EAL

CD: Neurological Outcomes (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To investigate the prevalence of neurological disorders identified before or after diagnosis of celiac disease, to examine the clinical couse of the neurological disoreder, particularly in relation to start of gluten-free diet, and anti-neuronal antibodies. The prevalence of anti-neuronal antibodies to the central and enteric nervous systems in celiac disease patients with and without neurological disorders (and controls) before and after gluten withdrawal was also investigated.

Inclusion Criteria:

Biopsy-proven celiac disease.

Exclusion Criteria:

None specifically mentioned.

Description of Study Protocol:

Recruitment

Consecutive patients, diagnosed between January 1985 - June 2001.

Design

Case-Control Study.

Blinding used (if applicable)

Lab tests used.

Intervention (if applicable)

Anti-neuronal antibodies to central/enteric nervous systems were investigated in all neurological patients, unaffected patients and controls.

Statistical Analysis

The Fisher exact test, two-tailed, was used to compare clinical findings and prevalence of anti-neuronal antibodies in celiac disease patients with and without neurological disorders.

Data Collection Summary:

Timing of Measurements

Celiac-disease related antibody testing and formal neurological assessment performed on presentation. Anti-neuronal antibodies tested separately on patient sera.

Dependent Variables

Anti-gliadin AGA, anti-endomysial (EmA) and anti-human recombinant tissue transglutaminase (h-tTG) tested in all patients
Formal neurological assessment performed on presentation
Anti-neuronal antibodies detected by indirect immunofluorescence

Independent Variables

Gluten-free diet not defined. Periodical dietary interviews were routinely performed in all patients to assess compliance.

Control Variables

Description of Actual Data Sample:

Initial N: 160 consecutive celiac disease patients (120 females, 40 males), 20 celiac disease patients without neurological dysfunction, 20 controls

Attrition (final N): See above

Age: Median age of patients: 37 years, range 18 - 79 years

Ethnicity: Not mentioned

Other relevant demographics: Not mentioned

Anthropometrics: Controls not well described

Location: Italy

Summary of Results:

	Number of Cases	Anti-neuronal antibodies to CNS (%)	Anti-neuronal antibodies to ENS (%)
Celiac Disease with neurological dysfunction	13	61%	15%
Celiac Disease without neurological dysfunction	20	5%	5%
Autoimmune hepatitis	10	0%	0%
Inflammatory bowel disease	10	0%	10%
Blood donors	10	0%	0%

Other Findings

13 (8%) of 160 patients had neurological disorders, including epilepsy (n=3), attention/memory impairment (n=3), cerebellar ataxia (n=2), peripheral neuropathy (n=2), multiple sclerosis (n=1), Moyamoya disease (n=1), and Steinert's disease (n=1).

No significant demographic or clinical differences (GI or other gluten-related signs) were found between patients with and without neurological involvement.

In 11 of the 13 cases, the neurological disorder preceded diagnosis of celiac disease.

Neurological symptoms improved or disappeared in 7 patients who started a gluten-free diet within 6 months of neurological onset (2 with epilepsy, 3 with memory impairment, 1 with cerebellar ataxia, and 1 with peripheral neuropathy), and in none of 4 patients who began later.

Prevalence of central nervous system anti-neuronal antibodies was significantly higher in celiac disease patients with neurological involvement than in those patients without neurological symptoms (61% vs 5%, P = 0.0007) or controls (0%, P = 0.00001).

In 6 of the 8 positive neurological patients, anti-neuronal antibodies to CNS disappeared after 1 year of strict gluten-free diet; in 5 of 6 cases, this was accompanied by improvement / disappearance of neurological symptoms.

Author Conclusion:

In conclusion, the present study strongly reinforces the concept that celiac disease can sometimes present in the guise of a neurological disorder. Our findings suggest that in such cases, the neurological picture can greatly improve when a gluten-free diet is started promptly. Closer interaction between neurologists and gastroenterologists should facilitate earlier identification of an underlying celiac disease. Therefore, the possible presence of celiac disease needs to be carefully considered in patients with cerebellar ataxia, epilepsy, attention/memory impairment or peripheral neuropathy.

Funding Source:

University/Hospital:

University of Bologna (Italy)

Reviewer Comments:

Compliance assessed through interview. Inclusion/exclusion criteria not well defined. Neurological assessment not well described. Controls were not described, unsure whether they were matched.

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?		???
	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?	???
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
3.	Were study groups comparable?		???
	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?	???
	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.)	???
	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%.)	Yes
	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?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	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?	Yes
	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?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	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?		???
	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?	???
	7.5.	Was the measurement of effect at an appropriate level of precision?	???
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	???
	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?		Yes
	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)?	Yes
	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?	Yes
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