University of Groningen

Infants at high risk of cerebral palsyHamer, Elisa Gerdina

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Citation for published version (APA):Hamer, E. G. (2016). Infants at high risk of cerebral palsy: Neuromotor characteristics and the effect of theearly intervention programme COPCA. Rijksuniversiteit Groningen.

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181

Chapter 10

General discussion

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The primary aim of this thesis was to enhance the identification of infants at risk

of cerebral palsy (CP) and to improve prediction of future neurodevelopment.

To this end, we first reviewed the literature on the predictive value of specific

neurological signs in high-risk infants (chapter 2). Next, we explored possible

relationships between slow pupillary light responses and type of brain lesion and

developmental outcome (chapter 3). We analyzed knee jerk responses by means of

surface electromyography (EMG) in both healthy newborns and high-risk infants

(chapter 4), and we investigated whether the development of knee jerk responses

was associated with a specific type of brain lesion or diagnosis of CP (chapter

5). Furthermore, we evaluated whether specific movement characteristics could

enhance the predictive power of definitely abnormal general movements (GMs;

chapter 6 and 7). Our secondary aim was to investigate the effect of the early

intervention programme COPCA (COPing with and CAring for infants with spe-

cial needs – a family centred programme) in infants identified as being at risk

of CP. We presented the follow-up data of the VIP project (Dutch: Vroegtijdig

Interventie Project, chapter 8) and the research design of the LEARN2MOVE 0–2

(L2M 0–2) years study (chapter 9).

Here I discuss first the main findings. Next, methodological consider-

ations and clinical implications are reviewed, followed by suggestions for future

research. The discussion ends with concluding remarks.

PART I: TRADITIONAL NEUROLOGICAL EXAMINATION IN INFANTS AT RISK OF CP

Our research underscores the notion that a single neurological sign in infancy

cannot discriminate between typical and atypical developmental outcome. The

data further emphasise the value of longitudinal assessments: “development

predicts development best” (M. Hadders-Algra, personal communication 2014).

During early development, neurological abnormalities may diminish,

resolve, or evolve into a clear neurological syndrome. Consequently, predic-

tion of CP becomes less difficult with increasing age. This is illustrated by the

age-dependent predictive power of the so-called primitive reflexes (chapter 2).

As responses like the Asymmetric Tonic Neck Reflex (ATNR), Moro, and plan-

tar grasp response typically disappear during early development, persistence of

these responses may indicate disturbances of the central nervous system. The

risk of developmental disorders – including CP – increases the longer these

reactions persist. However, in early infancy, it is the absence of the Moro and

plantar grasp response that may be suggestive of an adverse developmental out-

come. In contrast to the disappearing primitive reflexes, many functions of the

General discussion

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neuromotor system only appear with increasing age. It is therefore explicable

that the predictive value of a delayed emergence of the parachute reaction for

the development of CP increases with age. Also delayed achievement of motor

milestones becomes more pronounced with age in children who develop CP.1

For other neurological signs, like the pull-to-sit manoeuvre, the vertical

suspension test, the pupillary light reflex and the knee jerk, it is not so much their

presence or absence but the abnormal nature of the reaction that may enhance

the prediction of CP. Even so, the predictive powers of an abnormal pull-to-sit

manoeuvre and vertical suspension test slightly increase during infancy.2 Only

the repeated observation of a slow pupillary light reflex during development was

associated with worse outcomes (chapter 3). And although knee jerk responses

differ between high-risk infants and typically developing infants at three months

corrected age, it takes more time to identify those high-risk infants who will

develop CP (chapter 4 and 5).

A comprehensive examination that includes many neurological signs can

presumably improve prediction of CP, as the presence of more deviant signs may

indicate an increased risk of developmental disorders.3,4 The predictive validity of

existing infant neurological examinations, such as the Hammersmith neurologi-

cal examination (which is based on the Dubowitz examination of the newborn5)6,

the Touwen Infant Neurological Examination (TINE; which is adapted from

Prechtl’s assessment for newborns7)8 and the Amiel-Tison neurological exam-

ination9 is good.10 An infant neurological or neuromotor assessment will never be

able to predict neuromotor outcomes perfectly, considering the developmental

changes of the young nervous system (Figure 1, Chapter 1).11 The specificity of

a traditional neurological examination is hampered by transient abnormalities;

the sensitivity will never reach 100% because it takes time for the nervous system

to express a developmental disorder plus some complex neurological functions

can only be examined with increasing age (‘growing into a deficit’).

Pupillary Light Reflex

In the L2M 0–2 years cohort we observed slow pupillary light responses.

The slow responses appeared to be associated with the presence of periven-

tricular leukomalacia and a worse developmental outcome, at least if the slow

responses were present during the majority of the L2M 0–2 assessments. A slow

response at a single assessment was not associated with a specific type of brain

lesion or developmental outcome (chapter 3).

Slow pupillary light responses have been previously described in adults

with other neurological conditions. In patients with Multiple Sclerosis, prolonged

pupillary light reflex (PLR) latencies have been described in relation to unilateral

optic signs, e.g., optic neuritis, or as being reflective of delayed nerve conduction

in the efferent pupillary pathway.12 It has been hypothesised that a prolonged

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PLR latency in patients with Parkinson disease could be induced by neuronal

loss and gliosis of the Edinger-Westphal nucleus or autonomic nervous system

dysfunction.13,14 Prolonged PLR latencies, as well as lower maximum constriction

accelerations, are also reported in patients with cognitive impairments, such as

Alzheimer’s disease.15–17 Pupillometry studies in patients with Myasthenia Gravis

show a decrease in maximum constriction velocity and acceleration, probably

attributed by post-synaptic receptor deficits–either within the central PLR path-

way or related to the neuromuscular junction of the iris’ sphincter.18,19

In school-age children, prolonged PLR latencies have been described

in relation to neurodevelopmental disorders, especially Autism Spectrum Disorder

(ASD).20–22 Slow or absent near pupillary responses, i.e. pupillary constriction when

the eyes converge to view a nearby object, are reported in children with CP.23 To

our knowledge, only one study has published data on a slow PLR in infancy, as part

of typical PLR ontogeny: the slow PLRs observed between 27 and 32 weeks gesta-

tional age (GA) were followed by brisk responses from 32 weeks GA onwards.24

Not only the application of a bright light, but also a picture of the sun can

induce pupillary constriction; this suggests that high-level processes modulate

the classical pupillary pathway.25 The presence of subcortical-cortical PLR modu-

lation may explain our observation of a slow PLR in children with periventricular

leukomalacia, and the association with CP and a worse cognitive outcome. In this

light, the prolonged PLR latencies described in children with ASD and in adults

with cognitive impairments may also be brought about by altered PLR modulation.

Patellar Tendon Reflex

Chapter 4 demonstrated that knee jerk responses in three-month-old infants at

high risk of CP differ from the responses in typically developing infants. High-

risk infants demonstrated more often tonic responses, i.e. continuous muscle

activity occurring after the typical phasic response, and more often clonus and

contralateral phasic responses than typically developing infants (chapter 4).

Widespread reflex irradiation occurred in high-risk and typically developing

infants. Infants with definitely abnormal GMs more frequently exhibited tonic

responses and clonus than infants with mildly abnormal or normal GMs. Also the

presence of stiff movements was associated with the occurrence of both tonic

responses and clonus. Within our group of VHR infants, the knee jerk parameters

had at this age no additional predictive value for the development of CP (chapter

5). However, with increasing age, we demonstrated several differences in knee

jerk development between very high-risk children with and without CP.

The tonic component of stretch reflexes, like the knee jerk, is considered

a later phase of slow firing activity.26 We hypothesised that our observed tonic

responses resemble long-lasting self-sustained firing of motoneurons, produced

by so-called persistent inward currents (PICs)27,28 following disturbed central

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modulation.29–31 The changed supraspinal inhibition in high-risk infants could

attribute to a higher incidence of tonic responses in high-risk infants compared

to typically developing infants. It could also explain our reported associations

between the occurrence of tonic responses and both definitely abnormal GM

quality (chapter 4) and the presence of cystic periventricular leukomalacia (cPVL,

chapter 5). Next to possible disturbances in central modulation caused by a lesion

of the brain, the spinal circuitries of young infants are physiologically hyperex-

citable.32–34 Indeed, with increasing age, tonic responses were less often observed

in both infants with and without CP.

Meanwhile, from four months corrected age onwards, infants later diag-

nosed with CP showed significantly more tonic responses than their high-risk

peers without CP. A persistent tonic response could therefore be an early sign of

CP. Possibly, tonic responses are mainly related to evolving spasticity, which can

be defined as a velocity dependent increase in tonic stretch reflex activity, and

increased tendon jerks resulting from disinhibition of the stretch reflex.35–37 More

recently, also PICs are thought to play a role in the emergence of spasticity.31,38,39

Our results with regards to the clonus phenomenon–which we defined

as at least one repetitive phasic response in the quadriceps muscle – are in line

with the current knowledge on the significance of ankle clonus in infants: the

presence of a few beats can be accepted in the absence of other neurological

signs.34,40 Vice versa, the absence of clonus does not preclude the development of

CP (chapter 5). However, persistence of the clonus phenomenon after one year

of age was more often observed in children with CP than in their high-risk peers,

suggesting an association with an increased neural excitability.

The presence of reciprocal and contralateral responses in both high-risk

and typically developing infants suggests that these responses are a neurode-

velopmental phenomenon of early ontogeny. This may be attributed to the

physiological hyperexcitability of the spinal circuitries, the increased sensitivity

of muscles spindles, motoneuron pools and motor units and the presence of

excitatory projections to motoneurons of non-homonymous muscles in young

infants.33,34,41,42 Previously, Myklebust and Gottlieb already demonstrated the pres-

ence of reflex irradiation to muscles of the lower leg, following patellar tendon

taps in typical newborns.33 O’Sullivan et al. reported data on reflex radiation in the

upper arm.32 These responses typically disappear with increasing age – except

in subjects with CP41–43, which is in line with the finding of chapter 5. It has been

suggested that the typical excitatory antagonist responses in infancy gradually

change into inhibitory reciprocal muscle activity- a developmental process that

seems completed around three years of age in typically developing children.41–43

In children with CP these excitatory responses may persist and consequently

may attribute to the development of co-contraction and spasticity.41–43

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PART II: GENERAL MOVEMENT ASSESSMENT IN INFANTS AT RISK FOR CP

In high-risk populations, the predictive value of the GM assessment is high

(median sensitivity 98%, specificity 91%, positive predictive value 81%, negative

predictive value 98%).44–46 However, in the general population, the predictive

power of definitely abnormal GMs (which implies serious reduction in move-

ment complexity and variation) is lower. A prospective cohort study of 455 infants

demonstrated a sensitivity of 67%, a specificity of 97%, a positive predictive value

of 12% and a negative predictive value of 100%.47

This thesis demonstrates that the evaluation of fidgety movements (FMs)

and movement stiffness may enhance the predictive power of definitely abnor-

mal general movements (GMs) for the development of CP in infants at risk

(chapter 6 and 7). Within the VIP cohort, the absence of FMs and the presence

of consistently stiff movements were also related to a reduced quality of motor

behaviour at 18 months CA; the presence of both abnormal characteristics was

associated with worse functional motor outcomes at school age.

Our results on the predictive value of the absence of FMs for the develop-

ment of CP are in line with previous studies. Prechtl and coworkers were the first

to study FMs: video-recordings of 130 infants (70 low-risk and 60 high-risk) were

made every 3–4 weeks until the age of 20 weeks post-term and neurological out-

come was assessed at two years of age.48 Of the 44 infants who had never shown

FMs, 43 had CP; abnormal FMs were observed in 16 infants of whom 6 developed

CP. Subsequently, the predictive power of FMs in high risk populations has been

evaluated by several other studies, confirming a high sensitivity (range 38–100),

specificity (range 92–99), positive and negative predictive value (range 77–98

and range 84–99, respectively) for the development of CP.45,49–52 It is relevant to

mention that abnormal GM quality often co-occurs with the absence or sporadic

presence of fidgety movements: only in four of the 46 VIP-infants with definitely

abnormal GMs, fidgety movements had been frequently or continuously present.

The additional value of the assessment of fidgety movements in infants with

definitely abnormal GMs is therefore lower than reported above. The predictive

power also depends on the distinction between sporadic or absent fidgety move-

ments: this difference did matter in our cohort (chapter 6). However, a recent

study demonstrated that the presence of sporadic fidgety movements–in com-

parison to the absence of fidgety movements–was not related to less severe gross

motor problems in children with CP.53 Just as in abnormal GMs, the positive pre-

dictive value of abnormal fidgety movements for CP is also lower in the general

population.54

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Our findings with respect to the significance of the assessment of move-

ment stiffness are in accordance with the study of Groen et al. (2005).55 Three

out of the 47 infants whose GMs were examined at ‘fidgety age’ had predomi-

nantly stiff movements; two of these children developed CP and one child had

complex minor neurological dysfunction (MND) at school age.55 The presence

of consistently stiff movements may be regarded a stereotypy which is possi-

bly caused by increased stretch reflex activity via a loss of supraspinal control.

Our finding that infants with stiff GMs demonstrate more tonic responses and

clonus in response to the knee jerk than infants without stiff movements fits this

hypothesis (chapter 4).

In contrast to previous studies, we were not able to demonstrate an asso-

ciation between the presence of 1) cramped-synchronised movements nor 2)

the ATNR pattern and developmental outcome. The absence of an association

between cramped-synchronised movements and CP might be explained by the

relatively low prevalence of cramped-synchronised movements in the VIP

cohort. Of the original 46 participants, five children had shown cramped-syn-

chronised movements at 10 weeks CA; only one of them had exhibited this

movement pattern as a predominant pattern; this infant developed severe CP,

i.e., he was not able to sit independently at school age. The latter is in line with the

studies of Ferrari et al. (2002) and Bruggink et al. (2009a) who demonstrated that

the presence of (predominant) cramped-synchronised movements was espe-

cially predictive for severe CP.56,57 The low prevalence of this movement pattern

is presumably related to the relative good outcome of the VIP infants. Both the

low prevalence of cramped-synchronised movements and the relatively good

outcome may reflect improved perinatal and neonatal care over the past decades:

this is in accordance with the reported decrease in incidence and severity of CP

of Dutch NICU graduates.58 The absence of an association between the ATNR

pattern and CP might also depend on differences in criteria for abnormality.

Spontaneous ATNR activity may be part of typical motor behaviour at GM age

(chapter 2): indeed, the ATNR pattern was not or variably present in most of the

VIP infants (35 out of 46). Obligatory, consistently present ATNR activity could be

a sign of clear neurological dysfunction (chapter 2).7,59 We classified ATNR activity

as abnormal when it was frequently or consistently present; in most VIP infants

it was frequently but not consistently present. Presumably, frequently occurring

ATNR might better be regarded a mild abnormality.

The GM assessment appears also valuable in predicting developmental

outcomes beyond the motor domain. Several studies have reported asso-

ciations between abnormal GM quality and worse cognitive outcomes or

behavioural problems, especially in high-risk infants such as preterm born

infants.54,60–65 Correspondingly, our data indicated an association between a lack

of movement complexity and variation and behavioural problems at school age

(chapter 7). These studies support the notion that GM quality provides informa-

tion about the integrity of the brain, presumably with emphasis on periventricular

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connectivity.44,66 The presence of periventricular white matter injury, which is

especially encountered in preterm born infants, increases the vulnerability for

impairments in several domains, including motor, cognitive, and behavioural

functioning.67,68

As is the case with traditional neurological signs, none of the GM char-

acteristics alone is able to preclude or confirm the development of CP. Our

data indicated that a combination of GM characteristics, including GM quality,

presence or absence of FMs and stiff movements, might enhance the predic-

tion for CP. It appears that the presence of more deviant signs, either traditional

neurological signs or GM characteristics, puts the child at a higher risk of devel-

opmental problems. With regard to the development of CP, several studies have

demonstrated that in high-risk populations the predictive power of the GM

assessment outperforms traditional neurological examinations.10.44,45,51,52,69,70 In

high-risk infants, neuroimaging has a complementary role in predicting devel-

opmental outcomes.45,71,72

All infants included in the VIP project had shown definitely abnormal GMs,

and although only a small proportion of the infants developed CP, the majority did

have complex MND at 18 months CA. Both definitely abnormal GMs and complex

MND are likely to reflect early disturbances in neural connectivity. Indeed, most

of the participants were born preterm, which increases the risk of periventricular

white matter lesions.

PART III: EARLY INTERVENTION IN INFANTS AT RISK FOR CP

The VIP project demonstrated no differences in motor outcomes between infants

who had received three months of COPCA as early intervention and infants

who had received TIP, both at 18 months CA and at school age (chapter 7).73

With regards to cognitive outcomes at 18 months CA, a small beneficial effect of

COPCA was found when the maternal level of education was taken into account.

At school age, functional outcomes – including type of education – after

COPCA were similar to outcomes after TIP. One difference between COPCA and

TIP was found with regards to the educational attitude of the parents when their

school-aged child learns new skills: more parents in the COPCA group than

in the TIP group indicated that they let their child try (with trial and error) until

it succeeds, instead of letting their child try and starting to intervene when the

child seems unsuccessful.

Our results are in line with other studies on early intervention in high-risk

infants, reporting that cognitive benefits of existing intervention programmes

only persist into pre-school age and that there are no or inconclusive effects

on long-term outcomes.71 Another recently performed Dutch RCT on the effect

of early intervention in infants at risk demonstrated comparable results. At 6

General discussion

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months CA, i.e. directly after the intervention period, infants who had received

the Infant Behavioural Assessment and Intervention programme (IBAIP) showed

an improved motor, mental and behavioural development compared to children

who had received standard care.74 Only a positive effect on functional motor

development persisted until 24 and 44 months CA; the rate of CP was similar

in both groups.75,76 In line with our results, there were no differences in neurolog-

ical outcome, attendance at a school for special education, need for paramedical

support or behavioural problems between the IBAIP and control group at 5.5 years

of age.77 However, the authors were able to demonstrate small effects in favour of

the IBAIP on some of the subscales of their outcome measurements: the block

design and vocabulary subtests of the Wechsler Preschool and Primary Scale of

Intelligence, the aiming and catching component of the Movement Assessment

Battery for Children, and visual-motor integration as part of the Developmental

Test of Visual Motor Integration.77 They hypothesised that these differences may

be the result of the early positive and scaffolding neurobehavioral support that

the parents in the IBAIP group offered their child. It is unknown whether the

IBAIP parents still applied these principles after the end of the intervention, and

whether this may have affected outcomes. The VIP project did include parental

outcome assessments and found a difference between the COPCA and TIP group

in parental approach of the child when he/she learns new skills (chapter 7). There

were no differences in parental coping strategies between the two groups.

In our search for elements of early intervention that may be effective

in promoting better outcome, a process analysis was performed. The analysis of

physiotherapeutic actions revealed that the more time was spent on caregiver

training (i.e. an educational action and the opposite of caregiver coaching) and

giving strict instructions (i.e. a communicational action) during early intervention,

the poorer the child’s mobility at school age was. These associations correspond

with theories on active and problem-based learning.78,79 The development of

problem solving skills, with the professional acting as a coach, may have life-long

beneficial effects, whereas being trained on what to do in a specific situation pre-

sumably is less valuable when the situation changes – which is constantly the

case in child development. Another explanation for the reported associations may

be that they could reflect the physiotherapist’s behaviour in response to the neu-

rodevelopmental status of the child. The presence of more severe motor problems

could have tempted the physiotherapist to use the technique of training of the

caregivers instead of coaching. However, this is not likely as we found no asso-

ciations between physiotherapeutic actions and the child’s motor performance

before or directly after the intervention, i.e. at three and six months CA.73,80

Process analysis within the VIP project further demonstrated that some

physiotherapeutic actions were associated with parental educational attitude at

follow-up. In parents who reported that the early intervention had influenced

their educational attitude, more time had been spent on providing feedback.

Indeed, feedback can reinforce or adjust peoples’ behaviour by supporting them

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to reconstruct their knowledge, change their performance and feel motivated

for the future.81 However, the effect of feedback on performance is not auto-

matically positive82: more time spent on providing feedback was not associated

with a better functional outcome of the child. At RCT level, there was a difference

between COPCA and TIP with respect to parental approach when their child

learns new skills. Process analysis revealed that in parents who indicated that

they used the trial and error approach (i.e. an important neurodevelopmental

principle of COPCA), more time was spent on the COPCA-actions ‘coaching’

and ‘challenging the infant to self-produced motor behaviour‘, and less time was

spent on facilitation, i.e. a TIP-action based on NDT.83 The above indicates that

the professional attitude of the physiotherapist (e.g., by being a ‘coach’ rather than

an ‘instructor’) could influence the educational attitude of the parents. However,

the difference in parental approach was not related to the functional outcome of

the child, as measured in the VIP project.

At school age, only a small number of the children that participated

in the VIP project was diagnosed with CP: this precluded subgroup analysis for

children with and without CP. This distinction could be important, as different

elements of intervention might be effective for children with or without CP.73,80

To study the effect of COPCA in infants at very high risk for CP, we determined

other inclusion criteria for the L2M 0–2 years study than we had applied in the

VIP project, as we aimed to increase the a priori risk for CP (chapter 8). Indeed,

16 out of the first 30 children who participated in the L2M 0–2 years project

developed CP (chapter 3). Insight into the possible effects and working mech-

anisms of early intervention in this group of infants at very high risk of CP is

desirable, since randomised controlled studies of infants with brain lesions

are few. Hitherto, a pilot study on the effect of kicking and stepping exercise

in infants with periventricular leukomalacia (PVL) and a study on multisensory

(auditory-tactile-visual-vestibular) intervention demonstrated no effect of inter-

vention.84–86 A positive effect on neurobehavioural development and maternal

mental health was found in favour of an early intervention programme based

on the Neonatal Behavioral Assessment scale; this study of infants with a brain

lesion–mostly PVL–demonstrated no difference in motor or cognitive outcomes

between intervention and control.87 The Avon Premature Infant Project reported

improved cognitive outcome at two years of age in preterm born infants with

a brain lesion who received the developmental education programme Portage

compared to infants who received a social support intervention or standard

care.88 At five years of age, there were no differences in motor, cognitive, and

behavioural outcomes between the groups.89 Weindling and coauthors (1996)

compared early physiotherapy based on NDT with their standard approach (i.e.

delaying physiotherapy until abnormal neurological signs became apparent)

in infants with abnormal cranial ultrasounds: the follow-up assessments at 12

and 30 months of age demonstrated no differences in developmental outcome

between the groups.90 A non-randomised study on the effect of Vojta reported

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better motor outcome in children in which the physiotherapy programme was

consistently applied than in children who received no or an insufficient amount

of physiotherapy.91 However, a recent systematic review on the effect of inter-

vention in children with CP concluded that there is no convincing evidence that

early intervention based on Vojta or NDT is effective: the authors even discour-

age the use of NDT.92 Unfortunately, most of the above-mentioned studies were

underpowered44, implying that the effect of early intervention in infants at high

risk for CP remains inconclusive.

METHODOLOGICAL CONSIDERATIONS

The strength of our review on the significance of neurological signs in infancy

(chapter 2) is the systematic approach. The focus on high-risk infants makes

our overview applicable for clinicians who are involved in early diagnostics and

early intervention. Surprisingly, only six neurological signs fulfilled our criteria

of being studied in at least three different papers. A limitation of the review is

that we did not take the quality of the papers into account, e.g., by exclusively

selecting those studies that blinded the assessors for perinatal information or

previous neurodevelopmental status of the child. Furthermore, most of the stud-

ies did not report on the reliability of the neurological items. The use of such

quality criteria would presumably have resulted in even less available data on the

predictive power of these signs. The limitation of every study calculating predic-

tive values from relatively small sample sizes is that the sensitivity, specificity,

positive predictive value and negative prediction value of an item are largely

dependent on the characteristics of the study group. This also applies for studies

on the predictive power of GMs.93

Our observation of slow PLRs in infants at high risk for CP (L2M 0–2 years

cohort) inspired us to explore the possible underlying working mechanisms

of this phenomenon and its associations with future development (chapter 3).

The retrospective data analysis had both strengths and limitations. Ideally, all

infants would have undergone brain magnetic resonance imaging (MRI) at term

age with Diffusor Tensor Imaging techniques. However, infants for the L2M

0–2 years project were recruited after term age from eleven different hospitals

in the Netherlands, each applying their own imaging protocol and technique.

This limited a detailed analysis of the infant’s brain lesions and necessitated us to

classify the imaging data according to their predominant pattern only. The lack

of quantification of PLR parameters is another limitation, which is also due to the

design of the L2M 0–2 years study. We assessed the PLR as part of the Touwen

Infant Neurological Examination, which categorizes the response as normal,

mildly dysfunctional (e.g., slow reaction), clearly dysfunctional (e.g., one pupil no

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reaction) or absent.8 Practically, the clinical judgment whether the response was

normal or slow has the advantage of being an easy applicable tool. Considering

the effect of light condition on PLR parameters, the examinations could have

been influenced by the various ambient light conditions since the assessments

were performed at the infant’s home.94 A more general limitation concerns the

assessment of cognitive outcome in infants with motor disabilities. Reliability of

cognitive tests, such as the Mental Developmental Index of the Bayley Scales of

Infant Development, is reduced in these children since most of the test items

require a certain level of motor skills. In addition, our small and highly selective

study group of high-risk infants limits generalizability.

The strength of our studies on the knee jerk in both typically developing

infants and infants at high risk for CP (L2M 0–2 years cohort) is the blinded anal-

ysis of the EMG data (chapter 4 and 5). The assessment of TD and VHR infants

around three months of age provided the opportunity to examine associations

between reflex responses and GM quality. The age range of VHR infants at their

first assessment precluded a comparison between fidgety movements and reflex

parameters. The longitudinal design of the L2M 0–2 years study was used to fur-

ther study the development of these responses and to explore the associations

with the presence of cPVL and motor outcome. Again, the characteristics of the

L2M 0–2 years cohort limit generalizability. The manual application of taps on the

patellar tendon is less standardised but more corresponding to a standard clinical

examination than the use of an electromechanical tapper. Moreover, thresholds

for eliciting the reflex could not be determined as the force of our stimulus varied.

The amplitude of the responses was not studied because the use of surface EMG

precludes comparison of this parameter between assessments – including dif-

ferent assessments within individuals.

One of the main strengths of chapter 6 and 7 is the analysis of GM char-

acteristics by two highly experienced assessors who were blinded for any

clinical information on the child except for age. Other assessors, who were

in turn unaware of the presence of these GM characteristics, assessed outcomes

at 18 months CA and at school age. Where the age of 10 weeks CA is appropriate

to evaluate GM quality (i.e. movement complexity and variation), it is relatively

early in the ‘fidgety period’. Therefore, it cannot be excluded that some infants

developed fidgety movements after the assessment. In addition, cramped-syn-

chronised movements are mainly described within the ‘writhing’ GM phase.48,95

Our studies underscore that 18 months CA can be too early to diagnose CP; of

the 10 children who had clear neurological dysfunctions at that age, six were

diagnosed with CP at school age, three children ‘out-grew’ CP according to their

parents96, and one child was lost to follow-up. Our reported associations between

GM characteristics and both functional outcomes and behaviour at school age

further emphasise the importance of long-term follow-up. The small sample size

is a limitation of all studies within the VIP project (chapter 6–8).

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A randomised controlled study design is traditionally considered to be

the gold standard for determining the effect of a specific treatment.97 However,

such a design is less suitable for studies on early intervention, as the interven-

tions (e.g., COPCA and TIP) partly overlap.73,80 Besides, there is heterogeneity

in early intervention. The VIP project demonstrated the value of process analysis

by means of video-recordings of intervention sessions (chapter 8).73,80 Although

the reported associations between physiotherapeutic actions and outcome at

school age are plausible, it should be emphasised that correlations are not iden-

tical with causations. In line with the current focus of paediatric rehabilitation

on activities and participation, which is in accordance with the International

Classification of Functioning, Child and Youth version (ICF-CY), the design of

our VIP follow-up study was focused on the children’s functional performance

in daily life activities.98,99 However, the use of parental questionnaires could be

considered a limitation. A clinical assessment could have been valuable to con-

firm the diagnosis of CP or to evaluate mobility with a standardised test such as

the Movement ABC.100

The major strengths of the L2M 0–2 years study in comparison with the

VIP project are threefold: 1) the inclusion of infants with a higher a priori risk for

CP, 2) a longer intervention period, and 3) – presumably–an improved imple-

mentation of the COPCA programme. For example, preliminary data indicate

that in the L2M 0–2 years study in the COPCA intervention, more time is spent

on caregiver coaching and less time is spent on caregiver training than during

the VIP project (Hielkema T, personal communication 2016). Moreover, addi-

tional outcome measurements were applied, such as the Gross Motor Function

Measurement101, the Family Empowerment Scale102, and questionnaires on infant

and parental quality of life (chapter 9). It can be considered a limitation that the

age of the infants at inclusion varied. Nevertheless, this is comparable to standard

care for these high-risk infants.

CLINICAL IMPLICATIONS

Early diagnostics

Taking care of a high-risk infant can be challenging for both parents or caregiv-

ers and professionals. This thesis illustrates the possibility of identifying high-risk

infants with the help of traditional neurological signs and GM assessment, but it

also underscores that prediction of further development remains a challenge.

The studies in this thesis emphasise that 1) the predictive power of an item or

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assessment depends on the infant’s age, and 2) some criteria for abnormality relate

to the absence or presence of a sign or characteristic (e.g., primitive reflexes, fidgety

movements, tonic knee jerk responses) while others relate to movement quality (e.g.,

general movements, vertical suspension test). The additional value of the pupillary

light assessment for the prediction of developmental outcome is yet unclear.

It is important to realise that prediction of developmental outcomes will

never be perfect, due to age-specific characteristics and developmental changes

of the young nervous system. Moreover, there is a large variation in motor

development of typically developing children.103,104 Next to the traditional neuro-

logical examination and GM assessment, perinatal information, brain imaging

data, and neurophysiological tests can assist prediction. 44,72,105–108 The use of

multiple tools and longitudinal series of assessments are recommended to opti-

mise prediction.1,10,109–112

Information on the possibilities and impossibilities of prediction of devel-

opmental outcomes is of interest in counselling parents of a high-risk infant.

Uncertainty about the prognosis of the child complicates providing answers to

questions regarding adequate follow-up, need for early intervention or referral

to a rehabilitation specialist, but also on the expected quality of life and associ-

ated decisions.

Early intervention

Hitherto, none of the existing early intervention programmes appears to be able

to reduce the risk of developing CP. However, this does not imply that we have

to give up early intervention in high-risk infants. The long-term effects of early

intervention on functional outcomes – including motor, but also cognitive and

behavioural outcomes–are still unclear. Moreover, the effect of early intervention

on parameters such as family autonomy, empowerment, self-reliance and qual-

ity of life is scarcely investigated. Note that both VIP and L2M 0–2 years projects

studied the effect of COPCA in comparison with regular paediatric physiother-

apy; there was no control group of infants receiving no therapy at all.

The associations between physiotherapeutic actions and both functional

motor outcome and parental attitude, as reported in this thesis, give more insight

in which elements of intervention might be effective. Also the absence of associ-

ations between specific motor actions during early intervention and functional

outcome is interesting: e.g., it questions the value of ‘hands-on’ actions, such as

the use of facilitation techniques. Such information is of clinical importance as

some physiotherapeutic actions, like assisted stretching in children with CP, do

hurt to try.113,114

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Global Health

The research projects described in this thesis were performed in the Netherlands,

which limits generalizability – especially with regards to our data on early inter-

vention. For example, the content and availability of infant physiotherapy as well

as parental attitude may vary between countries. Moreover, it is not always and

everywhere common to apply early intervention in the home situation – as was

performed in the VIP and L2M 0–2 years projects.

The use of simple and non-invasive tools to identify infants at risk of CP,

such as traditional neurological items and the GM assessment makes it easier

to apply these instruments also in low- and middle-income countries. Although

this thesis focuses on the Dutch population, early identification and early inter-

vention are of global concern: it has been estimated that about 80% of people with

disabilities live in developing countries.115 It has to be realised that, next to differ-

ent economic and logistic conditions, the population of high-risk infants in these

countries is different from the Dutch population. This is attributed to differences

in neonatal care: in developed countries there are more possibilities to provide

intensive care for preterm born children, while severe jaundice, infections such

as meningitis and iodine deficiency occur less often.116–118 In developing coun-

tries, birth asphyxia is probably the main etiological factor of CP.116,119–121 It should

further be recognized that early identification of high-risk infants is particularly

relevant when early intervention or supportive programmes are available.

FUTURE RESEARCH

Most of the studies within this thesis were exploratory designs within a RCT,

which implies that repetition of our research within larger study samples is

desirable. Depending on the research question, the specifics of the study group

could be altered: e.g, both VIP and L2M 0–2 years projects deliberately included

infants at high risk of CP, thereby inducing a selection bias for our studies on the

pupillary light response, the knee jerk and the GM assessment.

Our review of the prognostic value of neurological signs in high-risk

infants could be used in the development of screening tools, for both NICU grad-

uates and the general population (e.g., in well baby clinics). Future research into

high-risk infants has to include more test items since our review illustrated that

hitherto data on the predictive power of only a few items was available.

Studies on the pupillary light response would benefit from standardised

MRI techniques including Diffusor Tensor Imaging. The use of Visual Evoked

Potentials (VEPs) could be considered to obtain information on the speed of pro-

cessing of visual stimuli. It is already known that during typical development,

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VEP peak latencies decrease in the same period when PLR latencies decrease, i.e.

just prior to term-equivalent age.122,123 The use of an infrared video pupillometer

with different stimulus intensities is needed to quantify the PLR (for example, see

reference 124). It is likely that our arbitrary difference between normal and slow

actually represents PLR latencies on a continuous scale. Also other visuomotor

functions could be included in a future study design, such as the examination

of strabismus, visual fixation, refractive errors and visual fields.125–128 In addition,

it would be interesting to study the possible relationship between slow PLRs and

cerebral visual impairments (CVI), as CVI is associated with both periventricular

leukomalacia and CP.129,130

Future research on the knee jerk in high-risk infants should further

distinguish between different types of brain lesions. Moreover, the influence

of a unilateral or bilateral brain lesion or type of CP would be interesting to

study. Also determining individual thresholds for eliciting the tendon reflex

would yield insight: the level of excitability could be investigated by using an

electromechanical tapper or by calculating the velocity of the reflex hammer

as a proxy for stimulus intensity. The question remains whether the knee jerk

phenomena described in our chapters are associated with the severity of the

spasticity. Such knowledge may assist in understanding the development of

spasticity. The ultimate goal would be to adapt our treatments for spasticity and

deformities accordingly.

With regard to the GM assessment, it could be worthwhile to study the pre-

dictive value of both fidgety movements and GM quality and movement stiffness

in infants at risk – and not only in infants with definitely abnormal movement

complexity and variation. The predictive power might be enhanced by a com-

bined assessment that includes all three characteristics or more: others recently

investigated the possibilities of optimising the GM assessment by paying atten-

tion to other movement characteristics, e.g., concurrent movements and postural

patterns by using the Motor Optimality List.54,61,63 However, while doing research

on the additional value of specific GM characteristics, we should keep in mind

that one of the strengths of the GM assessment is its simplicity. Other sugges-

tions for future research concern 1) the underlying developmental processes that

cause typical and atypical movement quality, and 2) the probability of ‘measur-

ing’ movement complexity and variation. Therefore, the use of surface EMG or

computer-based video analysis could be of assistance.131,132

From a global perspective, the traditional neurological examination and

GM assessment have, compared to MRI techniques, the advantage of being

simple and low-cost screening tools. At present, the ‘Ten Questionnaire’ is the

most frequently used tool to detect disabilities in low- and middle- income

countries; it is validated for 2–9 year olds.133,134 Future research may focus on the

applicability of neurological items and the GM assessment in these countries,

since there is a need for measures to monitor disabilities in children younger

General discussion

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than age two.135 Research on early identification should be extended while

exploring opportunities for intervention. It should be realised that physiothera-

peutical and educational early intervention are only specific means to improve

developmental outcome; additional developmental profit may be gained from

preventive strategies such as improved nutrition (including breastfeeding, vita-

min A supplementation, the use of iodized salt and sufficient protein intake) and

immunisation programmes and from increased awareness to include children

with disabilities in their society.115,135

Research in the field of early intervention should include long-term fol-

low-up and analysis of possible working mechanisms. In addition to determining

neuromotor outcomes and in line with the ICF-CY, attention has to be paid 1) to

functional outcomes, including mobility, self-care and communication, and 2) to

functioning of the family and 3) to the interaction between activities and partici-

pation and contextual factors. For example, within the L2M 0–2 years project we

also assessed family empowerment, quality of life and parental coping strategies.

Next to video-analysis of early intervention sessions, video-analysis of caregiv-

er’s behaviour during playing and bathing and EMG-analysis of the development

of postural control has to provide insight into possible working mechanisms. The

first results of the L2M 0–2 years study will be reported this year. It will be inter-

esting to see whether the increased application of coaching within the COPCA

intervention has an effect. The concept of parental coaching is currently also

being investigated by others, e.g., by coaching mothers of children with Autism

or by coaching families with multiple and complex problems.136–138 Also the effect

of parent-infant interaction on the development on high-risk infants is an inter-

esting research topic, as 1) not prematurity per se, but particularly the presence

of negative perceptions, seems predictive for difficulties in parent-infant interac-

tions139,140, and 2) interventions supporting responsive parent-infant interactions

may have a positive effect on developmental outcome.77,141,142 The increased use

of digital media expands the opportunities for informing and interacting with

parents. For example, future research might explore the possibilities of vid-

eo-assisted programmes. However, we should also be aware that the Internet

is associated with disadvantages, e.g., much of the online health information is

inaccurate.143 It is important that websites and applications offer reliable infor-

mation to the parents; one should be cautious of an overload of information or

giving parents false hope.

Another type of intervention for infants at high risk for CP that is currently

being studied is constrained-induced movement therapy (CIMT), which primar-

ily focuses on improving motor outcomes. A recent pilot study on the effect of

CIMT in infants at very high risk of CP (7–18 months of age) showed an improve-

ment in the children’s fine and gross motor performance (no control group).144 At

present, the effect of Baby-CIMT is being studied by means of a RCT in infants

at risk of developing unilateral CP.145 Two other RCTs in infants at risk of CP are

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currently studying the effect of a goal-oriented motor training and enrichment

intervention programme (‘GAME’)146 and the effect of action-observation training

(‘UPBEAT’: Upper Limb Baby Early Action-observation Training).147 Together with

the results from the L2M 0–2 years project, these studies will provide insight into

the effect of early intervention for infants at high risk of CP and their families.

Next to post-discharge intervention programmes, neonatal intensive

care continues to improve. For example, therapeutic hypothermia (‘cooling’)

has beneficial effects in term and late preterm newborns with hypoxic isch-

aemic encephalopathy.148 Other advances have decreased the mortality rate of

infants born preterm. However, these infants remain at risk of developmental

problems.149,150 New or improved interventions are likely to continue changing

the associations between specific risk factors, such as the presence of a brain

lesion or extreme preterm birth and developmental outcomes. One such future

intervention might be the application of stem cells.151,152 But today, as prevention

is better than cure, it is still worth trying to reduce the risk of preterm birth or

perinatal asphyxia.

CONCLUDING REMARKS

This thesis aimed to provide answers to questions with regards to early identifi-

cation and early intervention in infants at high risk of cerebral palsy. The main

conclusions of this thesis are:

— In high-risk infants, absence of the Moro response and an absent plantar

grasp response in early infancy may be predictive of an adverse developmen-

tal outcome. After early infancy, persistence of the Moro (beyond 4 months of

age), the Asymmetric Tonic Neck Reflex (beyond 5 months), and the plantar

grasp reflex (beyond infancy) is of clinical significance. The predictive value

of a delayed emergence of the parachute reaction (i.e. after 9 months of age)

increases with age. Abnormal performances on the pull-to-sit manoeuvre

and vertical suspension test have predictive significance throughout infancy.

— In high-risk infants, the clinical observation of predominantly slow pupil-

lary light reflexes during infancy might be associated with the presence of

periventricular leukomalacia, and might be associated with the development

of bilateral CP and a worse cognitive outcome.

— The knee jerk responses of high-risk infants differ from typically developing

children. Around three months of age, high-risk infants more often showed

tonic responses, clonus, and reflex irradiation to contralateral leg muscles. From

four months corrected age onwards, infants later diagnosed with CP showed

significantly more tonic responses than their high-risk peers without CP.

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— The predictive power of definitely abnormal general movements for the

development of cerebral palsy could be enhanced by including the evaluation

of fidgety movements and movement stiffness.

— On RCT level, functional outcomes at school age of children who received three

months of COPCA as early intervention are similar to functional outcomes

of children who received regular infant physiotherapy. Process evaluation

revealed that the professional attitude of the physiotherapist during the early

intervention might be related to child mobility at school age and parental edu-

cational attitudes.

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