scoring (Modified Ashworth Score) is about Grade 1+/2 on the
left side. Systemic examination is within normal limits.
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2.6.2
Neurological Status as of 13.09.2012
Neurological assessment
Able to fix eyes on people around him, able to laugh and smile when talked
to especially by parents.
Severe abnormal posturing of body, dyskinetic movements affecting limbs,
trunk and oro-motor including tongue.
Pupils: 2 mm reactive to light, reactive to threat.
Cries and groans, no comprehensible vocalization.
Posture post correction and at rest in ATNR.
Hearing appears intact
Head control still poor (floppy)
Minimal voluntary movement noted during examination
Feet in equinovarus position
Upper limb
Tone:
Right increased (MAS 2)
Left increased (MAS 3)
Power:
Unable to elicit objectively due to spasticity and dyskinetic
movements of both upper limbs, at least 1-2/5
Dystonic movements noted during the examination but some
voluntary resistance felt on attempt to passively extend right elbow,
right wrist
Reflexes:
RIGHT
LEFT
biceps
triceps
brisk
brisk
brisk
brisk
PROM
cannot get full range
cannot get full range
Lower limb
Tone:
Right increased (MAS 3)
Left increased (MAS 3)
Power:
Unable to elicit due to severe spasticity of both lower limbs
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RIGHT
LEFT
brisk
brisk
up going
brisk
brisk
up going
Reflexes:
knee
ankle
extensor
PROM
contracture at ankle
contracture at ankle
Sensation: appears intact
Function
Poor head control on sitting up with support
C- shaped trunk with extensor thrust on attempt to sit longer, flexible scoliosis
noted
Not able to stand with support
Stand: dependent
Not able to walk
Totally dependent
IMPRESSIONS
Hypoxic brain injury resulting in severe movement disorder (dystonia with
underlying spasticity)
Minimally conscious state
Unable to ascertain severity of cognitive impairment
Dysphagia needing modification in mode of feeding
RECOMMENDATIONS
In view of his current neurological and functional sta
it is recommended that the patient is to be managed as an inpatient in a
paediatric rehabilitation centre specializing in neurological rehabilitation.
The movement disorders need to be intervened optimally as it directly
affects his energy expenditure and his future functional gains. Optimization
of medications that would significantly reduce the dystonic movements
need to be explored.Further, dopaminergic drugs such as levodopa should
be looked into. Another option is trial of intrathecal baclofen if dystonia is
not well controlled with the above medications or if there is poor tolerance
to the above/develop adverse effects.
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Botulinum toxin injection for focal management of dystonia/spasticity
should be added into the management of high risk musculoskeletal regions
prone to developing contractures such as ankles, knees, wrist and hand. A
combination of management must be looked into i.e. use of appropriate
orthoses, medications and serial casting where appropriate.
Nutritional status should be optimized and feeding option and regime must
be explored in view of his current (at that time) gastrointestinal concern
and dsyphagia.
The proposed programme may take up to 6 months or so in a rehabilitation
setup specializing in neurological rehabilitation. Most children who have
sustained moderate to severe brain injury/insult will have some degree of
cognitive, physical and or behaviour deficits. Improvement (neurological
and functional) after a brain injury happens at a different rate for every
child but usually continues for a long time. It is pertinent to realize that the
recovery is most rapid in the early stages. Therefore, acomprehensive
paediatric rehabilitation team in an appropriate paediatric .rehab, setup
will be able to address the above concerns and work with the child and
family to maximise the recovery.
This is comprised of the following:
Continuous medical assessment and management.
Provision of therapy services (physiotherapy, occupational therapy, speech
and swallowing, psychology and behavior)
Neuropsychological and clinical psychology assessment and management
Case Management services where appropriate
Family Support
Ongoing Education about Brain Injury to caregiver
2.6.3
Physical and Occupational Therapy Status as of 12.9.2012
Current Intervention
The patient’s parents and carers have been shown how to continue on-going
programme of positioning and stretching to try to control his hypertonic
synergies, reduce his reflex uncontrolled movements and reduce the associated
risks, including:1
Range of motion exercises for both Upper and Lower extremities
Purpose; To maintain joint flexibility and muscle length
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2
24 hour positioning management;
Purpose:




To maintain the daytime intervention done by OT and PT. The
intervention will be ineffective if the child is left to adopt destructive
posture during the hours spent in bed.
inhibiting spasm by positioning (supine, sitting; prone and prone
standing)
normalize tone with weight bearing training
improve normal body alignment and symmetrical posture by
positioning, with the use of positioning aids and lycra suit.
Supine, Prone, Side lying - using grasshopper system
Sitting - Paediatric wheelchair, grasshopper system (current system does not
offer enough support for patient’s head control)
Standing –Jenx Humprey Prone Stander
3
Righting and equilibrium reactions facilitation:
Using gymball and grasshopper system.
4
Sensory stimulation:
Purpose:
To improve body awareness
Joint sensation
by weight bearing exercise (standing, 4 point
kneeling) to inhibit abnormal muscle tone
Tactile
by touching different type of textures and surfaces
Visual
by using RBW (Red, Black and White) colour to
encourage visual tracking and facilitate head
movement
Auditory
by singing and storytelling session
5
Head and Trunk Control Training: in prone and sitting facilitated using
Grasshopper system
6
Oral Placement Therapy Programme -initiated and supervised by paediatric
dysphagia specialised Speech and Language Pathologist (once per week)
and carried out daily by caregivers
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7
Speech:


Using positioning to help inhibit hypertonic patterns to aim to facilitate
head and shoulder control and to help promote efficient breathing
patterns
During all treatment interventions language, singing, stories etc are
used to encourage the patient’s involvement and enjoyment
Summary and Recommendations
A suggested Daily Schedule has been provided to give a possible framework for
Caregivers to follow for home/on-going interventions based on the patient’s
current physiotherapy, occupational therapy and speech and language
interventions which would also include the following:24 hour postural programme is recommended to be continued to try to
prevent musculoskeletal complications arising from long-term
hypertonic synergy patterns - a comprehensive mattress and sleeping
posture system has been ordered and awaiting delivery
Weight-bearing activity /standing should be continued with a minimum of 6
hours per week weight bearing through the acetabulum/hips to reduce risk
of pelvic migration and wind-swept hips.
It is also recommended that the patient continue with his physiotherapy,
occupational therapy and speech and language therapy upon return home or
if moving onto a specialised paediatric rehab facility which would then coverContinued detailed oral placement therapy programme to improve
swallowing
Continued communication work to find a suitable system to facilitate the
patient’s ability to communicate
Continued work to enhance any neuro-plasticity allowing improvements to
his dyskinesia with more voluntary movement control and inhibition of his
reflex patterns and involuntary dystonia and synergies.
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TARDIEU SCALES
UPPER LIMB : INITIAL (Approx. late June-early July)
RIGHT
R2-R1
Joint/ Muscle
LEFT
R2 (PROM)
X/Rl
140°
0/140°
Sh./Vertical Adductors
2/120°
R2
(PROM)
140°
40°
180°
1/140°
Sh. /Internal Rotators
1/140°
180°
0°
170°
0 /170°
Elb./Flexors
2/155°
170°
15°
0°
140°
0/l40°
Elb./Extensors
2/140°
130°
5°
0°
90°
0 /90°
Elb./Pronators
2 /45°
90°
45°
0°
90°
0 /90°
Elb./Supinators
1 /90°
90°
0°
0°
90°
0 /90°
Wr./Flcxors
1 /90°
90°
0°
0°
70°
0 /70°
Wr./Extensors
1 /70°
70°
0°
Hand/palmar Intcrossei
& FDS
Thumb in full palmar flexion
0°
Thumb in full palmar flexion
X/R1
R2-R1
20°
40°
Thumb
LOWER LIMB : INITIAL (Approx. late June-early July)
RIGHT
Joint/ Muscle
R2-R1
R2 (PROM)
X/Rl
25°
70°
2 /45°
Hip/ Extensors
25°
65°
2/ 40°
10°
130°
5°
25°
LEFT
X/R1
R2-R1
2/ 30°
R2
(PROM)
70°
ip/ Adductors
1/30°
65°
35°
2/ 130°
Kn./ Extensors
2/ 130°
130°
10°
180°
2/175°
Kn./ Flexors
2/165°
180°
15°
35°
2/10°
Ank./ Plantarflexors
4/35°
10°
25°
Vincent Foundation Clinical Case Compendium: Case 1
40°
Page 32 of 38
UPPER LIMB: 13 September 2012
RIGHT
Joint/ Muscle
R2-R1
R2 (PROM)
X/Rl
0°
140°
0/140”
Sh./Vertical Adductors
0°
180°
0/ 180”
0°
170°
0°
LEFT
X/R1
R2-R1
1/ 140”
R2
(PROM)
140”
Sh. /Internal Rotators
1/ 180”
180”
0”
0/170”
Elb./FIexors
1/170”
170”
0”
140°
0/140”
Elb./Extensors
0/140”
140”
0°
0°
90”
0 /90°
Elb./Pronators
0 /90”
90”
0°
0°
90”
0 /90°
Elb./Supinators
0 /90°
90”
0°
0° “
0°
90”
0 /90°
Wr./Flexors
0 /90°
90°
0°
70”
0 /70°
Wr./Extensors
0 /70°
70”
Hnd./palmar Interossei
& FDS
Thumb still in full palmar flexion
Thumb still in full palmar flexion
0”
0”
Thumb
LOWER LIMB : 13 September 2012
RIGHT
Joint/ Muscle
R2-R1
R2 (PROM)
X/Rl
0°
70°
1 /70°
Hip/ Extensors
0°
65°
1/65°
10°
130°
0°
5°
LEFT
X/R1
R2-R1
1/70°
R2
(PROM)
70°
Hip/ Adductors
1/65°
65°
0°
1 / 130°
Kn./Extensors
1/130°
130°
0°
180°
2/ 180°
Kn./ Flexors
1 /180°
180°
0°
35°
2 / 30°
Ank./ Plantar flexors
2 / 20°
35°
10°
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0°
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2.6.4
Speech and Language Evaluation as of 2.1.2013
Communicating what he wants with Yes /No:
The patient is able to shake his head for ‘No’. This is sometimes accompanied by a
vocalization that is heard as an /o/, a clear /no/ or an approximation of the word.
He blinks his eyes for ‘Yes’. This is usually accompanied by a slight nod of the head
or a vocalization of ‘ye’ or ‘eh’. His yes/no communication is in response to
questions by the clinician, Conductor or the nurse e.g. “Do you want to play with
bubbles?” His responses are consistent during speech therapy and at home.
Communicating what he wants by looking at a choice of four pictures:
The patient has a portable communication book containing pictures of objects
that he needs and daily activities. The pictures are arranged four per page, on
the top / bottom right and top / bottom left side of the A4 sheet. The patient is
able to scan all four pictures before looking at the picture of an activity or object
that he wants. The pictures are organized according to categories of ‘drinks’,
‘toys and leisure activities’, ‘favourite songs’, ‘seats’, and ‘body parts’. He also
has these pictures categorised and secured by keyrings.
Communicating by hand tapping or swiping on a picture/ icon :
The patient is trying out hand-tapping a Yes / No toggle on the iPad. He has
better control over his left hand and is able to tap ‘yes’ most of the time.
However, the iPad is touch sensitive and requires precision, so there are times
when he rests his hand on an icon too long or touches a wrong icon. The iPad’s
small size means that only two icons at most can be displayed, in order for the
patient to succeed in touching the correct icon.
Communicating with a yes/no switch
The patient has recently tried using a domed light switch to help him
communicate yes/no more effectively. He is able to slowly move his left hand to
touch the switch to answer yes/no questions. We may move on to using a Jelly
Bean switch for communication as appropriate.
Vocalising
At the moment, the patient is able to say /m/and /ah/, and approximations of
‘no’, ‘yes’ and ‘more’. However, due to difficulties controlling muscle
movements, these vocalisations are inconsistent.
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SECTION 3: CASE 1
Evaluations
and Guideline
Recommendations
EVALUATIONS AND GUIDELINE
RECOMMENDATIONS
3.1
PHARMACOLOGICAL INTERVENTIONS
Based on recent videos in the above patient, there is a symptom complex seen that
includes a disattention to verbal stimuli and a perpetuating restlessness, combined with
a fairly consistent dorsal hyperextension, dystonia/spasticity. One direction to approach
such a symptom complex from is the hypothesis of an impaired homeostasis of oxygen
based neurotransmitters in the brain, which may occur in addition to other features
after brain injury. Such a hypothesis would consider the possibility that the availability of
one or more of such neurotransmitters may be impaired, either due to a lack of
production in the brain or due to a leakage through an insufficient blood brain barrier
after brain damage.
There could be several neurotransmitters which could be affected, such as amino acid
or monoamine based neurotransmitters which could be underactive or overactive, or
whose neurologic outflow could have an imbalance between them. Important also is
to consider the “now” situation only, in the sense that although previous drug
applications may have resulted in previous reactions or homeostatic disturbance, or
even damage, their pharmacological actions will by now have played out due to
metabolic binding and breakdown, amongst others. That means the neurological
symptom complex that is seen in the above patient at the time of the videos was a
result of a stable “new” homeostatic neurotransmitter environment after brain injury. If
this is true, then one can postulate the following:

The observed symptom complex may be partially due an abnormality in the
Glutamate/ GABA based system with features of dystonia and deficient
attention. Zolpidem is a GABA agonist which, in uninjured persons causes
sedation, but in some patients after brain injury results in improvement of
neurological disabilities such as impaired consciousness, cognition or impaired
motor features and then, as the dose increases, leads to sedation.
In the above patient, there was no significant change seen in neurological
disability, and there was also no sedation, even after dose escalation.
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
There may be an abnormality in the monoamine based system with deficient
attention, which in the monoamine homeostasis may point to a relative
deficiency in noradrenaline and dopamine, and a relative overexpression of
serotonin activity.
A pharmaceutical that counters noradrenalin/ dopamine deficiencies is
methylphenidate, which blocks dopamine and noradrenaline transporters in the brain,
and hence results in an increased concentration of dopamine and noradrenalin within
synaptic clefts, countering such deficiencies.
The above patient received methylphenidate, which had a calming effect, but
resulted in a sad demeanour.
Upon concurrent application of zolpidem and methylphenidate, the zolpidem effect
dominated.
In theory, further insights could be gained from scans on brain metabolism such as
99mTcHMPAO SPECT and 18FFDG PET scans, as they would show metabolic changes
that may not be picked up clinically, but such procedures should be contemplated
only if information garnered from them could lead to a therapeutic benefit for the
patient.
3.2
NUTRITION AND NUTRITIONAL SUPPLEMENTS
(i.e. creatine, neurotransmitter precursors etc.)
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Case 1
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3.3
3.4
3.5
REHABILITATION INTERVENTIONS AND STRATEGIES
3.3.1
Physical Therapy
3.3.2
Occupational Therapy
3.3.3
Speech and Language Therapies
3.3.4
Education
COMPLIMENTARY AND ALTERNATIVE MEDICINE TREATMENTS
3.4.1
Acupuncture
3.4.2
Eastern Herbal treatment
ADDITIONAL INTERVENTIONS OF INTEREST
3.5.1
Intrathecal Baclofen
3.5.2
Deep Brain Stimulation
3.5.3
Botulinum Toxin
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Case 1
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