neurological/psychiatric mainfestations of celiac/gluten sensitivity

Neurological manifestations of celiac

Running head: NEUROLOGICAL MANIFESTATIONS OF CELIAC

Neurological and Psychiatric Manifestations of Celiac Disease and Gluten Sensitivity

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Neurological manifestations celiac

Psychiatric/Neurological Manifestations of Celiac Disease/Gluten Sensitivity

Celiac disease/gluten sensitivity has long been considered a disease of the gut.

Current research and theory suggests it may be more likely to manifest as a

neurological/psychiatric disorder in its early disease stages. Although a full

understanding of the pathophysiology has yet to be discovered, there is ample evidence

to associate celiac/gluten sensitivity to certain neurological/psychiatric conditions. These

include but are not limited to ataxia, neuropathy, migraines, schizophrenia, depression,

attention deficit, and autism spectrum. People suffering from these conditions often

initially present to primary care or psychiatric providers. Therefore, primary care

practitioners and psychiatric providers should have a basic understanding of

celiac/gluten sensitivity to assist with early detection and diagnosis.

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Celiac disease is an autoimmune disorder completely dependent on the ingestion

of the gluten protein, gliadin, found in wheat, rye, and barley. Gluten sensitivity is

considered to be the beginning stages of celiac but also may exist as a separate

disorder (Sapone et al. 2011). Physicians are trained to spot only a small subset of

symptoms, including malabsorption, diarrhea, wasting and failure to thrive. These are

considered to be classic signs of celiac along with damage to the villi of the small

intestine. Gluten sensitivity rarely manifests in this fashion, making diagnosis more

challenging. It is suggested that, only one-third of patients will present with diarrhea

(Rampertab et al. 2006) and 53% will have a BMI in the overweight or obese category

(Dickey and Kearney 2006).

Over the past 15 years the understanding of celiac and gluten sensitivity has

improved significantly. Once believed to be a disorder of the gut, celiac/gluten sensitivity

is now understood to be much more complex and continues to be a diagnostic

challenge. Some common presentations include liver and biliary tract disorders,

recurrent miscarriages, dental enamel defects, recurrent sinus infections, anemia,

migraines, peripheral neuropathy, and several psychiatric disorders. Also, it is quite

common for celiac to co-occur with many other autoimmune disorders (Collin et al.

2002). This makes it almost impossible to diagnose celiac/gluten sensitivity in the typical

15-minute practitioner visit.

Celiac disease is reported to affect roughly 1% of the population (Sanders et al.

2003, West et al. 2003). When combined with gluten sensitivity and wheat allergy the

numbers are suggested to be as high as 10% (Sapone et al. 2011, Catassi and Fasano

2008, Anderson et al. 2007). The mean age of diagnosis ranges from 40 to 50 and the

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average number of years from first presenting in primary care to diagnosis is 4.6 years

(Rampertab et al. 2006). Because of the myriad of symptoms and possible co-occurring

disorders, out of 3 million people suspected of having the disease, only 100,000 are

correctly diagnosed (Ravikumara, Nootigattu and Sandhu 2007).

Undiagnosed celiac complications include osteoporosis, malignancies, and

secondary autoimmune disease. When a gluten free diet is implemented there is clinical

improvement in the gut mucosa and a decreased mortality (Corrao et al. 2001, Murray

et al. 2004). Understanding that untreated celiac/gluten sensitivity puts the patient at

risk for other autoimmune disease and dangerous complications makes it important for

practitioners to have a better understanding of the early signs of celiac/gluten sensitivity.

This review will focus on the neurological/psychiatric manifestations of celiac/gluten

sensitivity and the proposed theoretical connection as well as appraise the current

diagnostic tools available.

The connection

Research in the field of celiac disease has grown in exponentially over the last

few years. As the pathophysiology behind this disease becomes better understood the

comprehension of its complexity also grows. Acceptance of the idea of celiac as a

multifactorial disease, which manifests in a multitude of ways, allows for a deeper

understanding of the current proposed theories.

Gliadin, the offending protein in gluten, causes an initial insult at the intracellular

tight junctions located on the luminal side of the intestine. These tight junctions are

responsible for maintaining the integrity of the intestinal wall and keeping out

macromolecules. Gliadin binds with CXCR3, a chemokine receptor responsible for

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leukocyte recruitment and eventually involvement of T-helper cells. Lammers and

colleagues (2008) reported a higher concentration of CXCR3 in the gut epithelium of

those with celiac disease as compared to those without.

CXCR3 recruits myD88, an adaptor protein, allowing the release of zonulin to the

apical side of the epithelium (Lammers et al. 2008, Clemente et al. 2003). Zonulin, in

celiac, is responsible for the changes in cellular structure and arrangement of the

cytoskeleton which allows for increased gut permeability. Interestingly, in non-celiac

intestinal epithelium, zonulin strengthens the tight junctions (Drago et al. 2006). While

both celiac and non-celiac tissue reacted to gliadin, only the celiac epithelial membrane

up-regulated the production of the mRNA for CXCR3 gene expression at a 9.6 fold

increase. When gliadin was removed, the expression of the CXCR3 in the tissues of

celiac patients decreased to what was seen in those without celiac disease (Lammers et

al. 2008). It is important to note that CXCR3 is expressed in several other cells including

natural killer cells, and CD3+/CD8+ T cells which could account for the instigation of the

innate immune response associated with celiac disease. In addition, toll like receptors,

which are also responsible for innate immune response, have been reported to be

increased in the duodenum of children with celiac as compared to healthy controls

(Szebeni et al. 2007). In gluten sensitivity it is suggested that adaptive suppressor T

cells may help to stop the toll like receptor process before damage is done to the

intestinal villi (Sapone et al. 2011).

Tight junctions in the epithelial wall are critical for maintaining the integrity of the

gut. The increased permeability seen in celiac disease appears to be associated with

the onset of other autoimmune disorders (Drago et al. 2006, Sapone et al. 2006, and

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Watts et al. 2005). Initially celiac symptoms were thought to be a result of the gut

reacting to the whole gliadin molecule. We now understand that there are several areas

within the gliadin chain and each sets off very diverse reactions depending on the HLA-

DQ (HLA-DQ2/DQ8 are most commonly seen in celiac) variant and its peptide-binding

properties (Vader et al. 2002). Without the proper functioning of the tight junction,

peptides up to three amino acids long are allowed to enter circulation (Lammers et al.

2008).

Innate Immune Response to Acquired Immune Response

Once allowed access, roaming gliadin peptides cause stimulation of the innate

and acquired immune system. In the innate response, a portion of the offending peptide

stimulates peripheral CD4+ T cells, which activates apoptosis of the epithelial tissue,

initiates macrophages, and IL-15(Londei et al. 2005, Maiuri et al. 2003). In acquired

immunity, tissue-transglutaminase (TG2 or tTG), which is normally responsible for

intermolecular bonding, apoptosis, and reinforcement of the cell matrix, deamidates

gliadin. This process creates a positively charged molecule and increases the affinity of

binding to the HLA-DQ2 DQ-8. Once bound there is a cyclical and progressive reaction.

The HLA DQ2/8 positive individuals can present the gliadin molecule on their antigen

presenting cells and relay the message to the CD4+ T-cells. The CD4 cells then

releases INFγ, an immunostimulator, which boosts HLA production. With continued

insult and tissue inflammation, TG2 is produced to help reconstruct the damaged areas

of the epithelium. More TG2 increases the rate of deamediation, which stimulates a

greater CD4 response, and so on. It is important to note the presence of TG2 is

generally in the gut, TG3 is associated with the skin and TG6 is primarily found in the

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brain. In patients with neurological disorders in combination with celiac, anti-TG6 has

been reported to be produced intrathecally (Schrödl et al. 2004).

The disease process related to celiac/gluten sensitivity is complex and vast.

Science has come a long way in researching this disease but much remains to be

learned. Fortunately, what we do know may help us understand how immune process of

celiac is related to neurological/psychiatric disorders and why their prevalence is up to

10-25% times higher in this disease (Hadjivassiliou et al. 1996).

Diagnosis

The first step in diagnosis is to test the patient for antibodies related to the

autoimmune reaction when gluten is ingested. Initially tTG (TG2), IgA-AGA, IgG-AGA,

and total IgA should be ordered (See Table 1: Diagnostic Tests). If any tests are above

the normal limit, the patient should be forwarded to a gastrointestinal specialist for an

upper endoscopy (EGD). If total IgA is below normal range there could be an IgA

deficiency, rendering all IgA type testing unreliable. If this is the case or all tests are

within normal limits, halotype testing can be done to rule out celiac but not gluten

sensitivity. Having HLA DQ8, DQ2, or DQ1 is not indicative of celiac but may help with

differential diagnosis (Hadjivassiliou et al. 2010).

During the EGD, samples of the small bowel are taken and then analyzed for

injury to the villi of the small intestine. If the histological results are Marsh Grade 0 with

normal villous architecture it would be prudent to request IgA tTG tests be performed on

the tissue sample. This test can catch celiac disease before mucosal damage is done.

Unfortunately, these tests are not widely available. Marsh grade 1 changes consist of

some lymphocytic infiltration of the mucosa which is considered to be predictive of

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celiac if there are more than 20 enterocytes per 100 villi. Marsh Grade 2 shows

lymphocytic infiltration as well as crypt hyperplasia and is considered to be pre-celiac or

celiac depending on amount of damage. Marsh grade 3 shows lymphocytic infiltration,

crypt hyperplasia and villous blunting to total villous atrophy. Marsh grade 3 is

considered full blown celiac (Oberhuber et al. 1999, Sapone et al. 2011).

It is important to note that the patient must be consuming gluten for valid testing.

If gluten has already been removed from the diet a gluten challenge may be necessary

for diagnosis. This consists of consuming the equivalent of 4 or more slices of bread per

day for at least six weeks. If the patient has already had positive results from a gluten

free diet, this reintroduction may not be ideal. Even if gluten has not yet been removed

from the diet some people choose not to undergo the biopsy procedure because of the

associated risks.

It is now understood and becoming increasingly accepted that gluten sensitivity

can exist without histological changes, making the endoscopy somewhat unreliable but

still considered the “gold star” diagnosis. Hadjivassiliou et al. 2006a, b, reported

neurological dysfunction related to gluten sensitivity with and without histological

changes in the mucosa. As evidence of this phenomenon is accumulating, many

practitioners are beginning to rely less on the biopsy and more on blood tests and trial

of the gluten free diet.

Understanding the complexities of celiac helps the practitioner to think outside of

the box when formulating a diagnosis. Celiac/gluten sensitivity should be thought of as a

multitude of different diseases brought on by the ingestion of gluten, manifesting in

distinct ways, all requiring the same treatment, a gluten free diet.

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Diagnostic Tests

Tests CD/GS Sensitivity Specificity Notes

tTG-IgA (TG2)

CD 95% 90%If positive it is villous atrophy highly likely but a negative does not rule out CD or GS

IgA-AGA GS 53-100% 65-100%Can positive with extra-intestinal symptoms, a negative does not rule out CD/GS

IgG-AGA GS 57-100% 42-100%

Can positive with extra-intestinal symptoms, a negative does not rule out CD/GSFalse positive in Crone’s, wheat protein allergy, and with recent diarrhea

Anti-deaminated gliadin-IgA/IgG

CD 90&92%Respectively

98&75%Respectively

Shows CD before intestinal damage occurs

Total IgA CD/GS No Data No Data IgA deficiency can cause all AGA tests to show false negative

TG6 GS No Data No Data Associated with neurological symptoms Not readily available yet

Genetic CD/GS % in CD % in GS Notes

HLA-DQ8 CD/GS 95% 50%30% of the general population will have this halotype, Helps with inconclusive serology

HLA-DQ2 CD/GS 5% 9% Helps with inconclusive serology

HLA-DQ1 GS 0 1% Helps with inconclusive serology

Biopsy resultsIncreased intraepithelial lymphocytes

Crypt Hyperplasia

Villous Atrophy

Notes

Marsh Grade I

PresentNot present

NotPresent

Found in pre-celiac and GS

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Tests CD/GS Sensitivity Specificity Notes

Marsh II Present PresentNot Present / Partial

Pre-Celiac/CD

Marsh Grade III

Present Present Total Celiac Disease

Table 1: Diagnostic Tests

Neurological Presentation

Ataxia

Ataxia is one of the most predominant neurological presentations of gluten

sensitivity. In 1996, Hadjivassiliou et al. coined the term “gluten ataxia” to represent

sporadic ataxia found in combination with celiac markers. The research included 500

patients over a 13 year time span. Of the 500 patients, 215 had idiopathic sporadic

ataxia and 101 of those patients had serological evidence of gluten sensitivity. In 2008,

Hadjivassiliou examined 400 patients presenting with ataxia. Of the 400, 91 had

idiopathic sporadic ataxia. When the two groups were compared, the autoimmune

prevalence in the genetic ataxia group was reported to be 6%, while the idiopathic

sporadic ataxia group was 47%. Anti-cerebellar antibodies were also found in 60% of

the idiopathic ataxia group and 5% of those with genetic ataxia. HLA DQ2, commonly

associated with autoimmune disease, was found in 71% of the sporadic ataxia, 34% in

genetic, 36% in the general population (Hadjivassiliou et al. 2008b).

While an exact understanding of the disease process is unknown, there

are some clues to suggest a gluten related inflammatory process. Researchers took

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serum from patients with gluten ataxia and analyzed the effect on brain tissue samples.

The serum was found to have antibodies directed toward neuronal Purkinje cells,

cortical neurons and the brain stem (Hadjivassiliou et al. 2002, Boscolo et al. 2007). In

the mouse model, serum from celiac subjects with and without ataxia caused transient

ataxia (Boscolo et al. 2007). Post-mortum autopsy preformed on patients suffeing from

gluten ataxia showed damage to the cerebellum from lymphocytic infiltration, some

damage to the periphrial nerves and posterior spinal column (Cooke and Smith 1966,

Hadjivassiliou et al. 1998). In addition, parivascular cuffing and anti-TG6 has been

reported in the brains of patients with gluten ataxia, an indication of an immune

response (Hadjivassiliou et al. 2008a).

The immune process involved in gluten ataxia is progressive in the presence of

gliadin. Therfore, prompt diagnosis and treatment with gluten free diet is essential.

Symptoms should be expected to remiss depending on the amount of damage done to

the Purkinje cells and continuation of gluten free diet (Hadjivassiliou et al. 2003). It is

essential that there is strict adhearance to the diet as reaction to gliadin can occur with

as little as 20ppm exposure. Serum testing is a good indication of adherence but it is

important to note that antibodies will continue to circulate for 6-12 months after gluten is

removed.

Neuropathy

Neuropathy is the second most common neurological disorder associated with

gluten sensitivity. The connection has been coined gluten neuropathy and

encompasses a combination of serological evidence of gluten sensitivity and sporadic

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idiopathic neuropathy with no alternative cause. There are several different

neuropathies correlated with celiac including sensory ganglionopathy, asymmetrical

neuropathy, and small fiber neuropathy but the most prevalent is peripheral neuropathy

(Hadjivassiliou et al. 2010, Kelkar, Ross and Murray 1996, Chin et al. 2006).

In a Swedish general population study, 84,000 people with celiac were identified.

Of those there was a 3-4 fold increase of polyneuropathy when compared to the general

public (Ludvigsson et al. 2007). In 2006, Hadjivassiliou and team reported 34% of 140

people who had idiopathic sporadic neuropathy also had significant level of IgG or IgA

antibodies (Hadjivassiliou et al. 2006a). Chin et al. report the prevalence of biopsy

proven celiac with neuropathy to be 2.5-8% as compared to the suggested 1% of the

healthy population. This data was gathered from a retrospective study of 400 people

presenting with neuropathy and does not include those who have gluten sensitivity

without intestinal damage (Chin et al. 2003).

Unfortunately, to date, neuropathological evidence is limited to a few case

studies but the findings are similar and consistent with an inflammatory process. In the

2006 Hadjivassiliou study, cited previously, 2 sural-nerve biopsies and one autopsy

were examined. The first endoneurial biopsy showed signs of inflammatory

degenerative process with axonal damage. The second biopsy also showed nerve

damage but lacked the inflammatory cells. The samples provided evidence of

decreased Purkinje cells, slight decrease of neurons in the olivary nucleus and

perivascular cuffing from lymphocytic infiltration (Hadjivassiliou et al. 2006a).

For most people with gluten neuropathy, a gluten free diet will improve

symptoms. In a study consisting of 35 patients with gluten neuropathy, 25 were placed

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on a gluten free diet while 10 refused treatment. There was a statistically significant

improvement in the treatment group and a progressive decline in the non-treatment.

Also, there was a correlation between disease progression and improvement. Those

who displayed symptoms for a longer period of pre-diet time and those with more

severe neuropathy experienced the least amount of improvement (Hadjivassiliou et al.

2006b).

Migraines/Headache

There is a growing body of evidence suggesting the association of migraines to

gluten sensitivity/celiac. In a retrospective study composed of 357 children with celiac

disease, 88 reported headaches before diagnosis. After implementation of a gluten free

diet the kids were asked about the quantity and quality of their headaches. Of the 88,

24.7% had full resolution, 50% improved, 24.9 had no change. Incidentally, 47.6 of the

no change were noncompliant with diet based on self-report. In the prospective part of

the same study, 79 children who presented with headache were tested for celiac. Four

patients were positive according to their biopsy results (5% of study population,

compared to 1% of general population). Three had total regression of headaches after

diet, 1 had marked improvement. None of the 79 subjects had classic signs (Lionetti et

al. 2009). In a smaller study of 10 patients with episodic headache and IgG and/or IgA

positive, 7 of 10 had full remission, 2 had partial recovery and 1 refused diet. All had

wide range of white matter abnormalities (Hadjivassiliou et al. 2001). Similar results

suggest that in 4.4-5.5% of people who present with headaches, gluten may be the

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trigger. In addition, the removal of gluten can decrease or ameliorated headache

symptoms (Gabrielli et al. 2003).

Although a complete understanding of the headache/celiac correlation is

unknown, there is evidence suggesting problems with regional cerebral blood flow and

cortical hypoperfusion. In several studies symptoms improved with a gluten free diet

(Addolorato et al. 2004, Leggio et al. 2004, Abenavoli, Gasbarrini and Addolorato 2008).

Addolorato et al. (2004) reported brain hypoperfusion in 73% of untreated celiac

patients who had no neurological symptoms. Interestingly, the treated celiac patients

had a slightly lower percentage of hypoperfusion than healthy controls. These reported

brain abnormalities suggest an inflammatory process where a gluten free diet may be

beneficial and non-treatment may be detrimental.

Schizophrenia

The connection between schizophrenia and celiac/gluten sensitivity has been

controversial since it was first suggested in 1966. However, within the last few years

researchers have made significant leaps in understanding the complexity of the, now

accepted, association.

In 1966 Dr. Curtis Dohan, a psychiatrist for the VA, reported a decrease in

schizophrenia admissions during the WWII grain shortage (Dohan 1966). Shortly after

his initial findings, another study was conducted using patients on a locked VA ward.

Patients were assigned either a high grain and milk diet or a grain/milk free diet.

Improvement was measured by the number of days before the patient was allowed full

ward privileges. Over 175 day, 62% of the grain/milk free diet patients were allowed “full

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privileges” compared to 36% who were on the high grain/milk diet. Furthermore, when

grains were added back to the diet almost 75% of the grain/milk free patients

decompensated and were returned to the locked ward (Dohan et al. 1969). In 1997, a

33 year old presented with persistent diarrhea and a previous diagnosis of

schizophrenia. Single proton emission computed tomography (SPECT) analysis was

preformed and she was found to have hypoperfusion of the left frontal cortex. She was

put on a gluten free diet and the follow up SPECT showed normalization of flow and

regression of psychiatric symptoms (De Santis et al. 1997). This was the first study to

show perfusion abnormalities in celiac.

It is estimated that celiac and schizophrenia separately affects 1% of the

population. Yet, according to a Danish National Registry study, people with celiac are at

a 3.2% increased risk for developing schizophrenia (Eaton et al. 2006). Other

population studies from the UK report conflicting results and suggest there is no

connection between schizophrenia and celiac (Wei and Hemmings 2005, West et al.

2006). It is important to note that these two studies only looked for classic celiac

disease and limited their serological evidence to anti-EMA and anti-tTG. If anti-gliadin

antibodies were included, there may be a more accurate picture.

Several more recent studies found moderate to high anti-gliadin antibodies in

patients with schizophrenia. Cascella (2011) used AGA, tTG, and EMA to assess 900

serum samples from the Clinical Antipsychotic Trials of Intervention Effectiveness

(CATIE). They reported 23.1% of serum was positive for AGA compared to 3.1 of the

control population. tTG, was elevated in 5.4% of the CATIE population and 0.08% of the

controls. There was no difference in the percentage positive for EMA (Cascella et al.

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2011, Dickerson et al. 2010, Samaroo et al. 2010). A smaller, yet similar, study of 129

patients with recent onset psychosis yielded similar results of increased IgA and IgG

(Dickerson et al. 2010). In 2010 researchers took serum from schizophrenia patients

who also had high anti-gliadin antibodies. They describe a very specific set of gluten

peptide chains caused an anti-gliadin reaction in this set of subjects. Interestingly, the

offending peptide is not the same set that causes a reaction in classic celiac disease.

The team suggests schizophrenia with gluten sensitivity is completely different disease

than classic celiac (Samaroo et al. 2010).

Other Psychiatric Disorders

Increased risk of depression has been reported in both the pre and post

diagnosis of celiac (Häuser et al. 2010, Addolorato et al. 2004). Although there is a

limited amount of available research and few case studies, several theories have

emerged. According to Hallert et al., (2009) loss of intestinal villi decreases nutrient

absorption causing a reduction in vitamin and mineral assimilation. The argument is

supported by a reduction of depressive symptoms and an increase in total homocyctine

levels in patients with celiac disease given supplemental B vitamins for 6 months. A

small, 30-person study reported a decrease in sleep quality for pre and post diagnosis

celiac patients, which could contribute to depressive symptoms (Zingone et al. 2010).

Pynnonen et al. (2005) discovered pre-diet, low tryptophan levels, in celiac patients with

depressed/anxious and aggressive behavior. After 3 months following a gluten free diet

there was an increase in tryptophan levels and a significant decrease in psychiatric

symptoms (Pynnönen et al. 2005). In addition, increased anti-gliadin antibodies were

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more common in depressed elderly patients without celiac, than in healthy subjects.

This suggests gluten sensitivity may also play a role in depressive symptoms

(Ruuskanen et al. 2010).

Research assessing the effect of a gluten free diet on ADHD symptoms reported

a significant improvement in daily functioning and behavioral issues. In addition, 74% of

patients expressed a desire to continue with the diet, due to a noticeable increase in

concentration and decrease in distractibility (Niederhofer and Pittschieler 2006). Others

have described a reduction in behavioral issues with a gluten free diet but the studies

were much smaller (Pynnönen et al. 2005). Regardless of the outcome of the gluten

free diet on symptoms there appears to be an increased risk of having celiac if ADHD is

present (Niederhofer and Pittschieler 2006, Young 2008).

In autism spectrum disorder (ASD), a gluten free diet continues to be surrounded

by conflicting evidence. A small study found no relationship between ASD and celiac

(Pavalone et al. 1997). This is in contrast to a larger study, done in 2008, which

reported celiac to have a prevalence of 3.3% in pervasive developmental disorders.

While evidence is mounting towards a connection between ASD and prevalence in

celiac, it is unclear if a gluten free diet would alleviate symptoms (Hill et al. 2004). That

being said, there is an association of a gluten free diet to regression of autistic

symptoms being reported (Genuis and Bouchard 2010). Furthermore, the recent focus

of the immunology component of ASD, allows for a new understanding of the probable

association. A few reports indicate an immune reaction in the gut of a subset of ASD

patients. These patients showed increased lymphocytic infiltration of the villi with mild to

moderate damage (Ashwood et al. 2003, Ashwood et al. 2004). Vojdani and colleagues,

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found an increased anti-gliadin antibody as well as autoantibody reactions in cerebellar

peptides related to gluten using sera from ASD patient (Vojdani et al. 2004a, Vojdani et

al. 2004b). This suggests an immune mediated association between the ingestion of

gluten and symptoms of ASD.

Conclusion

While celiac disease and gluten sensitivity are complex disorders they have a

simple cure. The person afflicted must stop eating gluten. Diseases like ataxia,

neuropathy, and migraines are often of unknown origin and treatment is focused on

minimizing the severity of symptoms. If gluten sensitivity or celiac is the etiology of

these symptoms, for even a small subset of patients, it is imperative to test each patient.

Schizophrenia is a severe and debilitating mental disorder that affects

approximately 24 million people worldwide. The cost to society is approximately 65

million dollars a year and in the United States, it is the 2nd leading cause of disability.

The person afflicted with schizophrenia has a decrease in life expectancy and an

increased probability of homelessness and/or prison time. If even the most modest

numbers of celiac disease presenting as schizophrenia are accurate, we owe it to our

patients to make screening a priority. This is equally true for depression, ADHD and

autism. While these diseases might not have the same impact as schizophrenia, they

are costly and have a huge influence on a person’s quality of life.

The connection between autoimmune disorders like celiac and a systemic

inflammatory process is gaining increasingly convincing evidence. Celiac/gluten

sensitivity therefore, should not be considered a disease of the gut but a neurological

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disorder. While it may begin in the gut, damage is certainly not limited to that area.

Understanding the pathophysiology, tests, and extra-intestinal manifestations of celiac

will assist in diagnosis and management of these complex diseases.

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