The assessment of minor neurological dysfunction in infancy using the Touwen Infant Neurological Examination: strengths and limitations

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1 DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE The assessment of minor neurological dysfunction in infancy using the Touwen Infant Neurological Examination: strengths and limitations MIJNA HADDERS-ALGRA MD PHD 1 KIRSTEN R HEINEMAN MD 2 AREND F BOS MD PHD 3 KARIN J MIDDELBURG MD 1 1 Department of Paediatrics & Developmental Neurology, University Medical Center Groningen, Groningen, the Netherlands. 2 Department of Neurology, University Medical Centre Groningen, Groningen, the Netherlands. 3 Department of Paediatrics & Neonatology, University Medical Centre Groningen, Groningen, the Netherlands. Correspondence to Dr Mijna Hadders-Algra at University of Groningen Medical Center, Developmental Neurology, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. m.hadders-algra@ med.umcg.nl PUBLICATION DATA Accepted for publication 1st February Published online 22nd July LIST OF ABBREVIATIONS HELLP Haemolysis, Elevated Liver enzymes, Low Platelets HINE Hammersmith Infant Neurological Examination MND Minor neurological dysfunction TINE Touwen Infant Neurological Examination AIM Little is known of minor neurological dysfunction (MND) in infancy. This study aimed to evaluate the inter-assessor reliability of the assessment of MND with the Touwen Infant Neurological Examination (TINE) and the construct and predictive validity of MND in infancy. METHOD Inter-assessor agreement was determined in a sample of 40 infants (24 males, 16 females) aged 3 to 12 months (25 born at term: gestational age 37 41wks, median 39; and 15 born preterm, gestational age 24 35wks, median 32). Thirty typically developing term infants (18 males, 12 females; gestational age 37 42wks, median 40) and 59 preterm infants (34 males, 25 females) born at <35 weeks gestation (gestational age 25 34wks, median 29) participated in the validity study. They were neurologically assessed with the TINE at the corrected ages of 4, 6, 10, and 12 months and with the Hempel assessment at 18 months. RESULTS The findings indicated that MND can be assessed reliably (inter-assessor agreement: kappa=0.83). MND during infancy was related to prenatal, perinatal, and social factors, and in particular to preterm birth. Neurological condition during infancy was prone to change, but was related to neurological condition at 18 months at all ages tested. INTERPRETATION We conclude that MND can be determined reliably in infancy. Important considerations in the construct of MND in infancy are its relation to prenatal and perinatal factors, its limited stability, and its moderate predictive value. Neurological assessment is one of the clinical tools used to monitor development in infants at risk for developmental disorders, such as infants born preterm. Multiple methods are available, such as the Amiel-Tison neurological examination, 1 the Touwen Infant Neurological Examination (TINE), 2 the Hammersmith Infant Neurological Examination (HINE), 3 and the neurofunctional assessment of Picciolini et al. 4 Little is known about the reliability of these widely used methods. 5 The validity of neurological assessments has been studied to some extent; marked neurological dysfunction during infancy has considerable power to predict developmental disability such as cerebral palsy (CP). 5 7 However, knowledge about the significance of signs of minor neurological dysfunction (MND) during infancy is scarce. Our knowledge of MND is based in particular on data of children above preschool age. Two distinct forms of MND have been distinguished: simple and complex MND. 8 Before the onset of puberty the distinction is based on the number of dysfunctions present; after the onset of puberty classification is based on the type of dysfunction. Simple MND may be regarded as the expression of a normal but non-optimally functioning nervous system (minor neurological difference). In contrast, complex MND is the form of MND which is strongly related to pre- and perinatal adversities and to learning and behavioural disorders. From an aetiological point of view, this suggests that it may be considered as a borderline form of CP. 8 It is uncertain whether the concept of simple and complex MND can also be applied during infancy, as neurological conditions during infancy are known for their instability. The instability is related to two opposing processes: restorative mechanisms may induce a resolution of early signs of dysfunction, whereas developmental progress may uncover dysfunction, the time needed for a full expression of CP being a case in point. 9 The aim of the present study was to assess the psychometric properties of the TINE with respect to MND. We chose to investigate the psychometric properties of the TINE as it is the infant assessment technique which includes not only the evaluation of traditional neurological signs such as dysfunctional muscle tone regulation, abnormal reflexes, or dysfunc- ª The Authors. Journal compilation ª Mac Keith Press 2009 DOI: /j x 87

2 tion of cranial nerves, but also pays substantial attention to the quality of spontaneous motility in terms of variation and stereotypy. 2,10 Other methods pay attention to the quality of motor behaviour, but either the method is restricted to early infancy 11 or quality is not strictly evaluated in terms of the size of the repertoire (HINE). 12,13 Recent studies indicate that the degree of variability in motor behaviour is a sensitive marker of the integrity of the infant s brain. 9,14 17 We determined reliability in terms of inter-assessor agreement and assessed construct and predictive validity. We restricted the evaluation of reliability to interassessor agreement because the assessment of intra-assessor agreement cannot be determined for a tool involving a number of hands-on techniques, such as the pull-to-sit manoeuvre, the assessment of muscle tone, tendon reflexes, and various reactions. Validity assessment was based on a longitudinal series of TINE assessments between 3 and 12 months corrected age in a mixed group of term and preterm infants. Construct validity was assessed by evaluating the relationship between MND and pre- and perinatal problems and by assessing stability during infancy. It was hypothesized that MND during infancy is related to pre- and perinatal problems, and that signs of MND have only a limited stability during infancy. Predictive validity was tested by evaluating the relationship between MND during infancy and MND at 18 months assessed with the Hempel examination. 18 The Hempel assessment was chosen as it is the only neurological assessment technique designed with the specific purpose of the assessment of MND at preschool age. 18,19 METHOD Participants The reliability and the validity part of the study were carried out with different groups of infants (Table I). Forty infants were enrolled in the reliability study. Twenty-five infants were seen as part of a follow-up study on possible neurodevelopmental sequelae of assisted reproductive technology (21 born at term, four preterm at postmenstrual ages of 33 35wks), and 15 were Table I: Characteristics of infants participating in the two parts of the study Reliability Validity Number of infants Females Males Term Preterm (<37wks) Birthweight, median (range) g Term infants 3525 ( ) 3588 ( ) Preterm infants 1389 ( ) 1285 ( ) Gestational age, median (range) wks Term infants 39 (37 41) 40 (37 42) Preterm infants 32 (24 35) 29 (25 34) Age at assessment Single assessment at 3 to 12mo (median 10mo) Longitudinal series: 4, 6, 10, 12, and 18mo seen during clinical follow-up of infants who had been hospitalized in the neonatal intensive care unit of the University Medical Center Groningen (UMCG). Reasons for admission to the neonatal intensive care unit had been preterm birth (n=11) and asphyxia near or at term (n=4). The infants were assessed once at ages that varied from 3 to 12 months (median 10mo). Two groups of infants participated in the validity study: (1) 30 typically developing infants born at term, and (2) 59 preterm infants born before 35 weeks postmenstrual age. The typically developing term infants were recruited among acquaintances of the investigators or at well-baby clinics with the aim of collecting information on typical motor and neurological development. The preterm infants had been admitted to the neonatal intensive care unit of the UMCG during the year Information on social and pre- and perinatal characteristics was collected on standardized charts. Six preterm infants had evidence of a serious lesion on neonatal ultrasound of the brain consisting of cystic periventricular leukomalacia (n=1), extensive periventricular haemorrhagic infarction (n=4), or a medial cerebral artery infarction (n=1). The characteristics of the infants studied are summarized in Table I. The infants were neurologically assessed at the corrected ages of 4, 6, 10, 12, and 18 months. The parents of all the infants signed an informed consent form. The project was approved by the ethics committee of the UMCG. Procedures The TINE assessments 2 of the reliability study were carried out by KJM and MHA and those of the validity study mainly by KRH or KJM. The assessors were aware of the infants main group allocation (reliability study: assisted reproductive technology group or infants followed up from the neonatal intensive care unit; validity study: term or preterm group), but they were blind to details of each infant s clinical history. The assessors also took care not to update themselves with information of previous neurological examinations. The absence of a clinical update in combination with the assessors high daily load of infant assessments resulted in a series of virtually independent assessments. Care was taken to have the infant in an awake, non-crying behavioural state. In the reliability study, both assessors were present while KJM carried out the assessment. MHA repeated the assessment of only the items that could not be determined on the basis of observation alone, e.g. muscle tone, tendon reflexes, and pull-to-sit manoeuvre. After each assessment both assessors immediately and independently recorded the results on a precoded assessment form (Appendix SI, supporting information, published online). The TINE assessment starts with the observation of motor behaviour in supine, prone, and sitting positions and during reaching and grasping, and, in older infants, during standing and walking. During this part of the assessment the pull-to-sit manoeuvre (traction test), the lateral support reaction, and postural behaviour during prone and vertical suspension are also evaluated. Critical to the evaluation of motor behaviour is variability in posture and motility. The last part of the assessment consists of an evaluation of brainstem reactions, visuo- 88 Developmental Medicine & Child Neurology 2010, 52: 87 92

3 motor function, and the evaluation of muscle tone and various reflexes (Appendix SI). The assessment takes 15 to 20 minutes. The procedures of the TINE can be learned in 1 day. However, it takes considerable experience ( assessments) to learn the distinction between typical and sign of MND. The book on the TINE 2 includes information on the procedures of the assessment and the criteria for age-appropriate performance, but it does not provide information on criteria for dysfunction. The latter information was available at the Institute of Developmental Neurology in Groningen, but it was only partially available for the international community. 10 The findings of the TINE were classified according to agespecific norms into clusters of dysfunction. The following five clusters were distinguished: dysfunctional reaching and grasping; dysfunctional gross motor function; signs of brainstem dysfunction; visuomotor dysfunction; and sensorimotor dysfunction (Appendix SII, supporting information, published online). Children were classified as neurologically abnormal in the presence of a full-blown neurological syndrome, such as a hemisyndrome, a hyperexcitability syndrome, or a clear hypoor hypertonia. Children were classified as MND when more than two clusters fulfilled the criteria for dysfunction. Two forms of normal neurological development were distinguished. These were normal-suboptimal when one or two clusters fulfilled criteria for dysfunction, and neurologically normal when none of the clusters met the criteria for dysfunction. The children in the validity study had another neurological assessment at the corrected age of 18 months. At that age the Hempel assessment was used. 18 On the basis of the Hempel assessment children were classified as having CP, complex MND, or simple MND, or being neurologically normal. 20 The classification CP implies the presence of a classical configuration of neurological signs, such as, in the case of bilateral spastic CP, the combination of a stereotyped posture and motility of the legs, an increased muscle tone, and brisk tendon reflexes in the legs and Babinski signs. The distinction between complex and simple MND was based on the child s cluster profile, where simple MND denoted the presence of one cluster of dysfunction and complex MND the presence of more than one cluster of dysfunction. 20 Inter-assessor reliability in the Hempel assessment was satisfactory and its construct validity was good. No data were available on predictive validity. 19 Statistical analyses To determine inter-assessor agreement on neurological classification Cohen s kappa (j) was used. In addition, McNemar s test was run to check for a systematic bias between the two assessors. Non-parametric tests were used for the analyses of relations between risk factors and MND. Associations between risk factors and MND were first evaluated with univariate tests such as v 2 and Mann Whitney U, andthenwith multivariate logistic regression analyses. Infants with an abnormal neurological condition were excluded from these analyses. The following risk factors were included in the analyses: maternal age during pregnancy (in years); maternal and paternal education (trichotomized as primary education junior vocational training, secondary education senior vocational training, university vocational college); maternal and paternal profession (low, middle, high); gravidity; parity; singleton twin; maternal smoking during pregnancy (yes no); preeclampsia Haemolysis, Elevated Liver enzymes, Low Platelets (HELLP; yes no); gestational age at birth; birthweight; Apgar scores at 1, 3, and 5 minutes; maximum bilirubin level; number of days on artificial ventilation; dexamethasone treatment; presence of pneumothorax; patent ductus arteriosus; necrotizing enterocolitis; sepsis; neonatal convulsions; and abnormalities on neonatal ultrasound of the brain. All variables for which neurologically normal normal-suboptimal children and children with MND differed at p<0.20 were entered into the multivariate analyses. Associations between neurological condition in infancy and at 18 months were tested with Spearman s rank correlations and in terms of predictive values (sensitivity, specificity, negative and positive predictive value). Differences and correlations with a p value of <0.05 were considered statistically significant. RESULTS The inter-assessor agreement on neurological classification of the 40 infants participating in the reliability part of the study was good (j=0.83, 95% confidence interval ). McNemar s test indicated that no systematic bias between the assessors had occurred (p=0.135). Consensus discussion revealed that 17 infants were classified as neurologically normal, 18 as normal-suboptimal, and five as having MND. Attrition in the validity part of the study was low. All term infants were assessed at each time point, whereas of the preterm infants 98% (n=58 out of 59) were seen at 4 months, 97% (n=57 out of 59) at 6 months, 92% (n=54 out of 59) at 10 and 12 months, and 97% (n=57 out of 59) at 18 months. The reason for missed assessments at 4 and 6 months was a minor illness of the infant. Two infants were lost to follow-up from 10 months onwards: one family lost interest in the study, and another family moved abroad. The other three missing assessmentsat10and12monthswereduetologisticdifficulties,i.e. fixing an appointment fitting the agendas of parents and the research team. The term infants participating in the validity study rarely showed MND (Table II). Twenty-eight infants had a stable normal neurological condition. One infant, whose mother had gestational diabetes, showed MND at the first assessment at 4 months but normalized thereafter. Another infant transiently showed MND at the age of 6 months. Neurological dysfunction occurred significantly more often in the preterm infants (Table II). At the various ages 7 to 22% of the preterm infants showed an abnormal neurological condition. The rate of CP at 18 months was 14%. At all testing ages MND was present in about half of the preterm infants. Throughout infancy MND was strongly related to gestational age at birth, with the risk of MND increasing with decreasing gestational age (Table III). The other factors contributing to MND varied with age. MND at 4 months was associated with lower maternal education and younger maternal age, MND at 6 months with increasing gravidity, MND at Minor Neurological Dysfunction in Infancy Mijna Hadders-Algra et al. 89

4 Table II: Neurological condition in term and preterm infants in validity study Term infants Preterm infants Age N, n (%) N-sub, n (%) MND, n (%) A Total N, n (%) N-sub, n (%) MND, n (%) A, n (%) Total p a 4mo b 21 (70) 8 (27) 1 (3) 30 3 (5) 14 (24) 28 (48) 13 (22) 58 < mo b 25 (83) 4 (13) 1 (3) 30 7 (12) 19 (33) 26 (46) 5 (9) 57 < mo b 29 (97) 1 (3) (22) 12 (22) 26 (48) 4 (7) 54 < mo b 28 (93) 2 (7) (20) 15 (28) 24 (45) 4 (7) 54 <0.001 N, n(%) S-MND, n(%) C-MND CP Total N S-MND, n(%) C-MND, n(%) CP 18mo c 23 (77) 7 (23) (19) 7 (12) 31 (54) 8 (14) 57 <0.001 a Difference in neurological condition between term and preterm infants; v 2 for trend. b Assessed with Touwen Infant Neurological Examination. c Assessed with neurological examination according to Hempel. 18 N, neurologically normal; N-sub, normal-suboptimal; MND, minor neurological dysfunction; S-MND, simple MND; C-MND, complex MND; A, neurologically abnormal. 10 months with lower paternal education and not being smallfor-gestational age, and MND at 12 months with the absence of preeclampsia or the HELLP syndrome. The presence of a serious lesion of the brain did not show a statistically significant relationship with the presence of MND. Neurological condition during infancy was correlated significantly with neurological condition at 18 months (Table IV). The correlation coefficients varied from 0.61 to This suggested stability of neurological condition over time. However, a stable condition was found in 28 of the 30 term infants (93%), but only in 18 of the 59 preterm infants (30%). Twenty-six different developmental trajectories could be distinguished. Examples of developmental trajectories at 4, 6, 10 and 12 months were the following: abnormal MND MND normal followed by complex MND at 18 months; MND normal normal MND followed by a normal condition at 18 months; and normal normal MND normal followed by complex MND at 18 months. The number of times Table III: Logistic regression analysis: factors explaining best minor neurological dysfunction (MND) in infancy Odds ratio (95% CI) MND at 4mo (explained variance 48%) Gestational age at birth, wks 0.67 ( ) <0.001 Maternal education a 0.18 ( ) Maternal age, y 0.84 ( ) MND at 6mo (explained variance 33%) Gestational age at birth, wks 0.71 ( ) <0.001 Gravidity 1.73 ( ) MND at 10mo (explained variance 38%) Gestational age at birth, wks 0.68 ( ) <0.001 Presence of SGA. birthweight 0.11 ( ) <10th centile) Paternal education a 0.34 ( ) MND at 12mo (explained variance 40%) Gestational age at birth, wks 0.62 ( ) <0.001 Presence of preeclampsia HELLP 0.08 ( ) a Trichotomized variable on education was recoded into a dichotomous variable: 0, primary education junior vocational training; 1, more education as a relatively low level of education contributed to developmental outcome. Note that the odds ratios indicate that a higher gestational age and a higher maternal age are associated with a lower risk for the development of MND. HELLP, Haemolysis, Elevated Liver enzymes, Low Platelets; SGA, small for gestational age; CI, confidence interval. p an infant had shown dysfunction and the severity of dysfunction predicted outcome best (Table V). Predictive values of a deviant neurological condition in infancy (MND + abnormal) for a deviant outcome at 18 months (complex MND + CP) revealed sensitivities of 83 to 91% and specificities of 62 to 84% (Table IV). Prediction of complex MND at 18 months on the basis of a single infant assessment was moderate at best, as it was hampered by false negatives. DISCUSSION The present study indicated that reliability of the TINE assessment in terms of inter-assessor agreement is good. This Table IV: Predictive validity: neurological condition in infancy and at 18 months Neurological classification at 18mo Normal, n (%) C-MND, n (%) CP, n (%) Total Neurological classification at 4mo (rho = 0.67, p <0.001) Normal 40 (87) 6 (13) 46 MND 6 (21) 19 (65) 4 (14) 29 Abnormal 2 (18) 5 (56) 4 (36) 11 Total Neurological classification at 6mo (rho = 0.64, p <0.001) Normal 42 (78) 12 (22) 54 MND 4 (15) 17 (66) 5 (19) 26 Abnormal 1 (20) 1 (20) 3 (60) 5 Total Neurological classification at 10mo (rho = 0.66, p <0.001) Normal 42 (78) 12 (22) 54 MND 4 (16) 18 (72) 3 (12) 25 Abnormal 3 (100) 3 Total Neurological classification at 12mo (rho = 0.61, p <0.001) Normal 42 (76) 13 (24) 55 MND 5 (22) 15 (65) 3 (13) 23 Abnormal 4 (100) 4 Total Predictive properties of deviant findings (MND + abnormal) in infancy to predict a deviant outcome (MND + CP) at 18mo: 4mo: sensitivity 84%, specificity 83%, negative predictive power 87%, positive predictive power 80%; 6mo: sensitivity 68%, specificity 89%, negative predictive value 78%, positive predictive value 84%; 10mo: sensitivity 67%, specificity 91%, negative predictive value 78%, positive predictive value 86%; 12mo: sensitivity 63%, specificity 89%, negative predictive value 76%, positive predictive value 81%. MND, minor neurological dysfunction; C-MND, complex MND; CP, cerebral palsy. 90 Developmental Medicine & Child Neurology 2010, 52: 87 92

5 Table V: Stability and change in neurological condition Neurological classification at 18mo, n Normal C-MND CP Total Number and type of neurological assessment outcomes Term infants 4 normal normal, 1 MND 2 2 Preterm infants 4 normal normal, 1 MND normal, 2 MND normal, 3 MND 2 a 6 a 8 4MND MND, 1 normal, 1 abnormal MND, 1 normal, 2 abnormal 1 1 2MND,1?,1abnormal 1 a 1 3 MND, 1 abnormal MND, 2 abnormal MND, 3 abnormal 2 b 2 4 abnormal 1 c 1 Total a Including one infant with periventricular haemorrhagic infarction. b One infant with periventricular haemorrhagic infarction and one infant with cystic periventricular leukomalacia. c Middle cerebral artery infarction. Neurological condition for missing assessment was classified according to neighbouring assessments.?, missing assessment; MND, minor neurological dysfunction; C-MND, complex MND; CP, cerebral palsy. means that the study demonstrated that agreement on the outcome of a TINE assessment by two well-trained assessors is good. It should be realized, however, that it takes considerable experience to become a well-trained assessor and to learn to appreciate the distinction between typical and sign of MND. In addition, the study showed that MND in infancy is related to prenatal, perinatal, and social factors, in particular to preterm birth, and that it has moderate predictive validity. The strength of the study was the longitudinal series of standardized TINE assessments with little attrition. A limitation of the validity part of the study was that the group of typically developing term infants could not be regarded as a representative sample of the general population of term infants. Previously we had learned that minor dysfunctions were slightly over-represented in children whose parents allowed their child to participate in a study on typical development. 21 However, the group of preterm infants included in the validity part of the study may be considered as a representative sample of a Dutch neonatal intensive care unit population (tertiary referral centre) during the past decade. This was illustrated, for instance, by the fact that gestational age, birthweight, and frequency of an Apgar score at 5 minutes of <7 (15%) and ventilatory support (68%) were similar to those of other groups of preterm infants admitted to Dutch neonatal intensive care units (Table I) This means that the nonrepresentative nature of the group of typically developing term infants may have partially occluded the differences between the preterm and term infants. A second limitation of the study was that assessors were not blinded to group allocation. This may have introduced a bias in the assessment of the neurological conditions of the preterm infants. However, it is virtually impossible to conceal preterm status, as the infant s appearance usually discloses preterm birth. The assessors were, nevertheless, blind to other details of each infant s clinical and developmental history. A third limitation of the study was the lack of long-term follow-up, which weakened the power to determine predictive validity. At the age of 18 months the clinical picture of CP is not yet always fully expressed. In addition, it is well known that the majority of minor developmental disabilities first emerge at school age. 8 A fourth limitation of the study was the absence of detailed neuroimaging data. Magnetic resonance imaging of the neonatal brain, including diffusion-weighted imaging, might have shed light on the structural background of the signs of MND. 25 Our study confirmed the relationship between preterm birth and MND in infancy. 4,25,26 Signs of MND may be an expression of the lesions of the developing brain associated with preterm birth, such as focal and diffuse damage of the periventricular white matter, and lesions of the thalamus, basal ganglia, and cerebellum. 25,27 Interestingly, we found that small-for-gestational age and preeclampsia were protective factors in the development of MND in the second half of infancy. Restricted fetal growth and preeclampsia are conditions of fetal stress. Fetal stress may induce a dual response. Initially the fetus adapts by means of an accelerated maturation of brain and lungs, but when the limits of compensation are reached, adaptation may be overruled which may result in neurological injury. 28 Yet the early favourable outcome induced by fetal stress may only be a transient phenomenon present in infancy, as Scherjon et al. 29 reported that it is associated with less favourable development at school age. Our study indicated that MND is related not only to purely biological factors. The association with parental education and maternal age suggests that environmental factors may have an additional positive or negative effect. 8 Our data confirmed that the neurological condition in infancy is prone to change. 4 The changes are related to the developmental transformations of the infant brain. 30 They are found in particular in infants at high risk of developmental disorders. The instability of the infant neurological condition precludes perfect prediction of later developmental outcome. Therefore, prediction is best when it is based on multiple assessments. Prediction on the basis of a single infant examination is most useful when it is aimed at the detection of children with a clear dysfunction, such as CP. 7,31,32 Early prediction of MND on the basis of a single assessment is more difficult, notwithstanding the fact that signs of MND during infancy are related to MND in later life. 6,33 CONCLUSION MND can be assessed reliably during infancy with the TINE. The presence of MND in infancy puts an infant at risk for developmental dysfunction in later life and invokes the need for careful follow-up. Further research, including long-term follow-up studies, is needed to determine the exact nature of the developmental risk associated with MND in infancy. Minor Neurological Dysfunction in Infancy Mijna Hadders-Algra et al. 91

6 ACKNOWLEDGMENTS We gratefully acknowledge the assistance of Cornill Blauw-Hospers, Victorine de Graaf-Peters, and Hylco Bouwstra for carrying out some of the neurological assessments in the validity study. SUPPORTING INFORMATION Additional supporting information may be found in the online version of this article: Appendix SI: Touwen Infant Neurological Examination. Appendix SII: Touwen Infant Neurological Examination: clusters of minor neurological dysfunction in infancy. Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author of the article). REFERENCES 1. Amiel-Tison C, Gosselin J. Neurological development from birth to six years. Guide for examination and evaluation. Baltimore: Johns Hopkins University Press, Touwen BCL. Neurological development in infancy. Clinics in Developmental Medicine No. 58. 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