- Integral Medicine | Alexander Smithers M.D., A.P.1014 N. East Ave.
Sarasota, Fl. 34237941-444-6336 - 1014 N. East Ave.
Sarasota, Fl. 34237941-444-6336 - Testimonials
I couldn’t be happier with the treatment I received from Dr Smithers. I had been having knee pain for several months, making it difficult to walk for an extended period of time. I finally decided to have Dr Smithers look at it, and he decided to do prolotherapy. After a few treatments, the pain was completely gone. I’m thrilled to have found this clinic! And I highly recommend Dr Smithers!
I would highly recommend Dr. A. Smithers if you are considering an alternative to orthopedic surgery. My shoulder has been in pain for months and after finding out I have some rotor cuff tears, I decided to pursue Prolotherapy with Dr. A. Smithers. The result so far has been outstanding! The first night after the shots was still painful, but woke up the next morning and pain was almost completely gone. I was equally impressed with his attentiveness to answering... Read more »Doctor Alex has been treating me for severe gut issues. I was tired of going to doctors that didn’t listen to me and would just prescribe a pill not ever trying to get to the real issues I was having. Dr. Alex has listened and treated me holistically and I am feeling great!! Thank you for everything Dr. Alex.
- Testimonials
Alex Smithers is not only smart and so helpful with my husband and his knee problems but he helped me with my stomach issues. I would go to him before I tried any other form of medicine. Thank you Alex!!
I would highly recommend Dr. A. Smithers if you are considering an alternative to orthopedic surgery. My shoulder has been in pain for months and after finding out I have some rotor cuff tears, I decided to pursue Prolotherapy with Dr. A. Smithers. The result so far has been outstanding! The first night after the shots was still painful, but woke up the next morning and pain was almost completely gone. I was equally impressed with his attentiveness to answering... Read more »I couldn’t be happier with the treatment I received from Dr Smithers. I had been having knee pain for several months, making it difficult to walk for an extended period of time. I finally decided to have Dr Smithers look at it, and he decided to do prolotherapy. After a few treatments, the pain was completely gone. I’m thrilled to have found this clinic! And I highly recommend Dr Smithers!
Hi
I had Prolozone therapy with Dr Alex Smithers. My knees and thumbs were injected due to meniscus issues in my knees and arthritis in my thumbs. Dr Alex was wonderful. He’s very gentle, kind and patient. I’m a very nervous patient and he took his time with me and did his best to make sure I was comfortable. I’m feeling better and continue to expect more and more improvement. I highly recommend Dr Alex and his staff. They... Read more »My husband had severe sciatic pain so bad he was bed ridden. Because our regular Dr. was out of town we went to our chiropractor to try to get some relief. He was not able to get as much relief a he needed so Dr. Daly asked us to see Dr. Smithers – another Dr. in his office.. What a BLESSING!! Dr. Smithers is the best of both worlds Eastern and Western medicine! He suggested something called PROLOZONE therapy... Read more »I became interested in pursuing ozone injections from Dr. Smithers after a friend received the treatmentsand recommended it to me. I just finished my second round of injections in my neck, lower back, hips and both knees. I have experienced lower back/hip pain most of my adult life, endured a knee injury while white river rafting in my 20’s and have had progressively worsening neck pain since a car wreck in my early 30’s. For reference I am 47... Read more »
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Probiotic Reduces Depression and Alters Brain Activity in IBS
Gastroenterology
Abstract
This abstract is available on the publisher’s site.
BACKGROUND & AIMS
Probiotics can reduce symptoms of irritable bowel syndrome (IBS), but little is known about their effects on psychiatric comorbidities. We performed a prospective study to evaluate the effects of Bifidobacterium longum NCC3001 (BL) on anxiety and depression in patients with IBS.
METHODS
We performed a randomized, double-blind, placebo-controlled study of 44 adults with IBS and diarrhea or a mixed-stool pattern (based on Rome III criteria) and mild to moderate anxiety and/or depression (based on the Hospital Anxiety and Depression scale) at McMaster University in Canada, from March 2011 to May 2014. At the screening visit, clinical history and symptoms were assessed and blood samples were collected. Patients were then randomly assigned to groups and given daily BL (n=22) or placebo (n=22) for 6 weeks. At week 0, 6 and 10, we determined patients’ levels of anxiety and depression, IBS symptoms, quality of life, and somatization using validated questionnaires. At week 0 and 6, stool, urine and blood samples were collected, and functional magnetic resonance imaging (fMRI) test was performed. We assessed brain activation patterns, fecal microbiota, urine metabolome profiles, serum markers of inflammation, neurotransmitters and neurotrophin levels.
RESULTS
At week 6, 14/22 patients in the BL group had reduction in depression scores of 2 points or more on the Hospital Anxiety and Depression scale, vs 7/22 patients in the placebo group (P=.04). BL had no significant effect on anxiety or IBS symptoms. Patients in the BL group had a mean increase in quality of life score compared with the placebo group. The fMRI analysis showed that BL reduced responses to negative emotional stimuli in multiple brain areas, including amygdala and fronto-limbic regions, compared with placebo. The groups had similar fecal microbiota profiles, serum markers of inflammation, and levels of neurotrophins and neurotransmitters, but the BL group had reduced urine levels of methylamines and aromatic amino acids metabolites. At week 10, depression scores were reduced in patients given BL vs placebo.
CONCLUSION
In a placebo-controlled trial, we found that the probiotic BL reduces depression but not anxiety scores and increases quality of life in patients with IBS. These improvements were associated with changes in brain activation patterns that indicate that this probiotic reduces limbic reactivity.
Benefits of Omega-3 Fatty Acids From Fish Oil After Acute MI (Heart Attack)
What is the deal with omega-3 supplements?
Omega-3 fatty acid has been shown to reduce death post-MI in some studies; but, yet, in other studies, it has no effect. So does it work or not?
In this study, instead of looking at hard endpoints like death or MI, the researchers used cardiac MRI to look for subtle changes in the myocardium. It was a small study of 358 post-MI patients. Half of the participants received 4 gm of omega-3 supplements, and, after 6 months, these patients had less non–infarct related myocardial fibrosis. They also had a reduced left ventricular systolic volume index by 5.8%. They had lower inflammatory markers in their blood, and the higher the levels of omega-3, the better the results; so, the effect seen with omega-3 seemed to be dose-dependent.
Now, before we go betting the farm on omega-3 supplements, let’s go back to some basics of what omega-3 fatty acids really are.
Fatty acids are long chains of carbons with hydrogens attached to them. The tail is referred to as the omega end. These fatty acids are named by where the first double bond is between the carbons. So, omega-3 means that the first double bond is at the third carbon counted from the tail end, the omega end. Omega-6 is a fatty acid that has the first double bond at the sixth carbon.
Both omega-3 and -6 are essential fatty acids, meaning that our bodies cannot make them so we need to eat them in our diet. Many chemicals needed by the body are made from both omega-3 and -6. However, one family of chemicals that can be produced from them is called eicosanoids. This family includes some very familiar chemicals like leukotrienes (inflammation), thromboxane (blood clots), and prostaglandins, which cause inflammation and other effects in the body.
Omega-6 is processed in the body much faster than omega-3, and so it creates more “bad” chemicals. A lot of omega-6 produces a lot of bad chemicals, but more omega-3 counterbalances this, which is why we think of omega-3 as good. In reality, however, omega-3 is simply not as bad as omega-6. Experts believe that we should be eating at a 1:1 ratio of omega-6 to omega-3.
Unfortunately, our western diet is more like 10:1 to 30:1 of omega-6 to omega-3. Too much omega-6 means we make a lot of inflammatory and thrombotic chemicals. Our diet has evolved to higher omega-6 content over the years. For example, corn oil is 46:1 omega-6 to omega-3. The ratio in grass-fed cows is 2:1, but it is more like 4:1 in grain-fed cows. There is less omega-3 in grains than in grass, and so grain-fed cows have less omega-3.
Perhaps to make sense of these studies we need to look at the omega-6 to omega-3 ratios. In the old studies, 1 gm of omega-3 was given to the participants, but if the participants had ratios of 30:1 then that 1 gm would not have had any impact. So, perhaps using the ratio to separate out the patients may give us more consistent outcomes.
For now, how should we improve the ratio? Omega-3 is made in plants, seaweed, and algae. So we can eat more plant-based foods and seaweed. Fish eat the algae, which is how they become rich in omega-3, so we can eat fish. Some estimates put omega-3 at seven times the level of omega-6 in fish; but, remember, that the larger the fish, the greater the amounts of heavy metals they accumulate. So, we should not eat too much of the big fish like tuna but perhaps should focus more on the small, oily fish, which have not lived long enough to accumulate these toxins. For meat, we should try for that from grass-fed livestock.
Perhaps the key is to balance our omega-3 and -6. Maybe it’s simpler to just take a supplement as was done by participants in this study; but, for the majority of us, perhaps we should choose foods that have a better ratio of omega-3 to omega-6. Remember, we can’t make these so our bodies will have to use what we eat. So choose wisely.
Abstract
This abstract is available on the publisher’s site.
BACKGROUND
Omega-3 fatty acids from fish oil have been associated with beneficial cardiovascular effects, but their role in modifying cardiac structures and tissue characteristics in patients who have had an acute myocardial infarction while receiving current guideline-based therapy remains unknown.
METHODS
In a multicenter, double-blind, placebo-controlled trial, participants presenting with an acute myocardial infarction were randomly assigned 1:1 to 6 months of high-dose omega-3 fatty acids (n=180) or placebo (n=178). Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and after study therapy. The primary study endpoint was change in left ventricular systolic volume index. Secondary endpoints included change in noninfarct myocardial fibrosis, left ventricular ejection fraction, and infarct size.
RESULTS
By intention-to-treat analysis, patients randomly assigned to omega-3 fatty acids experienced a significant reduction of left ventricular systolic volume index (–5.8%, P=0.017), and noninfarct myocardial fibrosis (–5.6%, P=0.026) in comparison with placebo. Per-protocol analysis revealed that those patients who achieved the highest quartile increase in red blood cell omega-3 index experienced a 13% reduction in left ventricular systolic volume index in comparison with the lowest quartile. In addition, patients in the omega-3 fatty acid arm underwent significant reductions in serum biomarkers of systemic and vascular inflammation and myocardial fibrosis. There were no adverse events associated with highdose omega-3 fatty acid therapy.
CONCLUSIONS
Treatment of patients with acute myocardial infarction with high-dose omega-3 fatty acids was associated with reduction of adverse left ventricular remodeling, noninfarct myocardial fibrosis, and serum biomarkers of systemic inflammation beyond current guidelinebased standard of care.
Prebiotic Reduces Body Fat and Alters Intestinal Microbiota in Overweight or Obese Children
- Written by
This small study of overweight children found that taking a prebiotic (oligofructose-enriched inulin, 8 g daily for 16 weeks) was associated with less weight gain than placebo and resulted in a shift in the microbiome to include more bifidobacteria. Bifidobacteria is established with breastfeeding and is associated with less weight gain (see graphic 1 for the results of the study).
But, before you Google “oligofructose-enriched inulin” for a supplement to recommend to your overweight patients, remember that this is simply a fiber combined with short-chain sugars found in plants. A prebiotic is generally a soluble fiber that bypasses absorption in the upper intestinal track, passing into the colon and providing fuel for bacterial growth and fermentation (gas; see graphic 2).
Foods rich in inulin include whole grains, onions, garlic, leeks, Jerusalem artichoke, and chicory root. Other prebiotic fibers that would likely work include psyllium, ground flax seed, and guar gum. The good news is that, other than gas and bloating, these products are very safe and may promote the establishment of a healthy microbiome at an early age, which may help with weight management as the child grows into an adult.
Abstract
This article is open access.
BACKGROUND & AIMS
It might be possible to manipulate the intestinal microbiota with prebiotics or other agents to prevent or treat obesity. However, little is known about the ability of prebiotics to specifically modify gut microbiota in children with overweight/obesity or reduce body weight. We performed a randomized controlled trial to study the effects of prebiotics on body composition, markers of inflammation, bile acids in fecal samples, and composition of the intestinal microbiota in children with overweight or obesity.
METHODS
We performed a single-center, double-blind, placebo-controlled, trial of 2 separate cohorts (March 2014 and August 2014) at the University of Calgary in Canada. Participants included children, 7 – 12 years old, with overweight or obesity (>85th percentile of body mass index) but otherwise healthy. Participants were randomly assigned to groups given either oligofructose-enriched inulin (OI, 8 g/day; n=22) or maltodextrin placebo (isocaloric dose, controls; n=20) once daily for 16 weeks. Fat mass and lean mass were measured using dual-energy-x-ray absorptiometry. Height, weight, and waist circumference were measured at baseline and every 4 weeks thereafter. Blood samples were collected at baseline and 16 weeks, and analyzed for lipids, cytokines, lipopolysaccharide, and insulin. Fecal samples were collected at baseline and 16 weeks; bile acids were profiled using high-performance liquid chromatography and the composition of the microbiota was analyzed by 16S rRNA sequencing and quantitative PCR. The primary outcome was change in percent body fat from baseline to 16 weeks.
RESULTS
After 16 weeks, children who consumed OI had significant decreases in body weight z-score (decrease of 3.1%), percent body fat (decrease of 2.4%), and percent trunk fat (decrease of 3.8%) compared to children given placebo (increase of 0.5%, increase of 0.05%, and decrease of 0.3%, respectively). Children who consumed OI also had a significant reduction in level of interleukin 6 (IL6) from baseline (decrease of 15%) compared with the placebo group (increase in 25%). There was a significant decrease in serum triglycerides (decrease of 19%) in the OI group. Quantitative PCR showed a significant increase in Bifidobacterium spp. in the OI group compared with controls. 16S rRNA sequencing revealed significant increases in species of the genus Bifidobacterium and decreases in Bacteroides vulgatus within the group who consumed OI. In fecal samples, levels of primary bile acids increased in the placebo group but not in the OI group over the 16-week study period.
CONCLUSIONS
In a placebo-controlled, randomized trial, we found a prebiotic (OI) to selectively alter the intestinal microbiota and significantly reduce body weight z-score, percent body fat, percent trunk fat, and serum level of IL6 in children with overweight or obesity.
Acupuncture Found to Be an Effective Analgesia Option in ER
May provide a safe alternative to opioids, researchers say
Acupuncture is a safe and effective alternative to pain medications for some emergency department patients, according to a study published in the June 19 issue of the Medical Journal of Australia.
MONDAY, June 19, 2017 (HealthDay News) — Acupuncture is a safe and effective alternative to pain medications for some emergency department patients, according to a study published in the June 19 issue of the Medical Journal of Australia.
The study — billed as the world’s largest randomized, controlled trial of acupuncture in the emergency department — included 528 patients. The study participants were seen at four Australian emergency departments for acute low back pain, migraines, or ankle sprains. Patients who said their level of pain was at least 4 on a 10-point scale received one of three treatments: acupuncture alone; acupuncture with pharmacotherapy; or pharmacotherapy alone.
One hour after treatment, 36.9 percent of all patients had significant pain reduction, meaning at least a 2-point decline on the 10-point scale. More than 80 percent still had a pain rating of at least 4, the researchers found. But two days later, most patients were satisfied. Overall, 82.8 percent of acupuncture-only patients said they would probably or definitely repeat their treatment, compared with 80.8 percent in the combined group and 78.2 percent in the pharmacotherapy-alone group.
“Emergency nurses and doctors need a variety of pain-relieving options when treating patients, given the concerns around opioids such as morphine, which carry the risk of addiction when used long-term,” lead investigator Marc Cohen, M.B.B.S., Ph.D., a professor in the School of Health and Biomedical Sciences at RMIT University in Melbourne, Australia, said in a university news release.
Neuropathy associated with gluten sensitivity
Abstract
Objectives
To prospectively study the clinical, neurophysiological and neuropathological characteristics of axonal neuropathies associated with positive antigliadin antibodies and the prevalence of such neuropathies in a cohort of patients with sporadic axonal neuropathy.
Methods
Prospective screening (using antigliadin, antiendomysium and tissue transglutaminase antibodies) of patients with peripheral neuropathy attending a neurology clinic.
Results
215 patients with axonal neuropathy were screened. 141 patients had symmetrical sensorimotor neuropathy, 47 had mononeuropathy multiplex, 17 had motor neuropathy and 10 had small‐fibre neuropathy. Despite extensive investigations of the 215 patients, 140 had idiopathic neuropathy. Positive immunoglobulin (Ig)G with or without IgA antigliadin antibodies was found in 34% (47/140) of the patients with idiopathic neuropathy. This compares with 12% prevalence of these antibodies in the healthy controls. The prevalence of coeliac disease as shown by biopsy in the idiopathic group was at least 9% as compared with 1% in the controls. The clinical features of 100 patients (47 from the prevalence study and 53 referred from elsewhere) with gluten neuropathy included a mean age at onset of 55 (range 24–77) years and a mean duration of neuropathy of 9 (range 1–33) years. Gluten‐sensitive enteropathy was present in 29% of patients. The human leucocyte antigen types associated with coeliac disease were found in 80% of patients.
Conclusions
Gluten sensitivity may be aetiologically linked to a substantial number of idiopathic axonal neuropathies.
Gluten sensitivity is a state of heightened immunological responsiveness to ingested gluten in genetically susceptible people.1 It represents a spectrum of diverse manifestations, one of which is gluten‐sensitive enteropathy. The term coeliac disease should now be restricted to describe gluten‐sensitive enteropathy (triad of villous atrophy, crypt hyperplasia and increased intraepithelial lymphocytes on histological examination of small‐bowel mucosa). The term gluten sensitivity describes a spectrum of diseases having in common an immune response to the ingestion of gluten, but with diverse manifestations such as an enteropathy (coeliac disease), dermatopathy (dermatitis herpetiformis) and neurological disorders (eg, gluten ataxia and neuropathy).2 Not surprisingly, the common aetiological trigger (gluten) means that these diseases overlap considerably. For example, most patients with dermatitis herpetiformis also have coeliac disease, as do a third of patients with gluten ataxia.3 Similarly, 8% of patients with established coeliac disease develop neurological manifestations.4
A review of all published papers from 1964 to 2000 (single and multiple case reports) of 83 patients with coeliac disease who then develop neurological illness shows that the most common neurological entities encountered were ataxia (n = 29) and peripheral axonal neuropathy (n = 29).5 We have previously reported that neurological manifestations can present even in the absence of an enteropathy. The most common neurological dysfunction encountered was ataxia (gluten ataxia) and peripheral axonal neuropathy.6,7 Of 28 patients with axonal peripheral neuropathy, 13 had positive antigliadin antibodies.6 Most neuropathies encountered were symmetrical sensorimotor axonal in type. There have since been additions to the literature on neuropathy and coeliac disease. One such study showed that among patients with established coeliac disease on a gluten‐free diet, 23% had evidence of axonal peripheral neuropathy.8 Another study found that 2.5% of all patients with neuropathy had coeliac disease.9 The figure was higher at 8% when patients with symptoms of neuropathy but normal neurophysiological assessment were included.9 Given that 1% of the healthy population has coeliac disease10 with no gastrointestinal symptoms and as many as 12% may have serological evidence of gluten sensitivity, the prevalence of gluten sensitivity‐related neuropathy in patients with sporadic axonal neuropathy merits more detailed investigation.
The first aim of this 10‐year study was to study prospectively the prevalence of gluten sensitivity and coeliac disease (using antigliadin, antiendomysium and transglutaminase antibodies as well as duodenal biopsies) in a large number of patients with axonal neuropathies. The second aim was to characterise gluten neuropathy in clinical, neurophysiological and neuropathological terms.
Patients and methods
Patient selection
All patients with clinical and neurophysiological evidence of axonal neuropathy were consecutively recruited over a period of 10 years (1994–2004) from a general neurology clinic at the Department of Clinical Neurology, The Royal Hallamshire Hospital, Sheffield, UK. The consultants running the clinic (initially GABD‐J and then MH) have a particular interest in patients with chronic idiopathic axonal neuropathy, and such patients are followed up regularly. Patients with a family history of neuropathy or positive genetic testing for familial neuropathies were excluded, as were patients with demyelinating neuropathies such as Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathies with conduction block. Tertiary referrals of patients with the diagnosis of gluten sensitivity and peripheral neuropathy referred to the gluten sensitivity/neurology clinic by consultant neurologists from Sheffield and other UK neurology centres were not included in the prevalence part of the study, but were included for the purpose of defining the clinical characteristics. For the estimation of prevalence of antigliadin antibodies and coeliac disease in the healthy population of the region (similar demographic characteristics), a separate parallel study (1999–2001) was conducted and the results have been published.10 The data from this study were used for the comparison of the prevalence of antigliadin antibodies and coeliac disease between healthy controls and patients with neuropathy.
Investigations of peripheral neuropathy
As part of the screening process for the aetiology of neuropathy, all patients underwent the following investigations at least once: full‐blood count, erythrocyte sedimentation rate, vitamin B12, red cell or serum folate, urea and electrolytes, liver function tests, thyroid function tests, random blood sugar, glycosylated haemoglobin (in selected cases, glucose tolerance test), serum angiotensin‐converting enzyme, immunoglobulins and electrophoresis (with immunofixation), antinuclear antibodies, double‐stranded DNA, extractable nuclear antibodies, antigliadin antibodies (IgG and IgA), IgA endomysium antibodies, IgA tissue transglutaminase antibodies (the antiendomysium and tissue transglutaminase assays became available half way through the study, which is why not all patients were tested at baseline), rheumatoid factor, antinuclear cytoplasmic antibodies and chest radiograph. Additional investigations were carried out if clinically indicated, and included borrelia serology, hepatitis B and C and HIV serology, complement levels, cryoglobulins, vitamins B1, B6 and E, paraneoplastic antibodies (Hu, Yo and Ri), lead levels, abdominal ultrasound scan, sural‐nerve biopsy, abdominal and chest computed tomography scan, skeletal survey, bone marrow examination and positron emission tomography scan.
Additional investigations for patients with neuropathy and gluten sensitivity
All patients with positive antigliadin antibodies (IgG or IgA) irrespective of the presence of antiendomysium and tissue transglutaminase antibodies were offered duodenal biopsy. Specimens were taken from the distal duodenum using biopsy forceps, through a conventional forward‐viewing endoscope (Key‐Med, Southend, UK). Four biopsy specimens were taken from the third part of the duodenum. The presence of gluten‐sensitive enteropathy was established by histological examination for evidence of crypt hyperplasia, villous atrophy and increase in intraepithelial lymphocyte count.11
Neurophysiological assessments
Nerve conduction studies and electromyography were carried out at least once in all patients where clinical evaluation suggested a diagnosis of peripheral neuropathy. All patients included in this study had evidence of axonal peripheral neuropathy on neurophysiological assessments (generalised sensory or motor peripheral neuropathy, mononeuropathy multiplex or small‐fibre neuropathy). Sensory and motor nerve conduction studies and EMG were carried out using standard techniques. Nerve conduction study results were usually deemed abnormal if values fell outside 99% confidence limits, but allowance was made in interpreting values with respect to age of the patient. Where nerve conduction studies were normal and the clinical features were suspicious of small‐fibre involvement, thermal threshold testing was performed. Thermal threshold results were considered to be abnormal if they fell outside 99% confidence limits obtained from age‐matched healthy controls.
Results
Prevalence
A total of 215 patients with axonal neuropathy participated in this study. Of these 141 had symmetrical sensorimotor axonal neuropathy, 47 had mononeuropathy multiplex, 17 had motor neuropathy and 10 had small‐fibre neuropathy.
After investigations, the aetiology of neuropathy was established in some patients as follows: diabetes mellitus was the cause of neuropathy in 24 of 215 (11%) patients (7 had type 1 and 17 had type 2 diabetes). In 16 of 215 (7%) patients, a connective tissue disease or vasculitis was confirmed to be the aetiological factor. A paraneoplastic neuropathy was diagnosed in 9 (4%) patients. Low vitamin B12 was found in 9 (4%) patients. Cases of monoclonal gammopathy of undetermined significance (n = 5, 2%), excessive alcohol intake (n = 4, 2%), drug related (n = 3, 2 amiodarone, 1 phenytoin, 1%) and hypothyroidism (with evidence of improvement of the neuropathy with thyroid replacement alone; n = 3, 1%) were noted. One patient was found to have low vitamin B6 and improved with nutritional support; in another patient the neuropathy was thought to be related to sarcoidosis (confirmed by biopsy). Thus, a possible aetiology for the neuropathy was established in 75 patients, leaving 140 patients with seemingly idiopathic neuropathy. Positive serology for gluten sensitivity (IgG or IgA antigliadin antibodies) was found in 47 of 140 (34%) patients with idiopathic neuropathy. This compared with 12% prevalence of these antibodies in the control population of Sheffield.10The difference in prevalence of antigliadin antibodies between the two groups was significant (p<0.001 by χ2test). In addition, 7 of 75 (9%) patients with neuropathy of known aetiology (two with type 1 diabetes and five with low vitamin B12) were found to have antigliadin antibodies. Of the 47 patients with gluten sensitivity, 45 underwent duodenal biopsies and 12 (27%) were found to have an enteropathy in keeping with coeliac disease. Thus, the prevalence of coeliac disease as determined by biopsy in the idiopathic group was at least 9% (12/140). This compares with 1% prevalence of coeliac disease in the controls.9 Table 11 summarises these data.
Clinical characteristics
The clinical and immunological characteristics of the 47 patients with gluten sensitivity and otherwise idiopathic neuropathy were then combined with those of 53 patients with gluten sensitivity and neuropathy who had been referred consecutively to the gluten sensitivity/neurology clinic from other neurologists from Sheffield and elsewhere in the UK. All the additional 53 patients were investigated in a similar manner and other causes of neuropathy were excluded. Table 22 outlines the clinical features of these 100 patients.
The mean age at onset of the neuropathy was 55 (range 24–77) years, with a mean symptom duration of 9 (range 1–33) years. In all, 67 patients had a symmetrical generalised sensorimotor axonal neuropathy, 17 had mononeuropathy multiplex, 9 had pure motor neuropathy and 7 had small‐fibre neuropathy. Antigliadin IgG antibodies alone were positive in 57%, antigliadin IgA alone in 16%, and both IgG and IgA were positive in the remaining 27%. Tissue transglutaminase antibodies were present in 16 of 44 (36%) patients and antiendomysium antibodies in 12 of 52 (23%) patients who underwent these additional tests. Gluten‐sensitive enteropathy was present in 26 of 89 (29%) patients who underwent duodenal biopsy. The human leucocyte antigen (HLA) types associated with coeliac disease were seen in 80% (62% HLA‐DQ2, 10% HLA‐DQ8, 8% HLA‐DR3, HLA‐DR5 or HLA‐DR7, without HLA‐DQ2 or HLA‐DQ8) of these patients. The remaining had HLA‐DQ1. We found no significant differences in any of the above characteristics between the 47 patients from the prevalence study and the 53 patients referred from elsewhere.
Neuropathological findings
Pathological data were available from three patients (sural‐nerve biopsies in two patients and an autopsy in one).
A sural‐nerve biopsy from a 65‐year‐old man (positive antigliadin antibodies, normal duodenal biopsy) with clinical and neurophysiological evidence of sensorimotor axonal neuropathy showed a focal inflammatory cell infiltrate in the epineurium and around a small endoneurial blood vessel in one fascicle (fig 11).). The inflammatory cells, which included plasma cells, were closely related to the vessel wall. Resin‐embedded thin sections showed a patchy loss of myelinated fibres and occasional degenerating fibres. Occasional thinly myelinated fibres were seen, but not demyelinated fibres. These appearances suggested axonal degeneration secondary to an inflammatory microvasculopathy. The patient’s condition is stable while on a gluten‐free diet.
Case 2 was a 49‐year‐old man with asymmetrical sensorimotor axonal neuropathy suggestive of mononeuropathy multiplex. He had positive antigliadin antibodies, and coeliac disease was confirmed on duodenal biopsy. He had never been strict with his gluten‐free diet (persistently positive antigliadin antibodies) and the neuropathy had progressed. He underwent a fascicular sural‐nerve biopsy, containing a single fascicle. This showed evidence of axonal degeneration, but no evidence of inflammatory cell infiltration.
Case 3 was a 32‐year‐old woman who died from a rapidly progressive neuropathy (symmetrical sensorimotor axonal neuropathy) and ataxia, whose onset coincided with the diagnosis of gluten sensitivity. She also had evidence of enteropathy on biopsy. Autopsy showed inflammatory changes in both the central and the peripheral nervous systems (represented by spinal nerve roots). Capillaries in the brain seemed prominent in some areas, with hypertrophic endothelial cells. These vascular changes were most conspicuous in white matter, including cerebral, cerebellar and brain stem white matter. However, similar changes were seen focally in grey matter areas, including the hippocampus and the inferior olivary nucleus. The capillary changes were associated with a vascular and perivascular inflammatory cell infiltrate, predominantly of histiocytes (CD68+) and a lighter population of small lymphocytes, which were mostly T cells (CD45Ro+). Occasional fragmenting nuclei, possibly representing apoptotic bodies, were seen, but there was no vascular necrosis. We observed no tissue necrosis or microinfarction, and only mild focal myelin loss. Similar changes were also seen in the spinal cord. The cerebellum showed loss of Purkinje cells (fig 2A2A)) with increased Bergmann glia, and there was a mild patchy loss of neurones in the inferior olivary nucleus. Spinal roots of peripheral nerve showed inflammatory cell infiltrate of both lymphocytes and macrophages (fig 2B2B),), some of which were positive for T cell markers.
Discussion
Demyelinating inflammatory neuropathies have been the focus of most research on peripheral neuropathies; yet axonal neuropathies are by far the most common type of neuropathies encountered in everyday neurological practice.12,13 This large prospective study has attempted to identify a prevalence figure (among patients with sporadic axonal neuropathy) and clinically characterise gluten sensitivity‐related neuropathy. Data on the prevalence of other causes of axonal neuropathies are also presented in this study, but are unlikely to represent the true prevalence of each aetiology in the general population because of referral bias. For example, in this study, diabetes accounted for 11% of all the neuropathies but was found to be the cause of neuropathy in >50% of patients in another study.12 In the UK, patients with established and poorly controlled diabetes who have a neuropathy are less likely to be referred to neurology clinics, given that the aetiology and treatment of their neuropathy is apparent. In this study for most patients with non‐insulin‐dependent diabetes, the diagnosis of diabetes was made on the basis of the aetiology of the neuropathy. The figures of prevalence for the different aetiologies of neuropathy found in this study reflect more closely what is seen in a long‐established general neurology clinic where patients with chronic axonal neuropathies are followed up long term.
The principal aim of this study was to investigate the prevalence of gluten sensitivity among patients with chronic idiopathic axonal neuropathy as defined by the presence of antigliadin antibodies. To avoid referral bias (in view of our interest in the neurological manifestations of gluten sensitivity), we deliberately excluded any patients referred to the gluten sensitivity/neurology clinic with an established diagnosis of gluten neuropathy. The prevalence of antigliadin antibody positivity was 34% in patients with otherwise idiopathic axonal neuropathy compared with 9% in patients with established cause of neuropathy and 12% in controls from the same region.10 The prevalence of coeliac disease among these patients was found to be at least 9% and compares with 1% in the controls from the same region.10 It is also possible that in those seven patients with neuropathy of known aetiology (two patients with type 1 diabetes and five patients with low vitamin B12) who also had antigliadin antibodies, the aetiology of the neuropathy could be linked to gluten sensitivity rather than to diabetes or low vitamin B12. We, however, found no correlation between vitamin B12deficiency and the presence of enteropathy.
A previous controlled study has shown that as many as 23% of patients with established coeliac disease on a gluten‐free diet showed axonal neuropathy on neurophysiological testing.8 Given that at least 1% of the healthy population in European countries and the US has coeliac disease and up to 12% has serological evidence suggestive of gluten sensitivity, such sensitivity may well prove to be a common aetiological link to chronic idiopathic axonal neuropathy.
Some clinicians choose to distinguish between those patients with gluten sensitivity who have an enteropathy (coeliac disease) and those without an enteropathy but with positive serological markers for gluten sensitivity. The rationale for this is not clear, as gluten sensitivity represents a spectrum ranging from antibody‐positive but normal small‐bowel mucosa (often referred to as potential coeliac disease or Marsh stage 01) to the presence of the classic small lesions on a biopsy sample, which define coeliac disease. The range of changes seen on examination of the small‐bowel mucosa, which may relate to gluten load, has been documented in detail and is now known as the Marsh classification.14 Thus, in the case of our patients with peripheral neuropathy associated with gluten sensitivity, there is nothing on clinical, genetic or immunological grounds to distinguish between patients with or without enteropathy. Extraintestinal manifestations can be the presenting feature of this disease (eg, dermatitis herpetiformis, gluten ataxia), and such manifestations can be successfully treated with a gluten‐free diet even in the absence of enteropathy.15 We therefore propose the term “gluten neuropathy” to describe this entity. Such a term encompasses patients with positive antigliadin antibodies with or without the bowel being affected (coeliac disease) and in the absence of an alternative aetiology for the neuropathy. The HLA type may offer additional diagnostic value, given that 80% of these patients have HLA‐DQ2 or HLA‐DQ8. Tissue transglutaminase and antiendomysium antibodies are good markers for the presence of an enteropathy (coeliac disease) but lack sensitivity when the bowel mucosa is normal and the disease presents with extraintestinal manifestations. Some patients reported in this study probably had a neuropathy that was coincidentally rather than aetiologically linked with the presence of circulating antigliadin antibodies. This is inevitable given that as yet there are no specific serological markers for the neurological spectrum of gluten sensitivity. Antigliadin antibodies currently remain the most sensitive markers of the whole spectrum of gluten sensitivity. The prospect of an additional marker seems imminent after the recent discovery that in vivo IgA deposits against tissue transglutaminase type 2 in the small‐bowel biopsy specimens of patients with diverse manifestations within the spectrum of gluten sensitivity are detected even in the absence of enteropathy. Such deposits have also been found in extraintestinal tissue, such as vessels in the cerebellum in patients with gluten ataxia. This marker seems to be highly specific for the whole spectrum of gluten sensitivity, as it was not found to be present in healthy and disease control subjects.16
The pathophysiology of gluten neuropathy remains unclear. Nutrient and vitamin deficiencies are unlikely to play a part, given that most of these patients have a normal nutritional status and no enteropathy. The mechanism is more likely to be immunological along the same lines as gluten ataxia.17 The pathology is that of an inflammatory process as outlined in this study and reported previously.7 This process can clearly affect peripheral nerves as well as the central nervous system.18,19,20 More often than not, however, the biopsy findings are those of axonal degeneration without evidence of inflammation. Patients with gluten sensitivity may rarely present with a rapidly progressive neuropathy, often associated with involvement of the central nervous system, as described for case 3 in Neuropathological findings. Such cases have previously been described by Cooke and Thomas‐Smith.20 On the basis of this study and the review of published case reports, the most common neuropathy encountered in the context of gluten sensitivity is that of a chronic slowly progressive symmetrical sensorimotor axonal distally predominant peripheral neuropathy. Further evidence in support of gluten neuropathy being immune mediated comes from a report on the presence of antiganglioside antibodies in patients with coeliac disease and neuropathy.21
Why the same disease (gluten sensitivity) results in both symmetrical and at times asymmetrical neuropathy (mononeuropathy multiplex), or even pure motor or sensory neuropathy remains unclear. This diverse pattern of peripheral nerve involvement is also seen in other diseases such as diabetes mellitus or neuropathy associated with connective tissue diseases. In one of our patients with gluten sensitivity, we observed progression of the motor neuropathy to involvement of sensory fibres with continuous exposure to gluten.22It is yet unclear whether the aetiology of the mononeuropathy multiplex seen in some of these patients with gluten sensitivity is mediated through a low‐grade vasculitic process.
We conclude that serological evidence of gluten sensitivity is commonly found in chronic idiopathic axonal neuropathies and may well be aetiologically linked. The effect of a gluten‐free diet on the neuropathy should confirm whether or not this is another manifestation of gluten sensitivity similar to gluten ataxia, dermatitis herpediformis and gluten‐sensitive enteropathy.
Footnotes
Competing interests: None.
Ethical approval: The South Sheffield Research Ethics Committee approved the study protocol, and all patients provided written informed consent.
Primary Care
Happy bacteria?
Irritable bowel syndrome (IBS) has a strong mind–gut connection. Depression and anxiety often correlate with the severity of symptoms. But can the microbiome influence depression and anxiety through the reverse gut–brain connection?
This small pilot study randomized 44 patients with IBS to receive either Bifidobacterium longum or placebo for 6 weeks. Depression and anxiety scores were followed at 0, 6, and 10 weeks, and functional MRI was performed at 6 weeks.
Depression scores (but not anxiety) improved, and functional MRI showed a down regulation of fear in the amygdala and frontolimbic areas of the brain, which correlated with the improvement in depression scores.
How might bacteria influence mood?
There were no significant differences in taxonomy of the microbiome in either group, and there was no difference in inflammatory markers. But there was a change in catecholamine metabolites seen in stool samples. The authors suggest that the bacteria may influence dopamine and norepinephrine as a pathway to improve mood through the central nervous system. Of concern were the low depression scores in the placebo group at baseline. The improvement in depression scores in the B. longum group could have been due to the regression to the mean.
Here is what we believe we know
Previous research suggests the Bifidobacterium species (more than Lactobacillus species) have a beneficial influence on IBS symptoms.1,2 Eating a high-fiber, low-fat diet promotes the growth of Bifidobacterium species.3 Mind–gut therapies like gut-directed hypnotherapy work really well,4 and even open-label placebos work on IBS!5
As with all diseases, therapy is complicated and requires that we adapt to the unique ecosystem that presents with each clinical encounter. Research like this reminds us of this complexity and that there really are no clear separations between gut and mind. It’s all interconnected.
References