Muscle Fasciculation Improvement With Dietary Change: Gluten Neuropathy
Muscle Fasciculations:
Key indexing terms:
- Fasciculation
- muscular
- Gluten
- Celiac disease
- Chiropractic
- Food hypersensitivity
Abstract
Objective: The purpose of this case report is to describe a patient with chronic, multisite muscle fasciculations who presented to a chiropractic teaching clinic and was treated with dietary modifications.
Clinical features: A 28-year-old man had muscle fasciculations of 2 years. The fasciculations began in his eye and progressed to the lips and lower extremities. In addition, he had gastrointestinal distress and fatigue. The patient was previously diagnosed as having wheat allergy at the age of 24 but was not compliant with a gluten-free diet at that time. Food sensitivity testing revealed immunoglobulin G�based sensitivity to multiple foods, including many different grains and dairy products. The working diagnosis was gluten neuropathy.
Intervention and outcome: Within 6 months of complying with dietary restrictions based on the sensitivity testing, the patient�s muscle fasciculations completely resolved. The other complaints of brain fog, fatigue, and gastrointestinal distress also improved.
Conclusions: This report describes improvement in chronic, widespread muscle fasciculations and various other systemic symptoms with dietary changes. There is strong suspicion that this case represents one of gluten neuropathy, although testing for celiac disease specifically was not performed.
Introduction:�Muscle Fasciculations
There are 3 known types of negative reactions to wheat proteins, collectively known as wheat protein reactivity: wheat allergy (WA), gluten sensitivity (GS),�and celiac disease (CD). Of the 3, only CD is known to involve autoimmune reactivity, generation of antibodies, and intestinal mucosal damage. Wheat allergy involves the release of histamine by way of immunoglobulin (Ig) E cross-linking with gluten peptides and presents within hours after ingestion of wheat proteins. Gluten sensitivity is considered to be a diagnosis of exclusion; sufferers improve symptomatically with a gluten-free diet (GFD) but do not express antibodies or IgE reactivity.1
The reported prevalence of WA is variable. Prevalence ranges from 0.4% to 9% of the population.2,3 The prevalence of GS is somewhat difficult to determine, as it does not have a standard definition and is a diagnosis of exclusion. Gluten sensitivity prevalence of 0.55% is based on National Health and Nutrition Examination Survey data from 2009 to 2010.4 In a 2011 study, a GS prevalence of 10% was reported in the US population.5 In contrast to the above 2 examples, CD is well defined. A 2012 study examining serum samples from 7798 patients in the National Health and Nutrition Examination Survey database from 2009 to 2010 found an overall prevalence of 0.71% in the United States.6
Neurologic manifestations associated with negative reactions to wheat proteins have been well documented. As early as 1908, �peripheral neuritis� was thought to be associated with CD.7 A review of all published studies on this topic from 1964 to 2000 indicated that the most common neurologic manifestations associated with GS were ataxia (35%), peripheral neuropathy (35%), and myopathy (16%). 8 Headaches, paresthesia, hyporeflexia, weakness, and vibratory sense reduction were reported to be more prevalent in CD patients vs controls.9 These same symptoms were more prevalent in CD patients who did not strictly follow a GFD vs those who were compliant with GFD.
At present, there are no case reports describing the chiropractic management of patient with gluten neuropathy. Therefore, the purpose of this case study is to describe a patient presentation of suspected gluten neuropathy and a treatment protocol using dietary modifications.
Case Report
A 28-year-old man presented to a chiropractic teaching clinic with complaints of constant muscle fasciculations of 2 years� duration. The muscle fasciculations originally started in the left eye and remained there for about 6 months. The patient then noticed that the fasciculations began to move to other areas of his body. They first moved into the right eye, followed by the lips,�and then to the calves, quadriceps, and gluteus muscles. The twitching would sometimes occur in a single muscle or may involve all of the above muscles simultaneously. Along with the twitches, he reports a constant �buzzing� or �crawling� feeling in his legs. There was no point during the day or night when the twitches ceased.
The patient originally attributed the muscle twitching to caffeine intake (20 oz of coffee a day) and stress from school. The patient denies the use of illicit drugs, tobacco, or any prescription medication but does drink alcohol (mainly beer) in moderation. The patient ate a diet high in meats, fruits, vegetables, and pasta. Eight months after the initial fasciculations began, the patient began to experience gastrointestinal (GI) distress. Symptoms included constipation and bloating after meals. He also began to experience what he describes as �brain fog,� a lack of concentration, and a general feeling of fatigue. The patient noticed that when the muscle fasciculations were at their worst, his GI symptoms correspondingly worsened. At this point, the patient put himself on a strict GFD; and within 2 months, the symptoms began to alleviate but never completely ceased. The GI symptoms improved, but he still experienced bloating. The patient�s diet consisted mostly of meats, fruit, vegetables, gluten-free grains, eggs, and dairy.
At the age of 24, the patient was diagnosed with WA after seeing his physician for allergies. Serum testing revealed elevated IgE antibodies against wheat, and the patient was advised to adhere to a strict GFD. The patient admits to not following a GFD until his fasciculations peaked in December 2011. In July of 2012, blood work was evaluated for levels of creatine kinase, creatine kinase�MB, and lactate dehydrogenase to investigate possible muscle breakdown. All values were within normal limits. In September of 2012, the patient under- went food allergy testing once again (US Biotek, Seattle, WA). Severely elevated IgG antibody levels were found against cow�s milk, whey, chicken egg white, duck egg white, chicken egg yolk, duck egg yolk, barley, wheat gliadin, wheat gluten, rye, spelt, and whole wheat (Table 1). Given the results of the food allergy panel, the patient was recommended to remove this list of foods from his diet. Within 6 months of complying with the dietary changes, the patient�s muscle fasciculations completely resolved. The patient also experienced much less GI distress, fatigue, and lack of concentration.
Discussion
The authors could not find any published case studies related to a presentation such as the one�described here. We believe this is a unique presentation of wheat protein reactivity and thereby represents a contribution to the body of knowledge in this field.
This case illustrates an unusual presentation of a widespread sensorimotor neuropathy that seemed to respond to dietary changes. Although this presentation is consistent with gluten neuropathy, a diagnosis of CD was not investigated. Given the patient had both GI and neurologic symptoms, the likelihood of gluten neuropathy is very high.
There are 3 forms of wheat protein reactivity. Because there was confirmation of WA and GS, it was decided that testing for CD was unnecessary. The treatment for all 3 forms is identical: GFD.
The pathophysiology of gluten neuropathy is a topic that needs further investigation. Most authors agree it involves an immunologic mechanism, possibly a direct or indirect neurotoxic effect of antigliadin anti- bodies. 9,10 Briani et al 11 found antibodies against ganglionic and/or muscle acetylcholine receptors in 6 of 70 CD patients. Alaedini et al12 found anti-ganglioside antibody positivity in 6 of 27 CD patients and proposed that the presence of these antibodies may be linked to gluten neuropathy.
It should also be noted that both dairy and eggs showed high responses on the food sensitivity panel. After reviewing the literature, no studies could be located linking either food with neuromuscular symp- toms consistent with the ones presented here. There- fore, it is unlikely that a food other than gluten was responsible for the muscle fasciculations described in this case. The other symptoms described (fatigue, brain fog, GI distress) certainly may be associated with any number of food allergies/sensitivities.
Limitations
One limitation in this case is the failure to confirm CD. All symptoms and responses to dietary change point to this as a likely possibility, but we cannot confirm this diagnosis. It is also possible that the�symptomatic response was not due directly to dietary change but some other unknown variable. Sensitivity to foods other than gluten was documented, including reactions to dairy and eggs. These food sensitivities may have contributed to some of the symptoms present in this case. As is the nature of case reports, these results cannot necessarily be generalized to other patients with similar symptoms.
Conclusion:�Muscle Fasciculations
This report describes improvement in chronic, widespread muscle fasciculations and various other systemic symptoms with dietary change. There is strong suspicion that this case represents one of gluten neuropathy, although testing for CD specifically was not performed.
Brian Anderson DC, CCN, MPHa,?, Adam Pitsinger DCb
Attending Clinician, National University of Health Sciences, Lombard, IL Chiropractor, Private Practice, Polaris, OH
Acknowledgment
This case report is submitted as partial fulfillment of the requirements for the degree of Master of Science in Advanced Clinical Practice in the Lincoln College of Post-professional, Graduate, and Continuing Education at the National University of Health Sciences.
Funding Sources and Conflicts of Interest
No funding sources or conflicts of interest were reported for this study.
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Obesity is a complex, multifactorial disease, and better understanding of the mechanisms underlying the interactions between lifestyle, environment, and genetics is critical for developing effective strategies for prevention and treatment [1].
Animal models provide unique opportunities for highly controlled studies that provide mechanistic insight into�the role of specific epigenetic marks, both as indicators of current metabolic status and as predictors of the future risk of obesity and metabolic disease. A particularly important aspect of animal studies is that they allow for the assessment of epigenetic changes within target tissues, including the liver and hypothalamus, which is much more difficult in humans. Moreover, the ability to harvest large quantities of fresh tissue makes it possible to assess multiple chromatin marks as well as DNA methylation. Some of these epigenetic modifications either alone or in combination may be responsive to environmental programming. In animal models, it is also possible to study multiple generations of offspring and thus enable differentiation between trans-generational and intergenerational transmission of obesity risk mediated by epigenetic memory of parental nutritional status, which cannot be easily distinguished in human studies. We use the former term for meiotic transmission of risk in the absence of continued exposure while the latter primarily entails direct transmission of risk through metabolic reprogramming of the fetus or gametes.
(i) Epigenetic Changes In Offspring Associated With Maternal Nutrition During Gestation
Maternal nutritional supplementation, undernutrition, and over nutrition during pregnancy can alter fat deposition and energy homeostasis in offspring [11, 13�15, 19]. Associated with these effects in the offspring are changes in DNA methylation, histone post-translational modifications, and gene expression for several target genes,�especially genes regulating fatty acid metabolism and insulin signaling [16, 17, 20�30]. The diversity of animal models used in these studies and the common metabolic pathways impacted suggest an evolutionarily conserved adaptive response mediated by epigenetic modification. However, few of the specific identified genes and epigenetic changes have been cross-validated in related studies, and large-scale genome-wide investigations have typically not been applied. A major hindrance to comparison of these studies is the different develop mental windows subjected to nutritional challenge, which may cause considerably different outcomes. Proof that the epigenetic changes are causal rather than being associated with offspring phenotypic changes is also required. This will necessitate the identification of a parental nutritionally induced epigenetic �memory� response that precedes development of the altered phenotype in offspring.
Emerging studies have demonstrated that paternal plane of nutrition can impact offspring fat deposition and epigenetic marks [31�34]. One recent investigation using mice has demonstrated that paternal pre-diabetes leads to increased susceptibility to diabetes in F1 offspring with associated changes in pancreatic gene expression and DNA methylation linked to insulin signaling [35]. Importantly, there was an overlap of these epigenetic changes in pancreatic islets and sperm suggesting germ line inheritance. However, most of these studies, although intriguing in their implications, are limited in the genomic scale of investigation and frequently show weak and somewhat transient epigenetic alterations associated with mild metabolic phenotypes in offspring.
Stable transmission of epigenetic information across multiple generations is well described in plant systems and C. elegans, but its significance in mammals is still much debated [36, 37]. An epigenetic basis for grand- parental transmission of phenotypes in response to dietary exposures has been well established, including in livestock species [31]. The most influential studies demonstrating effects of epigenetic transmission impacting offspring phenotype have used the example of the viable yellow agouti (Avy) mouse [38]. In this mouse, an insertion of a retrotransposon upstream of the agouti gene causes its constitutive expression and consequent yellow coat color and adult onset obesity. Maternal transmission through the germ line results in DNA methylation�mediated silencing of agouti expression resulting in wild-type coat color and lean phenotype of the offspring [39, 40]. Importantly, subsequent studies in these mice demonstrated that maternal exposure to methyl donors causes a shift in coat color [41]. One study has reported transmission of a phenotype to the F3 generation and alterations in expression of large number of genes in response to protein restriction in F0 [42]; however, alterations in expression were highly variable and a direct link to epigenetic changes was not identified in this system.
While many studies have identified diet-associated epigenetic changes in animal models using candidate site-specific regions, there have been few genome-wide analyses undertaken. A recent study focussed on determining the direct epigenetic impact of high-fat diets/ diet-induced obesity in adult mice using genome-wide gene expression and DNA methylation analyses [43]. This study identified 232 differentially methylated regions (DMRs) in adipocytes from control and high-fat fed mice. Importantly, the corresponding human regions for the murine DMRs were also differentially methylated in adipose tissue from a population of obese and lean humans, thereby highlighting the remarkable evolutionary conservation of these regions. This result emphasizes the likely importance of the identified DMRs in regulating energy homeostasis in mammals.
(i) Genetic association studies. Genetic polymorphisms that are associated with an increased risk of developing particular conditions are a priori linked to the causative genes. The presence of differential�methylation in such regions infers functional relevance of these epigenetic changes in controlling expression of the proximal gene(s). There are strong cis-acting genetic effects underpinning much epigenetic variation [7, 45], and in population-based studies, methods that use genetic surrogates to infer a causal or mediating role of epigenome differences have been applied [7, 46�48]. The use of familial genetic information can also lead to the identification of potentially causative candidate regions showing phenotype-related differential methylation [49].
From these studies, altered methylation of PGC1A, HIF3A, ABCG1, and CPT1A and the previously described RXRA [18] have emerged as biomarkers associated with, or perhaps predictive of, metabolic health that are also plausible candidates for a role in development of metabolic disease.
Epigenetic variation is highly influenced by the underlying genetic variation, with genotype estimated to explain ~20�40 % of the variation [6, 8]. Recently, a number of studies have begun to integrate methylome and genotype data to identify methylation quantitative trait loci (meQTL) associated with disease phenotypes. For instance, in adipose tissue, an meQTL overlapping�with a BMI genetic risk locus has been identified in an enhancer element upstream of ADCY3 [8]. Other studies have also identified overlaps between known obesity and T2DM risk loci and DMRs associated with obesity and T2DM [43, 48, 62]. Methylation of a number of such DMRs was also modulated by high-fat feeding in mice [43] and weight loss in humans [64]. These results identify an intriguing link between genetic variations linked with disease susceptibility and their association with regions of the genome that undergo epigenetic modifications in response to nutritional challenges, implying a causal relationship. The close connection between genetic and epigenetic variation may signify their essential roles in generating individual variation [65, 66]. However, while these findings suggest that DNA methylation may be a mediator of genetic effects, it is also important to consider that both genetic and epigenetic processes could act independently on the same genes. Twin studies [8, 63, 67] can provide important insights and indicate that inter-individual differences in levels of DNA methylation arise predominantly from non-shared environment and stochastic influences, minimally from shared environmental effects, but also with a significant impact of genetic variation.
Prenatal environment: Two recently published studies made use of human populations that experienced �natural� variations in nutrient supply to study the impact of maternal nutrition before or during pregnancy on DNA methylation in the offspring [68, 69]. The first study used a Gambian mother-child cohort to show that both seasonal variations in maternal methyl donor intake during pregnancy and maternal pre-pregnancy BMI were associated with altered methylation in the infants [69]. The second study utilized adult offspring from the Dutch Hunger Winter cohort to investigate the effect of prenatal exposure to an acute period of severe maternal undernutrition on DNA methylation of genes involved in growth and metabolism in adulthood [68]. The results highlighted the importance of the timing of the exposure in its impact on the epigenome, since significant epigenetic effects were only identified in individuals exposed to famine during early gestation. Importantly, the epigenetic changes occurred in conjunction with increased BMI; however, it was not possible to establish in this study whether these changes were present earlier in life or a consequence of the higher BMI.
Postnatal environment: The epigenome is established de novo during embryonic development, and therefore, the prenatal environment most likely has the most significant impact on the epigenome. However, it is now clear that changes do occur in the �mature� epigenome under the influence of a range of conditions, including aging, exposure to toxins, and dietary alterations. For example, changes in DNA methylation in numerous genes in skeletal muscle and PGC1A in adipose tissue have been demonstrated in response to a high-fat diet [75, 76]. Interventions to lose body fat mass have also been associated with changes in DNA methylation. Studies have reported that the DNA methylation profiles of adipose tissue [43, 64], peripheral blood mononuclear cells [77], and muscle tissue [78] in formerly obese patients become more similar to the profiles of lean subjects following weight loss. Weight loss surgery also partially reversed non-alcoholic fatty liver disease-associated methylation changes in liver [79] and in another study led to hypomethylation of multiple obesity candidate genes, with more pronounced effects in subcutaneous compared to omental (visceral) fat [64]. Accumulating evidence suggests that exercise interventions can also influence DNA methylation. Most of these studies have been conducted in lean individuals [80�82], but one exercise study in obese T2DM subjects also demonstrated changes in DNA methylation, including in genes involved in fatty acid and glucose transport [83]. Epigenetic changes also occur with aging, and recent data suggest a role of obesity in augmenting them [9, 84, 85]. Obesity accelerated the epigenetic age of liver tissue, but in contrast to the findings described above, this effect was not reversible after weight loss [84].
DNA methylation changes associated with obesity or induced by diet or lifestyle interventions and weight loss are generally modest (<15 %), although this varies depending on the phenotype and tissue studied. For instance, changes greater than 20 % have been reported in adipose tissue after weight loss [64] and associations between HIF3A methylation and BMI in adipose tissue were more pronounced than in blood [52].
Conclusions
Nutrition is increasingly recognized as a key component of optimal sporting performance, with both the science and practice of sports nutrition developing rapidly.1 Recent studies have found that a planned scientific nutritional strategy (consisting of fluid, carbohydrate, sodium, and caffeine) compared with a self-chosen nutritional strategy helped non-elite runners complete a marathon run faster2 and trained cyclists complete a time trial faster.3 Whereas training has the greatest potential to increase performance, it has been estimated that consumption of a carbohydrate�electrolyte drink or relatively low doses of caffeine may improve a 40 km cycling time trial performance by 32�42 and 55�84 seconds, respectively.4
Carbohydrate ingestion has been shown to improve performance in events lasting approximately 1 hour.6 A growing body of evidence also demonstrates beneficial effects of a carbohydrate mouth rinse on performance.22 It is thought that receptors in the oral cavity signal to the central nervous system to positively modify motor output.23
The �train-low, compete-high� concept is training with low carbohydrate availability to promote adaptations such as�enhanced activation of cell-signaling pathways, increased mitochondrial enzyme content and activity, enhanced lipid oxidation rates, and hence improved exercise capacity.26 However, there is no clear evidence that performance is improved with this approach.27 For example, when highly trained cyclists were separated into once-daily (train-high) or twice-daily (train-low) training sessions, increases in resting muscle glycogen content were seen in the low-carbohydrate- availability group, along with other selected training adaptations.28 However, performance in a 1-hour time trial after 3 weeks of training was no different between groups. Other research has produced similar results.29 Different strategies have been suggested (eg, training after an overnight fast, training twice per day, restricting carbohydrate during recovery),26 but further research is needed to establish optimal dietary periodization plans.27
There has been a recent resurgence of interest in fat as a fuel, particularly for ultra endurance exercise. A high-carbohydrate strategy inhibits fat utilization during exercise,30 which may not be beneficial due to the abundance of energy stored in the body as fat. Creating an environment that optimizes fat oxidation potentially occurs when dietary carbohydrate is reduced to a level that promotes ketosis.31 However, this strategy may impair performance of high-intensity activity, by contributing to a reduction in pyruvate dehydrogenase activity and glycogenolysis. 32 The lack of performance benefits seen in studies investigating �high-fat� diets may be attributed to inadequate carbohydrate restriction and time for adaptation.31 Research into the performance effects of high fat diets continues.
While protein consumption prior to and during endurance and resistance exercise has been shown to enhance rates of muscle protein synthesis (MPS), a recent review found protein ingestion alongside carbohydrate during exercise does not improve time�trial performance when compared with the ingestion of adequate amounts of carbohydrate alone.33
The purpose of fluid consumption during exercise is primarily to maintain hydration and thermoregulation, thereby benefiting performance. Evidence is emerging on increased risk of oxidative stress with dehydration.34 Fluid consumption prior to exercise is recommended to ensure that the athlete is well-hydrated prior to commencing exercise.35 In addition,�carefully planned hyperhydration ( fluid overloading) prior to an event may reset fluid balance and increase fluid retention, and consequently improve heat tolerance.36 However, fluid overloading may increase the risk of hyponatremia 37 and impact negatively on performance due to feelings of fullness and the need to urinate.
Performance supplements shown to enhance performance include caffeine, beetroot juice, beta-alanine (BA), creatine, and bicarbonate.40 Comprehensive reviews on other supplements including caffeine, creatine, and bicarbonate can be found elsewhere.41 In recent years, research has focused on the role of nitrate, BA, and vitamin D and performance. Nitrate is most commonly provided as sodium nitrate or beetroot juice.42 Dietary nitrates are reduced (in mouth and stomach) to nitrites, and then to nitric oxide. During exercise, nitric oxide potentially influences skeletal muscle function through regulation of blood ow and glucose homeostasis, as well as mitochondrial respiration.43 During endurance exercise, nitrate supplementation has been shown to increase exercise efficiency (4%�5% reduction in VO at a steady attenuate oxidative stress.42 Similarly, a 4.2% improvement in performance was shown in a test designed to simulate a football game.44
Consuming carbohydrates immediately 
An acute bout of intense endurance or resistance exercise can induce a transient increase in protein turnover, and, until feeding, protein balance remains negative. Protein consumption after exercise enhances MPS and net protein balance,58 predominantly by increasing mitochondrial protein fraction with endurance training, and myofibrillar protein fraction with resistance training.59
Fluid and electrolyte replacement after exercise can be achieved through resuming normal hydration practices. However, when euhydration is needed within 24 hours or substantial body weight has been lost (.5% of BM), a more structured response may be warranted to replace fluids and electrolytes.77
The availability of nutrition information for athletes varies. Younger or recreational athletes are more likely to receive generalized nutritional information of poorer quality from individuals such as coaches.78 Elite athletes are more likely to have access to specialized sports-nutrition input from qualified professionals. A range of sports science and medicine support systems are in place in different countries to assist elite athletes,1 and nutrition is a key component of these services. Some countries have nutrition programs embedded within sports institutes (eg, Australia) or alternatively have National Olympic Committees that support nutrition programs (eg, United States of America).1 However, not all athletes at the elite level have access to sports-nutrition services. This may be due to financial constraints of the sport, geographical issues, and a lack of recognition of the value of a sports-nutrition service.78
Supplement use is widespread in athletes.86,87 For example, 87.5% of elite athletes in Australia used dietary supplements88 and 87% of Canadian high-performance athletes took dietary supplements within the past 6 months85 (Table 2). It is difficult to compare studies due to differences in the criteria used to define dietary supplements, variations in assessing supplement intake, and disparities in the populations studied.85
A positive drug test in an athlete can occur with even a minute quantity of a banned substance.41,87 WADA maintains a �strict liability� policy, whereby every athlete is responsible for any substance found in their body regardless of how it got there.41,86,87,89 The World Anti-Doping Code (January 1, 2015) does recognize the issue of contaminated supplements.91 Whereas the code upholds the principle of strict liability, athletes may receive a lesser ban if they can��show �no significant fault� to demonstrate they did not intend to cheat. The updated code imposes longer bans on those who cheat intentionally, includes athlete support personnel (eg, coaches, medical staff), and has an increased focus on anti-doping education.91,99
