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Neuroscience Letters 611 (2016) 59–67
Contents lists available at ScienceDirect
Neuroscience Letters
j ournal homepage: www.elsevier .com/ locate /neulet
Research paper
Longitudinal study of children with perinatal brain damage in whomearly neurohabilitation was applied: Preliminary report
Thalía Harmony∗, Jesús Barrera-Reséndiz, María Elena Juárez-Colín,Cristina Carrillo-Prado, M. del Consuelo Pedraza-Aguilar, Aurora Asprón Ramírez,Manuel Hinojosa-Rodríguez, Thalía Fernández, Josefina Ricardo-Garcell
Unidad de Investigación en Neurodesarrollo,Departamento de Neurobiología Conductual y Cognitiva, Instituto de Neurobiología, UniversidadNacional
Autónoma de México, Campus Juriquilla, Mexico
h i g h l i g h t s
• It is a longitudinal study of perinatal brain damaged children.• Katona’s neurohabilitation procedure was used as treatment.• 89% of preterm ≤34 weeks treated had normal neurodevelopment.• Only 20% of non-treated preterm ≤34 weeks had normal neurodevelopment.• Application of neurohabilitation to perinatal brain damaged infants is recommended.
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 2015Available 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 fac-
tors 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 6–8 years of age.
All children showed abnormal clinical and MRI characteristics in the first 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% = 1.2–4.7; p< 0.005). In this latter group, only one out of five
(20%) children born at or before 34 weeks of gestational age hada normal outcome. In contrast, eight out
of nine treated preterm infants had normal outcomes (8/9 =89%, OR = 4.45, CI 95% = 0.7–26; p= 0.017).
Conclusions: This pilot trial confirms 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 significant improvements in
the survival of preterm infants over the last 10–20 years, the inci-
dence of births at risk for brain damage has not diminished; in
∗ Corresponding author at: Instituto de Neurobiología, UNAM Campus Juriquilla,
Querétaro 76230, México. Tel.: +52 442 1926101x113.
E-mail address: thaliah@unam.mx (T. Harmony).
fact, some evidence suggests that disability rates have increased
[1]. Data in the literature also showed that even preterm children
who survive without apparent motor disability, have a substantial
reduction in the mean intelligence quotient (IQ) and an increased
incidence of cognitive and educational difficulties [2–5].
A revision of the literature related to early interventions pro-
grams to study high risk premature infants has shown that when
applied to severe low weight preterm babies’ scores [6] or infants
with brain lesions [7] did not show any improvement on neurode-
velopment. Neurodevelopmental treatment (NDT) is the method
http://dx.doi.org/10.1016/j.neulet.2015.11.013
0304-3940/© 2015 Elsevier Ireland Ltd. All rightsreserved.
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60 T. Harmony et al. / Neuroscience Letters 611(2016) 59–67
most frequently used for intervention in children with a develop-
mental disorder [8]. NDT is generally applied later in life, when
there are symptoms and signs of brain injury, therefore as a reha-
bilitation procedure. The same happened with Vojta’s 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 five studies that evaluated NDT
effects demonstrateda statisticallysignificanteffect of intervention
in motor development [9–13]. In a report comparing NDT vs. Vojta
methods for the earlytreatment of cerebral palsy, Vojta’s 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 theneurologicaland cog-
nitive 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 [15–18] to differentiate this process from rehabilita-
tion. The maindifference between the two is thatneurohabilitatory
treatment should begin before the lesion sequelae have beenestab-
lished, during the first 3–4 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% hada normal outcome, 32% improved relative to their initial symp-
toms, and22% hadno change or their symptoms hadbecome worse
[15,16]. These results were obtained in Hungary where this tech-
nique 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 first 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 Neurobiología of
the Universidad Nacional Autónoma de México approved this
study, which also complies with the Ethical Principles for Medi-
cal 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 first 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 f or
each patient. After the infants were discharged from the hospital
where they were born, their parents were invited to participate ina special project of the Unit for Neurodevelopmental Research at
the National Autonomous University of Mexico in Querétaro. 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 [15–18], it is
against the Helsinki declaration to leave infants without the treat-
ment in order to have a control trial. The parents of 13 children
agreed to return to the unit for re-evaluation. They comprised the
non-treated group, and they did not have any type of treatment. In
thisgroup theclinical observationswere onlydone before 2 months
of corrected age (CA) and at 6-8 years old.
Then, from a pool of 1138 treated children from our data base,
20 were pseudo-randomly selected [19] f rom those who had fol-
lowed the treatment and all the evaluations and who were similar
to the non-treated group in terms of age, gender, weight at birth,
Apgar, risk factors and diagnosis. These 20 children formed the
treated group. Exclusioncriteria were: infants older than 2 months
of CA,presenceof geneticfactorsassociatedwith brain damage,car-
diovascular pathology, brain malformations and/or chromosomal
aberrations.
2.2. Evaluations
The initial evaluations were performed in the two groups and
they included:
(a) Clinical pediatric and neuropediatric examinations [20], (b)
Bayley scales [21] (c) Magnetic resonance imaging (MRI) using 1.0
T Philips equipment, and (d) Katona’s evaluations [17,18,22]. These
evaluations were repeated accordingto a time schedule only in the
treated group. Neuropediatric evaluations were done each month
during the first year, each 3 months during the second year, andeach 6 months after 3 years old. Bayley’s evaluationsand MRIs were
done each 4 monthsduring the first year and each 6 monthsduring
the second and third year. In the fourth year WIPPSI scales were
used and applied each 6 months and later on, WISC was applied
each year. After the fourth year, MRIs were obtained each year
if there was some abnormal finding. When the children reached
6–8 years of age, the following evaluations were performed: (a)
neuropediatric examination, (b) clinical psychological evaluations
and performance in the WISC-IV test [23], (c) clinical language
evaluations [24], and (d) MRI evaluations. At these ages MRI was
performed using a 3.0 T GE scanner. If in the first 3 examinations
the child showed normal results, or a borderline IQ, then her/his
outcome was considered “normal”. The abnormal outcomes were
classified as neurological when the last neuropediatric examina-tionshowed abnormalfindings, andas cognitive sequelae whenthe
clinical psychological evaluation and/or IQ values were abnormal
and/or language delays were observed.
2.3. Katona’s procedure (see Ref. [25], data in brief)
Katona’s methodology is both diagnostic and therapeutic.
Katona’s assessment is performed with some of the maneuvers
used in the therapy itself, where it has to take into account several
evaluation parameters such as: muscle tone (passive and active);
hemi bodies symmetry along the maneuver performance; atten-
tion, eye tracking and auditory monitoring; neurological signs
of alarm (thumb in fist, scissor gait, strabismus, irritability, axial
hyperextension, among others).Katona based the neurohabilitation procedure on the “ele-
mentary neuromotor patterns”. These early integrated complex
movements are chains of processes in which the neck, trunk and
extremities perform complex and continual movements in cer-
tain repetitive patterns. These motor patterns are characterized
by a high degree of organization, persistence and stereotypy and
can be divided in two groups: (1) complex chains of movements
directed to verticalization of the body and(2) complex movements
directed to locomotion [17,18,25]. Thesemovements are controlled
by the developing subcortical structures and can be activated by
determined positions of the head and the body that triggers the
activation of the vestibular nuclei andtheir projections to thespinal
cord, the reticular formation, thalamus, cerebellum, basal ganglia
[26]. Nearly all these tracts project to the motor cortex [27]. At the
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T. Harmony et al. / Neuroscience Letters 611 (2016) 59–67 63
Fig. 1. Main maneuversfor verticalization. (1)Lift trunk with hand drive.(1a) Doublelift trunk with hand drive.(2) From lying to sitting. (3)Lift thetrunkwith back andhip
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 findings.
Diagnosis Control Treated OR CI(95%) P
N % N %
Diffuse white matter damage 6 46 12 60 1.75 0.427–7.171 0.436
Increased LV volumes 5 38 4 20 2.50 0.522–11.955 0.251
Decreased CC volume 4 31 4 20 1.77 0.355–8.881 0.483
Cerebral atrophy 0 0 2 10
Table 4A
Outcome of the patients with ≤34 weeks of GA.
Group Normal outcome Abnormal outcome Total
Control≤34 weeks 1 4 5
Treated≤34 weeks 8 1 9
OR= 4.45, CI 95% =0.7–26; effect size= 0.68, CI 95% =0.1–0.9; p= 0.017.
same time, movements generate activation of different receptors,
which send afferent impulses. This constant feedback helps in the
organization of motor control.
A therapeutic program consists of training of a series of neu-
romotor patterns each day for a certain time. The generation of these movements repeated several times produce brain engrams
that improve motor development [28]. At the initiation of the
treatment, specialized therapistsconducted theKatona evaluations
to obtain a diagnosis and to program the exercises that parents
should learn to apply to their infants at home during the first
month of therapy. The therapy was intensive and specific for each
infant.
The differentpositions to generate the specific neuromotor pat-
terns are described in Refs. [22] and [25]. Figs. 1–5 show the
different maneuvers described in Ref. [25].
During the first 3 months, parents should go daily with the
therapist in order to learn how to stimulate the infant under the
supervision of the therapist. The therapy consists in the elaboration
of the individual program, a session consists in the repetition, 4–8
Table 4B
Outcome of the patients with >34 weeks of GA.
Group Normal outcome Abnormal outcome Total
Control > 34 weeks 4 4 8
Treated > 34 weeks 10 1 11
OR= 4.45, CI 95%= 0.1–22; effect size= 0.4, CI 95%= −0.07 to 0.7; p= 0.28.
times, of 6–9 sensoromotor patterns such as lift trunk with hand
drive [25]. One sessionhas a duration of 45min and sessions should
be repeated 3 or 5 times daily. Parents learn how to correctly per-
form the exercises since they are going to treat the infant at home.
Therapy must be integrated to the infant’s schedule and dividedinto periods according to patterns of sleeping and wakefulness as
well as feeding and nursing schedules.
Eachmonth,the infant was examinedevaluating not onlymotor
performance but also visual and auditory attention and the ages at
which the infant mastered various developmental milestones.
2.4. Statistics
Almost all comparisons between groups were performed using
Chi-square statistics. Odds ratio (OR) and 95% confidence intervals
(CI) were calculated for proportions. Effect size and 95% CI were
calculated following Cummings [29] software. The Student’s t -test
was used to compare WISC values between groups. As it is known
that the outcome of preterm infants with equal or less GA than
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64 T. Harmony et al. / Neuroscience Letters 611(2016) 59–67
Fig. 2. Maneuversto changeposture.(7) Rolling over ona blanket. (8)Rolled over with head support. (9)Halfroll over. (10) Sitting to four pointssupport.(11) From kneeling
to standing.
Fig. 3. Maneuvers to creeping. (12) Elementary horizontal creeping. (13) Elementary creeping downward on slide. (14) Elementary creeping upwardon a slide. (15) Shiftingsupport in knees (kneeling creeping).
34 weeks (GA≤34) is worst than the outcome of infants with GA
greater than 34 weeks (GA> 34), comparisons between treated and
non-treated groups were also done separately for infants GA≤34
and GA> 34 weeks.
3. Results
Tables 1 and 2 describe the characteristics of the treated and
non-treated groups. No significant differences between groups
were observed in the initial findings and diagnosis. All children
showed abnormal findings in the first clinical and MRI examina-
tions, indicating brain damage (see Table 3).
In terms of outcomes, the treated group had a significantly
higher percentage of children with normal neurodevelopment
(18/20) compared to the non-treated group (5/13= 38%; Odds
ratio=2.37, CI 95%= 1.2–4.7; effect size= 0.5, CI 95%= 0.2–0.7;
p< 0.005).
In relation to the children with a gestational age (GA)≤34
weeks, the results were significantly different between groups,
with higher percentage of normal outcomes in the treated
than in the non-treated group (OR =4.45, CI 95% =0.7–26; effect
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T. Harmony et al. / Neuroscience Letters 611 (2016) 59–67 65
Fig.4. Maneuversto crawling. (16)Elementaryassistedcrawling.(17) Modified assistedcrawling.(18) Crawling withlateral support.(19) Crawling legsupport.(20) Crawling
in an ascending plane. (21) Crawling a downward slide. (22) Crawling on stairs.
Fig. 5. Maneuversto walking. (23) Elementary walk. (24) Elementary walkon upward slide.
size = 0.68CI 95% = 0.1–0.9; p=0.017 ; see Tables 4A and B). Fig. 6
shows the MRI of two patients, one of each group.
However, no significant differences were observed between the
groups ininfants with >34weeks of GA. Total IQvalues areshown 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.Thischildwasnot takenintoaccount whenthe mean val-
ues of the subtests or the total IQ were compared between groups.
No significant differences between groups for the total or the IQ
subtests were observed for all the infants and for those subgroups
with GA≤34 orGA> 34.
Interestingly, although all the children of both groups had
abnormal findings 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 (12/20 = 6 0%) showed a nor-
mal MRI (see Fig. 6), the difference between groups was not
significant ( p=0.15). The children of both groups who finished
the study with normal MRI scans also showed significant dif-
ferences in outcome: two of four in the non-treated group
(50%) and twelve of twelve in the treated group (12/12= 100%;
OR= 2, CI 95% = 0.75–5.32; effect size= 0.6CI 95% = 0.07–0.85;
p= 0.05).
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T. Harmony et al. / Neuroscience Letters 611 (2016) 59–67 67
Erika Cruz-Rivero, Antonio Fernández-Bouzas †, Delia Figueroa-
Navarro,JohannaFlores-Arizmendi,Berta González-Frankenberger
†, Verónica Guidobono-Radesca, Rosa M. Hernández-Corona, Clau-
dia Jiménez-Sánchez, Alma Janeth Moreno-Aguirre, Juan José
Ortiz-Reséndiz, Erik Pasayé-Alcaraz, Tonatzin Pineda-Martínez,
Sara Elisa Ponce-Rodríguez, Eneida Porras-Kattz, Amaya Soberón-
García and Angeles Zavala. Authors also acknowledge the
anonymous reviewer for his/her suggestions, Dr. Dorothy Pless for
the revisionof theEnglishversionof the manuscript,andDr. Susana
Szava for the translation to Spanish from Hungarian of Katona’s
book Ontogenesis of the humannervous system.
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