EAL

NNNS: Adverse Effects (2011)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To investigate the validity of reports of seizures resulting from aspartame consumption, we conducted a randomized, double-blind, placebo-controlled cross-over study in 18 individuals who had experienced seizures reportedly related to aspartame consumption.

Inclusion Criteria:

Experienced an epileptic seizure, reportedly due to aspartame
Seizure must have occurred within 24 hours of ingestion of an aspartame product
Age range for children: 14 to 17 years; no age limit for adults
Those treated with anti-epileptic drugs were required to have received a stable regimen for at least 30 days before study entry.

Exclusion Criteria:

Subjects with phenylketonuria (PKU)
Had consumed aspartame products or who had clinical seizures less up to seven days before the start of the study
Serious medical or progressive neurologic diseases.

Description of Study Protocol:

Recruitment

From 1986 to 1990, 159 recruitment letters were sent to individuals who had become known to the FDA, CDC or the NutraSweet Company and who claimed to have experienced seizures after consuming aspartame or who had come to our attention as a result of our canvassing of 8,760 adult and pediatric neurologists by letter
Advertisements were placed in two neurologic journals, requesting neurologists identification of such individuals. Recruitment continued for five years.
Participants signed informed consent that was approved by the institutional review board.

Design

Five days of continuous EEG recording were performed by a seven-channel ambulatory cassette EEG recording
AEDs and other medications were administered according to the subject’s usual schedule
Continuous closed circuit television (CCTV) monitoring of adult subjects was used during the day to record behavior. At night, cassette recording without CCTV was used. Subjects remained in the monitoring room at all times except when permitted to make a telephone call or take an evening walk, accompanied by study personnel.
Treatment days: Subjects received either aspartame or identically packaged placebo (microcrystalline cellulose) capsules according to a computer generated random assignment
Aspartame was administered in capsules of 300mg in a 50mg per kg dose. The total dose was divided into three equal doses administered at 8:00 a.m., 10:00 a.m. and 12:00 p.m. the 8:00 and 12:00 doses were administered with standard meals and the 10:00 dose was administered with eight ounces of water.
Identical food intake was required on the two treatment days. Subjects were required to sip a small amount of sweet juice before taking the capsules to mask any residual sweetness that might adhere to the capsule surface.

Study Day Test and Procedure

Pre-admission: Medical history, physical examination, neurologic examination, adverse experience questionnaire, drug history, routine hematology, routine blood chemistries, urinalysis, plasma amino acids, standard EEG, AED, antiepileptic drugs concentrations, CT scan, computed tomography (if not done within six months of study)
Day One: Admission
Day Two: Baseline I; plasma amino acids (7:45 a.m.), AED concentrations (7:45 a.m.), contnuous 24-hour EEG telemetry
Day Three: Treatment I, plasma amino acids (7:45 a.m. and 11:45 a.m.), AED concentrations (7:45 a.m.), continuous 24-hour EEG telemetry, test article administration (8:00 a.m., 10:00 a.m. and 12:00 p.m.)
Day Four: Baseline II; same as Day Two
Day Five: Treatment II; crossover with treatment, same schedule as Day Three
Day Six: Baseline III, same as Day Two, plus physical examination, neurologic examination, routine hematology, routine blood chemistries, urinalysis.

Blinding Used

Patients blinded to treatment vs. placebo.

Statistical Analysis

McNema’s test was used for incidence variables
Amino acid data were assessed by analysis of variance appropriate to a two-period crossover study.

Data Collection Summary:

AED levels determined by homologous enzyme immunoassay (EMIT). Amino acid profiles were determined from whole blood collected in sodium heparin and analyzed with a Beckman amino acid analyzer.
The five cassettes from each subject, representing five days of continuous EEG monitoring, were randomized by the study coordinator and identified by the numbers one through five. EEGs were quantified for the presence of epileptiform discharges (ED), defined as spikes, sharp waves and spike-wave or polyspike-wave complexes. Discrete discharges were enumerated for each 16-second epoch and totals were tabulated for each hour of recording.

Description of Actual Data Sample:

Initial N

18 subjects; 16 adults and two children
36 individuals were screened to determine eligibility: 29 of the 36 potential subjects were judged eligible; seven did not meet the protocol criteria
18 agreed to participate, the remainder declined for personal reasons.

Age

Two children 10 and 15 years of age, 16 adults 20 to 70 years of age (mean 35 years).

Other Relevant Demographics

Resided in 15 states.

Summary of Results:

No clinical seizures or adverse experiences were seen during the course of the study.

AED Levels and EEG Discharge Rates

		AED Level (ug/ml)	AED Level (ug/ml)	EEG Discharges per 24 hours	EEG Discharges per 24 hours
Subject	ADA	APM	Placebo	APM	Placebo
1	None	-	-	0	0
2	VPA	32	86	0	0
3	PHT	8.7	16.2	25	26
	VPM	66.8	65.7
4	ESM	65	69	19	19
5	PHT	-	5.2	0	0
6	PB	14.7	15.4	TNTC	TNTC
7	PHT	13.1	13.2	1	3
8	PHT	12.0	8.9	151	131
	VPA	32.1	28.6
9	CBZ	4.6	5.0	0	4
10	CBZ	7.0	7.1	10	19
11	CBZ	3.8	3.2	29	28
12	CBZ	3.6	4.2	13	13
13	VPA	41.4	48.5	0	0
14	PB	16.6	16.8	33	13
	VPA	50.5	71.5
15	CBZ	4.2	3.9	0	0
16	PHT	14.6	15.3	22	9
17	none	-	-	0	0
18	CBZ	5.7	9.4	0	0

AED: Antiepileptic drug
APM: Aspartame
PLAC: Placeabo
TNTC: Too numerous to count
PB: Phenobartital
PHT: Phenytooin
CBZ: Carbamazepine
VPA: Valproate
ESM: Ethosuximide.
Mean (± SD) Phe concentrations at 12:00 p.m., after dosing at 8:00 a.m. and 10:00 a.m., were 83.6 21.2 uM for aspartame and 52.3 9.1 uM for placebo. The difference was statistically significant (P=0.0001).
Mean plasma ratio of Phe to the sum of all other large neurtral amino acids (LNAA: isoleucine, leucine, valine, tyrosine, trypthohan, and methionine) at 12:00 p.m. was also significantly increased (P=0.0001).

Author Conclusion:

Results suggest that aspartame, in acute dosage of abut 50mg per kg, is no more likely than a placebo to cause seizures in individuals who reported that their seizures were provoked by aspartame consumption
In the conditions of this study, no evidence is indicated that EEG epileptiform activity is activated by aspartame.

Funding Source:

Industry:

Nutrasweet

Food Company:

Reviewer Comments:

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	No
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	N/A
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		No
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	No
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		N/A
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	No
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	No
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes