Beruflich Dokumente
Kultur Dokumente
Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet
Research paper
h i g h l i g h t s
a r t i c l e
i n f o
Article history:
Received 31 March 2015
Received in revised form
26 September 2015
Accepted 10 November 2015
Available online 17 November 2015
Keywords:
Perinatal brain damage
Prenatal risk factors
Neurohabilitation
Preterm encephalopathy
Hypoxic ischemic encephalopathy
MRI
a b s t r a c t
Objective: The neurohabilitation treatment has been shown to be a successful method for decreasing the
sequelae of perinatal brain damage (PBD) in Hungarian population. The goal of this pilot trial was to
introduce this procedure by describing the results of its application in infants with PBD as demonstrated
by clinical, developmental and MRI studies. As this procedure has proved to be useful, according the
declaration of Helsinki, no control clinical trial was permitted.
Participants: Infants younger than 2 months of corrected age (CA) with prenatal and/or perinatal risk factors for brain damage. Two groups were considered. One group was treated using the neurohabilitation
method (n = 20), and the other was not treated (n = 13) because treatment was voluntarily discontinued
after the initial evaluation. Evaluations were carried out prior to 2 months of CA and at 68 years of age.
All children showed abnormal clinical and MRI characteristics in the rst study.
Results: The treated group had a higher percentage (90%) of children with normal outcome than did the
non-treated group (38%; OR = 2.37, CI 95% = 1.24.7; p < 0.005). In this latter group, only one out of ve
(20%) children born at or before 34 weeks of gestational age had a normal outcome. In contrast, eight out
of nine treated preterm infants had normal outcomes (8/9 = 89%, OR = 4.45, CI 95% = 0.726; p = 0.017).
Conclusions: This pilot trial conrms previous studies suggesting that Neurohabilitation decreases the
neurological and cognitive sequelae of preterm and at-term infants with PBD.
2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Despite advances in medicine and signicant improvements in
the survival of preterm infants over the last 1020 years, the incidence of births at risk for brain damage has not diminished; in
60
most frequently used for intervention in children with a developmental disorder [8]. NDT is generally applied later in life, when
there are symptoms and signs of brain injury, therefore as a rehabilitation procedure. The same happened with Vojtas method. On
the other hand, the effectiveness of the NDT approach and other
pediatric therapies is currently an issue generating considerable
professional debate [9]. None of ve studies that evaluated NDT
effects demonstrated a statistically signicant effect of intervention
in motor development [913]. In a report comparing NDT vs. Vojta
methods for the early treatment of cerebral palsy, Vojtas procedure
showed to normalize more infants than NDT method [14].
Although decreasing the number of births at risk for brain
damage should be the priority to decrease the neurological and cognitive sequelae, the early diagnosis and treatment of brain damage
in newborns at risk may also decrease these sequelae. This is the
goal of the therapy known as neurohabilitation, as proposed by
Ferenc Katona [1518] to differentiate this process from rehabilitation. The main difference between the two is that neurohabilitatory
treatment should begin before the lesion sequelae have been established, during the rst 34 months after birth, to try to reduce or
abolish the neurological sequelae that may result from perinatal
brain damage. The results of the application of this therapy to 2189
infants of less than 6 months old with suspected perinatal brain
damage showed, at 18 months of corrected age (CA), that 46% had
a normal outcome, 32% improved relative to their initial symptoms, and 22% had no change or their symptoms had become worse
[15,16]. These results were obtained in Hungary where this technique has been applied for more than 30 years; however, it is not
well known in other countries. The results obtained in Hungary led
us to evaluate this procedure in our group of patients in Mexico. To
our knowledge, this is the rst report describing the longitudinal
results obtained in the application of neurohabilitation to infants
with perinatal brain damage demonstrated by magnetic resonance
images (MRI) as well as by clinical and psychological evaluations.
2. Patients and methods
The Ethics Committee of the Instituto de Neurobiologa of
the Universidad Nacional Autnoma de Mxico approved this
study, which also complies with the Ethical Principles for Medical Research Involving Human Subjects established by the Helsinki
Declaration. Informed written parental consent for participation in
this study was obtained for all subjects.
2.1. Patients
Inclusion criteria: infants during the rst 2 months of corrected
age (CA) with prenatal and/or perinatal history of risk factors for
brain damage. These risk factors are described in Tables 1 and 2 for
each patient. After the infants were discharged from the hospital
where they were born, their parents were invited to participate in
a special project of the Unit for Neurodevelopmental Research at
the National Autonomous University of Mexico in Quertaro. This
Unit currently has a data base with 1138 subjects from 0 to 8 years
old.
Two groups of children were considered: the treated and the
non-treated groups. To build a non-treated group who did not
undergo treatment but who had initiated the protocol with all the
indicated studies, we looked for children between 6 and 8 years
old that voluntarily discontinued the treatment after one month.
We used these criteria for ethical reasons. If it had been shown that
the neurohabilitation procedure is useful to improve development
even in the case of infants with severe brain lesions [1518], it is
against the Helsinki declaration to leave infants without the treatment in order to have a control trial. The parents of 13 children
Table 1
Group without therapy.
GA weeks/gender
Weight at birth
Apgar
Risk factors
Initial clinical
ndings/diagnosis
First MRI
Final MRI
C1
34/F
2100 gr.
8/9
5.8
2100 gr.
9/9
5.8
LV2
Frontal SAS
Subarachnoid
space
LV
C3
38/M
3600 gr.
8/9
6.3
Oligohydramnios hypoxia
Subarachnoid space,
diffuse white matter
damage
Normal
C4
39/F
3280 gr.
9/9
5.6
Normal,
IQ = 81, low average
Subarachnoid space
LV
C5
27/M
1000 gr.
7/8
6.4
LV
34/M
1725 gr.
7/9
4.9
LV
Subarachnoid space
LV
C7
35/M
2830 gr.
5/6
5.5
Generalized
hypotonia/preterm
encephalopathy
Generalized hypertonia,
Right central VII palsy/
Preterm encephalopathy
Severe incoordination
problems, learning
problems,
IQ = 54,
Cerebral palsy epilepsy,
IQ = 93, average
LV
Subarachnoid space
C6
Right LV
C8
36/M
2260 gr.
8/9
7.3
Preterm hyaline
membranes, respiratory
distress, icterus,
enterocolitis
Preterm, respiratory
distress, sepsis,
hyperbilirubinemia
Preterm
Pre-eclampsia
Lung hemorrhage
Acute fetal distress
Preterm
hyperbilirubinemia
Generalized
hypotonia/hypoxic
ischemic encephalopathy
Sarnat 2
Hypotonia/Hypoxic
ischemic Encephalopathy
Sarnat 2
Mixed hypotonia and
hypertonia/preterm
encephalopathy
Normal,
IQ = 121
Superior
Moderate coordination
problems,
Adiadochokinesis,
IQ = superior
Normal,
IQ = 86 low average
LV
34/F
Generalized
hypotonia/preterm
encephalopathy
Generalized
hypotonia/preterm
encephalopathy
Subarachnoid
space, LV
C2
Preterm twin II
Premature rupture of
membranes
Preterm twin I
Premature rupture of
membranes
Generalized hypotonia/
Preterm encephalopathy
Normal,
IQ = 82, low average
C9
39/F
3000 gr.
9/9
Seizures
Hypocalcemia
C10
29/F
1200 gr.
8/9
6.3
Preterm, twin I,
pneumonia, sepsis, anemia
Hypotonia/hypoxic
ischemic encephalopathy
Sarnat 2
Hypotonia
Preterm encephalopathy
Diffuse leukomalacia
Corpus callosum
Normal
C11
40/F
2850 gr.
7/8
Bradycardia
Normal development,
Dyscalculia,
IQ = 80, low average
Cerebral palsy: Right
hemiparesia, attention
decits,
IQ = 78, borderline
Hearing loss,
IQ = 77, borderline
Occipital leukomalacia
Normal
C12
40/F
2375 gr.
8/9
Seizures,
hyperbilirubinemia,
Diffuse leukomalacia
Corpus callosum
Corpus callosum
C13
39/M
5.1
Chickenpox during
pregnancy (3rd Trimester)
Corpus callosum
Subarachnoid space
Normal
X=
SD=
35.69
4.13
2375 gr.
8/9
2361/7.46
764/1.71
Generalized hypertonia
Hypoxic ischemic
Encephalopathy Sarnat 2
Generalized hypotonia/
hypoxic ischemic
Encephalopathy Sarnat 3
Generalized hypertonia
LV
Id.
61
62
Table 2
Treated group.
Id.
GA weeks/gender Weight
Apgar
Risk factors
First MRI
Final MRI
E1
33/F
5.11
Normal,
IQ = 100, average
Normal,
IQ = 75, borderline
39/M
5.11
E4
34/M
E5
30/F
2250 gr.
8/9
1550 gr.
8/9
1350 gr.
8/9
5.2
Hypoglycemia, in utero
growth restriction
Preterm, pre-eclampsia,
acute fetal distress
Preterm
Leucoencephalopathy,
Periventricular
hemorrhage, LV
Diffuse leukomalacia
Normal
E3
Generalized hypotonia/preterm
encephalopathy
Generalized
hypotonia/hypoxic-ischemic
encephalopathy Sarnat 2
Generalized hypotonia
Normal
37/M
Preterm, pre-eclampsia,
respiratory distress
Pre-eclampsia, icterus,
apnea
Leucoencephalopathy
E2
1950 gr.
8/9
1800 gr.
9/9
E6
39/M
3750 gr.
5/8
4.6
Eclampsia
E7
39/F
3950 gr.
5/7
4.6
E8
36/M
1680 gr.
8/8
E9
30/M
6.2
E10
36/M
1680 gr.
8/8
2000 gr.
7/8
E11
39/F
E12
35/M
3800 gr.
9/10
3775 gr.
3/7
E13
40/F
Preterm pre-eclampsia,
hyperbilirubinemia, sepsis,
apnea
Preterm, twin I, icterus,
sepsis
Preterm pre-eclampsia,
hyperbilirubinemia, sepsis,
apnea
Condylomatosis, maternal
urinary infections
Preterm premature rupture
of membranes,
resuscitation
Seizures, sepsis
E14
30/F
E15
32/F
1400 gr.
6/8
5.6
E16
27/M
800 gr.
5.8
E17
39/F
E18
40/M
2475 gr.
9/9
3100 gr.
7/8
E19
32/M
E20
33/M
6.4
Generalized hypotonia/preterm
encephalopathy
Generalized hypotonia/preterm
encephalopathy
Generalized
hypotonia/hypoxic-ischemic
encephalopathy Sarnat 2
Generalized
hypotonia/hypoxic-ischemic
encephalopathy Sarnat 2
Hypertonia
Hyperbilirubinemic
encephalopathy
Generalized hypotonia/preterm
encephalopathy
Generalized hypotonia/preterm
encephalopathy
Normal
IQ = 113, average
Normal
IQ = 79, borderline
Normal
IQ = 87, low average
Normal
IQ = 84, low average
Leukoencephalopathy
Occipital white matter
hyperintensity, Corpus
callosum
Leucoencephalopathy
Normal
Left temporal arachnoidal
cyst, LV
Normal
LV
Normal
IQ = 81, low average
Subarachnoid space
Normal
Normal
IQ = 116, high average
Leucoencephalopathy
Normal
Normal
IQ = 88, low average
Normal
IQ = 82, low average
Corpus callosum
Normal
Diffuse leukomalacia
Normal
Left LV
LV
Generalized hypotonia/preterm
encephalopathy
Normal
IQ = 86, low average
Normal
IQ = 87, low average
Subarachnoid space
Normal
Hypoxic-ischemic encephalopathy
Sarnat 2
Generalized hypotonia/preterm
encephalopathy
Normal
IQ = 77, borderline
Normal
IQ = 94, average
Leukomalacia
Normal
Leukomalacia,
Subarachnoid space
Left LV
Normal
IQ = 107, average
Leukomalacia
Normal
Preterm, sepsis
Icterus, RH incompatibility
Generalized hypertonia
Perinatal asphyxia
Generalized hypertonia
1750 gr.
5/7
9.2
Generalized hypotonia/preterm
encephalopathy
2240 gr.
9/9
6.3
Preterm, respiratory
distress, perinatal
asphyxia, sepsis
Preterm, twin II,
respiratory distress
4700 gr.
6/9
1250 gr.
8/9
2362/7.16
1094/8.42
6.9
5.4
Generalized hypotonia
LV
Subarachnoid space
Corpus callosum
Atrophy of the parietal
cortex
Cyst in left
cerebellopontine angle
Normal
IQ = 90, average
Delay language
development, attention
decits,
IQ = 40 very low
Normal
IQ = 82, low average
Corpus Callosum
Subarachnoid space
LV
Cerebral atrophy
Normal
Normal
IQ = 72, borderline
Subarachnoid space
Corpus callosum
LV
35
X=
SD= 3.98
5.9
63
Fig. 1. Main maneuvers for verticalization. (1) Lift trunk with hand drive. (1a) Double lift trunk with hand drive. (2) From lying to sitting. (3) Lift the trunk with back and hip
support. (3a) Lift trunk with back support. (4) Sitting in the air. (5) Front protection to support thighs and chest. (6) Lateral and anterior protections.
Table 3
MRI Initial ndings.
Diagnosis
Control
Treated
6
5
4
0
46
38
31
0
12
4
4
2
60
20
20
10
Table 4A
Outcome of the patients with 34 weeks of GA.
OR
CI(95%)
1.75
2.50
1.77
0.4277.171
0.52211.955
0.3558.881
0.436
0.251
0.483
Table 4B
Outcome of the patients with >34 weeks of GA.
Group
Normal outcome
Abnormal outcome
Total
Group
Normal outcome
Abnormal outcome
Total
Control 34 weeks
Treated 34 weeks
1
8
4
1
5
9
4
10
4
1
8
11
OR = 4.45, CI 95% = 0.122; effect size = 0.4, CI 95% = 0.07 to 0.7; p = 0.28.
64
Fig. 2. Maneuvers to change posture. (7) Rolling over on a blanket. (8) Rolled over with head support. (9) Half roll over. (10) Sitting to four points support. (11) From kneeling
to standing.
Fig. 3. Maneuvers to creeping. (12) Elementary horizontal creeping. (13) Elementary creeping downward on slide. (14) Elementary creeping upward on a slide. (15) Shifting
support in knees (kneeling creeping).
3. Results
Tables 1 and 2 describe the characteristics of the treated and
non-treated groups. No signicant differences between groups
were observed in the initial ndings and diagnosis. All children
showed abnormal ndings in the rst clinical and MRI examinations, indicating brain damage (see Table 3).
In terms of outcomes, the treated group had a signicantly
higher percentage of children with normal neurodevelopment
(18/20) compared to the non-treated group (5/13 = 38%; Odds
ratio = 2.37, CI 95% = 1.24.7; effect size = 0.5, CI 95% = 0.20.7;
p < 0.005).
In relation to the children with a gestational age (GA) 34
weeks, the results were signicantly different between groups,
with higher percentage of normal outcomes in the treated
than in the non-treated group (OR = 4.45, CI 95% = 0.726; effect
65
Fig. 4. Maneuvers to crawling. (16) Elementary assisted crawling. (17) Modied assisted crawling. (18) Crawling with lateral support. (19) Crawling leg support. (20) Crawling
in an ascending plane. (21) Crawling a downward slide. (22) Crawling on stairs.
Fig. 5. Maneuvers to walking. (23) Elementary walk. (24) Elementary walk on upward slide.
size = 0.68CI 95% = 0.10.9; p = 0.017 ; see Tables 4A and B). Fig. 6
shows the MRI of two patients, one of each group.
However, no signicant differences were observed between the
groups in infants with >34 weeks of GA. Total IQ values are shown in
Tables 1 and 2. In the non-treated group there was one child with
very severe mental retardation who was not able to perform the
WISC test. This child was not taken into account when the mean values of the subtests or the total IQ were compared between groups.
No signicant differences between groups for the total or the IQ
subtests were observed for all the infants and for those subgroups
with GA 34 or GA > 34.
66
Fig. 6. MRIs of patients E-02 and E-15. Patient E-02. On the upper line, at 2 months CA, lateral ventricles (LV) have an abnormal shape and increased volume, there is increased
volume of subarachnoidal space, and there are small periventricular hemorrhages. On the second line at 5.9 years old, the volumes of the LV are normal and the MRI is normal,
and on the third line the tractographies of the corticospinal tracts (CST) and the corpus callosum (CC) are normal. Patient E-15. The MRI at 2 weeks CA, shows PVL and the
LV with abnormal shapes. On the second line the MRI at 5.6 years old is normal, and the CST and the CC are normal.
4. Discussion
It is well known that premature fetuses and neonates are at
increased risk for brain injury compared to term infants. In a
national study in Norway of the prevalence of sequelae according to GA [1], from 1822 infants that were born before or at 34
weeks of GA, the incidence of cerebral palsy was 17%, of mental
retardation 7.2%, and of sensory disabilities 6.8%. The nding in the
present paper that eight out of nine treated preterm infants born
before or at 34 weeks of GA had normal outcomes at school age,
whereas only one of the similar, non-treated children did, is a very
promising result that suggests the benets of neurohabilitation in
preterm infants. In the patients with GA greater than 34 weeks in
the non-treated group, four out of eight infants had a normal outcome while in the treated group ten out of eleven had a normal
outcome. However, this difference was not signicant. Thus, the
signicant difference observed for the total number of infants in
each group was mainly due to the infants with GA 34.
The improvement in neurodevelopment of the treated group
may be explained by the plastic changes produced by the intensive treatment. The repetition of the maneuvers used to generate
the sensoromotor response facilitates the performance of normal
movements, changing the representations of these movements in
the brain. Numerous references show that learning motor skills,
even in adults, produces a reorganization of the motor system, and
even structural changes have been reported [3033].
In relation to our results although all the children of both groups
had abnormal ndings in the initial MRI evaluation, in the last MRI
study four of thirteen of the non-treated group (31%) and twelve
of twenty in the treated group (60%, p = 0.15) showed normal MRI
(see Fig. 6). The children of both groups who nished the study with
normal MRI scans also showed signicant differences in outcome:
two of four in the non-treated group (50%) and twelve of twelve
in the treated group (100%; p = 0.05). These results may imply that
the myelination of the corpus callosum and of the white matter
surrounding the lateral ventricles not only improves with development but may improve even more with the treatment. Therefore,
our results although preliminary, point to be very promising.
Finally, the drawbacks of this study should be discussed. It is
not a clinical control trial since previous studies have shown the
Erika Cruz-Rivero, Antonio Fernndez-Bouzas , Delia FigueroaNavarro, Johanna Flores-Arizmendi, Berta Gonzlez-Frankenberger
, Vernica Guidobono-Radesca, Rosa M. Hernndez-Corona, Claudia Jimnez-Snchez, Alma Janeth Moreno-Aguirre, Juan Jos
Ortiz-Resndiz, Erik Pasay-Alcaraz, Tonatzin Pineda-Martnez,
Sara Elisa Ponce-Rodrguez, Eneida Porras-Kattz, Amaya SobernGarca and Angeles Zavala. Authors also acknowledge the
anonymous reviewer for his/her suggestions, Dr. Dorothy Pless for
the revision of the English version of the manuscript, and Dr. Susana
Szava for the translation to Spanish from Hungarian of Katonas
book Ontogenesis of the human nervous system.
References
[1] D. Moster, R.T. Lie, T. Markestad, Long-term medical and social consequences
of preterm birth, N. Engl. J. Med. 359 (2008) 262273.
[2] I.N. Philip, D.K. Stevenson, W.E. Benitz, P. Sunshine, S.R. Hintz, M.L. Druzin,
Fetal and Neonatal Brain Injury, 4th ed., Cambridge University Press, New
York, NY, 2009.
[3] J.J. Volpe, Neurology of the Newborn, 5th ed., Saunders Elsevier, Philadelphia,
PA, 2009.
[4] J.H. Chen, A. Claessens, M.E. Msall, Prematurity and school readiness in a
nationally representative sample of Australian children: does typically
occurring preschool moderate the relationship? Early Hum. Dev. 90 (2) (2014)
7379.
[5] P.J. Anderson, Neuropsychological outcomes of children born very preterm,
Semin. Fetal Neonatal Med. 19 (2) (2014) 9096, Review.
[6] J. Brooks-Gunn, C.M. McCarton, P.H. Casey, M.C. McCormick, C.R. Bauer, J.C.
Bernbaum, J. Tyson, M. Swanson, F.C. Bennett, D.T. Scott, et al., Early
intervention in low-birth-weight premature infants. Results through age 5
years from the Infant Health and Development Program, JAMA 26272 (16)
(1994) 12571262.
[7] F.M. Ohgi, T.G. Akiyama, Effect of an early intervention programme on low
birthweight infants with cerebral injuries, J. Paediatr. Child Health 40 (2004)
689695.
[8] K. Bobath, B. Bobath, The very early treatment of cerebral palsy, Dev. Med.
Child Neurol. 9 (1967) 373390.
[9] J.D. Cartwright, M.A. van der Velde, Effect of early neurodevelopmental
therapy in normal and at-risk survivors of neonatal intensive care, Lancet 14
(1985) 13271330.
[10] M.C. Piper, V.I. Kunos, D.M. Willis, B.L. Mazer, M. Ramsay, K.M. Silver, Early
physical therapy effects on the high-risk infant: a randomized controlled trial,
Pediatrics 78 (1986) 216224.
[11] A.D. Rothberg, M. Goodman, L.A. Jacklin, P.A. Cooper, Six-year follow-up of
early physiotherapy intervention in very low birth weight infants, Pediatrics
88 (1991) 547552.
[12] A.M. Weindling, P. Hallam, J. Gregg, H. Kenka, L. Rosenbloom, J.L. Hutton, A
randomized controlled trial of early physiotherapy for high-risk infants, Acta
Paediatr. 85 (1996) 11071111.
[13] M. Goodman, A.D. Rothberg, J.E. Houston-McMillan, P.A. Cooper, J.D.
Cartwright, M.A. van der Velde, Effect of early neurodevelopmental therapy in
normal and at-risk survivors of neonatal intensive care, Lancet 14 (2(8468))
(1985) 13271330.
67