EVIDENCE-BASED CASE REPORT

PYRIDOXINE OR MAGNESIUM SUPPLEMENTATION IN

CHILDREN WITH AUTISTIC SPECTRUM DISORDERS

Written by:
Sekarpramita D 0606138991

Supervised by:
dr. Tjhin Wiguna, SpKJ (K)

Child and Adolescent Psychiatry Division

Department of Psychiatry
Cipto Mangunkusumo National Referral Hospital
Faculty of Medicine University of Indonesia
April 2012
 ACKNOWLEDGEMENT

This report is submitted by:

Name : Sekarpramita D.

Student number : 0606138991

Study program : Medical Profession Education Program

Title of manuscript : Pyridoxine or magnesium supplementation in children

with autistic spectrum disorders

This manuscript is submitted as an evidence-based case report for Psychiatry

Department, Faculty of Medicine University of Indonesia and has been approved by

Supervisor : Dr. dr. Tjhin Wiguna, SpKJ (K)

Date : 30 April 2012

Signature :

1
 STATEMENT OF ORIGINALITY

I hereby declare that this submission is my own work and to the best of my knowledge it
contains no materials previously published or written by another person, or substantial
proportions of material which have been accepted for the award of any other degree or
diploma at University of Indonesia or any other educational institution, except where due
acknowledgement is made in the thesis. Any contribution made by others is explicitly
acknowledged in the thesis.

If in the ensuing date, I was proven to conduct a plagiarism, I will take full responsibility
and penalty as ratified by University of Indonesia to me.

Jakarta, 30 April 2012

Sekarpramita D.
0606138991

2
 TABLE OF CONTENT

Acknowledgement.............................................................................................................. 1
Statement of originality....................................................................................................... 2
Table of content.................................................................................................................. 3
List of abbreviation............................................................................................................. 4
Abstract............................................................................................................................... 5
Case illustration.................................................................................................................. 6
Introduction......................................................................................................................... 7
Clinical question................................................................................................................. 9
Methodology....................................................................................................................... 9
Results............................................................................................................................... 11
Critical appraisal for Tolbert et al (1993)..........................................................................12
Critical appraisal for Findling et al (1997)........................................................................14
Critical appraisal for Kuriyama et al (2002)......................................................................16
Discussion......................................................................................................................... 18
Conclusion........................................................................................................................ 23
Recommendations............................................................................................................. 23
Bibliographies................................................................................................................... 24
Appendices.........................................................................................................................26

3
 LIST OF ABBREVIATIONS

ARR Absolute Risk Reduction

ASD Autistic Spectrum Disorders
CAM Complementary and Alternative Medicine
CARS Childhood Autism Rating Scale
CGI Clinical Global Impression
CI Confidence Interval
CPRS Children’s Psychiatric Rating Scale
EEG Electroencephalogram
HDPM High Doses of Pyridoxine and Magnesium
IQ Intelligent Quotient
IRM Instalasi Rehabilitasi Medik
Mg Magnesium
NNT Number Needed to Treat
OCS Obsessive-Compulsive Symptoms
PDD Pervasive Developmental Disorders
PPD-NOS Pervasive Developmental Disorders – Not Otherwise Specified
RCT Randomized Controlled Trial
RF Rivto-Freeman Real-Life Rating Scale for Autism.
RR Relative Risk
RRR Relative Risk Reduction
RSCM Rumah Sakit Cipto Mangunkusumo
SD Standard Deviation
SQ Social Quotient

4
 Pyridoxine and magnesium supplementation in children with
autistic spectrum disorders
Sekarpramita D*, Tjhin Wiguna‡
* Faculty of Medicine University of Indonesia
‡ Faculty of Medicine University of Indonesia, Department of Psychiatry

Background: Pyridoxine or vitamin B6 is commonly prescribed empirically as an

adjunctive treatment in children with autistic spectrum disorders with little awareness of
the physician regarding the efficacy and safety of the supplementation.

Aim: To answer the clinical questions whether combination of pyridoxine/Mg

supplementation is superior to placebo for controlling core symptoms in autistic children
and to assess the efficacy of pyridoxine supplementation in children with autistic
spectrum disorders.

Methods: A systematic search of Cochrane, EMBASE, PubMed, and PsycINFO

database. After screening with inclusion and exclusion criteria and conducting a critical
appraisal on the articles, we found three articles, which were significantly appropriate to
answer the clinical question.

Result: Three randomized double-blinded placebo-controlled trials are identified as

qualified to answer the clinical question. These three journal articles studied different
population using different dosage, administration time, and outcome measures. However,
these journal articles reported a consistent result that pyridoxine is not beneficial to
improve neurodevelopment disorders in autistic spectrum disorders children. Pyridoxine
is reported to have minimal, if none, side effect.

Conclusion: Pyridoxine supplementation has no significant beneficial effects on autistic

spectrum disorders main domains (social, communication, and behavioral responses)
when compared with its placebo/no treatment group counterparts.

Keywords: pyridoxine, vitamin B6, autism, ASD, pervasive developmental disorders

5
CASE ILLUSTRATION

A 7-year old boy with autistic specturm disorder accompanied by her mother
came for a routine control at the Child and Adolescent Psychiatry Policlinic. Two years
ago, his mother realized that he could not behave calmly, frequently got temper tantrum,
and easily got upset and uneasy. He also could not communicate verbally or non-verbally.
The was no significant eye contact, and he did not follow simple instructions. He
repeatedly talked “ti-ti” or “bi-bi” without any meanings. However, there was not any
self-destructive behavior nor any attempt to harm other people. He was taken to IRM
RSCM to have speech and occupational therapy.

Two months ago, a therapist in IRM RSCM told his mother that the patient is
diagnosed as autistic spectrum disorder and could not be helped only with the speech and
occupational therapy only. He also needed a medication for reducing his autistic
behavior.

Currently, he cannot express his communication verbally and is quite difficult in

expressing his needs by using a non-verbal behavior. Although he is getting better at
maintaining his eye contact, but he is still reported to have few friends at his school, have
no social reciprocity and lack of social judgment. Additionally, he also shows a
stereotyped, repetitive, or idiosyncratic language. He did not show any response when
another child asked him to play together. During examination, he kept on interested in the
washing bin, walked around the examination room, and even climbed up the chair.
According to his mother, he likes to flap his fingers every time he feels extremely happy
or extremely upset. He was given Risperidone 2x0.5 mg and pyridoxine 2x5 mg.

6
INTRODUCTION

Autism is defined as a neurodevelopmental disorder, characterized by social

withdrawal, communication deficits, and repetitive behaviors. The disease has variable
cognitive manifestations, ranging from a non-verbal child with mental retardation to a
high-functioning college student with above average IQ with inadequate social skills. 1, 2 It
predominantly occurs in males (male:female ratio = 4:1).2

Clinical signs (Figure 1) are usually

present by age 3 years, but typical language
development might delay identification of
symptoms.3 Other behavior problems, eg.
self-harmed, aggressiveness, hyperactivity,
and irritable emotion are also reported in
children with autistic spectrum disorder.4

No definite cause of autism has

Figure 1. Core domains of autism. Taken from: Levy SE,
Mandell DS, Schultz RT. Autism. Lancet. 2009;
374:1627-38.
been identified to date. Herbert et al (2006)
hypothesized that genetic factors alone
likely cannot account for an epidemic
within a short period of ~20 years.5 Hence,
possible causes and risk factors being
researched are includes genetics, epigenetic
(physical environment, psychological expe-
riences, and immune system), nutritional,
and environmental factors.2, 3

ASD has a wide range of therapeutic approaches. Psychosocial approach is as

described at Figure 2 below. Existing pharmacotherapeutic agents are not effective for
treatment of core symptoms of ASD. However, several medications are reported having a
helpful in improving socialization, communication, and behavior deficit, are including
atypical antipsychotics (eg. risperidone and aripiprazole), methylphenidate, and SSRIs.3

Complementary and alternative medicine (CAM) is widely used by families of

children with autism spectrum disorders. CAM has been defined as “a broad domain of
healing resources that encompasses all health systems, modalities, and practices and their

7
accompanying theories and beliefs, other than those intrinsic to the politically dominant
health system of a particular society or culture in a given historic period”.6

The administration of pyridoxine as

CAM for ASD was first reported by
Bonish (1968). He stated there is
improvements in speech and language in
some children with ASD.7 Combining
pyridoxine with Magnesium (B6/Mg)
lessened some adverse effects when only
pyridoxine is given, including peripheral
neuropathy,8 enuresis, irritability, and
sensitivity to sound, and led to additional
improvements.9 This is perhaps because
magnesium acts on dopamine storage.
Martineau et al (1988) and suggested to
administer pyridoxine at pharmacological
doses of 30 mg/kg/day with supplemental
magnesium (10 mg/kg/day) for 2 months.10
However, inconsistent results have been
reported.11

Figure 2. Examples of treatments for core symptoms of

autism spectrum disorder. Taken from: Levy SE, Mandell
DS, Schultz RT. Autism. Lancet. 2009; 374:1627-38.

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CLINICAL QUESTIONS

“Is combination of pyridoxine/Mg supplementation is superior than placebo for

controlling social, communication, and behavioral responses in ASD children?”
Patient : children with ASD (age 0-18 year old)
Intervention : pyridoxine or pyridoxine/Mg supplementation
Comparison : placebo or no treatment
Outcome : social, communication, and behavioral responses

METHODOLOGY

Search and selection strategy

The “Cochrane”, “EMBASE”, “PubMed”, “PsycINFO” database was searched on
9-17 April 2012 for all journal articles related with the comparison of pyridoxine/Mg and
placebo in improving social, communication, and behavioral responses for children with
autism. Searches were limited to humans (children 0-18 years) as subjects (Table 1). Year
of publication is not limited. Details on the search process were further shown in the
flowchart (Figure 3).

Table 1: Search strategy

Database Search strategy (9-17 April 2012) Hits Selected

(“Autis*” OR “child pervasive development disorders” OR
“speech disorders” OR “language delay” OR “PDD”) AND
Cochrane 643 1
(“vitamin B6” OR “pyridoxine” OR “magnesium” OR
“vitamin B complex” OR “vitamin B”)
(“Autis*” OR “child pervasive development disorders” OR
“speech disorders” OR “language delay” OR “PDD”) AND
EMBASE 368 1
(“vitamin B6” OR “pyridoxine” OR “magnesium” OR
“vitamin B complex” OR “vitamin B”)
(“Autis*” OR “child pervasive development disorders” OR
“speech disorders” OR “language delay” OR “PDD”) AND
PubMed 241 1
(“vitamin B6” OR “pyridoxine” OR “magnesium” OR
“vitamin B complex” OR “vitamin B”)
(“Autis*” OR “child pervasive development disorders” OR
“speech disorders” OR “language delay” OR “PDD”) AND
PsycINFO 209 0
(“vitamin B6” OR “pyridoxine” OR “magnesium” OR
“vitamin B complex” OR “vitamin B”)

9
Figure 3: Flowchart of the searching and selection strategy

“Autis*” OR “child pervasive development A “Vitamin B6” OR “pyridoxine” OR PsycINFO

EMBASE
Cochrane
PubMed
disorders” OR “speech disorders” OR N “magnesium” OR “vitamin B complex”
“language delay” OR “PDD”
368
209
643
241
D OR “vitamin B”

Limits to: Humans

Exclusion criteria:
Inclusion criteria:
- Inappropriate
Full text is available
topic
- Non-data
Age: 0 to based
18 yearpapers
old (eg. reviews,
- Diagnosed as PDDetc)
topic discussions, or ASD
Screening title / abstract, useful articles:
- Randomized controlled trial design

EMBASE PubMed PsycINFO

Cochrane 10
EMBASE 5
PubMed 8
Cochrane EMBASE PubMed
2 1 2
1 1 1 Cochrane
Excluding doubles, useful articles:
Reading full-text, useful articles: 12

PsycINFO
0

PsycINFO
0

10
RESULTS

Tolbert (1993)12 Findling (1997)13 Kuriyama (2002)14

Research questions To assess the safety and efficacy To assess the short-term safety and To assess the effectiveness of pyridoxine in
of the study of low-dose pyridoxine/Mg efficacy of pyridoxine/Mg improving IQ and SQ scores in PDD children.
Randomized, double-blind controlled,
Randomized, double-blind con- Randomized, double-blind controlled,
Study design cross-over trial; outcome assessor and statistician
trolled, asymmetric cross-over trial cross-over trial
also blinded
12 participants; age: 3–12.9 yrs old
Participants 20 participants; age 6–18 yrs old. 8 PDD participants; age 6–17 yrs old
- 10 completed the program
1. B6/Mg (20 wks)  placebo
(10 wks) 1.B6 1x100 mg (2 wks)  B6 2x100 mg (2 wks)
1. B6/Mg (4 wks)  placebo (4 wks)
Interventions 2. B6/Mg (10 wks)  placebo 2.Placebo 1x1 (2 wks)  placebo 2x1 (2 wks)
2. Placebo (4 wks)  B6/Mg (4 wks)
(10 wks)  B6/Mg (10 wks) 3.Parent’s diary
3. Control  receive nothing.
Pyridoxine 200 mg/70 kg/day 30 mg/kg/day (max: 1 gram/day) 1x100 mg/day followed with 2x100 mg/day
Magnesium 100 mg/70 kg/day 10 mg/kg/day (max: 350 mg/day) -----
Performance on CARS, CGI, CPRS, IQ (Wechsler Intelligence Scales for Children-
Outcome Scores on Rivto-Freeman Real- III) test 9.
OCS, Conners teacher, and Conners
measurements Life Rating Scale for Autism.
parent scale SQ scores (Social Maturity Scale test).
Low dose pyridoxine/Mg is Pyridoxine/Mg is ineffective as autistic No significant increase of total IQ, verbal IQ,
Results
ineffective in ASD; safety unclear. disorder treatment; safe for short-term. performance IQ and SQ scores.
Length of follow up 35 weeks 10 week 4 week
Loss of follow up None 16.67% does not complete the program None
Risk of bias: Unclear; Reported data not in
Allocation useable form for analysis, control Unclear Unclear
concealment group not randomly assigned.

11
Critical appraisal for Tolbert et al (1993)12
Validity
Are the results of this therapeutic trial valid?
Tolbert et al
(1993)12
Was the assignment of patients to treatments randomised?
Yes; unclear concealment
Was the randomisation list concealed?
Was follow-up of patients sufficiently long and complete? Yes
Were all patients analysed in the groups to which they were
Yes
randomised?
Were patients and clinicians kept “blind” to treatment? Yes
Were the groups treated equally, apart from the
Yes
experimental treatment?
Were the groups similar at the start of the trial? Yes

Validity Valid

Tolbert et al (1993) described and randomized their treatment assignment (control

group, group 1, and group 2). However, it is not stated in their report of the details of the
randomizing process. Participants of the groups do not have any significant differences.
Total participants sample is 20 people (15 male and 5 females) with chronological ages
ranging from 6 to 18 years, mental ages ranging from 2.0 to 6.7 years and IQ scores from
less than 20 to 65. Participants are followed up sufficiently long and complete (35
weeks), analyzed in the groups they belonged to, and were treated equally apart from the
experimental treatment. Participants and clinicians are kept blinded to treatment.12

Importance
Are these randomised trial important?

The importance of this journal article is cannot be assessed as the data given is not
sufficient to count the RR, ARR, RRR, and NNT (using appraisal sheet from Centre of
Evidence Based Medicine University of Oxford15); nor using pooled SD and effect size
(using appraisal sheet from Critical Appraisal Worksheet from Dartmouth College:
Therapy study with continuous outcome calculations16).

Applicability
Can you apply this evidence about therapy in caring for your patient?

12
 Do these results apply to your patient?
Is your patient so different from those in the study that its results
cannot apply? No

Is the treatment feasible in your setting?

What are your patient’s potential benefits and harms from the therapy?
Tolbert et al reported that significant reduction of RF scores in all treatment phases in
all group. However, effects on treatments (control, group 1, and group 2 treatment
groups) were reported of no different. Hence, participants may not be benefited from
the therapy and only cause additional unnecessary cost for the therapy for the patient.
Tolbert et al reported no adverse effect observed in any of the participants studied.12
In addition, Tolbert et al also stated that they did not necessarily contradict other
studies as they used much lower doses of pyridoxine/Mg.12

Are your patient’s values and preferences satisfied by the regimen and its
consequences?
Do your patient and you have a clear assessment of their values Have not been
and preferences? assessed
Have not been
Are they met by this regimen and its consequences?
assessed

Applicability analysis of this article reveals that it cannot be applied to the patient
although the sample characteristic of the study is similar with the patient’s condition and
related with the clinical question asked. Additionally, Tolbert et al also reported no
benefits and no harm is gained from administering low doses of pyridoxine/Mg therapy. 12
Values and preferences of the patient have not been assessed. Hence, applicability in this
patient is still questionable.

13
Critical appraisal for Findling et al (1997)13
Validity
Are the results of this therapeutic trial valid?
Findling et al
(1997)13
Was the assignment of patients to treatments randomised?
Yes; unclear concealment
Was the randomisation list concealed?
Was follow-up of patients sufficiently long and complete? Yes
Were all patients analysed in the groups to which they were
Yes
randomised?
Were patients and clinicians kept “blind” to treatment? Yes
Were the groups treated equally, apart from the
Yes
experimental treatment?
Were the groups similar at the start of the trial? Yes

Validity Valid

Findling et al (1997) described and randomized their treatment assignment

(control group and HDPM). However, it is not stated in their report of the details of the
randomizing process. Participants of the groups do not have any significant differences.
Total participants sample is 12 people (11 male and 1 females) with chronological ages
ranging from 3 to 12.9 years). Two participants withdraw from the study. Participants are
followed up sufficiently long and complete (10 weeks), analyzed in the groups they
belonged to, and were treated equally apart from the experimental treatment. Participants
and clinicians are kept blinded to treatment.13

Importance

Mean (SD) Mean (SD) Mean

Comparison 95% CI
pyridoxine placebo difference
CPRS 32.0 (7.1) 31.2 (7.8) 0.80 ?
CGI 5.7 (0.9) 5.6 (1.0) 0.10 -1.08 – 1.28
OCS 8.7 (3.6) 6.4 (3.2) 2.30 -6.52 – 1.92
Conners teacher 8.8 (6.0) 9.4 (5.0) 0.60 -6.25 – 7.45
Conners parent 5.3 (3.3) 5.0 (2.4) 0.30 -3.88 – 3.28

The importance of this journal article is cannot be assessed as the data given is not
sufficient to count the RR, ARR, RRR, and NNT (using appraisal sheet from Centre of

14
Evidence Based Medicine University of Oxford15). Hence, it is assessed using appraisal
sheet from Critical Appraisal Worksheet from Dartmouth College: Therapy study with
continuous outcome calculations16.

An intervention review by Nye and Brice (2009)11 provided the necessary mean
difference and 95% CI of the study. These two studies found the study showed no
significant results for CPRS, CGI, OCS, Conners teacher, and Conners parent scores.
Hence, pyridoxine statistically showed no beneficial effect on improving behavioral
deficits in ASD children. Another disadvantage of Findling studies is 25% of Conners
teacher and 16.7% of Conners parent questionnaires are not completed.13

Applicability
Can you apply this evidence about therapy in caring for your patient?

Do these results apply to your patient?

Is your patient so different from those in the study that its results
No
cannot apply?

Is the treatment feasible in your setting?

What are your patient’s potential benefits and harms from the therapy?
No potential benefit of pyridoxine/Mg compared to placebo is reported in the study. No
significant difference in CARS, CGI, CPRS, OCS, Conners teacher or Conners parent
scale scores. Adverse effects stated include loose stool and symptoms of upper
respiratory infection during pyridoxine administration.13

Are your patient’s values and preferences satisfied by the regimen and its
consequences?
Do your patient and you have a clear assessment of their values Have not been
and preferences? assessed
Have not been
Are they met by this regimen and its consequences?
assessed

Applicability analysis of this article reveals that it can be applied to the patient,
however have no beneficial effect. The sample characteristic of the study is similar with
the patient’s condition and related with the clinical question asked. However, since the
study reported no beneficial effect on scales, which are studied, with additional mild
adverse effect, application of pyridoxine to our patient shall be considered. Additionally,
patient’s value and preferences have not been assessed yet.

15
Critical appraisal for Kuriyama et al (2002)14
Validity
Are the results of this therapeutic trial valid?
Kuriyama (2002)14
Was the assignment of patients to treatments randomised?
Yes; unclear concealment
Was the randomisation list concealed?
Was follow-up of patients sufficiently long and complete? Unclear
Were all patients analysed in the groups to which they were
Yes
randomised?
Were patients and clinicians kept “blind” to treatment? Yes
Were the groups treated equally, apart from the
Yes
experimental treatment?
Were the groups similar at the start of the trial? Yes

Validity Unclear

Kuriyama et al (2002) described and randomized their treatment assignment

(control group and pyridoxine group). However, it is not stated in their report of the
details of the randomizing process. Participants of the groups do not have any significant
differences. There are a total of 8 participants (4 males and 4 females) with chronological
ages ranging from 6 to 12 year. Exclusion criteria included history of epilepsy or
epileptiform EEG at examination to exclude children with late-onset or atypical
pyridoxine dependent epilepsy; use of a psychotropic agent or vitamin supplement within
3 months of the start of the study; inability to measure IQ scores; image abnormalities in
the brain on MRI; or history of homocystinuria or fragile X syndrome. Participants are
followed up within a short term (4 weeks), analyzed in the groups they belonged to, and
were treated equally apart from the experimental treatment. Participants and clinicians are
kept blinded to treatment.14

Importance
Mean (SD) Mean (SD) Mean
Comparison 95% CI
pyridoxine placebo difference
Total IQ 82.75 (23.67) 77.5 (10.5) 5.25 -20.13 – 30.63
Verbal IQ 85.5 (17.56) 83.5 (10.83) 2.00 -18.22 – 22.22
Performance IQ 73.5 (17.56) 80.25 (10.59) -6.75 -26.85 – 13.35
Social quotient 80.5 (14.5) 93 (11.02) -12.50 -30.35 – 5.35

16
 The importance of this journal article is cannot be assessed as the data given is not
sufficient to count the RR, ARR, RRR, and NNT (using appraisal sheet from Centre of
Evidence Based Medicine University of Oxford15). Hence, it is assessed using appraisal
sheet from Critical Appraisal Worksheet from Dartmouth College: Therapy study with
continuous outcome calculations16.

Kuriyama et al (2002) did not report the details on their research, 14 however an
intervention review by Nye and Brice (2009)11 is conducted and provided Kuriyama’s
study data. From these data, it is found that the study showed no significant results for
total IQ, verbal IQ, performance IQ, or social quotient scores. Hence, pyridoxine
statistically showed no beneficial effect on IQ or SQ compared with placebo.

Applicability

Can you apply this evidence about therapy in caring for your patient?

Do these results apply to your patient?

Is your patient so different from those in the study that its results cannot apply?
Quite different. The patient is autistic, not Asperger’s syndrome or PDD-NOS as
Kuriyama’s study participants.

Is the treatment feasible in your setting?

What are your patient’s potential benefits and harms from the therapy?
Kuriyama et al showed no beneficial effect of pyridoxine on IQ or SQ score compared
with placebo group. Kuriyama also reported no adverse effect observed in any of the
PDD participants studied.14

Are your patient’s values and preferences satisfied by the regimen and its
consequences?
Do your patient and you have a clear assessment of their values Have not been
and preferences? assessed
Have not been
Are they met by this regimen and its consequences?
assessed

Applicability analysis of this article reveals that it cannot be applied to the patient
as it does not match our patient characteristics; is not feasible; and values and preferences
of the patients have not been assessed yet.

17
DISCUSSION

The patient showed the characteristic of autistic spectrum disorders such as social
withdrawal; communication deficits; and repetitive behaviors. Behavioral problems in
autism, such as stereotype repetitive mannerism; self-harmed; aggressiveness;
hyperactivity; and prolonged tantrum, are strongly associated with neurotransmitter
imbalances in brain, especially in structures which control social, communication, and
motoric function such as amygdala, prefrontal lobus, and other limbic system.3

Figure 3. Prefrontal–limbic system circuitry important in mood disorders. BD, bipolar disorder; CBF, cerebral blood
flow; HPA, hypothalamic–pituitary–adrenal axis; MDD, major depressive disorder. Taken from:
http://www.sciencedirect.com/science/article/pii/S0166223611001962

Researchers in Yale University are using MRI to reveal what structures of the
brain are involved in autism as well as what circuits light up when an autistic person
performs some task.17 Their findings are summarized below:

18
Table 2. Differences between healthy control brain and autism brain. 17

Healthy brain Autism brain

Size and weight Average Larger and heavier
Fusiform face area, involved in social
Lights up Impaired
knowledge; activated when processing faces
Amygdala, the emotion center; activated
Active; the pathways Less active; the
when viewing images of emotional faces or
lights up pathways remain dark
reading facial expressions
Prefrontal cortex, play a role in empathizing
behavior; activated when figuring out what Active Less active
other people are thinking or feeling
Superior temporal sulcus; activated when a
Pathway may be
person tries to understand what’s going on in Lights up
missing or incomplete
the mind of another

Figure 4. Healthy control vs. Autism fusiform face area activation. Taken from: http://whyfiles.org/209autism/4.html

Biomedically, autism is hypo-

thesized to have a link with elevation of
catecholamines pathways neurotrans-
mitter, such as dopamine, epinephrine, and
norepinephrine. Excitatory neurotrans-
mitters, such as glutamate, PEA, and
histamine also increase. However,
serotonin in autistic children is commonly
Figure 5. Dopaminergic and serotoninergic pathways.
Taken from: http://www.sciencedirect.com/science/ article/ found to be lower than normal level.18, 19
pii/S000991200800372X

19
 Considering the hypotheses that behavioral problems in children with autism
spectrum disorder are highly associated with the neurotransmitter imbalances,
psychotropic medications (eg. atypical antipsychotics, SSRIs, and psychostimulants)
which works on dopamine and serotonin receptors are empirically administered. The
administrations of these medication showed an observable suppression of core symptoms
and behavior problems in autistic spectrum disorder children, hence they can perform
optimally.4 Additionally, children who are given psychotropic have a high response rate
for approximately 48-56% proven to be beneficial for the autistic children.4

Aside from the vast use of psychotropic medication in autism, several authors
also stated many novel, unconventional and off-label treatments for ASD (Figure 6).
However, up to 74% of children with ASD using these treatments and the treating
physicians are often not aware of this usage.20

Figure 6. Summary of treatments leading to improvements in certain autistic behaviors.

Taken from: Rossignol DA. Novel and emerging treatment for autism spectrum disorders: a
systematic review. Annals of Clinical Psychiatry. 2009;21(4):213-36.

20
 Many authors stated that pyridoxine is involved in the formation of several
neurotransmitters, including serotonin, γ-aminobutyric acid, dopamine, norepinephrine,
and epinephrine.21 Additionally, several studies also pointed that infantile autism is
associated with pyridoxine deficiency, low serum magnesium, elevated serum zinc, but
no difference in copper serum levels. Hence, it is hypothesized that autism is caused by
excess of aluminum, zinc, or copper. These toxic elements would be removed by
supplemental magnesium treatment; pyridoxine acting as a cofactor with zinc especially
would protect against excessive copper augmentation.22

Based on these hypotheses, pyridoxine is frequently prescribed empirically, as in

our patient. However, after screening with inclusion and exclusion criteria and
conducting a critical appraisal on three randomized double-blinded placebo-controlled
trials, we found that pyridoxine supplementation has no significant beneficial effect for
children with autism or pervasive developmental disorders.

In terms of safety issues, pyridoxine is often reported to may cause peripheral

neuropathy (eg. numbness or tingling, weakness, feelings of burning, tickling, or pricking
in the distal extremities); uncoordinated movements; breathing difficulties; fatigue, and
vomiting when administer in high dose (more than 200 mg/day for adults) and in
prolonged time.8, 23 Another adverse effects, which are commonly reported are enuresis,
irritability, and sensitivity to sound.9

Pfeiffer et al (1995) reviewed 12 studies about the usage of pyridoxine/Mg when

compared to placebo group conducted from 1980 to 1989. It is not limited to randomized,
double-blinded, placebo-controlled trial. Their review suggests that pyridoxine/Mg
treatment may be an adjunctive treatment in autism.21 However, a newer review by
Rossignol et al (2009) graded pyridoxine/Mg as grade C treatment. Rossignol et al (2009)
also describes the recommended adjunctive treatment for autism spectrum disorders as
follows:20

 Grade A (supported by at least 2 prospective RCTs or 1 systematic review):

melatonin, acetylcholinesterase inhibitors, naltrexone, and music therapy;
 Grade B (supported by at least 1 prospective RCT or 2 non-RCT): carnitine,
tetrahydrobiopterin, vitamin C, alpha-2 adrenergic agonists, hyperbaric oxygen
treatment, immunomodulation and anti-inflammatory treatments, oxytocin, and vision
therapy; and

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 Grade C (supported by at least 1 non-RCT or 2 case series): carnosine,
multivitamin/mineral complex, piracetam, polyunsaturated fatty acids,
pyridoxine/Mg, elimination diets, chelation, cyroheptadine, famotidine, glutamate
antagonists, acupuncture, auditory integration training, massage, and neurofeedback.

Considering the efficacy and safety of pyridoxine; Rossignol et al (2009)

systematic review; and availability, feasibility, and cost-effectiveness of the
supplementations reviewed, vitamin C may be a better adjunctive treatment for
Risperidone in autistic spectrum disorder children compared to pyridoxine/Mg
supplementation in administration of pulverized medication.

Several case reports of scurvy in children with autism have been reported. 24-28
Dolske et al (1993) also carried out a randomized double-blinded placebo-controlled
crossover study of vitamin C (8 g/70 kgBW/day) in 500 mg tables, divided into 2-3
separate doses in 18 children with ASD. The study reported significant improvements in
stereotypical behaviors, including rocking, pacing, and whirling without any adverse
effect were noted.29 No study is found regarding the drug interaction between vitamin C
and risperidone or aripiprazole, as the FDA-approved medication for autism spectrum
disorder.

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CONCLUSION
Pyridoxine/Mg supplementation has no significant beneficial effects on autistic spectrum
disorders main domains (social, communication, and behavioral responses) when
compared with its placebo/no treatment group counterparts.

RECOMMENDATIONS
Recommendations for the patient and the family:
 Education psychotherapy for patient and family
 Continue medical rehabilitation: music therapy, vision therapy, integrated sensory
stimulation, occupational therapy, speech therapy.
Recommendations for the medical clinical field:
 Change the empirical prescription of pyridoxine as adjunctive therapy of
Risperidone in children with autism spectrum disorders into vitamin C.
 Recommend patient and the family to undergone music therapy and vision
therapy.
Recommendations for the medical research field:
 Further studies regarding vitamin C supplementation and autism is recommended;
 Further studies regarding the superiority of vitamin C compared to pyridoxine/Mg
as an adjunctive therapy in ASD; and
 Further studies to assess the drug interaction between psychotropic medications
and vitamin C.

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BIBLIOGRAPHIES

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