Multiple sclerosis, or MS, is a chronic disease of the central nervous system, or CNS. While the etiology of the disease remains unknown, research studies have found that environmental factors, such as nutrition, may have an impact on the occurrence and development of MS. Other research studies specifically analyzed the association between certain dietary factors in multiple sclerosis, such as fat, dairy and meat consumption. Multiple sclerosis, or MS, epidemiology suggests that dairy is primarily involved in the clinical expression of the disease. The purpose of the following article is to show the effects of cow’s milk allergy in multiple sclerosis patients.
Contents
Abstract
Background: Exposure to some environmental agent such as different nutrition and contact with allergens may have a role in developing multiple sclerosis (MS). The present study was aimed to evaluate the cow’s milk allergy (CMA) in MS patients compared to healthy controls.
Materials and Methods: Between March 2012 and July 2012, 48 MS patients were selected and compared with 48 healthy subjectsto assess the frequency of CMA in MS patients compared to healthy control. Cow’s milk specific immunoglobin E (IgE) was determined by Immuno CAP. Sex and the frequency of CMA were compared between study groups by Chi-square test.
Results: Total of 96 subjects were assessed (22% male and 78% female). The mean age of the study subjects was 30.8 � 6.6 years. Mean age of case and control groups was 30.7 (�6.9) versus 30.9 � 6.3, respectively (P value = 0.83). There were no detection of cow’s milk specific IgE in serum of MS patients and healthy subjects.
Conclusion: There was no difference between MS and healthy subjects regarding CMA.
Keywords:Allergy, cow’s milk, multiple sclerosis
Introduction
Multiple sclerosis (MS) is achronic inflammatory demyelinating disease of the central nervous system (CNS)[1] and it is one among the common causes of neurological disability in young adults especially, women.[2] Autoimmune processes due to defects in regulatory T cells and failing of suppression auto-reactive CD4+ and CD8+ cells is suggested have a role in pathogenesis of disease.[3]
Although, the etiology of MS is unknown, there are some evidences for convolution with both genetic and environmental influences on susceptibility. Relative vitamin D deficiency,[4,5] Epstein-Barr virus,[6] and smoking[7] are among environmental factors that all have been associated with increased susceptibility to MS. Nutrition is another environmental factor thatpossibly involved in pathogenesis of MS.[8] Furthermore, dietary factors are frequently mentioned as a possible cause, there are very few clinical trials based on specific diets or dietary supplements in MS and there is no evidence in this respect.[9] Higher intake of different food compounds were considered to be associated with increased risk of MS[9] such as sweets,[10] alcohol,[11,12,13] smoked meat products,[10] coffee, tea,[11] and yet, none of these data were approved by subsequent studies. In 1991, in a study, it has been reported that dietary factors or food allergies may be among major causes of MS beginning and progression.[14] In the other hand, vitamin D has been implicated as being a risk-factor in MS,[15,16,17] and it is reported that decreased levels of 25-hydroxyvitamin D are associated with an increased risk to develop MS.[18] Furthermore, the totality of evidence for a protective role of vitamin D in MS has been supposed strong enough by some to warrant recommending vitamin D supplementation to people with MS.[19] Cow’s milk allergy (CMA) has an indirect potential to cause 25-hydroxyvitamin D deficiency from affected individuals tend to avoid dairy of cow’s milk products.[20]
In infancy, cow’s milkis the most frequently encountered dietary allergen, and the incidence of CMA varies with age.[21] In infants and adult the reported prevalence of CMA varies between studies; however, it is clear that CMA is common allergy in early childhood, with a prevalence of 2-6%,[22] and decreases with age.[23]
It is believed that exposure to some environmental agent that occurs before puberty may begin autoimmune process and pre-dispose a genetically susceptible person to develop MS later on. Based on this fact, the hypothesis of a link between milk consumption and MS has been considered since many years ago and epidemiological studies were carried out to support this correlation.[24]
It is considered that improvement of immunological defenses effect on treatment of MS patients, therefore, detection of allergens and elimination of them from the diet could decrease disability of patients,
The present study was aimed to evaluate the CMA in MS patients compared to healthy controls.
Materials and Methods
Between March 2012 and July 2012, 48 MS patients (referring to MS clinic of the referral universityhospital in Isfahan) were selected and compared with 48 healthy subjects (among patients� companions and acquaintances as control group) to assess the association between CMA and MS. MS patients were diagnosed to definitely develop MS according to the McDonald Criteria.[25] Patients were eligible if they had not received corticosteroids during last month and immunosuppressants over the last 3 months. This study was investigated and approved by the ethics committee at the Isfahan University of Medical Sciences and all subjects were explained about the aim and the purposes of the study and written informed consent was obtained from all of them.
Controls were matched with the patients in regard to age and gender. To determine the allergen-specific immunoglobin E (IgE) of cow’s milk, blood samples were taken from both groups of subjects and serum samples were transferred to the laboratory of Immunology.
ImmunoCAP (Phadia, Uppsala, Sweden) was used for allergen-specific IgE antibody in the serum of the subjects to be obtained. This technique is approved by Food and Drug Administration in US and has high-sensitivity and many good features[26,27,28] also in Iran are applicable only in the Asthma and Allergy Research Institute, Tehran University of Medical Sciences. Moreover, specific IgE antibody against cow’s milk was determined and applying statistical techniques, calculations were performed and results were extracted.
Data are presented as means � standard deviation or number (%) as appropriate. Independent sample t-test was used to compare age between groups. Furthermore, sex and the frequency of CMA were compared between study groups by Chi-square test. All analysis was carried out by the Statistical Package for the Social Sciences (SPSS)-20 and statistical significance was accepted at P < 0.05.
Multiple sclerosis, or MS, is a multifactorial, inflammatory, and neurodegenerative disease of the central nervous system which has been demonstrated to be closely associated with environmental factors like nutrition. Recent research studies on the role of diet in MS provided evidence that certain dietary factors, such as the consumption of dairy products like cow’s milk, influence multiple sclerosis incidence, disease course and symptomatology. According to these research studies, particular types of proteins found in cow’s milk have been demonstrated to stimulate the immune system of people with MS.
Dr. Alex Jimenez D.C., C.C.S.T.
Results
A total of 96 subjects were assessed and results of all blood samples were analyzed. On the total subjects, 22% were male and 78% were female and the mean age of the study subjects was 30.8 � 6.6 years. Table 1 shows the comparison of age, gender, and the frequency of CMA between study groups. As shown mean age of in case and control groups was similar and there was no statistical significant difference between groups (30.7 � 6.9 vs. 30.9 � 6.3 respectively, P value = 0.83). Of 22 male subjects, 50% were MS patients and 50% were controls. There was no significant difference between study groups in regard to gender composition. Results of CAP technique to determined allergen-specific IgE antibody against cow’s milk in MS patients and healthy subjects showed that, there was no any positive CMA in these subjects and there was no difference between MS patients and healthy subjects.
Discussion
Since many years ago the effect of diet such as fat intake in MS has been postulated.[29] There is a higher extent consumption of saturated fat, dairy products, and cornflakes (cereals) and a decrease in the consumption of unsaturated fat in area with high prevalence of MS.[29]
Though, the findings of these studieswere not confirmed by a large number of case-control studies, epidemiological studies have proposed the association between MS prevalence and animal fat consumption.[11,12,13] Because MS is believed to have an autoimmune basis, many factors such as dietary can induce autoimmunity and myelin breakdown by molecular mimicry.[30]
It seems that molecular mimicry may disrupt immunological self-tolerance to CNS myelin antigens in genetically susceptible individuals. CMA is one of the most common food allergen in infancy. It seems that immune system identifies some of proteins of milk as harmful and makes IgE antibodies to neutralize it. IgE antibodies recognize these proteins in next contact and signal the immune system to release some chemicals.[31]
Therefore, cow’s milk as a dietary protein has potential molecular mimicry with myelin autoantigens and may induce autoimmune process, so consumption of milk in MS patients may have a possible role in progression or relapse of disease. Furthermore, as mentioned earlier, vitamin D has been implicated as being a risk-factor in MS patients[18] and CMA transmits nutritional implications as affected individuals have a tendency to evade dairy products and have been shown to be lacking in 25-hydroxyvitamin D.[20]
Measurement of specific IgE confirmed an IgE-mediated sensitivity to cow’s milk and is a prognostic marker for persistence of CMA.[31]
In present study, we evaluated the cow’s milk IgE to find allergy to milk in MS patients compare to control as a marker of persistence CMA. The result of study did not show positive CMA in MS group and no difference between MS patients and control subjects.
Our findings was similar to result of Ramagopalan et al. study.[32] Ramagopalan, in a population-based cohort in 2010, investigated whether or not childhood CMA influences the subsequent risk to develop MS. They collected data by telephone interview from mothers of 6638 MS index cases and 2509 spouse controls in Canada and compared the frequency of CMA between index cases and controls and could not find any significant differences. Therefore, author concluded that childhood CMA does not appear to be a risk-factor for MS.
Another study suggested that factors of liquid cow milk influence on the clinical appearance of MS.[25]
Although, medical interest in the influence of diet on the rate and severity of MS disease were carried out,[33] as our best knowledge, there are few studies in food allergens and MS, so further studies are suggested to be carried out to investigate food allergens, in a large number of MS patients and healthy individuals based on individuals recall, then positive responses assess using advanced technique and results compared between MS patients and healthy subjects.
In summary, findings of our study investigated that there is no difference between subjects developing MS and healthy subjects regarding CMA and we could not find any association between CMA and MS.
Conclusion
This study evaluated the frequency distribution of cow milk allergy in MS patients compared to healthy controls. Although, there was no significant difference between two groups, the small sample size of MS patients may effect on the association of this hypothesis.
Footnotes
Source of Support: Nil
Conflict of Interest: None declared.
Multiple sclerosis, or MS, is a chronic disease of the central nervous system, or CNS which is believed to be associated with environmental factors, such as nutrition. Research studies analyzing the association between certain dietary factors in multiple sclerosis demonstrated that dairy is primarily involved in the clinical expression of multiple sclerosis. The purpose of the article above was to show the effects of cow’s milk allergy in multiple sclerosis patients. According to the research study, dairy may have some effect on the prevalence of MS, although further research studies are still required to further conclude these findings. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
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Additional Topic Discussion:�Acute Back Pain
Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.
Vincent Garcia trains in martial arts as a part of his activities. However, after he developed turf toe and he started to undergo knee pain, Vincent’s performance was affected. Dr. Alex Jimenez, a doctor of chiropractic, helped treat Vincent Garcia’s knee pain along with turf toe, gradually restoring his overall health and well-being. Dr. Alex Jimenez has also helped treat a variety of other sport-related injuries. Chiropractic care utilized corrections and manipulations that were manual to carefully restore the original integrity of the backbone, allowing the human body to heal itself. Vincent Garcia highly recommends Dr. Alex Jimenez as the non-invasive pick for many different accidents and/or conditions, including several sports accidents, among other problems.
Many healthcare professionals highly recommend that patients with multiple sclerosis, or MS, avoid dairy. Several research studies have demonstrated a high correlation between MS and dairy, especially cow�s milk. By way of instance, some of the proteins in cow�s milk are targeted by the immune cells of patients with multiple sclerosis. These include butyrophilin and bovine serum albumin, or BSA. Moreover, injecting those same cow�s milk proteins into test animals caused lesions to appear in their central nervous systems.
Some proteins in cow�s milk imitate part of the myelin oligodendrocyte glycoprotein, or MOG, the section of myelin believed to initiate the autoimmune reaction associated with multiple sclerosis. Furthermore, this can trick the immune system into initiating an attack on the MOG, subsequently causing demyelination. Another research study involving more than 135,000 men and women in the United States determined a connection between cow�s milk and the degenerative neurological disorder, Parkinson�s Disease. Researchers have speculated that dairy products, especially cow’s milk, may have a generally toxic effect on nervous tissue.
Lactose intolerance is common throughout the general population, and it is most notably frequent in Mediterranean, Asian, and African populations. People with lactose intolerance experience a variety of symptoms, including bloating, cramps, diarrhea, and nausea. Given the high potential risks for people with MS consuming dairy products, despite a lack of conclusive evidence, healthcare professionals recommend avoiding the consumption of dairy products, among other types of foods. The purpose of the article below is to discuss the nutrition facts in multiple sclerosis, including which types of foods patients with MS should avoid, such as dairy.
Contents
Abstract
The question whether dietary habits and lifestyle have influence on the course of multiple sclerosis (MS) is still a matter of debate, and at present, MS therapy is not associated with any information on diet and lifestyle. Here we show that dietary factors and lifestyle may exacerbate or ameliorate MS symptoms by modulating the inflammatory status of the disease both in relapsing-remitting MS and in primary-progressive MS. This is achieved by controlling both the metabolic and inflammatory pathways in the human cell and the composition of commensal gut microbiota. What increases inflammation are hypercaloric Western-style diets, characterized by high salt, animal fat, red meat, sugar-sweetened drinks, fried food, low fiber, and lack of physical exercise. The persistence of this type of diet upregulates the metabolism of human cells toward biosynthetic pathways including those of proinflammatory molecules and also leads to a dysbiotic gut microbiota, alteration of intestinal immunity, and low-grade systemic inflammation. Conversely, exercise and low-calorie diets based on the assumption of vegetables, fruit, legumes, fish, prebiotics, and probiotics act on nuclear receptors and enzymes that upregulate oxidative metabolism, downregulate the synthesis of proinflammatory molecules, and restore or maintain a healthy symbiotic gut microbiota. Now that we know the molecular mechanisms by which dietary factors and exercise affect the inflammatory status in MS, we can expect that a nutritional intervention with anti-inflammatory food and dietary supplements can alleviate possible side effects of immune-modulatory drugs and the symptoms of chronic fatigue syndrome and thus favor patient wellness.
Keywords:complementary alternative medicine, gut microbiota, inflammation, lifestyle, multiple sclerosis, nutrition
Introduction
Multiple sclerosis (MS) is a chronic, inflammatory, and autoimmune disease of the central nervous system (CNS), leading to widespread focal degradation of the myelin sheath, variable axonal and neuronal injury, and disabilities in young adults, mostly women. The disease is characterized by disseminated and heterogeneous perivascular inflammatory processes at the blood�brain barrier (BBB), with involvement of autoreactive T cells, B lymphocytes, macrophages, and microglial cells against brain and spinal cord white matter (McFarland and Martin, 2007; Constantinescu and Gran, 2010; Kutzelnigg and Lassmann, 2014).
Antibodies (Krumbholz et al., 2012), activated complement (Ingram et al., 2014), cytokines, mitochondrial dysfunction (Su et al., 2009), reactive oxygen species (ROS; Gilgun-Sherki et al., 2004), and matrix metalloproteinases (MMPs; Liuzzi et al., 2002; Rossano et al., 2014) may cooperate to yield the pathology.
From the clinical point of view, there are at least two main forms of the disease: the relapsing-remitting MS (RRMS; about 85% of clinical cases) and the primary-progressive MS (PPMS; about 15% of the clinical cases) (Dutta and Trapp, 2014; Lublin et al., 2014). In RRMS, which usually evolves in secondary-progressive MS (SPMS), relapses are associated with increased systemic inflammation and formation of lesions in the brain, followed by more or less complete remissions, whereas the pathogenesis of PPMS is characterized by progressive neurological damages rather than relapses and remissions.
At present, there are at least 10 disease-modifying therapies that have been found to slow disease progression and prevent some disability symptoms, but only in the case of RRMS. However, as the disease is complex in nature and unique in the individual course, no patient responds to therapy in the same way (Loleit et al., 2014). Similarly, there are no truly reliable biomarkers that allow for everyone to evaluate the effectiveness of treatment and it is therefore important to discover novel markers of the disease (Fernandez et al., 2014).
The lack of response to immune-modulatory therapies in the case of PPMS, otherwise effective in the treatment of RRMS, may be due to different pathogenic mechanisms acting in RRMS and PPMS. However, this is not true with regard to inflammation: A significant association between inflammation and neurodegeneration has been observed in the brain not only in acute and relapsing MS but also in the secondary and primary progressive MS (Frischer et al., 2009; Lassmann, 2013), and active MS lesions are always associated with inflammation (Kutzelnigg and Lassmann, 2014). Thus, inflammation must be the target for the treatment of both forms of the disease.
Linking Inflammation with Dietary Habits and Lifestyle
What causes the inflammatory processes in MS? MS is a complex disease, and the genetic and the immunological components are not sufficient to explain its origin. Actually, MS has a multifactorial nature and various environmental factors or metabolic conditions may have a role in its development (Ascherio, 2013): viral infections (Ascherio et al., 2012; Venkatesan and Johnson, 2014), heavy metal poisoning (Latronico et al., 2013; Zanella and Roberti di Sarsina, 2013), smoking (Jafari and Hintzen, 2011), childhood obesity (Munger, 2013), low vitamin D status (Ascherio et al., 2014), or incorrect lifestyle, including wrong dietary habits (Riccio, 2011; Riccio et al., 2011; Riccio and Rossano, 2013).
None of the above-mentioned environmental factors alone can explain the disease; however, the following considerations make more attractive the involvement in MS of dietary habits and lifestyle, rather than infections or smoking, as factors that may influence the course of the disease:
Geographical distribution: MS is more prevalent in Western countries with the highest income and most distant of the equator. Features of these countries are a sedentary lifestyle, a high-calorie diet rich in saturated fats of animal origin (Western diet), and low sunshine exposure (WHO and MSIF, 2008).
Effect of migration: With the migration from an area of high incidence of MS to another place with low incidence before age of 15 years, the low risk is acquired, while the migration after this age does not change the level of risk. This aspect may be linked with nutritional, rather than with infectious or toxicological environmental factors (McLeod et al., 2011).
Low availability of vitamin D: Another environmental factor related to diet and geographical distribution is the availability of vitamin D, which is lower at latitudes with lower exposure to sunlight. Patients with MS have a low content of vitamin D (Ascherio et al., 2014), but this is true also for other chronic inflammatory diseases (Yin and Agrawal, 2014).
Postprandial inflammation: High animal fat/high sugar and refined carbohydrate diet is associated with postprandial inflammation (Erridge et al., 2007; Ghanim et al., 2009; Margioris, 2009).
High body mass index: High body mass index (BMI) before age 20 is associated with 2� increased risk (Hedstr�m et al., 2012). Note that BMI is correlated with gut microbiota status.
Similarity with other inflammatory diseases related to wrong dietary habits: MS has some similarities with inflammatory bowel disease (IBD; Cantorna, 2012): both have low vitamin D and are influenced from environmental factors (Dam et al., 2013). Furthermore, glatiramer acetate (GA, or Copolymer 1/Copaxone) is beneficial in both diseases (Aharoni, 2013) and there is an increased incidence of IBD among MS patients.
How Food Affects the Course of Inflammatory Diseases: A Basic Approach
The observations reported above suggest that the nutritional status may influence the course of MS. However, the question arises of how dietary molecules could exacerbate or ameliorate MS symptoms, and in general how they could favor or downregulate inflammation at molecular level. In particular, it is important to clarify what are the targets of dietary molecules and the molecular mechanisms involved, if any.
Fundamentally, we can say that the food we consume has a broad impact on our development, behavior, health condition, and lifespan by acting on two main targets: (A) the cells of our body and (B) the commensal gut microbiota (Figure 1).
On one hand, different kind and amount of dietary factors can interact with enzymes, transcription factors, and nuclear receptors of human cells. This may induce specific modifications of cellular metabolism toward either catabolism or anabolism and modulate the inflammatory and autoimmune responses in our body (Desvergne et al., 2006).
On the other hand, we have to consider the impact of diet and lifestyle on our intestinal microflora. We are indeed metaorganisms living with trillions (1014) of microbial cells (roughly 10 times the cells of our body) and thousands of different microorganisms known as the gut microbiota. This complex ecosystem is an essential part of our organism and influences both our immune system and our metabolism. Therefore, it has a strong impact on our health.
In health, there is a close mutualistic and symbiotic relationship between gut microbiota and humans, and gut microbiota provides a number of useful metabolic functions, protects against enteropathogens, and contributes to normal immune functions. This is the normal state of the human intestinal microbiota, called eubiosis. Distortion from eubiosis, linked with a decrease of intestinal biodiversity and increase of pathogenic bacteria, is called dysbiosis. The most common consequence of a dysbiotic gut microbiota is the alteration of the mucosal immune system and the rise of inflammatory, immune, metabolic, or degenerative diseases (Chassaing and Gewirtz, 2014).
Different kinds and amounts of dietary factors elicit the selection of specific gut microbial populations changing type and number of microbial species toward eubiosis or dysbiosis, simply acting through the preferential feeding of one or the other microbial population. If our diet favors the change to a dysbiotic gut microbiota, this may lead to gut inflammation, alteration of intestinal immunity, and then to systemic inflammation and chronic inflammatory diseases.
How Dietary Factors Influence the Metabolism of Human Cells and Modulate Inflammation
To understand how dietary molecules can directly influence the metabolism of human cells, it is necessary to describe first what are the enzymes and transcription factors involved in catabolism or anabolism in the cell.
As shown on the left in Figure 2, oxidative metabolism is upregulated by two enzymes and a nuclear receptor. The enzymes are the AMP-activated protein kinase (AMPK; Steinberg and Kemp, 2009) and the Sirtuins (SIRT), a group of histone deacylating enzymes, which are activated by NAD+ (Zhang et al., 2011; Rice et al., 2012). The nuclear receptor is represented by the isotypes of the peroxisome proliferator-activated receptors (PPARs; Desvergne and Wahli, 1999; Burns and VandenHeuvel, 2007).
�
PPAR isotypes upregulate the transcription of genes involved in the beta-oxidation of fatty acids in mitochondria and peroxisomes and form a network with AMPK and Sirtuins pathways. The AMPK-Sirtuins-PPAR pathway is activated by a lifestyle based on calorie restriction and physical exercise, as well as by some bioactive molecules (polyphenols, found in vegetables and fruits, and omega-3 (n-3) long-chain polyunsaturated fatty acids [PUFA], found in fish). Ligand-activated PPAR isotypes form heterodimeric complexes with the retinoid X-receptor (RXR), which, in turn, is activated by 9-cis-retinoic acid (RA).
Conversely, as shown on the right in Figure 2�like on the other dish of an imaginary balance�high intake of energy-dense nutrients leads to the upregulation of anabolism, including lipogenesis and cell growth, through the activation of the sterol regulatory element-binding proteins, SREBP-1c and SREBP-2 (Xu et al., 2013), and the carbohydrate responsive element-binding protein, ChREBP (Xu et al., 2013). SREBP-1c and SREBP-2 are under the control of the nuclear receptors called the liver X receptors (LXR; Mitro et al., 2007; Nelissen et al., 2012). LXR isotypes, which are activated by the cholesterol derivatives oxysterols and glucose, have a relevant role in the synthesis of lipids by activating SREBP-1c and the synthesis of triacylglycerols, while inhibiting SREBP-2 and the synthesis of cholesterol.
Central to the understanding of the link between diet and inflammation are two transcription factors involved in inflammation and autoimmunity: the nuclear transcription factor-kB (NF-kB) and the activator protein (AP-1; Yan and Greer, 2008). In MS, both NF-kB and AP-1 are activated and induce the expression of several proinflammatory genes and the production of proinflammatory molecules. The cause of their activation in MS is not known but, as shown in Figure 2 for NF-kB, this can be activated not only by viruses, cytokines, and oxidative stress but also by some dietary components such as saturated fatty acids or trans unsaturated fatty acids, which therefore can be considered proinflammatory.
Downregulation of the proinflammatory NF-kB can be achieved by the inhibitory binding of the RA-activated forms of the retinoid X-receptor isotypes (RXRs; P�rez et al., 2012; Zhao et al., 2012; Fragoso et al., 2014).
As shown in the center of Figure 2 and more in detail in Figure 3, the active forms of RA-RXRs are heterodimers resulting from their association with specific ligand-activated nuclear receptors, namely PPARs, LXRs, and vitamin D receptor (VDR).
All three nuclear receptors�PPAR, LXR, and VDR�must be activated by specific ligands. As indicated in Figure 2, the ligands can be specific dietary factors and this clarify how cells respond to changes in nutritional status and regulate energy homeostasis but represents also the molecular key to understanding how nutrients can influence the course of chronic inflammatory diseases (Heneka et al., 2007; Zhang-Gandhi and Drew, 2007; Krishnan and Feldman, 2010; Cui et al., 2011; Schnegg and Robbins, 2011; Gray et al., 2012).
Therefore, each of the three nuclear receptors�PPAR, LXR, and VDR�competes for the binding to RA-RXR and forms hetero-complexes that can inhibit NF-kB and exert a tight control over the expression of inflammatory genes, thus integrating metabolic and inflammatory signaling. It is clear that there is competition between the three receptors PPAR, LXR, and VDR-D, for the binding with RA-RXR, but this competition should have an influence only on metabolism and not on inflammation, because it is not yet known which of the three heterodimers is more effective in inhibiting NF-kB.
Obviously, the production of proinflammatory molecules in the course of relapses is a biosynthetic process: It is sustained by hypercaloric diets and counteracted by low-calorie diets. In principle, what favors anabolism will promote the inflammatory processes, while what favors catabolism will contrast them (Figure 4).
How Dietary Factors Influence Composition and Biodiversity of Gut Microbiota and Alter Host�Microbiota Relationship
The Link Between Lifestyle, Dietary Habits, and Gut Microbiota Composition
The composition of the intestinal microflora is highly individual and is influenced by many factors such as diet, physical activity, stress, medications, age, and so forth. Each of us has a unique set of at least 100 to 150 species of bacteria.
An easy way to discuss about the effect of food and lifestyle on gut microflora is to restrict the overview to only two dominant bacterial divisions�the Bacteroidetes and the Firmicutes�accounting for about 90% of the total, as it has been shown that the ratio Bacteroidetes/Firmicutes (B/F) is influenced by long-term dietary habits (Cani and Delzenne, 2009; Wu et al., 2011; Lozupone et al., 2012; Tremaroli and B�ckhed, 2012; Panda et al., 2014).
A comparative study of De Filippo et al. (2010) in children from Florence and from Burkina Faso in Africa showed that long-term dietary habits have significant effects on human gut microbiota.
In this study, the Burkina Faso diet was based on the consumption of plant polysaccharides such as millet and sorghum (10 g fibers/day and 662�992 kcal/day), whereas the diet of Italian children was Western style, based on proteins, animal fat, sugar-sweetened drinks, and refined carbohydrates (5.6 g fibers/day and 1,068�1,512 kcal/day). Analysis of fecal samples in the children from Africa showed the prevalence of the Bacteroidetes (73%)�mainly Prevotella and Xylanibacter�and low levels of Firmicutes (12%). On the contrary, a prevalence of Firmicutes (51%) over the Bacteroidetes (27%) was observed in Italian children, but the Bacteroidetes shifted from Prevotella and Xylanibacter to Bacteroides. These latter are usually selected among the Bacteroidetes because they can use also simple sugars in addition to complex glycans, and simple sugars are normal components of Western diets.
In conclusion, the B/F ratio increases in association with a diet rich in complex carbohydrates (nondigestible by our enzymes) because the symbiotic and usually nonharmful Bacteroidetes, such as Prevotella and Xylani bacter, love to have complex glycans to eat. Bacteria consuming complex glycans produce butyrate, which down regulate the activation of proinflammatory NF-kB (Figure 3).
Conversely, Western, energy-dense diets change the gut microbiota profile and increase the population of Firmicutes (including the Mollicutes), more suited to extract and harvest energy, but often pathogenic (Moschen et al., 2012).
The Link Between Dysbiotic Gut Microbiota and Chronic Inflammation
In a dysbiotic gut microbiota, the B/F ratio is low and the possibly pathogenic Firmicutes prevail over Bacteroidetes (Figure 5). The failure of microbial balance and the decrease of biodiversity occurring in dysbiosis lead to the disruption of the complex interplay between the microbiota and its host and contribute to low-grade endotossemia, and chronic intestinal and systemic inflammation. With the onset of systemic inflammation, the risk of chronic inflammatory and immune-mediated diseases increases (Tilg et al., 2009; Brown et al., 2012; Maynard et al., 2012).
Actually, in the presence of a dysbiotic microbiota, gut endotoxin/lipopolysaccharide (LPS) is increased, regulatory T cells (Treg) are defective, and the aryl hydrocarbon receptors and proinflammatory Th17 cells are activated (Cani et al., 2008; Veldhoen et al., 2008).
LPS leads to the dysfunction of the mucosal barrier and affects other tissues when its plasma level increases above 200 pg/ml serum. The increased gut permeability due to the dysbiotic gut microbiota may be exemplified by the passage of IgA and IgG antibodies against gluten and gliadin, also observed in MS patients (Reichelt and Jensen, 2004).
The Link Between Dysbiotic Gut Microbiota and MS
In our previous work, we have proposed that the model linking microbiota alteration�due to Western diet and lifestyle�and the failure of the correct communication between the microbiota and the intestine, leading to low-grade endotoxemia and systemic autoimmune inflammation, might be valid also for the pathogenesis of MS (Fern�ndez et al., 2012; Riccio, 2011). In fact, MS shares with other chronic inflammatory diseases common mechanisms, all probably based on the persistence of low-grade endotoxemia related to wrong lifestyle and dietary habits together with a latent dysbiosis. Moreover, the existence of a gut microbiota-brain axis, which is now more than an emerging concept, suggests that intervention on gut microbiota may be a fruitful strategy for future treatment of complex CNS disorders (Cryan and Dinan, 2012).
The possible direct link between gut microbiota and MS has been shown experimentally by Berer et al. (2011). Using transgenic mice, Berer et al. have shown that gut commensal bacteria can trigger a relapsing-remitting autoimmune disease driven by myelin-specific CD4+ T cells and demyelination, given the availability of MOG�the autoantigen myelin oligodendrocyte glycoprotein. In another study, it was shown that antibiotic treatment directed to alter gut microflora suppresses experimental allergic encephalomyelitis (EAE; Yokote et al., 2008).
These findings suggest that gut microbiota may play a crucial role in the starting phase of MS and may also predispose host susceptibility to other CNS autoimmune diseases as well as to neuropsychiatric disorders such as autism, depression, anxiety, and stress. A new concept of gut microbiota-brain axis is emerging (Wang and Kasper, 2014).
On these grounds, understanding the role of gut microbiota in health and disease can lay the foundation to treat chronic diseases by modifying the composition of gut microbiota through the choice of a correct lifestyle, including dietary habits. Moreover, direct manipulation of the gut microbiota may improve adaptive immune response and reduce inflammatory secretions. For example, because a specific role of intestinal Th17 cells has been suggested in MS immunopathology (Sie et al., 2014), promoting Treg cell differentiation and reducing pathogenic Th17 cells might prevent recurrence of autoimmunity in MS patients (Issazadeh-Navikas et al., 2012).
On these grounds, the discovery that the defect of the Treg/Th17 balance observed in MS models is also present in MS patients, could have important clinical implications, as this defect can be modulated by changes in the microbiota composition, which in turn is modulated by dietary changes (David et al., 2014).
Proinflammatory Dietary Factors
The components of the diet whose intake must be controlled to avoid the rise of inflammatory processes in MS, as well as in other chronic inflammatory diseases, are as follows:
Saturated fatty acids of animal origin;
Unsaturated fatty acids in the trans configuration (hydrogenated fatty acids);
Red meat;
Sweetened drinks, and in general hypercaloric diets rich in refined (low-fiber) carbohydrates, in addition to animal fat;
Increased dietary salt intake;
Cow�s milk proteins of the milk fat globule membrane (MFGM proteins).
Fat of Animal Origin
Saturated fatty acids of animal origin, which are found in foods such as whole milk, butter, cheese, meat, and sausages, are the components of the diet taken into account more frequently for their deleterious influence on the course of MS.
In 1950, Swank suggested that the consumption of saturated animal fat is directly correlated with frequency of MS, but a link between restricted intake of animal fat and remission of MS was reported only in 2003 (Swank and Goodwin, 2003). According to Swank and Goodwin, high-fat diets lead to the synthesis of storage lipids and cholesterol and cause a decrease of membrane fluidity and possible obstruction of capillaries, and the onset or increase of inflammation.
Other more recent studies indicate that the action of saturated fat is controlled at the transcriptional level and influence both gene expression, cell metabolism, development, and differentiation of cells. More in general, the assumption of animal fat is often linked to a high-calorie intake, which is on its own a detrimental factor for many chronic inflammatory diseases. Finally, as described later in this article, an excess of saturated animal fat leads to a dysbiotic intestinal microbiota, dysfunction of intestinal immunity, and low-grade systemic inflammation and represents a possible cause of some human chronic disorders.
Trans Fatty Acids
Trans fatty acids (TFAs) are unsaturated fatty acids that contain at least one nonconjugated double bond in the trans configuration (Bhardwaj et al., 2011).
As products of partial hydrogenation of vegetable oils, they were introduced in the 1960s to replace animal fat, but only much later it was found that they have the same deleterious effect on the metabolism and, as the saturated fatty acids, increase the levels of cholesterol and promote the formation of abdominal fat and weight gain. TFAs intake was found to be positively associated with gut inflammation and the upregulation of proinflammatory citokines in Th17 cell polarization (Okada et al., 2013). Moreover, TFAs interfere with the metabolism of natural unsaturated fatty acids, which have the cis configuration.
TFAs are found in margarine and other treated (hydrogenated) vegetal fat, in meat and dietary products from ruminants and in snacks. They may be present also in French fries and other fried food, as they are also formed in the frying.
Red Meat
Red meat contains more iron heme than white meat. The iron is easily nitrosylated and this facilitates the formation of endogenous nitroso-compounds (NOCs; Joosen et al., 2010). Red meat intake shows indeed a dose�response relation with NOCs formation, whereas there is no such relation for white meat. NOCs are mutagenic: induce nitrosylation and DNA damage. Processed (nitrite-preserved) red meat increases the risk. Heterocyclic amines are formed during cooking of meat at high temperatures, but this is not specific for red meat (Joosen et al., 2010).
Abnormal iron deposits have been found at the sites of inflammation in MS (Williams et al., 2012) and consumption of red meat is associated with higher levels of ?-GT and hs-CRP (Montonen et al., 2013).
Noteworthy, we do not have N-glycolylneuraminic acid (Neu5Gc), a major sialic acid, because an inactivating mutation in the CMAH gene eliminated its expression in humans. Metabolic incorporation of Neu5Gc from dietary sources�particularly red meat and milk products�can create problems, as humans have circulating anti-Neu5Gc antibodies and this implies the possible association with chronic inflammation (Padler-Karavani et al., 2008).
Finally, meat contains arachidonic acid (the omega-6 (n-6) PUFA, which is the precursor of proinflammatory eicosanoids [prostaglandins, thromboxanes, and leukotrienes]) and activates the Th17 pathway (Stenson, 2014).
High Intake of Sugar and Low Intake of Fiber
The high intake of sugar-sweetened beverages and refined cereals, with low fiber content, increases rapidly the number of calories and glucose level. The subsequent increase of insulin production upregulates the biosynthetic pathways and inter alia the production of arachidonic acid and its proinflammatory derivatives.
Increased Dietary Salt Intake
Increased dietary salt intake might be an environmental risk factor for the development of autoimmune diseases, as it has been found that it can induce pathogenic Th17 cells and related proinflammatory cytokines in EAE (Kleinewietfeld et al., 2013; Wu et al., 2013). Th17 cells have been involved in the development of MS.
Cow�s Milk Fat and the Proteins of the Milk Fat Globule Membrane
Milk fat is dispersed in a homogeneous way and protected from oxidation, thanks to a membrane made of lipids and particular proteins called proteins of the milk fat globule membrane (MFGM; Riccio, 2004). These proteins, which account for only 1% of milk proteins, have an informational rather than a nutritional value. In human lactation, they are needed for the correct formation of the digestive, nervous, and immune systems in infants. This flow of information is obviously not relevant, or not required at all, in adulthood and, as well, in the case of cow�s milk taken for human nutrition. In adult age, MFGM proteins of cow�s milk no longer have an informational role and may be eliminated from the diet together with milk fat.
The removal of MFGM proteins from whole cow�s milk is particularly relevant in the case of MS. The most representative MFGM protein (40% of total MFGM proteins), butyrophilin (BTN), is indeed suspected to have a role in MS, as it is very similar to MOG, one of the candidate autoantigen in MS. BTN and MOG share the same behavior in MS experimental models, and MOG/BTN cross-reactive antibodies have been found in MS, in autism and in coronary heart disease (CHD; Riccio, 2004). On these grounds, the patient with MS should avoid the intake of whole cow�s milk and prefer skimmed milk, which, in addition, has no animal fat.
Another point of view is that of Swanson et al. (2013). They have found that BTN or BTN-like molecules might have a regulatory role in immunity and therefore they suggest that BTN or BTN-like molecules could be useful to induce Treg development.
Hypercaloric Diets and Postprandial Inflammation
After each meal, we may experience a transient and moderate oxidative stress and a moderate inflammatory response depending on type and quantity of food. Dietary habits based on a frequent and persistent exposure to meals with high intake of salt/animal fat and trans fat/sugar-sweetened drinks stresses our immune/metabolic system and the subsequent possible failure of homeostasis may lead to immune and metabolic disorders of diverse nature.
Taken together, the diet-dependent stress might be due to following reasons: (a) calorie intake: the higher the calories, the more the oxidative stress induced; (b) glycemic load of a meal: acute postprandial glycemic peaks may induce a release of insulin much higher than necessary; (c) lipid pattern: saturated animal fat, trans fatty acids, and omega-6 (n-6) long-chain PUFA promote postprandial inflammation. As reported in the following sections, postprandial inflammation is attenuated or suppressed by n-3 PUFA and polyphenols, calorie restriction, and physical exercise.
Anti-Inflammatory Natural Bioactive Compounds: Useful to Tackle MS and Prevent Relapses?
Specific bioactive dietary molecules are able to counteract the effects of pathogenic microbial agents and downregulate the expression of inflammatory molecules. Among them, the most important compounds are the polyphenols and carotenoids from vegetables, n-3 PUFA from fish, vitamins D and A, thiol compounds such as lipoic acid, and oligoelements such as selenium and magnesium.
Most of the above-mentioned compounds, with exception of PUFA, which are not antioxidant, are known for their antioxidant properties. The rationale for the use of antioxidants in MS is based on the observation that oxidative stress is one of the most important components of the inflammatory process leading to degradation of myelin and axonal damage. However, it is now known that dietary antioxidants have additional biological properties going far beyond the simple antioxidant activity. Indeed, they are able to counteract the negative effects of microbial agents and saturated or trans fatty acids, downregulating the expression of proinflammatory molecules, oxidative stress, and angiogenesis.
Polyphenols
All polyphenols�which are present in vegetables, cereals, legumes, spices, herbs, fruits, wine, fruit juices, tea, and coffee�have anti-inflammatory, immune-modulatory, anti-angiogenic, and antiviral properties and stimulate the catabolic pathways (Gupta et al., 2014; Wang et al., 2014). They are found in plants in the form of glycosides, esters, or polymers, too large to enter the intestinal membrane. Aglycons released from gut microbiota are conjugated to glucuronides and sulfates in intestine and liver. Their solubility and bioavailability are very poor (�M; Visioli et al., 2011).
From a structural point of view, polyphenols include flavonoids and nonflavonoids molecules (Bravo, 1998). The most important flavonoids are quercetin (onions, apples, citrus fruit, and wine; Min et al., 2007; Sternberg et al., 2008), catechins (green tea; Friedman, 2007), and daidzein and genistein (soy; Castro et al., 2013; Zhou et al., 2014). The most important nonflavonoids are resveratrol (chocolate, peanuts, berries, black grapes, and red wine; Das and Das, 2007; Cheng et al., 2009; Shakibaei et al., 2009), curcumin (spice turmeric of ginger family, curry; Prasad et al., 2014), and hydroxytyrosol (olive oil; Hu et al., 2014).
It has been found that the anti-inflammatory effect of polyphenols in vitro may depend on their chemical structure (Liuzzi et al., 2011). Thus, a mixture of flavonoids and nonflavonoids may be more effective than supplementation with only one polyphenol.
Two examples of the most studied polyphenols are quercetin and resveratrol. Quercetin is present mainly as a glucoside. Most of its effects are additive to those of interferon-?. Quercetin is not toxic, but its oxidation product, quercetin quinone, is very reactive toward the SH groups of proteins and glutathione and may be toxic (Boots et al., 2008). Addition of lipoic acid or N-acetylcysteine can limit the toxic effects.
Resveratrol is glucuronated in the liver and absorbed in this form mainly in the duodenum but only in very limited amount. Depending on its concentration, resveratrol can induce the death of a wide variety of cells by necrosis or apoptosis. In this regard, it is commonly accepted that resveratrol has neuroprotective effects; however, it has been also reported that it can exacerbate experimental MS-like diseases (Sato et al., 2013). These discrepancies can be attributed to the different concentrations used in vitro or bioavailable in vivo, as resveratrol has opposite effects at concentrations of 10?5 M (proliferation of human mesenchimal cells) and 10?4 M (inhibition of proliferation). In our experience, resveratrol has a neurotrophic effect on cortical neurons in culture only at very low concentration, whereas at higher concentration, it may have toxic effect. But in the case of oxidative stress, resveratrol has neuroprotective properties also at the higher concentrations.
Vitamin D, Vitamin A, Carotenoids, Other Vitamins, and Oligoelements
Other compounds and elements that may be useful as supplements in MS are the vitamins D, A, E, C, B12 (Mastronardi et al., 2004), and niacin (Penberthy and Tsunoda, 2009), and oligoelements such as selenium (Boosalis, 2008) and magnesium (Galland, 2010).
Vitamin D has immune-modulatory roles and represents the most promising dietary molecule for the treatment of chronic inflammatory diseases such as MS (Smolders et al., 2008; Pierrot-Deseilligny, 2009; Cantorna, 2012; Ascherio et al., 2014). As already mentioned, it is generally believed that the special geographical distribution of MS in the world can also be attributed to the reduced availability of vitamin D3, due to insufficient exposure to sunlight in some countries, and the lack of active vitamin D may be another possible cause of environmental origin of MS. However, low levels of active vitamin D may be due also to its altered metabolism or function not only to the exposure to sunlight. In fact, the failure of vitamin D3 (cholecalciferol) supplementation to show beneficial effects on body weight or on the course of inflammatory diseases may be due to the persistence of its deficiency despite its administration.
Vitamin D3 (cholecalciferol), formed after exposure to sunshine, is hydroxylated in the liver to 25-(OH) D3 (calcidiol) by the P450 enzymes CYP27A1 or CYP2R1, and subsequently activated in the kidney by CYP27B1 to 1?, 25-(OH)2 D3 (calcitriol). This latter, the active form of vitamin D, is inactivated by CYP24A1 to 1?, 24,25-(OH)3 D3 (calcitroic acid). This means that the levels of active vitamin D depend on the relative rates of its synthesis via CYP27B1 and its modifications via CYP24A1 (Schuster, 2011). High CYP24A1 expression, induced by endogenous compounds and xenobiotics, might lead to low levels of vitamin D and cause or enhance chronic inflammatory diseases and cancer. On these grounds, it is important to follow up the level of vitamin D in the course of vitamin D administration. If vitamin D levels remain low, the expression of CYP24A1 mRNA should be examined, and determination of CYP27B1 and CYP24A1 activities and their inhibition should be tested (Chiellini et al., 2012, K�sa et al., 2013).
Another important aspect regards the VDR. The active metabolite of vitamin D�1?, 25-dihydroxyvitamin D�binds to VDR, and the complex VDR-D controls the expression of several genes involved in processes of potential relevance to chronic diseases. As represented in Figures 2 and and3,3, the VDR-D complex competes with ligand-activated PPARs or LXRs for the binding to RA-RXR. The heterodimeric complexes bind to the proinflammatory transcription factor NFkB and downregulate the synthesis of proinflammatory molecules. In this context, when evaluating the effectiveness of vitamin D supplementation in the course of MS, one should consider the eventual polymorphisms affecting the VDR, which has been recently associated with obesity, inflammation, and alterations of gut permeability (Al-Daghri et al., 2014).
Moreover, the finding that that VDR-D activate the Sirtuin SIRT-1 (An et al., 2010; Polidoro et al., 2013) suggests that vitamin D has an influence also on cell metabolism and therefore may have properties similar to those of many other natural dietary supplements: upregulate oxidative metabolism and downregulate inflammation.
Finally, it should be considered that there are differences between data in humans and experimental models. Actually, in humans, unlike in mice, obesity is associated with poor vitamin D status (Bouillon et al., 2014).
Among the carotenoids, the most important is lycopene (tomato, water melon, and pink grape fruit; Rao and Rao, 2007). Besides to be a very strong antioxidant, lycopene can give beta-carotene and retinoic acid, and the latter can activate the RXR receptor (Figure 2). Although higher intakes of dietary carotenoids, vitamin C, and vitamin E did not reduce the risk of MS in women (Zhang et al., 2001), the relevance of lycopene and vitamin A against inflammation cannot be disregarded.
Omega-3 (n-3) Essential Fatty Acids and Poly-Unsaturated Fatty Acids from Vegetables, Seafood, and Fish Oil
n-3 essential fatty acids (EFA) and PUFA represent a valid alternative to saturated fatty acids of animal origin.
Vegetable and vegetable oils contain the essential fatty acids linoleic acid (n-6) and linolenic acid (n-3). n-6 and n-3 fatty acids have opposite effects and their presence in the diet should be equivalent (Schmitz and Ecker, 2008). However, in Western diets, the ratio n-6/n-3 is increased from 6 to 15 times and this leads to a higher incidence of cardiovascular and inflammatory diseases. In fact, the linoleic acid leads to the formation of arachidonic acid (20:4), the precursor of the proinflammatory eicosanoids prostaglandins-2, leukotrienes-4, and thromboxanes-2. The synthesis of these eicosanoids is favored by insulin, and inhibited by aspirin, as well as by the n-3 long-chain PUFA EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), which derive from n-3 linolenic acid.
Both DHA and EPA are found in seafood and fish oil. Both show remarkable anti-inflammatory, anti-thrombotic, and immune-modulatory activities, comparable with those of statins (Calder, 2006; Farooqui et al., 2007). n-3 PUFA inhibit inflammatory processes and the synthesis of fatty acids and cholesterol, and instead they stimulate the oxidation of fatty acids. On this basis, in chronic inflammatory diseases such as MS, n-3 essential fatty acids (EFA) and n-3 PUFA should prevail in the diet over the n-6 fatty acids. It is interesting to note that DHA is present in high concentrations in the brain and its levels decrease in patients with MS.
In cultured microglial cells activated by LPS, fish oil is as effective as interferon-? in inhibiting the expression of MMP-9 (gelatinase B), an important mediator of neuro-inflammation (Liuzzi et al., 2004, 2007). Moreover, n-3 PUFA significantly decreased MMP-9 levels in few clinical trials, indicating that n-3 PUFA may represent a good complementary treatment in the course of MS (Weinstock-Guttman et al., 2005; Mehta et al., 2009; Shinto et al., 2009). Fish oil has been also found to improve motor performances in healthy rat pups (Coluccia et al., 2009).
n-3 PUFA act in synergy with aspirin on AMPK and COX enzymes but with different mechanisms. Noteworthy, in the presence of aspirin, EPA and DHA form new anti-inflammatory bioactive molecules called resolvins, protectins, and maresins, which are able to reduce cellular inflammation and inflammatory pain (Xu et al., 2010; Hong and Lu, 2013; Serhan and Chiang, 2013). This may be a relevant aspect related to the nutritional intervention in MS. Indeed, the inflammatory processes associated to MS could be also due to the low ratio omega-3 (anti-inflammatory)/omega 6 (inflammatory) PUFA and thereby to the low production of adequate amounts of resolution-inducing molecules lipoxins, resolvins, and protectins that suppress inflammation. Hence, administration of omega-3 PUFA together with aspirin or directly of lipoxins, resolvins, and protectins may form a new approach in the prevention and treatment of MS and other neuroinflammatory diseases. Furthermore, other anti-inflammatory and antiangiogenic eicosanoids can also be produced by the P450 CYP enzymes from EPA and DHA (Yanai et al., 2014). In this context, it should be taken into consideration that statins may interfere negatively with the metabolism of n-3 and n-6, as they can decrease the n-3/n-6 ratio. Thus, treatment with statins should be associated with n-3 PUFA supplementation (Harris et al., 2004).
Seeds oils, from sunflower, corn, soybean, and sesame, contain more n-6 fatty acids than n-3 fatty acids and therefore their assumption should be limited in MS, in order to limit the level of proinflammatory eicosanoid production. On the other hand, coconut oil has a high content of saturated fatty acids. Among vegetable oils, olive oil should be preferred for the good ratio between saturated and unsaturated fatty acids, and because it contains the antioxidant hydroxytyrosol.
Thiolic compounds as Dietary Supplements
Compounds containing thiol groups (�SH) such as ?-lipoic acid (ALA), glutathione, and N-acetylcysteine (NAC) should be taken into consideration as possible dietary supplements to be used for the complementary treatment of MS.
As polyphenols, ALA (Salinthone et al., 2008; green plants and animal foods) has immunomodulatory and anti-inflammatory properties. ALA stabilizes the integrity of the BBB and stimulates the production of cAMP and the activity of protein kinase A. Also NAC might be useful in neurological disorders. It passes through the BBB and protects from inflammation (Bavarsad Shahripour et al., 2014).
The Mediterranean Diet
A recent systematic review and meta-analysis of intervention trials provide evidence that Mediterranean diet patterns reduce inflammation and cardiovascular mortality risk and improves endothelial functions (Schwingshackl and Hoffmann, 2014). These findings are as much encouraging as you think that the true Mediterranean diet is a little different from the one currently described.
It is generally agreed that the Mediterranean diet is based on consumption of extra-virgin olive oil, unrefined cereals, legumes, diverse vegetables (in particular tomatoes) and fruits, dairy products (mostly as pecorino cheese, ricotta, mozzarella, and yogurt), fish and fishery products, and low consumption of animal fat and meat. However, currently, the Mediterranean diet tends to a high consumption of pasta and bread, which means a high intake of gluten.
Once, in true Mediterranean diet, in Southern Italy, meat was eaten two or at most three times a week, only olive oil was used for cooking (extra-virgin quality and the most possible raw), but notably the intake of gluten was about half compared with the current intake. The pasta was eaten with the classic home-made tomato sauce, but in alternative, it was most often mixed with other gluten-free foods. The most common recipes were pasta and potatoes; pasta with either green beans, or artichokes, zucchini, eggplant, turnips, or cabbage; pasta with a mix of vegetables and legumes (minestrone: vegetable soup); and pasta with chickpeas, beans, or lentils. The sugar-sweetened drinks of today were not known. A high assumption of gluten-rich food may lead to nonceliac asymptomatic gluten sensitivity, mucosal intestinal damage, changes in gut microbiota, and low-grade intestinal inflammation. In conclusion, the Mediterranean diet is good, but the intake of gluten must be limited and must be whole grains.
Inflammatory and Anti-Inflammatory Lifestyle
Smoking (Proinflammatory)
Only a few studies have been carried out on the impact of smoking on the course of MS and results are conflicting, perhaps because its effects are difficult to ascertain and enucleate from other factors. Weiland et al. (2014) have found no association between smoking and relapse rate or disease activity, but do not exclude that smokers might have a significantly lower health-related quality of life than non-smokers, whereas Manouchehrinia et al. (2013) found that smoking is associated with more severe disease.
However, as it is shown in Figure 2, it can be expected that cigarette smoke may worsen the course of MS, as it may inhibit the anti-inflammatory activity of Sirtuins (Caito et al., 2010). The oxidative and carbonyl stress induced by cigarette smoke can be reversed by resveratrol (Liu et al., 2014).
Alcohol Consumption (Proinflammatory)
Recent studies shows that alcohol (beer, wine, or liquor) consumption is not associated to MS risk (Massa et al., 2013; Hedstr�m et al., 2014). However, as also shown in Figure 2, alcohol may inhibit the Sirtuin SIRT1 and activate the transcriptional activity of SREBP-1c (You et al., 2008), thus promoting the biosynthesis of lipids and inflammation at the expense of oxidative metabolism.
There are other two aspects of ethanol that should be considered. First, the metabolism of ethanol converts a large number of NAD+ molecules to NADH, limiting the availability of NAD+ required for the activity of Sirtuins. Second, as a substrate of the P450 enzymes, ethanol can interfere with the metabolism of drugs, which are transformed by the same enzymes. The result may be the prolongation and the enhancement of drug action. Altogether, alcohol should be considered as a molecule that interferes with the normal metabolism and facilitates the inflammatory process, complicating the possibility of improving the wellbeing of the patient.
Calorie Restriction (Anti-Inflammatory)
High-calorie intake and a meal rich in refined carbohydrates and sugar increase insulin level and favors biosynthesis, including the production of proinflammatory molecules and the production of free radicals. Calorie restriction, obtained by decreasing food intake or by intermittent fasting (one day and the other not), upregulates the level of SIRT1 (Zhang et al., 2011), increases the level of AMP and upregulates AMPK, increases adiponectin levels and upregulate or activate its receptors (Lee and Kwak, 2014), and downregulates oxidative damage, lymphocyte activation, and the progression of experimental models of MS (Piccio et al., 2008, 2013). The effects of calorie restriction can be mimicked by agonists (resveratrol and other polyphenols), acting on the same targets (SIRT1, AMPK).
Physical Exercise (Anti-Inflammatory)
Physical exercise is now an almost accepted practice also for MS patients and is commonly applied in order to decrease the symptoms of chronic fatigue and prevent or slow the onset of disability. However, the importance of physical exercise goes beyond that of simple muscle activity and should be rather considered in a holistic context in which diet, exercise, therapy, and social interchange, all play a role for the wellness of MS patients (Gacias and Casaccia, 2013).
Dietary control and exercise practice have been proposed by the WHO (2010) to attenuate or prevent human chronic diseases.
From a molecular point of view, physical exercise exerts its beneficial effect by acting on the protein kinase AMPK axis and the AMPK�Sirtuins�PPAR-? network, upregulating oxidative metabolism and downregulating biosynthetic pathways and inflammation (Narkar et al., 2008). As AMPK has a key role in energy balance, it is important to mention its agonists. Resveratrol and AMPK agonists such as metformin, a drug used in type 2 diabetes, can mimic or enhance the effect of physical activity and are effective in experimental encephalitis (Nath et al., 2009).
Physical exercise influences the quality of life and may stimulate the production of anti-inflammatory cytokines (Florindo, 2014). Furthermore, physical exercise lowers plasma levels of leptin and reduces gene expression of leptin receptors in the liver (Yasari et al., 2009), while increasing adiponectin levels and adiponectin receptors activity (Lee and Kwak, 2014).
The association of physical exercise with calorie restriction leads to a significant reduction of inflammatory markers (Reed et al., 2010).
Recent studies carried on adult C57BL/6 J male mice have shown that exercise stimulate brain mitochondrial activity, potentiate neuroplasticity, and is associated to mood improvement, as it decrease anxiety-like behaviors in the open field and exert antidepressant-like effects in the tail suspension test (Aguiar et al., 2014). Other studies performed on rats showed that exercise can alter the composition and diversity of gut bacteria (Petriz et al., 2014).
On these grounds, MS patients should practice mild physical exercise (brisk walking, swimming, or even dancing), if possible in the course of a rehabilitation program.
Nutritional Clinical Trials in MS So Far
Unfortunately, nutritional clinical trials in MS are only very few. Some of them were based on diets low in saturated fat, either without supplements (Swank and Goodwin, 2003) or with omega-3 fat supplements (Nordvik et al., 2000; Weinstock-Guttman et al., 2005). Other clinical trials were based on the administration of single dietary supplements only: either vitamin D, or fish oil (n-3 PUFA), or lipoic acid. Clinical trials with single polyphenols were performed only in cancer. Dietary supplements have never been used together and have never been associated with dietary prescription.
Taken together, clinical attempts to clarify the role of nutrition in MS were considered only promising of poor quality or with no clear results (Farinotti et al., 2007, 2012). In particular, as reported by Farinotti et al. in their Cochrane review (2012), supplements such as n-3 PUFA seem to have no major effect on the main clinical outcome in MS, but they may reduce the frequency of relapses over 2 years. Data available were considered to be insufficient or of uncertain quality to assess a real effect from PUFA supplementation. In some studies, slight possible benefits in relapse outcomes were found with omega-6 fatty acids, but data were characterized by the reduced validity of the endpoints. In general, trial quality was found to be poor. Studies on vitamin supplementation were not analyzed as none met the eligibility criteria, mainly due to lack of clinical outcomes. Thus, evidence on the benefits and risks of vitamin supplementation and antioxidant supplements in MS is lacking.
Suggestions for a Nutritional Intervention in MS: The Choice of Diet and Dietary Supplements
At the end, the goal of a nutritional intervention in MS must be the control of inflammation and this, as shown in this review, can be achieved mainly by controlling postprandial inflammation, the composition of gut microbiota and intestinal and systemic inflammation, and immunity. This can be achieved by a long-term dietary intervention, with a hypocaloric diet, prebiotics, probiotics, and dietary supplements.
As reported in this article, healthy dietary molecules, calorie restriction, and exercise are able to direct cell metabolism toward catabolism and downregulate anabolism and inflammation by interacting at different levels with specific enzymes, nuclear receptors, and transcriptional factors. Furthermore, in association with fiber, they can shift gut dysbiosis to eubiosis.
As a result, low-calorie meals (1,600�1,800 kcal) based on vegetables, whole cereals, legumes, fruit, and fish may slow down the progression of the disease and ameliorate the wellness of MS patients, whereas hypercaloric diets with high intake of salt, saturated animal fat, fried food, and sugar-sweetened drinks may lead to the onset of postprandial inflammation and systemic low-grade inflammation.
Diet should be integrated with prebiotics, probiotics, specific vitamins (D, A, B12, and nicotinic acid), oligoelements (magnesium and selenium), and dietary supplements such as polyphenols, n-3 PUFA, and lipoic acid.
Prebiotics for MS should include inulin, bran, lactosucrose, and oligofructose, preferential nutrients for colonocytes and capable to inactivate NF-kB. Probiotics, such as lactococcus lactis, bifidobacterium lactis, and clostridium butyricum, which can improve the intestinal microbial balance, can be used to change the composition of colonic microbiota. The combination of prebiotics and probiotics is highly recommended. Bowel functions and weight should always be under control.
A more drastic therapeutic approach aimed to restore gut eubiosis and downregulate inflammation may be represented by fecal microbiota transplantation (FMT; Smits et al., 2013). The method seems to be very effective but still primitive, not completely safe, and in a way also disgusting. The field should move beyond fecal transplants, identify the organisms that may be essential for a particular condition, and provide those organisms in a much simpler fashion than FMT (�Critical Views in Gastroenterology & Hepatology,� 2014).
Dietary supplements, with the only exception of omega-3 PUFA, which are normal constituents of our body, are useful at the beginning of the nutritional intervention, or in the course of relapses, to facilitate the recovery of a healthy condition, but their use should be restricted to only a limited period of time (3�4 months). This is particularly valid for the polyphenols. Polyphenols are not well-known molecules with regard to their bioavailability and their biological effects and special precautions should be used when supplementing the diet with them. On one hand, they can downregulate the synthesis of proinflammatory molecules in the course of inflammatory processes; on the other hand, they can stimulate cell activity in resting cells, but a persistent stimulation can induce the apoptosis of healthy cells. Taken together, these considerations suggest that administration of purified polyphenols should be performed on the basis of preliminary clinical trials to test their effectiveness as dietary supplements and to determine their long-term safety and the right dosage.
In general, a nutritional intervention with anti-inflammatory food and dietary supplements decreases the biosynthesis of proinflammatory compounds and therewith makes more effective the use of immune-modulatory drugs, and eventually might limit their possible adverse effects, alleviate the symptoms of chronic fatigue syndrome, and favor patient wellness. However, diet and dietary supplements should not be treated as drugs and as a substitute of therapy. Similarly, proinflammatory food is not toxic and there is no need to exclude it completely. You can eat a nice steak or fried food without risk or guilt, if you are in a basically healthy condition. What hurts are the wrong eating habits in the long run.
Multiple sclerosis, or MS, is a chronic, progressive disease involving damage to the myelin sheaths of nerve cells. The epidemiology of MS suggests that various factors are often involved in the clinical expression of the health issue. However, numerous research studies have primarily evaluated the role of diet on the development of multiple sclerosis. For several years, healthcare professionals believed there was a correlation between the consumption of dairy in patients with multiple sclerosis. According to various research studies, a significant correlation between cow milk and the prevalence of multiple sclerosis was found, suggesting a possible role of dairy products in the multifactorial etiology of MS. Dr. Alex Jimenez D.C., C.C.S.T.
Conclusions
So, at first glance, MS does not seem to have any of the characteristics of chronic inflammatory diseases, which could be related to wrong dietary habits and lifestyle, or even to a dysbiotic gut microbiota. There is apparently nothing in an exacerbation of the disease that may be linked to food or the state of the intestinal microbiota. In fact, when we began our studies on the impact of nutrition on MS, there was not even the slightest clue that there could exist a real link between them, and the idea of the involvement of gut microbiota in MS was considered only very speculative. To date, the idea that dietary habits might influence the course of MS is still struggling to establish itself. Not so in cardiovascular diseases and other chronic inflammatory conditions, in which the influence of dietary habits is almost accepted, and not even in cancer, which is increasingly considered as a metabolic disorder (Seyfried et al., 2014).
At present, MS therapy is not associated to any particular diet, probably due to lack of information on the effects of nutrition on the disease. However, the majority of patients with MS is looking for complementary and alternative treatments (CAM), and in particular is trying to change dietary habits, almost without the advice of the physician (Schwarz et al., 2008; Leong et al., 2009). A recent study based on data provided by MS patients in response to a questionnaire on their dietary habits seems to support a significant association of healthy dietary habits with better physical and mental health-related quality of life and a lower level of disability (Hadgkiss et al., 2014). These data reinforce the idea of the need for randomized controlled trials of nutritional intervention for people with MS. It should be emphasized that nutritional treatments should be complementary, but not alternative to therapy, be part of a holistic approach and performed under medical control.
As there are no data available from clinical trials yet, our work is aimed to rationalize dietary choices on the basis of known and established effects of dietary factors and lifestyle at the molecular level. Data reported in Figure 2 are obviously not complete but may be useful to provide guidelines for nutritional interventions. In principle, proinflammatory food upregulate the biosynthetic and inflammatory pathways, as shown on the right and at the bottom of Figure 2, whereas anti-inflammatory food upregulates oxidative metabolism and downregulates anabolism and inflammation.
As shown in this article, the finding that calorie restriction, exercise, and particular dietary factors can influence the degree of inflammatory responses by acting on both cellular metabolism (Figure 2) and composition of gut microbiota (Figure 5), suggests that an appropriate nutritional intervention may ameliorate the course of the disease and may be therefore taken in consideration as a possible complementary treatment in MS. As inflammation is present in both RRMS and PPMS, nutritional advices are indicated for both forms of the disease. This is particularly important in the case of PPMS, for which no cure is presently available. Conversely, as specific dietary habits may be detrimental and may promote a chronic state of low-grade inflammation, a wrong diet may be considered a possible contributory cause of relapses in MS.
Taken together, we have now a better knowledge of the possible influence of dietary factors on cell metabolism and gut microbiota, and on their possible effects on the disease, but, clearly, we are only just beginning to understand the role of nutrition and gut microbiota in MS and much work remains in terms of understanding the nature of the interactions of gut microbiota with the host�s immune system, especially at sites distal to the intestine.
On these grounds, future prospects in MS research should regard the following points: (a) assess gut microbiota composition; (b) evaluate defects in intestinal immune system; (c) clarify the role of polyphenols and vitamin D metabolism; (d) study the impact of dietary factors, herbs, and drugs on AMPK, Sirtuins, PPAR, or directly on NF-kB. Noteworthy, some drugs used to treat type II diabetes, such as the PPAR-? agonists thiazolidinediones (Bernardo et al., 2009), and the AMPK agonist metformin (Nath et al., 2009) have anti-inflammatory effects comparable with those of anti-inflammatory dietary factors; (e) define possible interferences between dietary supplements and MS drugs; (f) promote a campaign aimed to educate about the importance to follow a healthy diet during therapy, for instance, encouraging patients to include fiber or complex carbohydrates in their diet, supplementing with probiotics, choosing n-3 fats over proinflammatory n-6 fats, and limiting meat and animal fat consumption. The choice of good recipes, such as those described by Mollie Katzen (2013), can make the diet more acceptable.
Overall, immune-modulatory conventional MS therapies have been almost successful; however, drugs that can protect and favor repair mechanisms are still missing. We can decide to help people stay healthy by providing nutritional guidance and physical activity opportunities. For the moment, there are only good prospects for improving the wellbeing of patients with MS. We are only at the beginning of the story.
Summary
As both relapsing-remitting MS and primary-progressive MS are inflammatory diseases, they can be influenced by proinflammatory or anti-inflammatory dietary habits and lifestyle through their action on cell metabolism and gut microbiota. Nutritional advice to MS patients may favor their wellness.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported by the Italian Foundation for Multiple Sclerosis (FISM) with grants 2007/R/15 for the Project �Healthy and Functional Foods for MS patients,� 2010/R/35 for the Project �The Molecular Basis for Nutritional Intervention in Multiple Sclerosis,� and 2014/S/2 (2014�2015) for the project �Nutritional Facts in Multiple Sclerosis: Why They Are Important and How They Should Be Managed� to P. R.
Many doctors greatly recommend that patients with multiple sclerosis, or MS, avoid dairy because various research studies have demonstrated a high correlation between MS and dairy, especially cow�s milk. This is largely due to the fact that the proteins in cow�s milk are generally targeted by the immune system of patients with multiple sclerosis. Furthermore, some proteins in cow�s milk imitate part of the myelin oligodendrocyte glycoprotein, or MOG, the section of myelin which triggers the autoimmune response in multiple sclerosis that can trick the immune system to attack and destroy the MOG. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief. �
Adhesive capsulitis, also known as frozen shoulder, is a condition that causes pain and stiffness in the shoulder joint. The onset of symptoms is gradual, steadily worsening over time, then resolves. The entire process occurs over a one to three-year period. The limited range of motion in the shoulder that is a primary symptom is also one of the signs that doctors use to diagnose the condition. An x-ray may be used to determine if an underlying condition such as a broken bone or arthritis may be causing the problem.
Contents
What Causes Frozen Shoulder?
The shoulder is one of the most dynamic joints in the body. It has a very wide range of motion and endures a lot of wear and tear with normal use. The joint is a network of ligaments and tendons that connect bone and muscle. It is all encased in connective tissue capsule. When that tissue thickens, it constricts to tighten around the shoulder joint. This restricts movement and causes pain.
In some cases, the cause is due to an injury or other conditions, but in other cases the cause is unknown. There is some evidence that suggests people with diabetes and other chronic diseases are more likely to develop the condition. It is also more prevalent in people who have had an arm fracture or surgery � something that causes them to keep their shoulder immobilized for an extended period of time. Women (particularly postmenopausal women) tend to be at higher risk and it most often occurs in people who are 40 to 70 years old.
Treatment for Frozen Shoulder
Most treatments for frozen shoulder focuses on preserving the joint�s range of motion and minimizing pain. Over the counter medications like ibuprofen and aspirin are usually the first line of defense. They help reduce inflammation and pain. However, in more severe cases a doctor may prescribe anti-inflammatory drugs and pain medication. Physical therapy may also be an option.
Other treatments for frozen shoulder include:
Shoulder manipulation � while the patient is under a general anesthetic, the doctor moves the shoulder to loosen the tightened tissue.
Joint distension � sterile water is injected into the joint capsule. This stretches the tissue and improves range of motion.
Steroid injection � corticosteroids are injected directly into the shoulder joint.
Surgery � this is a last resort so it�s very rare, but the doctor may go in and remove the adhesions and scar tissue from inside the shoulder joint.
Chiropractic for Frozen Shoulder
Chiropractic is an effective treatment for frozen shoulder. Many patients see their general practitioner first to get a diagnosis and to make sure that there are no underlying conditions that should be treated before chiropractic is pursued. However, most chiropractors do have the capabilities to use x-rays and other diagnostic tools to adequately assess the patient.
A 2012 study involved reviewing the case files of 20 males and 30 female patients with frozen shoulder who underwent chiropractic treatment. All subjects sought treatment between 11 and 51 days with the median being 28 days. Of the 50 cases:
16 resolved completely
25 were 75% to 90% improved
8 were 50% to 75% improved
1 was 0% to 50% improved
Chiropractic can help reduce the pain, improve the shoulder�s range of motion, and speed recovery. The treatment depends on the symptoms that are present, how progressed the condition is, and how long the patient has had the condition.
One common chiropractic technique used to treat frozen shoulder is the Niel Asher Technique. It involves the manipulation of the joints and muscle tissues. The chiropractor applies pressure and stretches key points to help reduce pain and resolve the condition. It can make a tremendous difference in the patient�s life.
Gale Grijalva was a victim of a car crash. As a result, she started to experience severe pain symptoms which tremendously affected her ability to perform her regular tasks. Gale Grijalva describes the conditions that resulted in the auto accident as well as how her symptoms that are specific began to manifest after the incident. Gale Grijalva visited Dr. Alex Jimenez, chiropractor, to receive chiropractic care for her car crash injuries and she was grateful to get the pain relief she deserved. Chiropractic care is an effective and secure, alternative treatment option which focuses on the identification, prevention, and treatment of many different injuries and/or conditions. Gale Grijalva highly recommends Dr. Alex Jimenez as the noninvasive choice for car accident injuries and whiplash, among other problems.
Can exercise slow down the progression of multiple sclerosis? Multiple sclerosis, or MS, is a chronic, neurological disease characterized by damage to the myelin sheaths of nerve cells in the central nervous system, or CNS. Common symptoms of multiple sclerosis include pain, fatigue, vision loss and impaired coordination. Exercise is frequently recommended as a form of treatment for several types of injuries and/or conditions, including MS. While exercise has been determined to help improve the management of symptoms of multiple sclerosis as well as decrease the progression of the disease, further evidence is still required. The purpose of the following article is to demonstrate how exercise can affect disease progression of multiple sclerosis and improve quality of life in patients.
Contents
Abstract
It has been suggested that exercise (or physical activity) might have the potential to have an impact on multiple sclerosis (MS) pathology and thereby slow down the disease process in MS patients. The objective of this literature review was to identify the literature linking physical exercise (or activity) and MS disease progression. A systematic literature search was conducted in the following databases: PubMed, SweMed+, Embase, Cochrane Library, PEDro, SPORTDiscus and ISI Web of Science. Different methodological approaches to the problem have been applied including (1) longitudinal exercise studies evaluating the effects on clinical outcome measures, (2) cross-sectional studies evaluating the relationship between fitness status and MRI findings, (3) cross-sectional and longitudinal studies evaluating the relationship between exercise/physical activity and disability/relapse rate and, finally, (4) longitudinal exercise studies applying the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Data from intervention studies evaluating disease progression by clinical measures (1) do not support a disease-modifying effect of exercise; however, MRI data (2), patient-reported data (3) and data from the EAE model (4) indicate a possible disease-modifying effect of exercise, but the strength of the evidence limits definite conclusions. It was concluded that some evidence supports the possibility of a disease-modifying potential of exercise (or physical activity) in MS patients, but future studies using better methodologies are needed to confirm this.
Keywords:disease activity, exercise therapy, physical activity, training
Introduction
Multiple sclerosis (MS) is a clinically and pathologically complex and heterogeneous disease of unknown etiology [Kantarci, 2008]. In 28 European countries with a total population of 466 million people, it is estimated that 380,000 individuals are affected with MS [Sobocki et al. 2007]. The disorder is progressive but more than 80% of all MS patients have the disease for more than 35 years [Koch-Henriksen et al. 1998], the number of years of life lost to the disease being 5 to 10 [Ragonese et al. 2008]. The fact that MS is a chronic, long-lasting and disabling disease makes MS rehabilitation an important discipline in maintaining an independent lifestyle and the associated level of quality of life [Takemasa, 1998]. Despite the fact that MS patients for many years were advised not to participate in physical exercise because it was reported to lead to worsening of symptoms or fatigue, it has become generally accepted to recommend physical exercise for MS patients during the last two decades [Sutherland and Andersen, 2001]. Exercise is well tolerated and induces relevant improvements in both physical and mental functioning of persons with MS [Dalgas et al. 2008]. It is an open question whether exercise can reverse impairments caused by the disease per se, or whether exercise simply reverses the effects caused by inactivity secondary to the disease. However, most likely exercise may reverse the effects of an inactive lifestyle adopted by many patients [Garner and Widrick, 2003; Kent-Braun et al. 1997; Ng and Kent-Braun, 1997; Stuifbergen, 1997]. Nonetheless, it has been suggested that exercise might have the potential to have an impact on MS disease progression by slowing down the disease process itself [Heesen et al. 2006; Le-Page et al. 1994; White and Castellano, 2008b]. In other disorders exercise has been shown to pose the potential to have an impact on brain function and, as recently summarized by Motl and colleagues, exercise in older adults with or without dementia leads to cognitive improvement relative to a control condition [Motl et al. 2011b]. Based on this and the few existing findings in MS patients, Motl and colleagues suggested that exercise may similarly improve cognitive functioning in MS patients. However, in MS it has not been reviewed whether physical exercise has a more general disease-modifying effect.
To gain more insight on this important topic, we therefore conducted a systematic literature search aiming at identifying studies linking exercise (or physical activity) to disease progression in MS patients or in the experimental autoimmune encephalomyelitis (EAE) animal model of MS. A secondary purpose of the review was to discuss possible mechanisms explaining this link if it does exist and to discuss future study directions within this field.
Methods
The included literature was identified through a comprehensive literature search (PubMed, SweMed+, Embase, Cochrane Library, PEDro, SPORTDiscus and ISI Web of Science) that was performed in order to identify relevant articles regarding MS and exercise up to 4 September 2011. The search was performed using the subject headings �exercise�, �exercise therapy�, �physical education and training�, �physical fitness�, �motor activity� or �training� in combination with �multiple sclerosis� or �experimental autoimmune encephalomyelitis�. No limitations regarding publication year and age of subjects were entered. If possible, abstracts, comments and book chapters were excluded when performing the search in the different databases. This search yielded 547 publications. A screening of these publications based on title and abstract revealed 133 publications relevant for further reading. The reference lists of these 133 publications were checked for further relevant publications that were not captured by the search. This resulted in further six publications and in a total of 139 closely read publications. Studies that turned out to be nonrelevant (n = 65), meta-analyses (n = 3), reviews (n = 22), conference abstracts (n = 8) and articles not written in English (n = 2) were excluded from the final analysis (see Figure 1). Relevant cross- sectional and longitudinal studies were included.
According to Goldman and colleagues measures thought to reflect disease progression (or activity) in MS can be evaluated with objective or subjective outcome measures [Goldman et al. 2010]. Objective measures include (1) clinical outcome measures such as the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) and (2) nonclinical measures such as MRI. The subjective measures include (3) patient-reported measures thought to reflect disease progression or disability such as the Late-Life Function and Disability Inventory. Studies applying patient-reported measures that included a measure of physical activity were also included in this category. Furthermore, we added a category containing studies applying (4) the EAE animal model of MS as study population. Based on this framework the localized articles were divided into the following four groups (see Table 1):
�
disease progression evaluated with clinical outcome measures (n = 12);
disease progression evaluated with nonclinical measures (n = 2);
disease progression evaluated with patient-reported measures (n = 10);
disease progression evaluated in animal studies (n = 3).
Results
Disease Progression Evaluated with Clinical Measures
A number of studies evaluating structured exercise interventions lasting from 3 to 26 weeks have included clinical scales reflecting disease progression as an outcome measure. The applied clinical scales include the EDSS [Bjarnadottir et al. 2007; Dalgas et al. 2009; Fimland et al. 2010; Golzari et al. 2010; Petajan et al. 1996; Pilutti et al. 2011; Rodgers et al. 1999; Romberg et al. 2004; White et al. 2004], the MSFC [Pilutti et al. 2011; Romberg et al. 2005], the Guys Neurological Disability Scale (GNDS) [Kileff and Ashburn, 2005; van den Berg et al. 2006] and the Functional Independence Measure (FIM) [Romberg et al. 2005]. Studies applying the EDSS have generally not found any change after either endurance training [Petajan et al. 1996; Pilutti et al. 2011; Rodgers et al. 1999], resistance training [Dalgas et al. 2009; Fimland et al. 2010; White et al. 2004] or combined training interventions [Bjarnadottir et al. 2007; Romberg et al. 2004]. Only one study by Golzari and colleagues evaluating the effects of 8 weeks of combined training (3 days/week) reported an improvement in EDSS score [Golzari et al. 2010]. This finding was not confirmed in a long-term study (26 weeks) [Romberg et al. 2005] also evaluating the effects of combined training. In the study by Romberg and colleagues no effect on EDSS and FIM were found, but a small positive effect was seen in the MSFC. A few studies applied the GNDS with one reporting an improvement after 12 weeks of biweekly endurance training [Kileff and Ashburn, 2005] and one reporting no effects of 4 weeks endurance training completed 3 days a week [van den Berg et al. 2006].
In summary, structured exercise intervention studies of different exercise modalities lasting 3�26 weeks have generally found no effects on EDSS scores. A few exercise studies have shown positive effects when applying other clinical scales (MSFC and GNDS).
Disease Progression Evaluated with Non-Clinical Measures
Two studies by Prakash and colleagues have evaluated the effects of cardiorespiratory fitness on brain function and structure by applying (functional) MRI [Prakash et al. 2007, 2009]. One study [Prakash et al. 2007] investigated the impact of cardiorespiratory fitness on cerebrovascular functioning of MS patients. Twenty-four female participants with relapsing�remitting MS were recruited for the study and all participants went through fitness assessment (VO2 peak) and were scanned in a 3-T MRI system while performing the Paced Visual Serial Addition Test (PVSAT). Higher fitness levels were associated with faster performance during the PVSAT that could be related to greater recruitment of a specific region of the cerebral cortex (right inferior frontal gyrus [IFG] and middle frontal gyrus [MFG]) known to be recruited by MS patients during performance of PVSAT to purportedly compensate for the cognitive deterioration attributable to MS. In contrast, lower levels of fitness were associated with enhanced activity in the anterior cingulate cortex (ACC), thought to reflect the presence of a larger amount of conflict increasing the potential for error in lower fit MS participants. The authors interpreted the results as supporting aerobic training as an intervention to support the development of additional cortical resources in an attempt to counter the cognitive decline resulting from MS. Among a number of cognitive tests, only the Paced Auditory Serial Addition Test (PASAT) showed a weak correlation (p = 0.42) to VO2 peak leading the authors to suggest that fitness does not have an influence on measures of general cognitive functioning.
In another study by Prakash and colleagues the relationship between cardiorespiratory fitness (VO2 max) and measures of gray matter atrophy and white matter integrity (both of which have been associated with the disease process) were studied [Prakash et al. 2009]. A voxel-based approach to analysis of gray matter and white matter was applied on brainscans from a 3-T MRI system. More specifically it was examined whether higher levels of fitness in 21 female MS patients were associated with preserved gray matter volume and integrity of white matter. A positive association between cardiorespiratory fitness and regional gray matter volumes and higher focal fractional anisotropy values were reported. Both preserved gray matter volume and white matter tract integrity were associated with better performance on measures of processing speed. Recognizing the cross-sectional nature of the data, the authors suggested that fitness exerts a prophylactic influence on the structural decline observed early on, preserving neuronal integrity in MS, thereby reducing long-term disability.
In summary, (f)MRI studies suggesting a protective effect of cardiorespiratory fitness on brain function and structure in MS patients have started to emerge. However, the cross-sectional nature of the few existing studies limit conclusions regarding the existence of a causal relationship.
Disease Progression Evaluated with Patient-Reported Measures
A number of studies have addressed the relationship between exercise or physical activity and disease progression in large-scale questionnaire studies applying patient-reported measures.
In a large descriptive longitudinal survey study, Stuifbergen and colleagues examined the correlations between the change in functional limitations, exercise behaviors and quality of life [Stuifbergen et al. 2006]. More than 600 MS patients completed a number of questionnaires every year for a period of 5 years. The self-reported longitudinal measures were analyzed by applying latent curve modeling. The Incapacity Status Scale provided a measure of functional limitations due to MS, whereas the Health Promoting Lifestyle Profile II provided a measure of exercise behavior. At the first test point (baseline test) cross-sectional data showed a significant negative correlation (r = ?0.34) between functional limitations and exercise behaviors, suggesting that at the start of the study higher levels of functional limitations were associated with lower levels of exercise. Longitudinal data from the study showed that increasing rates of changes in functional limitations correlated with decreasing rates of change in exercise behaviors (r = ?0.25). In other words these findings are suggesting that increases in exercise behaviors correspond with decreased rates of change in functional limitations. No correlation between the initial degree of limitation and continuing rate of exercise was found which led the authors to suggest that persons with MS with varied levels of limitations might slow the trajectory of increasing limitations over the long term with consistent exercise participation.
A series of studies from Motl and colleagues have addressed the relationship between physical activity, symptoms, functional limitations and disability in MS patients. In a cross-sectional study [Motl et al. 2006] in 196 MS patients, the number of symptoms within 30 days (MS-related Symptom Checklist) and physical activity (Godin Leisure-Time Exercise Questionnaire and 7-day accelerometer data) were collected. After modeling data a direct relationship between symptoms and physical activity were found (r = ?0.24) indicating that a greater number of symptoms resulted in lower amounts of physical activity. However, the authors noted that the cross-sectional design precludes inferences about the direction of causality, and physical activity might affect symptoms as symptoms affect physical activity participation. When modeled this way a moderate inverse correlation between physical activity and symptoms was found (r = ?0.42) indicating fewer symptoms when the physical activity level is high. This led the authors to suggest the existence of a bi-directional relationship between physical activity and symptoms.
In a following questionnaire study Motl and colleagues examined physical activity (Godin Leisure-Time Exercise Questionnaire and 7 day accelerometer data) and symptoms (Symptom Inventory and MS-related Symptom Checklist) as correlates of functional limitations and disability (Late-Life Function and Disability Inventory) in 133 MS patients [Motl et al. 2007, 2008b]. A model based on the disablement model proposed by Nagi (1976) was tested as the primary model and this showed that physical activity and symptoms were negatively correlated (r = ?0.59) and those who were more physically active had better function (r = 0.4). Furthermore, those with better function had less disability (r = 0.63) which led the authors to conclude that the findings indicate that physical activity is associated with reduced disability (through an association with function) consistent with Nagi�s disablement model (Nagi 1976), but again the cross-sectional design limited definite conclusions on the direction of the relationships.
Motl and colleagues then published a longitudinal (case report) study examining the relationship between worsening of symptoms and the level of physical activity throughout a 3- to 5-year period [Motl et al. 2008a]. The study showed that worsening of symptoms (interview) was significantly associated with lower levels of self-reported physical activity (International Physical Activity Questionnaire [IPAQ]) in a group of 51 subjects with MS. The study supports symptoms as a possible explanation for the rate of physical inactivity among MS patients but the direction of the cause and effect relationship could still not be established. Based on the results the authors suggest that managing symptoms might be important for the promotion of physical activity, but also that symptoms may be both an antecedent and consequence of physical activity.
After that Motl and colleagues published a cross-sectional study examining the correlation between physical activity and neurological impairment and disability in a group of 80 MS patients [Motl et al. 2008c]. Physical activity (7-day accelerometer day), impairment and disability (Symptom Inventory and self-reported EDSS) was measured and significant correlations were found between physical activity and both EDSS (r = ?0.60) and Symptom Inventory (r = ?0.56). The authors concluded that physical activity was associated with reduced neurological impairment and disability, but also stated that no causal relationship could be established due to the cross-sectional nature of the study.
Motl and McAuley then published a large-scale longitudinal questionnaire study examining the changes in physical activity (Godin Leisure-Time Exercise Questionnaire and 7-day accelerometer data) and symptoms (Symptom Inventory and MS-related Symptom Checklist) as correlates of changes in functional limitations and disability (Late-Life Function and Disability Inventory) [Motl and McAuley, 2009]. A total of 292 MS patients were followed for 6 months. Again a model based on the disablement model proposed by Nagi (1976) was tested as the primary model and this showed that change in physical activity was associated with residual change in function (r = 0.22) and change in function was associated with residual change in disability (r = 0.20). This led the authors to conclude that the findings indicate that change in physical activity is associated with change in disability (through an association with function) consistent with Nagi�s disablement model, but other models may be applied during analysis and a causal interpretation, therefore, still could not be adopted.
In a 6-month longitudinal study Motl and colleagues then tested the hypothesis that a change in physical activity (Godin Leisure-Time Exercise Questionnaire and International Physical Activity Questionnaire) would be inversely associated with a change in walking impairment (Multiple Sclerosis Walking Scale-12) in patients with relapsing�remitting MS [Motl et al. 2011a]. Data from 263 MS patients were analyzed using linear panel analysis and covariance modeling. Findings showed that a standard deviation unit change of 1 in physical activity was associated with a standard deviation unit residual change of 0.16 in walking impairment. These findings, therefore, support physical activity as an important approach, when trying to avoid walking impairments.
Finally, Motl and McAuley published a paper on longitudinal data (6 months) from 292 MS patients evaluating the relationship between a change in physical activity (7-day accelerometer data) and change in disability progression (Patient Determined Disease Steps Scale) [Motl and McAuley, 2011]. Panel analysis showed that a change in physical activity was associated with a change in disability progression (path coefficient: �0.09). This led the authors to conclude that a reduction in physical activity is a behavioral correlate (but not necessarily a cause) of short-term disability progression in persons with MS.
Recently, Tallner and colleagues evaluated the relationship between sports activity (Baecke Questionnaire � sports index) and MS relapses during the last 2 years (based on self-reports) in 632 German MS patients [Tallner et al. 2011]. Patients were divided into four groups based on their sports index. The study showed no overall differences between the four groups concerning the number of relapses within the last 2 years. However, the most active group had the lowermost mean and standard deviation of all groups. Consequently, these data suggest that exercise does not negatively influence relapse rate and the data further indicate that exercise actually reduce relapse rate.
In summary, patient-reported measures of the association between exercise or physical activity and disease progression (expressed as symptoms, functional limitations or disability) or activity (relapse rate) provide evidence of an association with more physical activity providing protection. However, due to the nature of the studies the causality of this association has not been established.
Disease Progression Evaluated in Animal Studies
Some obvious methodological difficulties exists in designing a human study clarifying whether or not exercise has an impact on disease progression in MS patients. Therefore, the question has been addressed in the EAE animal model of MS.
In a preliminary study by Le-Page and colleagues four groups of EAE rats were followed from day 1 to day 10 after injection with an agent inducing EAE [Le-Page et al. 1994]. The injection resulted in three different disease courses in the rats, namely acute (rats rapidly developed serious clinical signs and died without signs of recovery), monophasic (rats developed only one bout of disease followed by complete recovery) and chronic relapsing (CR-EAE, more than one bout of disease followed by remission). The CR-EAE disease course is characterized by the development of an initial acute paralytic attack 10�20 days after immunization with neuroantigens and the development of spontaneous relapses thereafter. A female and a male group of rats exercised and a female and male group served as control. Exercise consisted of running on a treadmill from day 1 to day 10 after injection. The protocol was progressively adjusted with the duration increasing from 60 min towards 120 min and the running speed increasing from 15 to 30 m/min. The study showed that in the exercised CR-EAE rats of both sexes the onset of the disease was significantly delayed compared with the onset in control CR-EAE rats. Also, the duration of the first relapse was significantly reduced in exercised CR-EAE rats compared with control rats whereas no effect was seen on the peak severity of the disease. No effects of exercise were observed in the acute and monophasic EAE rats. The authors concluded that endurance exercise during the phase of induction of EAE diminished lightly one type of EAE (CR-EAE) but also that exercise did not exacerbate the disease.
In a complementary study Le-Page and colleagues conducted further four experiments in the monophasic EAE model [Le-Page et al. 1996]. Experiments 1 and 2 showed that 2 consecutive days of intensive exercise (250�300 min/day) performed just after injection had a lowering effect on the course of the clinical signs of disease as compared with control rats. Also, the onset of the disease and the day of maximal severity were both delayed in the exercising rats, whereas no change was observed in disease duration. When the 2 consecutive days of exercise were performed before injection no effects were observed. In experiments 3 and 4 it was tested how 5 days of more moderate exercise at either constant (15�25 m/min for 2 hours) or variable speed (3 min at 2 m/min and then 2 min at 35 m/min for a total of 1 hour) affected the course of the disease and the clinical parameters. No effects were observed on the disease course and on the clinical parameters. The authors concluded that severe exercise contrary to more moderate exercise slightly influenced the effector phase of monophasic EAE, and confirmed that physical exercise performed before onset of EAE did not exacerbate the clinical signs.
More recently, Rossi and colleagues further explored the effects of physical activity on disease progression in the CR-EAE mice model [Rossi et al. 2009]. In this study one group of mice had their cage equipped with a running wheel on the day of immunization, while the control group had no running wheel. The amount of physical activity was not controlled and it was therefore the amount of voluntary physical activity in the running wheel that constituted the intervention. In a further experiment EAE mice in standard cages were compared with EAE mice in cages equipped with a blocked wheel. This was done to dissect the role of physical activity from that of sensory enrichment caused by the wheel itself, and showed not to influence the clinical course of the disease. During the initial phase (13 days after injection) of the disease the exercising mice ran spontaneously an average of 760 turns/day in the running wheel which dropped to 18 turns/day when motor impairment peaked (20�25 days after injection). The study showed that the severity of EAE-induced clinical disturbances was attenuated in both acute and chronic phases of EAE in the physically active mice, who consistently exhibited less severe neurological deficits compared with control EAE animals during a time period of 50 days after EAE induction. Furthermore, it was shown that both synaptic and dendritic defects caused by EAE were attenuated by physical activity.
In summary, aerobic exercise (or voluntary physical activity) has the potential to influence the clinical course of the disease in the EAE animal model of MS.
Participating in physical activities and exercise can be beneficial for anyone, especially for people with multiple sclerosis, or MS. Exercise can help ease multiple sclerosis symptoms, however, patients have to be careful with the amount of physical activity they engage in. Several research studies like the one discussed in this article have determined that physical activities and exercises can help improve symptoms as well as slow down the progression of multiple sclerosis. It’s essential to talk to a healthcare professional to discuss the details of each workout program in order to make the best of the benefits of exercise for MS. Dr. Alex Jimenez D.C., C.C.S.T.
Discussion
Recent evidence from studies applying nonclinical and patient-reported measures as well as from studies applying the EAE animal model of MS indicate a possible disease-modifying effect of exercise (or physical activity) but the strength of the evidence limits definite conclusions. Furthermore, these findings are not confirmed in intervention studies evaluating disease progression by clinical outcome measures. Despite the obvious associated difficulties future long-term exercise intervention studies in a large group of MS patients are needed within this field.
MS Disease Progression
Some major methodological problems arise when trying to measure MS disease progression. The ideal MS outcome measure would quantify irreversible sustained disease progression, but in MS this has proven difficult. The pleiotropic expression of MS makes it challenging to measure all facets of the disease and it may be necessary to focus on specific symptoms. Furthermore, great patient heterogeneity, population variability in the disease course and tempo of progression, subclinical MRI changes of uncertain impact on delayed disability progression, multifaceted neurological deficits with varied abilities for individual patients to compensate and patient comorbidities complicate things further [Goldman et al. 2010].
Clinical Outcome Measures
EDSS, MSFC and relapse rate are the standard clinical outcome measures for MS therapeutic trials and the most widely used measure of disease progression is the EDSS [Goldman et al. 2010]. Our literature review shows that exercise studies (resistance, endurance and combined training) applying EDSS generally do not report any change after an exercise intervention. In medical studies applying EDSS, large sample sizes and interventions lasting 2�3 years are typically required to measure changes in exacerbation rates between treatment and placebo [Bates, 2011]. This corresponds poorly to the short intervention periods (3�26 weeks) and the small sample sizes applied in most exercise studies. This is due to the overall low responsiveness and sensitivity to change of the EDSS as reported in a number of studies (for references see Goldman et al. [2010]). Also, the EDSS have been criticized for its noninterval scaling, emphasis on ambulation status and absence of adequate cognitive and visual components [Balcer, 2001]. Despite the emphasis on ambulation and that a recent meta-analysis concluded that exercise impacts walking positively [Snook and Motl, 2009], no changes were seen in the EDSS in most of the reviewed studies, indicating low scale responsiveness towards exercise interventions. In clinical trials the MSFC is claimed to be more sensitive to change than the EDSS [Goldman et al. 2010]. This suggestion is supported by the finding from one exercise study applying both the EDSS and the MSFC. In this long-term study (26 weeks) [Romberg et al. 2005] the effects of combined training on EDSS and MSFC were evaluated. Only the MSFC showed a significant effect which led the authors to conclude that the MSFC was more sensitive than the EDSS in the detection of improvement of functional impairment as a result of combined exercise. In future exercise studies evaluating disease progression it should therefore be considered to add the MSFC as a clinical outcome measure.
In addition to low scale responsiveness, short-term interventions and small sample sizes other explanations for the general lack of effects on clinical outcome measures can be hypothesized. Despite no clear pattern in the existing data, the type of exercise (e.g. endurance versus resistance training) may influence the effect captured by clinical scales. Also, most studies have evaluated mild to moderately impaired (EDSS <6) MS patients. Perhaps the clinical scales would be more sensitive to change in more severely impaired patients. Finally, findings can be biased if it is generally more physically fit patients that accept to be enrolled in exercise studies. If so, the baseline fitness level may be above average in these patients further lowering the possibility of a change on clinical scales with low responsiveness.
Only a few studies [Bjarnadottir et al. 2007; Petajan et al. 1996; Romberg et al. 2004; White et al. 2004] present clear data on relapse rate but due to the short intervention periods and the small sample sizes in most studies changes in the relapse rate, would not be expected to be evident. However, Romberg and colleagues found a total of 11 relapses (five in the combined training group and six in the control group) during a 6-month intervention period [Romberg et al. 2004]. Similarly, Petajan and colleagues (endurance training group four relapses and control group three relapses) [Petajan et al. 1996] and Bjarnadottir and colleagues (combined training group one relapse and control group one relapse) [Bjarnadottir et al. 2007] reported identical relapse rates in exercise and control groups. In the study by White and colleagues no participants experienced relapses during the 8-week intervention evaluating resistance training [White et al. 2004]. Recently, Tallner and colleagues collected self-report questionnaires on relapse rates and physical activity from MS patients to examine the relationship of different levels of sports activity and relapses [Tallner et al. 2011]. Based on these data the authors concluded that exercise had no significant influence on clinical disease activity. Taken together the few existing data do not indicate that any type of exercise increases relapse rate among MS patients. However, these data should be interpreted with caution due to the small number of participants (not stratified according to disease type or severity) and the short intervention periods in most studies. Consequently, future long-term studies with a large number of participants should, therefore, include relapse rate as an outcome measure.
Nonclinical Measures
Application of MRI has revolutionized the diagnosis and management of patients with MS [Bar-Zohar et al. 2008]. In regard to clinical trials, MRI offers several advantages over the accepted clinical outcome measures for MS, including an increased sensitivity to disease activity and a better association with histopathology findings. Also, MRI provides highly reproducible measures on ordinal scales, and the assessment of MRI can be performed at the highest degree of blinding [Bar-Zohar et al. 2008]. Consequently, a surrogate MRI measure reflecting disease progression such as lesion activity (gadolinium-enhanced lesions and new or enlarged T2-hyperintense lesions) or disease severity (total T2-hyperintense lesion volume, total T1-hypointense lesion volume and whole-brain atrophy) [Bermel et al. 2008] may reduce the required sample sizes needed to evaluate the effects of exercise therapy on disease progression considerably. Until now only two cross-sectional studies have evaluated the effects of exercise (expressed as the current cardiorespiratory fitness level) on different MRI measures limiting the conclusions that can be drawn from this type of study. However, the promising findings do encourage the inclusion of MRI as an outcome measure, in future longitudinal trials evaluating the effects of exercise on disease progression.
Patient-Reported Measures
Patient-reported measures of the association between exercise or physical activity and disease progression (expressed as symptoms, functional limitations or disability) provide evidence of an association with more physical activity providing protection. However, the nature of the studies does not allow conclusions on the causality of this association. In the group of studies applying patient-reported measures we decided to include not only measures of exercise, but also measures of physical activity. It is acknowledged that a measure of physical activity is not necessarily a surrogate measure of exercise, but the many interesting findings from particularly the group of Motl and colleagues caused this. In a recent paper, based on their own studies, Motl and colleagues concludes that recent research has identified physical activity as a behavioral correlate of disability in MS. This made the authors suggest, that physical activity might attenuate the progression of what they call �mobility disability� by improving physiological function in persons with MS, particularly those who have achieved a benchmark of irreversible disability (EDSS >4) [Motl, 2010]. It might be more cost effective to offer the more disabled (EDSS >4) MS patients exercise therapy, but it must be noted that most exercise studies do not indicate that a relationship between the degree of training adaptation and neurological disability exist. In fact, studies indicate that MS patients with an EDSS score below 4.5 experience the largest improvements after a period of endurance training as compared with more disabled MS patients [Ponichtera-Mulcare et al. 1997; Schapiro et al. 1988] or that no differences exists [Petajan et al. 1996]. It must be noted that none of these studies were powered to evaluate the effects of exercise in MS patients with different levels of disability. However, a recent study by Filipi and colleagues specifically evaluated whether 6 months of resistance training improves strength in MS patients with different levels of disability (EDSS 1�8) and concluded that all individuals with MS, despite different disability levels, showed parallel improvement in muscle strength [Filipi et al. 2011]. This leads to the suggestion, that exercise may be equally important during the early phases of the disease, also in regard to impact on disease progression.
An important advantage of applying patient-reported measures is the opportunity to collect data from large sample sizes in longitudinal studies. Furthermore, it seems important to collect data on patient perspective when evaluating the effects of exercise on disease progression. Future studies including patient-reported measures should also include clinical and/or nonclinical outcome measures if possible.
Animal Studies
Our review showed that aerobic exercise (or activities) has the potential to influence the clinical course of the disease in the EAE animal model of MS. The obvious question is whether or not the findings from the EAE animal model of MS can be extrapolated to humans. At the moment no clear answer can be given to this question. A recent review summarized whether the current disease-modifying treatments are justified on the basis of the results of EAE studies. Here it was concluded that although EAE is certainly an imperfect mirror of MS, many clinical, immunopathological and histological findings are impressively replicated by animal models, making EAE invaluable in elucidating the basic immunopathological mechanisms of MS and providing a testing ground for novel therapies [Farooqi et al. 2010]. Consequently, a direct transfer of findings into human subjects cannot be made, but testing of difficult hypotheses can start here. Also, it should be noted that in EAE you cannot control the relative exercise intensity since no maximal exercise test (such as a VO2 max test) can be performed. As a consequence the applied relative exercise intensity may differ between animals. This is also why it is very difficult to evaluate the effects of aerobic exercise on aerobic capacity in EAE. Nonetheless, the EAE model offers a number of advantages compared to human studies. In addition lower costs, easy control with adherence to the intervention and controlled environmental and genetic factors the EAE model also allows evaluation of possible mechanisms located in the central nervous system (CNS), which should have attention in future studies. Another review stated that the genetic heterogeneity, which is so critical in the MS population, is only reflected when multiple different models of EAE are studied in parallel [Gold et al. 2006]. This aspect should also be incorporated in future studies.
Possible Mechanisms
Several mechanisms have been proposed as a possible link between exercise and disease status in MS. Some of the most promising candidates include cytokines and neurotrophic factors [White and Castellano, 2008a].
Cytokines. Cytokines play an important role in the pathogenesis of MS and are a major target for treatment interventions. In particular, interleukin (IL)-6, interferon (IFN)-? and tumor necrosis factor (TNF)-? have a prominent role in the process of demyelination and axonal damage experienced by persons with MS [Compston and Coles, 2008].
Changes in the concentrations of certain cytokines, in particular IFN-? and TNF-?, have been associated with changes in disease status in MS, and elevated concentrations of pro-inflammatory Th-1 cytokines (such as TNF-?, IFN-?, IL-2 and IL-12) may contribute to neurodegeneration and disability [Ozenci et al. 2002]. This has led to the suggestion that exercise may counteract imbalances between the pro-inflammatory Th1 cytokines and the anti-inflammatory Th2 cytokines (such as IL-4 and IL-10) by enhancing anti-inflammatory mechanisms, and thereby potentially be able to alter the disease activity in MS patients [White and Castellano, 2008b].
In MS both the acute and/or chronic effects of resistance [White et al. 2006], endurance [Castellano et al. 2008; Heesen et al. 2003; Schulz et al. 2004] and combined training [Golzari et al. 2010] on several cytokines have been evaluated. A study by White and colleagues reported that resting levels of IL-4, IL-10, C-reactive protein (CRP) and IFN-? were reduced, while TNF-?, IL-2 and IL-6 levels remained unchanged after 8 weeks of biweekly resistance training [White et al. 2006]. These results suggest that progressive resistance training may have an impact on resting cytokine concentrations and, thus, could have an impact on overall immune function and disease course in individuals with MS. However, the study was not controlled and only 10 participants were included obviously limiting the strength of the evidence. Heesen and colleagues evaluated the acute effects of 8 weeks of endurance training on IFN-?, TNF-? and IL-10 and compared this to both a waitlist MS control group and a group of matched healthy subjects [Heesen et al. 2003]. After completing 30 minutes of endurance training (cycling) an increase in IFN-? were induced similarly in all groups while trends towards smaller increases in TNF-? and IL-10 were observed in the two groups of MS patients. Based on these data the authors concluded, that no deviation in pro-inflammatory immune response to physical stress could be demonstrated in MS patients. These findings, therefore, supports that a single bout of endurance training can influence the cytokine profile at least for a period of time in MS patients. In another publication from the same study Schulz and colleagues were not able to demonstrate any differences between the resting level or the acute IL-6 response after 30 minutes of endurance exercise in the MS training group (8 weeks of bicycling) and the MS control group [Schulz et al. 2004].
A study by Castellano and colleagues evaluated the effects of 8 weeks of endurance training (cycling, 3 days/week) on IL-6, TNF-? and IFN-? in 11 MS patients and 11 healthy matched controls. In MS patients both resting IFN-? and TNF-? was elevated after endurance training whereas no changes were observed in healthy controls [Castellano et al. 2008]. Like in the study by Heesen and colleagues [Heesen et al. 2003], Castellano and colleagues also studied the acute effects of a single bout of endurance training and similarly found no differences when compared to the healthy controls, but in this study no increase in IFN-? and TNF-? were observed in any of the groups contrasting the findings by Heesen and colleagues.
In the most recent study Golzari and colleagues performed a randomized controlled trial (RCT) evaluating the effects of 8 weeks of combined endurance and resistance training on IFN-?, IL-4 and IL-17 [Golzari et al. 2010]. The study showed significant reductions in the resting concentrations of IFN-? and IL-17 in the exercise group, whereas no changes were seen in the control group, but no group comparisons were made.
In summary, no clear pattern can be seen in the reported cytokine responses to exercise probably reflecting large methodological differences between the studies (study type, type of exercise intervention, time of measurements, standardizations, etc.) and a low statistical power which is critical due to the great variation in this type of measurements. Nonetheless, a single bout of exercise have been reported to influence a number of (pro-inflammatory) cytokines in MS patients and also chronic changes in the resting concentration of several cytokines have been reported after a training period. Furthermore, the response seems to be comparable to that of healthy subjects. Cytokines, therefore, may link exercise and disease progression in MS, but large-scale future RCTs have to evaluate this further.
Neurotrophic factors. Neurotrophic factors are a family of proteins that are thought to play a role in preventing neural death and in favoring the recovery process, neural regeneration and remyelination throughout life [Ebadi et al. 1997]. Some of the more well-characterized neurotrophic factors include brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) [White and Castellano, 2008b].
Gold and colleagues evaluated the acute effects of a single exercise bout (30 min cycling at 60% VO2 max) on NGF and BDNF in 25 MS patients and compared this with a group of matched healthy controls [Gold et al. 2003]. The study showed that baseline concentrations of NGF were significantly higher in MS patients compared with controls. Thirty minutes after exercise a significant increase was observed in BDNF while a trend towards an increase in NGF was observed. However, the changes did not differ from the changes observed in the healthy subjects. This made the authors conclude that moderate exercise can be used to induce neutrophin production in subjects with MS possibly mediating the beneficial effects of physical exercise. In a study from the same group Schulz and colleagues evaluated the effects of biweekly cycling for 8 weeks on BDNF and NGF in a RCT in MS patients [Schulz et al. 2004]. The study showed no effects on the resting concentration and on the response to acute exercise after the intervention period, and only a trend towards lower resting NGF levels was found. Castellano and White also evaluated whether 8 weeks of cycling (three times a week), would affect serum concentrations of BDNF in MS patients and in healthy controls [Castellano and White, 2008]. In contrast to the findings of Gold and colleagues, resting BDNF was lower at baseline in MS patients as compared with controls, but no difference (a trend) between groups was found after 8 weeks. In MS patients BDNF concentration at rest was significantly elevated between weeks 0 and 4 and then tended to decrease between weeks 4 and 8, whereas resting BDNF concentration remained unchanged at 4 and 8 weeks of training in controls. Also, the response to a single bout of exercise was evaluated showing a significant reduction in BDNF 2 and 3 hours after exercise in both groups again contrasting with the findings by Gold and colleagues. The authors concluded that their findings provided preliminary evidence showing that exercise may influence BDNF regulation in humans.
In summary contrasting findings on the effects of exercise on neurotrophic factors exists in MS patients, making more studies warranted. However, findings do imply that exercise may influence several neurotrophic factors known to be involved in neuroprotective processes.
Conclusions
It cannot be clearly stated whether exercise has a disease-modifying effect or not in MS patients but studies indicating this do exist. Future long-term intervention studies in a large group of MS patients are therefore needed to address this important question.
Acknowledgments
The authors would like to thank research Librarian Edith Clausen for a substantial contribution to the comprehensive literature search.
Footnotes
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
UD has received travel grants and/or honorary from Biogen Idec, Merck Serono and Sanofi Aventis. ES has received research support and travel grants from Biogen Idec, Merck Serono and Bayer Schering and travel grants from Sanofi Aventis.
Multiple sclerosis, or MS, is a chronic disease identified by symptoms of by pain, fatigue, vision loss and impaired coordination caused by damage to the myelin sheaths of nerve cells in the central nervous system, or CNS. Exercise has been demonstrated to help improve the management of symptoms of multiple sclerosis as well as decrease the progression of the disease, although further evidence is still required, the article above summarizes these outcome measures. The purpose of the article above demonstrates how exercise can change the progression of multiple sclerosis and improve overall health and wellness. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief. �
De Quervain’s Tenosynovitis, also called �washerwoman sprain,� is a condition of the hand that typically affects people who do continuous, fast, repetitive movements. The patient can experience a sudden onset of the condition or it can be gradual, beginning with tenderness in the thumb area and slowly progressing. It can restrict activity, but it doesn�t have to be a long-term disability. Chiropractic care can help relieve the symptoms of De Quervain�s Tenosynovitis and the hand can return to normal function.
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What Is De Quervain’s Tenosynovitis?
De Quervain’s Tenosynovitis is a condition affecting the thumb side of the wrist. It is a very painful condition that makes many everyday activities difficult or impossible. Many activities like playing golf, lifting a child, garden work, and racket sports can worsen the condition.
What are the Symptoms ofDe Quervain’s Tenosynovitis?
There are several distinctive symptoms of De Quervain�s tenosynovitis which include:
Pain near or at the base of the thumb
Difficulty moving or controlling the thumb and wrist when doing activities that involve pinching or grasping
Swelling near or at the base of the thumb
A �catch� or �sticking� sensation when moving the thumb
If the condition is allowed to progress or goes untreated it can involve the forearm and entire thumb, causing pain and swelling in those areas. The pain and symptoms can be exacerbated by movements that involve the wrist and thumb. The symptoms can last for a long time, weeks or even months.
What causes De Quervain’s Tenosynovitis?
The exact cause of De Quervain�s Tenosynovitis is not known, but the condition is commonly associated with chronic overuse of the wrist. There are tendons that connect the wrist and lower thumb, enabling movement like grasping, gripping, pinching, and wringing. The tendons slide through a sheath as they facilitate the movement. Over time, the sheath can swell and thicken which inhibits the amount of the tendon�s movement. When the movements are repetitive, it can cause irritation of the sheath, resulting in inflammation.
Who is at Risk for De Quervain’s Tenosynovitis?
Research has identified several groups that are at risk for developing De Quervain�s Tenosynovitis:
30 to 50 years of age with a higher concentration statistically around 40
Female
African ethnicity or descent
Pregnant
Caring for a child or baby
Works at a job that involves repetitive wrist and hand motions
This condition has typically been considered to be one that affects people who are middle-aged. However, with the popularity of texting, many young people experience symptoms of De Quervain�s. In one study, more than half of students who texted extensively were labeled positive for De Quervain�s.
What are the Treatments for De Quervain’s Tenosynovitis?
Treatment for De Quervain�s Tenosynovitis include:
Resting the affected thumb and wrist
Bracing or immobilization
Ice to the affected area
Anti-inflammatory medications like ibuprofen and naproxen
If standard treatment is not effective it may be necessary to seek medical attention. If the condition is severe or chronic, the doctor may inject corticosteroid directly into the tendon sheath. Surgery for De Quervain�s is not common, but it may be deemed necessary in order to release the thumb. The speed of healing and the�degree of normal use of the thumb depends on the treatment chosen and if the activity that exacerbates the condition is stopped.
Can Chiropractic Help De Quervain’s Tenosynovitis?
A chiropractor may recommend rest, ice, and bracing for a patient with De Quervain�s Tenosynovitis. Upon reviewing the patient�s lifestyle and habits, he or she may also advise ergonomic changes, modification of activity, and reduce exposure to positions that exacerbate the symptoms. Soft tissue therapies may be used to quickly bring relief to the soft tissue, minimizing the inflammation and pain. As the pain decreases, the chiropractor will recommend specific strengthening and stretching exercises that involve the wrist, thumb, and forearm.
With regular care and modification to activities, the condition can be healed and full mobility of the thumb and wrist can be restored.
Daniel Alvarado, owner of PUSH Fitness, in order to participate in his activities that are physical, he depends on his health. After fighting with shoulder pain during the course of several months, Daniel Alvarado went to visit Dr. Alex Jimenez, chiropractor, to receive shoulder pain rehabilitation. Chiropractic care is a treatment for subluxations, which might be causing symptoms, or an alternative treatment option used to cautiously help restore any misalignments. Dr. Alex Jimenez assisted Daniel Alvarado to enhance his strength, flexibility, and freedom through using spinal adjustments and manual manipulations. Daniel Alvarado was able to come back to his daily physical tasks after receiving shoulder pain rehabilitation together with Dr. Alex Jimenez, chiropractor. Daniel Alvarado highly recommends Dr. Alex Jimenez because he is the non-surgical pick for shoulder pain.
Chiropractic Rehab
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We want you to live a life that is fulfilled with more energy, positive attitude, better sleep, less pain, proper body weight and educated on how to maintain this way of life. I have made a life of taking care of every one of my patients.
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Note generations of the tracheal-bronchial tree, lobes, segments, and fissures. Note secondary pulmonary lobule (1.5-2-cm)-the basic functional unit of lungs observed on HRCT. Note important structural organization of the alveolar spaces with communications in between (pores of Kohn & canals of Lambert) that permit air drift and by the same mechanism allow exudative or transudative fluid to spread through the lung and stopped at the fissure. Note the anatomy of the pleura: parietal that is a part of the endothoracic fascia and the visceral that forms a lung edge � pleural space in between.
Mediastinum: surrounded by the pleura and the lung. Accommodates major structures contains numerous lymph nodes (see diagramme showing mediastinal nodes and their involvement in Lymphoma
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General Approach to Investigating Chest Complaints
Decubitus views right and left: help to evaluate subtle pleural effusion, pneumothorax and other pathology
Normal CXR PA & Lateral views. Ensure good exposure: T-spine discs and vessels through the heart are visualized on PA view. Count 9-10 right posterior ribs to confirm adequate inspiratory effort. Begin a thorough survey using the following approach: Are There Many Lung Lesions A-abdomen/diaphragm, T-thorax wall, M-mediastinum, L-lungs individually, Lungs-both. Develop a good search pattern
1) Airspace disease aka alveolar lung disease? Filling of the lung’s alveoli, acini and subsequently the entire lobe with fluid or substance of any composition (blood, pus, water, proteinaceous material or even cells) Radiographically: lobar or segmental distribution, airspace nodules may be noted, tendency to coalesce, air bronchograms and silhouette sign present. Batwing (butterfly) distribution noted as in (CHF). Rapidly changing over time, i.e., increase or decrease (days)
2) Interstitial disease: infiltration of pulmonary interstitium (alveoli septum, lung parenchyma, vessel walls, etc.) by for example by viruses, small bacteria, protozoans. Also infiltration by cells such as inflammatory/malignant cells (e.g., lymphocytes) Presented as an accentuation of lung interstitium with a reticular, nodular, mixed reticulonodular pattern. Different etiologies: inflammatory autoimmune diseases, fibrosing lung disease, occupational lung disease, viral/mycoplasma infection, TB, sarcoidosis lymphoma/leukemia and many other.
Recognizing different patterns of pulmonary disease can help with DDx. Mass vs. Consolidation (left). Note different patterns of pulmonary disease: airspace disease as lobar consolidation indicative of pneumonia, diffuse consolidation indicative of pulmonary edema. Atelectasis (collapse and volume loss). Interstitial patterns of pulmonary disease: reticular, nodular or mixed. SPN vs. Multiple focal consolidations (nodules) likely representing mets infiltrates vs. septic infiltrates
A = intraparenchymal
B = pleural
C = extrapleura
Recognize important location of chest lesions
Important signs: Silhouette sign: help with localization and DDx. Example: Bottom left image: radiopacity in the right lung, where is it located? Right MM because the right heart border that is adjacent to right middle lobe is not seen (silhouetted) Air bronchograms: air containing bronchi/bronchioles surrounded by fluid
Chest Trauma
Pneumothorax (PTX): air (gas) in the pleural space. Many causes. Complications:
Tension PTX: continuous increase of air in the pleural space that rapidly compresses mediastinum and lung rapidly reducing venous return to the heart. It can be fatal if not treated rapidly
Spontaneous PTX: primary (young adults (30 -40) especially tall, thin men. Additional causes: Marfan�s syndrome, EDS, Homocystinuria, a – 1 -antitrypsin deficiency. Secondary: older pts with parenchymal disease: neoplasms, abscess, emphysema, lung fibrosis and honeycombing, catamenial PTX d/t endometriosis and others.
CXR: note visceral pleural line aka lung edge. An Absence of pulmonary tissue/vessels beyond the visceral pleural line. Subtle pneumothorax can be missed. On erect position, air rises and PTX should be sought at the top.
Rib fractures: v.common. Traumatic or pathological (e.g., mets, MM) Rib series x – rays are not very useful because CXR and/or CT scanning are more important to evaluate posttraumatic PTX (bottom left) lung laceration and another major path
Infection
Pneumonia: bacterial vs. viral or fungal or in the immunocompromised host (e.g., Cryptococcus in HIV/AIDS) Pulmonary TB
Pneumonia: community-acquired vs. hospital-acquired. Typical bacterial pneumonia or Lobar (non-segmental) pneumonia with purulent material filling the alveoli and spreading to the entire lobe. M/C organismStreptococcus Pneumonia or the Pneumococcus
Others: (Staph, Pseudomonas, Klebsiella esp. in alcoholics potentially leading to necroSIS/lung gangrene) Mycoplasma (20-30s) aka walking pneumonia, etc.
Clinically: a productive cough, fever, pleuritic chest pain sometimes hemoptysis.
CXR: confluent airspace opacity confined to the entire lobe. Air bronchograms. Silhouette sign help with location.
Viral: Influenza, VZV, HSV, EBV, RSV, etc. presents as interstitial lung disease that can be bilateral. May lead to respiratory compromise
Atypical pneumonia and Fungal Pneumonia: Mycoplasma, Legionnaire’s disease, and some fungal/Cryptococcus pneumonia may present with interstitial lung disease.
Pulmonary abscess: an infectious collection of purulent material in the lungs that often necrotizes. May lead to significant pulmonary and system complications/life-threatening.
On CXR or CT: round collection with thick borders and central necrosis containing air-fluid level. DDx from empyema that distorts the lung and pleural-based
Rx: antibiotics, antifungal, antiviral agents.
Pneumonia needs to be followed up with repeat CXR to ensure complete resolution
Lack of radiographic improvement of pneumonia may represent declined immunity, antibiotic resistance, underlying lung carcinoma or other complicating factors
Pulmonary TB
Common infection worldwide (3rd world countries). 1 in 3 persons worldwide is affected by TB. TB is caused by Mycobacterium TB or Mycobacterium Bovis. Intracellular bacillus. Macrophage plays a key role.
Primary Pulmonary TB & Post-primary TB. Requires repeated exposure through inhalation. In most immunocompetent hosts, the active infection does not develop
TB presents as 1) cleared by the host, 2) suppressed into Latent Tuberculosis Infection (LTBI) 3) cause active disease TB. Patients with LTBI are not spreading TB.
Imaging: CXR, HRCT. Primary TB: pulmonary airspace consolidation (60%) lower lobes, lymphadenopathy (95%- hilar & paratracheal), pleural effusion (10%). The Spread of primary TB most likely in immunocompromised and children.
Milliary TB: pulmonary and system complication dissemination that can be fatal
Post-primary (secondary) or reactivation infection: Mostly in the Apices and posterior segments of the upper lobes )high PO2), 40%-cavitating lesions, patchy or confluent airspace disease, fibrocalcific. Latent features: nodal calcifications.
Dx: Acid-fast bacilli (AFB) smear and culture (sputum). HIV serology in all patients with TB and unknown HIV status
Rx: 4-drug regimen: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin.
Pulmonary Neoplasms (primary lung cancer vs. pulmonary metastasis)
Lung cancer: m/c cancer in men and 6th most frequent cancer in women. Strong association with carcinogens inhalation. Clinically: late discovery, depending on the location of the tumor. Pathology (types): Small cell (SCC) vs. Non-small cell carcinoma
Small cell: (20%) develops from neuroendocrine aka Kultchitsky cell, thus may secrete biologically active substances presenting with paraneoplastic syndrome. Typically located centrally (95%) at or near the mainstem/lobar bronchus. Most show poor prognosis and unresectable.
Non-small cell: Lung adenocarcinoma (40%) (M/C lung cancer), M/C in women and non-smokers. Others: Squamous cell (may present with cavitating lesion), Large cell and some others
Plain film (CXR): new or enlarged focal lesion, widened mediastinum suggestive of lymph node involvement, pleural effusion, atelectasis, and consolidation. SPN-may represents potential lung cancer especially if it contains irregular borders, feeding vessels, thick wall, in the upper lungs. Multiple lung nodules are likely to represent metastasis.
Best Modality: HRCT with contrast.
Other chest neoplasms: Lymphoma is v. common in the chest especially in mediastinal and internal mammary notes.
Overall M/C pulmonary neoplasms are a metastasis. Some tumors show a higher predilection for lung mets, e.g., Melanoma, but any cancer can metastasize to the lungs. Some mets referred as �Cannonball� metastasis
Rx: radiation, chemotherapy, resection
Pulmonary edema: a general term defines abnormal fluid accumulation outside vascular structures. Broadly divided into Cardiogenic (e.g., CHF, mitral regurgitation) and Non-cardiogenic with a multitude of causes (e.g., fluid overload, post-transfusion, neurological causes, ARDS, near drowning/asphyxiation, heroin overdose, and others)
Causes: increased in Hydrostatic pressure vs. decreased in oncotic pressure.
Imaging: CXR and CT: 2-types Interstitial and Alveolar flooding. Imaging presentation depends on stages
In CHF: Stage 1: redistribution of vascular flow (10- 18-mm Hg) noted as �cephalization� of the pulmonary vasculature. Stage 2: Interstitial edema (18-25-mm Hg) Interstitial edema: peribronchial cuffing, Kerley lines (lymphatics filled with fluid) A, B, C lines. Stage 3: Alveolar edema: airspace disease: patchy consolidations developing into diffuse airspace disease: Batwing edema, air bronchograms
Rx: 3 main goals: Initial O2 to keep O2 at 90% saturation
Next: (1) reduction of pulmonary venous return (preload reduction), (2) reduction of systemic vascular resistance (afterload reduction), and (3) inotropic support. Treat underlying causes (e.g., CHF)
Lung atelectasis: incomplete expansion of pulmonary parenchyma. The term “collapsed lung” is typically reserved for when the entire lung is collapsed
1) Resorptive (obstructive) atelectasis occurs as a result of complete obstruction of an airway (e.g. tumor, inhaled objects, etc.)
2) Passive (relaxation) atelectasis occurs when contact between the parietal and visceral pleura is disrupted (pleural effusion & pneumothorax)
3) Compressive atelectasis occurs as a result of any thoracic space-occupying lesion compressing the lung and forcing air out of the alveoli
4) Cicatricial atelectasis: occur as a result of scarring or fibrosis that reduces lung expansion as in granulomatous disease, necrotizing pneumonia, and radiation fibrosis
5) Adhesive lung atelectasis occurs from surfactant deficiency and alveolar collapse
6) Plate-like or discoid often developed after following general anesthesia
7) Imaging features: lung collapse, migration of lung fissures, deviation of the mediastinum, rising of the diaphragm, hyperinflation of adjacent unaffected lung
Mediastinum: pathology can be divided into those that result in a focal mass or those that result in diffuse disease involving the mediastinum. Additionally, air may track into the mediastinum in pneumomediastinum. Knowledge of mediastinal anatomy helps the Dx.
Pulmonary emphysema: loss of normal elastic tissue/elastic recoil of the lung with the destruction of capillaries and alveolar septum/interstitium.
Destruction of lung parenchyma due to chronic inflammation. Protease-mediated destruction of elastin. Air trapping/airspace enlargement, hyperinflation, pulmonary hypertension, and other changes. Clinical: progressive dyspnea, irreversible. By the time the forced expiratory volume in 1 second (FEV1 ) has fallen to 50% the patient is breathless upon minimal exertion and adapts to lifestyles.
COPD is the third leading cause of global death. Affects 1.4% of adults in the US. M:F = 1 : 0.9. Pts 45 years and older
Causes: Smoking and a-1-Antitrypsin deficiency (divided into centrilobular (smoking) and panacinar.
Imaging; signs of hyperinflation, air trapping, bullae, pulmonary hypertension.
Truide Torres recibe atenci�n quiropr�ctica con el Dr. Alex Jimenez por su dolor en el nervio ci�tico. La ci�tica es una colecci�n de s�ntomas caracterizados por dolor lumbar que se irradia a trav�s de los muslos hacia las piernas, rodillas y pies. El dolor del nervio ci�tico puede afectar uno o ambos lados de las extremidades inferiores. Truide Torres luch� para participar en sus actividades f�sicas diarias debido a sus s�ntomas de ci�tica. A trav�s de ajustes espinales y manipulaciones manuales, el Dr. Alex Jimenez restaur� cuidadosamente la alineaci�n original de su columna, aliviando sus s�ntomas dolorosos. Truide Torres recomienda al Dr. Alex Jimenez y su personal como la opci�n no quir�rgica para la ci�tica.
Terapia
Nos complace presentarle a la Cl�nica Premier de Atenci�n de Lesiones y Bienestar de El Paso.
Nuestros servicios est�n especializados y enfocados en lesiones y en el proceso completo de recuperaci�n. Nuestras �reas de pr�ctica incluyen Bienestar y nutrici�n, Dolor cr�nico, Lesiones personales, Cuidado de accidentes automovil�sticos, Lesiones en el trabajo, Lesi�n en la espalda, Dolor en la espalda baja, Dolor en el cuello, Tratamiento de migra�a, Lesiones deportivas, Ci�tica severa, Escoliosis, Discos herniados complejos, Fibromialgia, Cr�nica Dolor, manejo del estr�s y lesiones complejas.
Como Cl�nica de Rehabilitaci�n Quiropr�ctica y Centro de Medicina Integrada de El Paso, nos enfocamos apasionadamente en el tratamiento de pacientes despu�s de lesiones frustrantes y s�ndromes de dolor cr�nico. Nos enfocamos en mejorar su capacidad a trav�s de programas de flexibilidad, movilidad y agilidad dise�ados para todas las edades y discapacidades.
Queremos que viva una vida que se cumpla con m�s energ�a, actitud positiva, mejor sue�o, menos dolor, peso corporal adecuado y educaci�n sobre c�mo mantener esta forma de vida. He hecho una vida cuidando a cada uno de mis pacientes.
Te aseguro que solo aceptar� lo mejor para ti …
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