Impact of L-Arginine on Language Skills in Children with Hypoxic

Impact of L-Arginine on Language Skills in Children with

Hypoxic–ischemic Encephalopathy

Address for correspondence: Gokhan Ozer, MD. Sanko Universitesi Tip Fakultesi Noroloji Anabilim Dali, Gaziantep, Turkey

Phone: +90 342 211 53 12 E-mail: [email protected]

Submitted Date: August 19, 2017 Accepted Date: December 22, 2017 Available Online Date: February 05, 2018

ypoxic–ischemic encephalopathy (HIE) has multiple

causes, and its treatment methods have not been fully

established. HIE occurs in 1–8 per 1000 live births in devel-

oped countries. Possible disorders of higher cortical func-

tions can generate an important impact on activities of dai-

ly living. Moreover, language acquisition may be delayed,

and children with HIE may exhibit changes in articulation,

speech, uency, and prosody.

In this condition, several areas of the central nervous sys-

tem are aected, with profound adverse eects on lan-

guage, motor, behavioral, auditory, and visual develop-

ment. Therefore, a multidisciplinary approach is required.

[1]

This study aimed to analyze improvement of language skills

in children diagnosed with HIE through standardized test-

ing, classication of development of skills, and clinical obser-

vations. The Classication of Oral Language Skills proposed

by Bevilacqua et al. was used for this study (Table 1).

[2]

L-Arginine is a basic natural amino acid. Its occurrence in

mammalian protein was discovered by Hedin in 1895.

[3]

L-Ar-

ginine is engaged in several metabolic pathways within the

human body. It serves as a precursor for the synthesis of not

only proteins but also urea, polyamines, proline, glutamate,

creatine, and agmatine.

[4]

L-Arginine is also required for the

synthesis of creatine, an essential energy source for muscle

contraction. Agmatine, which has a clonidine-like action on

blood pressure, is also formed from L-Arginine, although its

Gokhan Ozer

Department of Neurology, Sanko University Faculty of Medicine, Gaziantep, Turkey

Abstract

Objectives: The aim

of this study was to investigate the impact of L-Arginine on speech and language development in

pediatric patients with hypoxic–ischemic encephalopathy (HIE).

Methods: The oral language skills of 24 pediatric patients with HIE using L-Arginine were classied and the impact of

L-Arginine on language skills was evaluated retrospectively. While there is no standard dose of L-Arginine, the usual

dosage is 2.5 g orally for children younger than 5 years of age and 5 g orally for children older than 5 years of age.

Results: The study enrolled 24 pediatric patients with a mean age of 3.9 years (range: 1.25–12 years). A pre-treatment

median rating of 1 for oral language development increased to 3 post treatment, according to the results of a Wilcoxon

signed-rank test used to examine the statistical signicance of the dierence between 2 variables. The dierence was

statistically signicant.

Conclusion: Although the exact pathophysiology of HIE has not been fully elucidated, it is associated with diuse

cerebral damage that leads to impaired motor and language development; moreover, HIE has no cure. In this study,

L-Arginine therapy had a positive and signicant impact on language development in children aected by HIE. Addi-

tional, larger series are needed to confirm these preliminary findings.

Keywords: Hypoxic–ischemic encephalopathy, language skills, L-Arginine

Cite This Article: Ozer G. Impact of L-Arginine on Language Skills in Children with Hypoxic–ischemic Encephalopathy.

EJMO. 2018; 2(2): 70-72

DOI: 10.14744/ejmo.2017.53824

EJMO 2018;2(2):70-72

Research Article

EJMO

physiological function is not yet fully understood. However,

current interest in L-Arginine is focused mainly on its close

relationship with the important signal molecule nitric ox-

ide (NO). L-Arginine is the only substrate in the biosynthe-

sis of NO, which plays a critical role in diverse physiological

processes in the human body including neurotransmission,

vasorelaxation, cytotoxicity, and immunity.

L-Arginine is traditionally classied as a semi-essential or

conditionally essential amino acid; it is essential in children

and non-essential in adults. Homeostasis of plasma L-Argi-

nine concentrations is regulated by dietary arginine intake,

protein turnover, arginine synthesis, and metabolism. This

may explain why, under certain conditions, L-Arginine may

become an essential dietary component.

[4,5]

L-Arginine nor-

mally constitutes approximately 5%–7% of the amino acid

content of a typical healthy adult diet. This accounts to an

average intake of 2.5–5 g/day, which only meets the body’s

minimal requirements for tissue repair, protein synthesis,

and immune cell maintenance.

Very few articles have investigated the eects of L-Arginine

supplementation on CNS function. A previous study has

shown its anti-aging properties and its positive eects on

memory impairment and dementia.

[6]

The role of NO in the long-term potentiation of neuronal

activity. The NO produced diuses back to the presynaptic

neuron, where it enhances the release of glutamate. The

increased glutamate release leads to greater activation of

postsynaptic glutamate receptors, thereby increasing the

eectiveness of that synapse. Plus signs indicate stimula-

tion, and L-arg denotes L-Arginine

[7,8]

Methods

Pediatric patients with established HIE aged 1–12 years

who received L-Arginine therapy were retrospectively eval-

uated by an expert neurologist. L-arginine therapy used as

a supplement by the parents of the patient. The Classica-

tion of Oral Language Skills proposed by Bevilacqua et al.

was used to monitor the language development of study

patients. Patients were included in the study if they had

taken L-Arginine for a minimum of eight weeks. While there

is no standard dose of L-Arginine, the usual dosage is 2.5 g

orally for children less than 5 years of age and 5 g orally for

children older than ve years of age. The classication of

language skills of children was assessed and rated before

and after L-Arginine use by contacting their parents on two

occasions, and the ratings were compared statistically.

Statistical Method

The normality of distribution was tested using Shapiro–

Wilk test for continuous variables. Wilcoxon signed-rank

test was used for comparison of two dependent measure-

ments. Statistical analysis was performed using SPSS for

Windows (version 24.0), and a P-value of <0.05 was consid-

ered statistically signicant.

Results

The study enrolled 24 patients diagnosed with HIE, includ-

ing 18 boys and six girls, with a mean age of 3.98±2.41

years (range, from 15 months to 12 years). Using Wilcoxon

signed-rank test, the pre-treatment median rating of the

Classication of Language Skills was found to be 1 and the

post-treatment median rating was found to be 3 (Table 2),

with a statistically signicant dierence (p=0.001).

Experiments in animals also suggested that NO is involved

in memory, because inhibiting NO synthesis in vivo impairs

learning behavior.

[9]

In 16 elderly patients with senile de-

mentia, L-Arginine (1.6 g/day) has been found to be eec-

tive in reducing lipid peroxidation and increasing cognitive

function.

[10]

In their recent report, Ohtsuka et al. explored

the possible role of L-Arginine in Alzheimer’s disease, tak-

ing into consideration known functions of L-Arginine in

atherosclerosis, redox stress and the inammatory process,

regulation of synaptic plasticity and neurogenesis, and

modulation of glucose metabolism and insulin activity.

[11,12]

L-Arginine is commercially available in several countries in

variable dosage forms and mostly indicated as a nutrition-

al supplement. It is available as capsules, tablets, powder,

eervescent granules, injection, infusion, and cream, with

a very wide range of doses. Studies have shown that L-Ar-

ginine, through its versatile metabolic and physiological

Table 1. Classication of oral language skills proposed by

Bevilacqua et al. (1996)

Classication Language development

1 Does not speak, only produces undierentiated

vocalizations

2 Speaks only isolated words

3 Construct simple sentences, with two or three

words

4 Constructs sentences with four or ve words

5 Child is uent in oral language

Table 2. Pre-treatment and post-treatment median ratings by

the classication of language skills tool

Variable Pre-treatment Post-treatment P†

Classication of 1[1-1] 3[2-5] 0.001*

language skills

‡

*Signicant at 0.05 level

†

Wilcoxon Signed-Rank Test

‡

Median [25%-75%]

Ozer et al., Impact of L-Arginine on Language Skills / doi: 10.14744/ejmo.2017.53824

pathways, can improve many body functions. To summa-

rize some of its eects, L-Arginine is involved in the pro-

duction of a variety of enzymes, hormones, and structural

proteins. Arginine has a positive eect on cerebral as well

as systemic circulation.

Conclusion

In this study, the positive eects of L-Arginine on language

development were demonstrated in children with HIE. A

limitation of the study was the reliance on a single classi-

cation system for assessment of the patients. However, it

should be noted that feedback obtained from the parents

and caregivers of the patients was signicantly more in-

forming and promising than the study’s statistical ndings.

In light of our study data and clinical observations, it is clear

that L-Arginine is associated with a positive and signicant

impact not only in language domain but also in sensory,

motor, and visual domains. Therefore, further studies on

larger series are needed to establish the benets of L-Argi-

nine in these patients.

Disclosures

Ethics Committee Approval: The study was approved by the

Local Ethics Committee.

Peer-review: Externally peer-reviewed.

Conict of Interest: None declared.

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