Neurobehavioral & Cognitive Disorders
Mental status examination
Jun. 17, 2026
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Neurologic disorders associated with obesity
- Updated 10.25.2025
- Released 02.17.2020
- Expires For CME 10.25.2028
Neurologic disorders associated with obesity
Introduction
Overview
The “globesity” (global obesity) pandemic is a severe threat to human health. Obesity is creating a challenging myriad of secondary and associated medical maladies involving various organ systems. Our species, given multiple factors, is further trending toward being swathed in adiposity. This has the associated, identifiable array of particularly elicited neurologic disorders discussed in this article.
Key points
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• Obesity, including morbid obesity, is common and will remain common. Obesity begets obesity. In the 2021 Nutrients Review, Basolo states “it has been predicted that the prevalence of individuals with obesity will approach 50% of the worldwide population by 2030 (07).” | |
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• The modern society’s environment is obesogenic. | |
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• There is a multitude of medical disorders that clearly stem from corpulence and adiposity. | |
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• Certain specific neurologic abnormalities can be interlinked with obesity. | |
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• The neuropathologic entities reviewed in this manuscript that are related to obesity include: multiple sclerosis, idiopathic intracranial hypertension, headache, carpal tunnel syndrome, meralgia paresthetica, peripheral polyneuropathy, amyotropic lateral sclerosis, attention deficit hyperactivity disorder, stroke and dementia via obstructive sleep apnea, and obesity hypoventilation syndrome. | |
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• Bariatric surgery is reviewed as a sound option toward management of severe obesity with comorbidities. |
Historical note and terminology
Human fat, historically, had purported medicinal value. The product, Axungia hominis, was used in pharmaceuticals such as ointments aimed at the treatment of bone pain, toothache, and gout. Human fat was considered a panacea for cachexia and an analgesic for rheumatism. It had a reputation as “magical.” Executioners in Germany recovered the fat, and it was sold under the trade name Humanol. It was an injectable targeting scar treatment and wound revisions and infections. Human fat fell from favor after fat embolisms were perceived as complications. It was later used to grease railways and was applied to bells to achieve better sound.
The human race has gone from revering fatness as a sign of affluence to now recognizing obesity as a global chronic public health care crisis of grand scale. Addressing the trend toward girth and managing its consequences, including medical and economic ramifications, will be an ongoing world-wide challenge. Alarmingly, over 40% of people in the United States are considered obese (41).
Kushner and Shapiro approach the issue of obesity as energy imbalance and appetite dysregulation (27). They perceive treatment to rely on principles of primordial, primary, secondary, and tertiary prevention. Primordial prevention is population-based and addresses contributors to obesity risk factors, such as energy-dense, processed foods. Primary prevention addresses improvements in psychological health and in nutritional and physical activity-related behaviors aimed at lowering risk. Secondary prevention alludes to screening for obesity and its related health conditions along with actual treatments, including medications and bariatric surgery. Tertiary prevention, per their perception across the care continuum, includes limiting downstream complications, including health consequences.
Clinical manifestations
Presentation and course
The World Health Organization espouses the following classifications, based on body mass index, or BMI:
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Nutritional status |
BMI (kg/m2) |
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Underweight |
Less than 18.5 |
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Normal range |
18.5 to 24.9 |
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Overweight |
25.0 or more |
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- Preobese |
25.0 to 29.9 |
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Obese |
More than 30.0 |
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- Class I |
30.0 to 34.9 |
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- Class II |
35.0 to 39.9 |
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- Class III |
40.0 or more |
Bergman espouses the use of BAI or body adiposity index instead of BMI. The argument is that BMI is of limited accuracy (09). There is a difference between males and females with a similar percentage of body adiposity. The BAI, as an anthropometric measure, can be used without weighing as it is based on hip circumference and height.
In 2013, the American Medical Association classified obesity as a disease. The comorbidities associated with obesity, in general, include:
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• Malignancy: prostate, colon, breast, lung, pancreas, endometrium | |
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• Cardiovascular: ischemic heart disease, hypertension, atherosclerotic peripheral vascular disease, cor pulmonale, deep vein thrombosis, pulmonary embolus | |
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• CNS: stroke or increased intracranial hypertension (pseudotumor cerebri) | |
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• Respiratory: obstructive sleep apnea, obesity hypoventilation syndrome, asthma, infections | |
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• Obstetric: infertility, stillbirth, stress incontinence (pelvic), polycystic ovary syndrome | |
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• Psychological: depression or social stigmatization | |
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• Gastrointestinal: gastroesophageal reflux disease; nonalcoholic fatty liver disease | |
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• Orthopedic: osteoarthritis | |
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• Metabolic: diabetes mellitus, metabolic syndrome X (to include comorbid obstructive sleep apnea), dyslipidemia |
The following aspects of obesity have been associated with comorbidity:
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• Fat distribution (visceral or android vs. subcutaneous) |
Secondary causes of obesity include:
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• Hypothyroidism |
Clinical signs of obesity could include:
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• Striae |
Regarding an endocrine etiology, the clues that obesity stems from a hormonal abnormality (eg, hypothyroidism or growth hormone deficiency) include:
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• Weight gain out of character |
Prognosis and complications
“Childhood obesity is associated with a higher chance of obesity, premature death, and disability in adulthood. But in addition to increased future risks, obese children experience breathing difficulties, increased risk of fractures, hypertension, early markers of cardiovascular disease, insulin resistance, and psychological effects” (18).
Hippocrates wrote that “corpulence is not only a disease itself, but the harbinger of others.”
Insurance companies increase premiums for the obese. The prognosis is dire; if the BMI of a male is greater than 40 kg/m2, life expectancy is reduced 20 years; for females, the reduction is 5 years. Overall, obesity is estimated to increase the cardiovascular mortality rate 4-fold and the cancer-related mortality rate 2-fold.
Many comorbidities remit or resolve after bariatric surgical intervention. These include obstructive sleep apnea, diabetes mellitus, hypertension, heart failure, peripheral edema, respiratory insufficiency, asthma, dyslipidemia, reflux esophagitis, pseudotumor cerebri (idiopathic intracranial hypertension), osteoarthritis, operative risk, thromboembolism, and urinary incontinence. Weight loss reduces the volume of several upper airway soft tissues – especially tongue fat – in persons with obesity and obesity syndrome and is the basis for the improved Apnea-Hypopnea Index (70).
A common pathway of obesity’s medical complications includes metabolic syndrome, or syndrome X. This is comprised of abdominal obesity, hypertension, hyperglycemia (from insulin resistance), hypertriglyceridemia, low HDL, and type 2 diabetes mellitus. Metabolic syndrome affects 60% of the United States population older than age 50 years. The prevalence of metabolic syndrome in patients with coronary heart disease is 50%. It is linked with sleep apnea (11).
Binge eating disorder is known to be strongly related to metabolic syndrome. They hold shared mechanisms (behavioral and genetic and biological) and shared clinical implications (02). The behavioral factors include high-fat and -carb diet, decreased weight cycling episodes and regular skipping of meals. Prognosis is generally poor, with sorry cerebrovascular outcomes.
The International Diabetes Federation offers definitions for metabolic syndrome, including:
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• Triglycerides greater than 150 |
In metabolic syndrome, the free fatty acids accumulate in tissue causing lipotoxicity with activation of inflammatory pathways.
A particularly concerning form of obesity is termed sarcopenic obesity. This involves the combination of low skeletal muscle mass and high fat mass, or bodyweight. The decline in myo-mass is an important cause of disturbance in physical performance, along with alterations in energetics, muscle aerobic capacity, excitation-contraction coupling, and skeletal integrity (68).
Clinical vignette
Fictitiously, a 53-year-old male with a BMI of 42 presented with obstructive sleep apnea and obesity hypoventilation syndrome per polysomnogram. He was referred to bariatric surgery for a gastric bypass procedure because he failed CPAP as a management attempt for his severe obstructive sleep apnea. He had early evidence of dementia and had a full-blown metabolic syndrome requiring multiple medications. He had depression and psychosis (circumscribed delusions), which militated against his valid candidacy for interventionary weight-loss surgery. He had insomnia stemming from his obstructive sleep apnea with arousals but also from gastroesophageal reflux disease with nighttime heartburn and from pain due to carpal tunnel syndrome and meralgia paresthetica. The fractionated sleep rendered an endogenous imbalance of ghrelin and leptin such that he was gaining weight at a rapid pace, given hyperphagia and reduced caloric expenditure.
Biological basis
Etiology and pathogenesis
The etiology of obesity is far more complex than simply an imbalance between energy intake and energy expenditure. Unwaveringly, the prevalence of inactivity is an issue.
Societal stress is an important but rather overlooked public policy target in regard to curtailment of obesity. Stress interferes with cognitive processes, such as executive function and self-regulation. Stress can affect behavior by inducing overeating and consumption of foods that are high in calories, fat, or sugar; by decreasing physical activity; and by shortening sleep. Stress triggers physiological changes in the hypothalamus-pituitary-adrenal axis, reward processing in the brain, and possibly in the gut microbiome. Stress can stimulate production of biochemical hormones and peptides, such as leptin, ghrelin, and neuropeptide Y (01; 63; 66).
A group from the University of California at Los Angeles explored the relationship of the brain-gut axis to obesity (21). The gut microbiome and fecal amino acid metabolites impact brain-structured volumes in reward regions. Obesity and metabolic syndrome are known to be associated with phylum-level changes in the microbiota (increased phyla Firmicutes and Proteobacteria; decreased Bacteroidetes), reduced bacterial diversity, and alteration of the bacterial genes and metabolic pathways. The gut microbiota output of certain amino acids (aromatic and branched chain) influence neurodevelopmental processes. Kumar notes that gut dysbiosis has associated biofilm (extracellular matrices that elude immune clearance) microbial imbalances that fuel chronic inflammation (elevated interleukin 6 and 8; plasma CRP) and a milieu that compromises the blood-brain-barrier and induces neurodegeneration/dementia via microglial activation (26). They list the microbes implicated in human disease processes in table format.
In the International Journal of Pharmaceutics, Roy and colleagues share that there is surging interest in the “GBMA” or gut-brain-microbiome axis and that it is a bidirectional system (56). Interest is growing in reference to potential treatment with silica nanoparticle-based delivery systems for probiotic spores and composite hydrogels and biomimetic nanosystems designed for targeted therapeutic delivery. Photobiomodulation therapy holds promise as well.
The dietary, aka metabolic health, viewpoint, stresses the importance of UPFs or ultra-processed foods (39). They contend that UPFs exert effects on the brain beyond “just” contributing to obesity. UPFs are seen to induce dysregulation of the network of cortical feeding-related brain structures, such as the nucleus accumbens. This seems to create a self-reinforcing cycle of increased UPF consumption. They hold a high reinforcement value with a signal that drives behavior – addictionologic of sorts.
Obesity-related reduction in neuronal fiber bundle length, as well as smaller cortical thickness and reduced subcortical gray matter volumes, has been well documented.
Obesity begets hyperleptinemia but, concurrently, there is systemic leptin resistance. Leptin is a hormone from fat tissue responsible for body weight regulation and satiety. Its counterpart, ghrelin, originates from the gut and induces hunger behavior; it is also involved in depression. There is a noted subtype of obesity, named metabolically healthy obesity, whereby there is yet the absence of metabolic abnormalities such as dyslipidemia, insulin resistance, hypertension, and an unfavorable inflammatory profile (25). Orexin plays a role; the neuropeptide regulates body weight, glucose homeostasis, and insulin sensitivity. Orexins (A and B), furthermore, promote energy expenditure and protect against obesity by interacting with brown adipocytes and endocrine pancreatic functions (61).
There is a link between the dysfunction of cognitive control-related brain regions with obesity and the burden of white matter hyperintensities detected by FLAIR imaging and by resting state fMRI. Chronic (especially visceral) obesity is associated with complications, including cognitive impairment and dementia (38). The low-grade systemic inflammation conveys endocrinopathies, including diabetes mellitus and hypertension as well as dyslipidemia. The comorbidities are causally related to cerebrovascular dysfunction. The vascular damage in white matter leads to demyelination, loss of oligodendrocytes, and gliosis. Cortical thickness is reduced, ie, there is discernable gray matter volume loss in the bitemporal regions and entorhinal, orbitofrontal, amygdalohippocampal, and cingulate zones. Clinically, the presentation is that of mild cognitive impairment, with reduced working memory and impaired executive functioning (65). The orbitofrontal cortex showed key interaction (functional connectivity) effects between periventricular white matter hyperintensity burden and the degree of obesity. The perturbed connections apparently disrupt the balance between cognition and reward systems, leading to binge eating disorders. There is an encoding of food-related reward responses and the induction of the feeling of hunger. This orbitofrontal cortex is also involved in the cognitive control of inhibitory processing. Further, hormones, such as leptin and ghrelin, convey appetite-related information to the hypothalamus in the regulation of eating behavior. High-fat diets are known to trigger an inflammatory response in the hypothalamus, which actually precedes weight gain (47). Obesity has various deleterious effects on health that are largely associated with peripheral metabolic abnormalities, such as aberrant glucose and lipid homeostasis; one mechanism likely involves systemic alteration of inflammatory adipokine (adiponectin, interleukin-6, CRP, cytokines) signaling (30).
Morys and colleagues conclude that the mechanisms linking obesity with brain atrophy are likely independent of those governing Alzheimer disease–related protein (dysfunctional tau; amyloid-beta) deposition (40).
Obstructive sleep apnea renders arousals and intermittent hypoxemia. The deoxygenation or desaturation is associated with hyperadrenergic autonomic activity that fuels the stress response (epinephrine and corticoids) and is, thus, obesogenic; there is adipogenic differentiation (71). Hypercortisolism increases the risk of metabolic syndrome (31).
A developmental cascade perspective exists for onset pediatric obesity; low self-esteem causes consumption of sugary foods, which disrupts sleep quality and contributes further to obesity (62).
Reduction in total sleep time is causative toward obesity. This reduction stems from certain environmental and cultural changes, such as increased environmental light, increased industrialization, growing numbers of people with shift work (irregular sleep/wake cycles), and the advent of television and digital gadgetry. Reduced sleep duration is associated with reduced leptin, increased ghrelin, and increased body mass index, along with higher levels of measurable endocannabinoids, which govern hedonic hunger, food overconsumption, and positive energy balance in relation to weight gain. This source of obesity is a combination of low-quality (high carbohydrate) “Western diet” (non-Mediterranean) and reduced physical activity combined with sleep restriction, driven in part by screentime. Sleep deprivation and dysregulation renders changes in energy homeostasis, insulin resistance, and beta cell function and, thus, engenderment of type 2 diabetes mellitus and cardiovascular disease, microvascular complications, mortality, and grave economic impact (05). Marques and colleagues theorize that this “modern lifestyle” is a source of induction of low-grade chronic systemic and neural inflammation, with vast detriment via neuroimmunoendocrine pathways over time (33). Short sleep duration has been associated with increased inflammatory cytokines, such as interleukin-6 and tumor necrosis factor as well as C-reactive protein, gamma-glutamyltranspeptidase, and uric acid. Wheaton and Claussen noted that beyond obesity and type 2 diabetes mellitus, early exposure to insufficient sleep renders an increased risk of injury, poor cognitive development, poor mental health, and attention and behavioral problems (72).
Some purport an infective theory for obesity; increased adenovirus-36 was found clustering.
Certain scientist authors blame environmental pollutants (organochlorines, in particular) as causal toward metabolic dysfunctionality and the pandemic of obesity (67).
Blossom and colleagues submitted a comprehensive review concerning neuroinflammation (10). To simplify, neuroinflammatory responses arise from ischemia, infection, trauma, and stress. The A2 astrocytes, M2 microglia, and endothelial cells release inflammatory cytokines and chemokines. Acute neuroinflammation may be beneficial, but chronic neuroinflammation is deleterious, as shown at the experimental and clinical levels. Beyond the activation of glial cells and astrocytes, there is blood-brain-barrier dysfunction and oxidative stress with neuronal damage; this cycle perpetuates.
Epidemiology
The prevalence of obesity has been increasing for 30 years in industrialized countries. Worldwide obesity has nearly tripled since 1975. According to data from the Centers for Disease Control, in 2015 to 2016 the prevalence of obesity was 39.8% in the United States (18). Almost 5% of the United States population was extremely obese (BMI 40 or greater) (37).
Obesity takes a heavy toll on morbidity and mortality as well as economics and medical care outlay. The medical costs attributable to obesity in the United States were over 200 billion dollars, or 20% of all medical expenditures.
Most individuals are able to attain weight loss in the short term, but weight re-gain is, unfortunately, a common pattern.
Of note, in the United States, 30% of dogs are overweight, and this is related to whether their owners are, similarly, obese. This is not true for cats, however.
Prevention
Weight management programs are difficult to achieve. Self-monitoring of caloric intake and physical activity are key. There must be goal setting, stimulus control, non-food rewards, and relapse prevention. In the motif of motivational interviewing and behavioral therapy in “Behavioral Approaches to Obesity Treatment,” the authors emphasize a “nontraditional, nonpaternal model of medicine,” with accentuation on empathy and listening and evocation (73). The summary points out issues of concern, including weight regain and perpetuation.
Popular diets (basically low in high-fat, high-sugar, high-salt, energy-dense and micronutrient-poor foodstuffs) include Atkins, Ornish, and South Beach diets. An increased consumption of fruits and vegetables plus nuts and legumes and whole grains, is advised. A shift away from saturated fats is important; industrial trans fats should be eliminated; total fat should not exceed 30% of the total energy intake. Sugars should be limited to less than 5% to 10% of the total energy intake. According to a questionnaire, nonvegetarians suffered from insomnia or sleepiness more often than vegetarians (50). Insomnia and sleepiness were also more prevalent among respondents who declared consumption of fruit and vegetables less often than those who consumed them daily. Respondents with a body mass index within the recommended limit (18.5 – 24.99) suffered from insomnia less often than those who were either underweight or overweight. These findings may be useful for public health workers and medical professionals.
Physical activity has multifaceted impacts beyond increasing caloric expenditure, including improved sleep, better mood, increased energy levels, enhanced self-esteem, reduced stress, and heightened sense of well-being (58). See the World Health Organization “Let’s Be Active” Global Action Plan at: www.who.int/news-room/initiatives/gappa.
Weight loss programs are, ideally, multidisciplinary and involve close partnership with the patient. Increased free water intake is advised. The greatest value of exercise is from the aerobic isotonic form with a goal of 30 to 60 minutes, five to seven times per week. Again, curtailment of shift work is advised, if tenable, given its impact on circadian rhythms.
Childhood obesity stems from four types of habits; namely
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• Eating habits: skipped breakfast ?; fast foods intake ? |
Differential diagnosis
Associated or underlying disorders
Idiopathic intracranial hypertension (pseudotumor cerebri). The incidence of idiopathic intracranial hypertension is rising as obesity becomes more and more prevalent. This condition is generally found in obese women of childbearing age, ie, their reproductive years. Rapid weight gain appears to be a major risk factor for idiopathic intracranial hypertension; the condition is in spectrum of severity. The inverse – weight loss – is a disease-modifying factor. The chronic inflammatory state associated with obesity and biofilm formation leads to raised intracranial pressure via compensatory hypersecretion of CSF in the setting of outflow obstruction stemming from an impacted blood-brain barrier (32). Clinically, this is characterized by transient visual obscurations and pulsatile tinnitus early on with, later, papilledema and visual loss. Neck pain, diplopia, and torticollis are also reported (69). The management approach includes weight loss and the prescription of carbonic anhydrase inhibitors such as acetazolamide. Serial lumbar punctures or optic nerve sheath decompression and CSF diversion via lumbo-peritoneal shunting may be indicated. Bariatric surgery may help in the long term (16).
Nerve entrapment syndromes. Regarding meralgia paresthetica, weight gain or obesity makes underwear, belting, or the waistband of pants gradually exert higher levels of pressure against the lateral femoral cutaneous nerve of the thigh. This compression manifests clinically with constant pain on the outer side of the thigh with hypersensitivity to heat and supersensitivity to light touch. The lateral femoral cutaneous pathology is managed with weight loss, wearing looser clothing, physiotherapy, anti-inflammatory agents, and some reduction in physical activity in relation to pain level. Local nerve blocks may be indicated; membrane stabilizing agents, such as gabapentin or carbamazepine, can prove beneficial.
Obesity is a known risk factor, given encroachment, associated with median nerve entrapment or carpal tunnel syndrome (57). Modalities to remediate include wrist splints to keep the joint at anatomical neutral and anti-inflammatory agents. Possible surgical decompression may be required if neuromotor and neurosensory complaints of the hand prevail.
Multiple sclerosis. Studies support the association of obesity and onset central demyelinative processes such as multiple sclerosis (43). Pathogenetic mechanisms are not fully elucidated. Proposed possibilities include via vitamin D pathways or via increased secretion of adipokines, such as leptin, which can modulate immune system function (42). Curbing early-in-life onset obesity may reduce the preponderance of multiple sclerosis later in life, according to the Danish study.
Cerebrovascular disease. Obesity is known to induce a generalized proinflammatory state. Also, obesity renders, anatomically, airway crowding and compromised ventilation. This can present as obstructive sleep apnea syndrome (49; 24) or obesity hypoventilation syndrome (22). These sleep disorders are known to induce intermittent hypoxia (44) and sympathetic storm and hypercortisolemia. They can also elicit, secondarily, further obesity by way of leptin resistance in the setting of hyperleptinemia along with overexpression of ghrelin, the gut hormone responsible for cravings. As oxidative stress takes a dire toll on the vasculature and neuroglia, emerging disorders, such as stroke and dementia, arise.
Peripheral neuropathy. The rendering of demyelination of peripheral nerves via obesity involves either dietary micronutrient deficiencies in the corpulent patient de novo or, after bariatric surgical intervention for morbid obesity, a malabsorption syndrome. The typical culprits, in terms of depletion, include: B12 (cobalamin), B9 (folate), B6 (pyridoxine), vitamin E, B1 (thiamine), vitamin D, and copper (important enzyme cofactor). Post-gastroplasty neuropathy is best prevented by proper dietary supplementation, including vitamins. The neuropathy can be motor, sensory, or autonomic in nature.
The B12 deficiency state can yield onset of the known neurologic disorder termed subacute combined systems degeneration (of the dorsal columns and lateral corticospinal tracts), manifesting as rombergism and proprioceptive difficulty and astasia stemming from weakness and sensory ataxia. Low levels of cyanocobalamin (B12) have also been implicated in other myelopathies and other peripheral polyneuropathies as well as in optic atrophy, dementia, and neuropsychiatric disturbances. The disorder is detected by measurement of serum methylmalonic acid and homocysteine levels, which are elevated. Replacement therapy can be either parenteral or oral, at high dose.
Gastric bypass evokes (as malabsorption or malnutrition), most commonly, thiamine deficiency and then B12 and pyridoxine deficiency states. Thiamine deficiency can induce onset of Wernicke-Korsakoff syndrome, a neurologic disorder characterized by dementia and psychosis.
Folate deficiency can clinically manifest beyond the megaloblastic anemia neurologically to include irritability and forgetfulness and possible neuromyelopathy. Neurodevelopmental anomalies, such as neural tube defects or dysraphism, can be induced in offspring. Beyond insufficient dietary intake, folate deficiency can arise in cases of alcoholism or intestinal dysfunction.
Pyridoxine deficiency can manifest as a sensory neuronopathy along with CNS manifestations, including depression, irritability, and confusion. This, like B12 and folate intake, can coexist with alcoholism.
Headache. The Neurology Department at Albert Einstein College in New York City note that population studies suggest that obesity is associated with migraine progression from episodic to chronic daily headaches. Obesity is perceived as an exacerbating factor for migraine. It is linked to both an increased prevalence of migraine as well as an increased frequency of migraine attacks. Per a large population-based study, total body obesity was associated with migraine prevalence and attack frequency independent of abdominal obesity, in a dose-response relationship. The association holds up primarily in individuals less than 50 years of age. The adipose tissue produces multiple substances suspected to be involved in the pathophysiology of migraine. The markers of systemic inflammation include, suppositionally, adiponectin and leptin. They are suspected to have nociceptive traits and are increased in migraineurs. The leptin levels are also increased in correlation with proinflammatory cytokines IL-6 and TNF-alpha. Weight reduction improves the frequency and duration of attacks, independent of the type of intervention, be it gastric bypass or diet based (28). There is also, awkwardly in debate, evidence in the other direction, ie, that migraine disorder is a risk factor for obesity given common mechanistic pathways (23).
Attention deficit hyperactivity disorder. There is a strong and significant association of attention deficit hyperactivity disorder with obesity. The possible mechanisms are unclear. Factors contributing to the comorbidity between attention deficit hyperactivity disorder and obesity include genetic factors, fetal programming, executive dysfunctions, psychosocial stress, factors directly related to energy balance, and sleep pattern alterations (20).
Dementias. Dementias are detailed under Etiology and pathogenesis.
Diagnostic workup
Diagnostic lab studies in the evaluation could include thyroid function testing, fasting lipid panel, fasting blood sugar and A1C (glycosylated hemoglobin), leptin, parathyroid hormone, growth hormone, adrenal function, reproductive hormones (including prolactin), and MR imaging of the hypothalamus or diencephalon.
Management
Management of obesity is, in general, discussed in the Prevention section of this article, which included references to diet and exercise. A caveat exists regarding special diets; one must avoid starvation ketosis, electrolyte derangements, and cholelithiasis.
The Endocrine Society Guidelines on the treatment of obesity are:
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• Diet, exercise, and behavioral modification if BMI is greater than 25 kg/m2 | |
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Other management measures include prescribable agents as well as bariatric surgical interventions.
The medications primarily include CNS stimulants, such as methylphenidate, thyroid, or caffeine, which carry adverse effects. A legendary combination of prescription phentermine/topiramate is marketed as an anorexiant. There is a concern over sympathomimetic-onset tachycardia and palpitations. Serotonergic and norepinephrine/adrenergic agents may suppress food intake; hemorrhagic diathesis may arise. Fat substitutes are available, such as Olean. Certain available agents block cholesterol absorption and, thus, curb caloric ingestion. Prescription orlistat impedes intestinal fat hydrolysis; it prevents the gastrointestinal absorption of approximately one third of the dietary triglycerides by inhibiting pancreatic lipases. There is reported improvement in steatosis and reduction in alanine aminotransferases as well as favorable cardiovascular disease profile and safety data. Finally, there has been discussion regarding rimonabant, a cannabinoid type 1 receptor antagonist, in curbing hunger (52).
Bariatric surgical procedures are continuously increasing in popularity.
The principal bariatric surgical procedures offered include either:
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• Roux-en-Y gastric bypass. This common and permanent surgery is designed to reduce the amount of food a person is able to eat by cutting away part of the stomach. Adverse effects, arising in 15% of cases, can include dumping syndrome, malabsorption (03), and osteopenia with fractures. The malabsorption/nutritional deficiency state was typically in patients with repeated attacks of vomiting, lack of adequate dietary intake, and inappropriate supplementation of vitamins and minerals. | |
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• Gastroplasties. The stomach is reduced to about 15% of its original size by surgical removal of a large portion of the major curve. Stomach size becomes approximately 150 mL. The procedure, performed laparoscopically, is comparable in effectiveness to the Roux-en-Y gastric bypass. Reportedly, 3.5% of patients develop anastomotic strictures or leakage or ulcers. Alternatively, vertical band gastroplasty (procedure of choice; suture line failures or gastrogastric fistulas as potential complications) is an option. | |
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Bariatric surgery candidates are likely to have concurrent obstructive sleep apnea; this requires careful consideration in the preoperative evaluation as well as in the postoperative period (35).
Postoperatively, compression peripheral neuropathies may arise, resultant from rapid weight loss and incorrect postures.
Despite its proven safety and efficacy, bariatric or metabolic surgery is an underutilized therapy for severe obesity. Eligible patients are experiencing long wait times in pursuit of surgery (04).
Increasing sleep duration and curtailment of gadget-related blue wave luminosity may be beneficial in obese patients. Sleep hygiene can be emphasized to include interventions such as changes in the sleep environment, consistent bedtimes and waketimes, and avoidance of behaviors affecting sleep (TV, etc.), along with cognitive behavioral therapy for insomnia.
Public policy must be addressed regarding health and nutritional education plus encouragement of curtailment of inactivity. Better biking trails and walkable parks are basic; getting out of the chair at the office and out of the vehicle are key, too.
Screening for obstructive sleep apnea can be approached, expediently, by way of the STOP-BANG Questionnaire:
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S |
Snore loudly ? | |
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B |
BMI greater than 35 kg/m2 ? | |
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A major dysregulated condition in obesity is elevation of circulating proinflammatory cytokines (eg, TNF-alpha and IL-1 beta). They render CNS oxidative stress at the level of the endoplasmic reticulum and mitochondria, with resultant harm to both neurons and supporting glial cells (astrocytes and microglia, which otherwise protect neurons). The free radical production (reactive oxygen species) and accumulation impact the hypothalamus (an integrative energy center) and other brain regions (hippocampus, prefrontal cortex, caudate, amygdala, thalamus) over time. Certain anti-inflammatory and natural antioxidant compounds are potentially beneficial in regard to their therapeutic value. These include flavonoids and polyphenols. Quercetin, a flavonoid found in fruit, vegetables, and grains, possesses biological functions, including antioxidant, anti-inflammatory, and anti-obesity activity. Curcumin, within turmeric, is reported to contain similar beneficial effects, including delay in cognitive decline as aging and stress eventuates. Cardamom extract is perceived to be an anti-inflammatory and antioxidant agent. Resveratrol, present in red wine and in grape seeds, contains neuroprotective functions as well. Epigallocatechin-3-gallate, an extract within green tea, attenuates whole brain and, specifically, hypothalamic neuroinflammation. Grape seed and skin extract exert a wide range of beneficial effects, including free-radical-scavenging properties and the enhancement of antioxidant defense systems within the brain. Therefore, in an effort to curb the cognitive and motor impairments associated with obesity, avoidance of a high-fat, high-fructose, low-fiber diet along with an increased intake of the aforementioned antioxidant, anti-inflammatory, and anti-obesity compounds would conceivably curtail this ever-growing global pandemic health problem of obesity (41).
Outcomes
There is typically resumption of weight gain after weight loss, ie, “relapse” or recidivism.” This is unfortunate and largely based on human behavior. A multidisciplinary approach toward optimized weight control is advantageous. Coaching and active partnership participation is key.
Many comorbidities associated with obesity remit after bariatric surgery. This includes, for example, obstructive sleep apnea, which leads to a reduced likelihood of cerebrovascular issues. The Apnea-Hypopnea Index (AHI) drops approximately 50% to 75% postoperatively (74; 51; 60). Another example would be curtailment of type 2 diabetes mellitus, which leads to lessened incident peripheral neuropathy, blindness, and vasculopathy.
Surgically, through bariatric medicine, some 2% of patients, post-gastroplasty, exhibit severe malabsorption and nutritional deficiency. Accurate supplementation is warranted. After bariatric surgery, psychiatric issues can arise in patients confronted with a new set of adaptive challenges (64).
Established risk factors for complications after bariatric surgery include age, male gender, BMI, obstructive sleep apnea syndrome, insulin resistance and type 2 diabetes mellitus, tobacco abuse, cardiovascular disease, inability to lose weight before surgery, hypoalbuminemia, and functional disability (53).
It is believed that the longer one has a sleeve gastrectomy, the higher the risk of failure, unlike the Roux-en-Y gastric bypass. Typically, the failure is either resultant onset gastroesophageal reflux disease or failure, by definition, at adequate excessive weight loss.
The weight loss typically reported in gastric bypass operations is 65% to 80% of excess body weight. This reduction largely persists over time; and quality of life improves per patient attestation. That is, most patients improve in regard to psychosocial well-being (36).
Special considerations
Bariatric (metabolic) surgical intervention, aimed toward older patients and also young patients, has borne out to be safe and efficacious (29). In children, gastroplasty warded off other potential incipient “downstream” comorbidities.
It is crucial that obese bariatric surgical candidates be screened adequately for obstructive sleep apnea (54) and be regarded as pertains to nutritional and metabolic and nonsurgical support (34).
Theoretically, after profound weight loss, such as would be rendered from bariatric surgery, there is endogenous pollutant body hyperconcentration because the previous body fat had represented a dilution space for deleterious, toxic compounds. Sufficient clearance mechanisms must exist to rid this greater burden of contamination (67).
Sarcopenic obesity is an emerging and threatening issue in an aging population. This involves obesity with low skeletal muscle mass and function (quality); this holds a strong negative prognostic impact leading to frailty, disability, and increased morbidity and mortality (06).
Shen and colleagues investigated the relationship between obesity and complications arising from pediatric epilepsy surgery (59). Obesity is relatively common in children with epilepsy due to the side effects of prescribed antiepileptic drugs. Conducting early weight management is critical in this population. Obesity is a known, important risk factor regarding poor surgical outcomes. This stems from prolonged operative time (difficulty in exposing and dissecting the surgical site; the blood supply in tissue is robust due to obesity-related hyperactive angiogenesis), poor wound healing, and comorbidities.
A final special consideration would include that of obesity as it correlates with postoperative complications after posterior cervical spine fusion. There is a significant increase in mechanical failure and in wound infection (48).
Obese modifying agents / anorexigenic agents
The explosion in focus on a particular class of obese modifying agents/anorexigenic agents warrants special mention. These agents include incretin mimetics, including glucagon-like polypeptide (GLP-1s), receptor agonists, glucose-dependent insulinotropic polypeptides (GIPs), sodium-glucose co-transporter inhibitors (SGLT2s), and glucagon receptors.
Historically, GLP-1s were initially FDA-approved for type 2 diabetes. As an anti-diabetic agent, authorization criteria were established, and treatment reauthorization hinged on showing improvement in HbA1C. These agents are mechanistically thought to have central action on the hypothalamus, including a neuroprotective effect (13). Papaetis shares that direct electrical stimulation of the hypothalamic proopiomelanocortin neurons of the arcuate nucleus is involved (46). Some scientists imagine that perhaps certain morphotypes are predisposed toward pathologic obesity stemming from innate deficiency of endogenous GLP-1s; this elevates the condition to a fundamental neurologic disorder.
Regarding weight loss while participating in the ongoing therapy, data has revealed up to 20% reduction (17). Collins reports that this class of pharmacotherapy promotes an average sustained weight loss of 2.9 kg compared to placebo (13). This reduction may be adipose tissue although muscle mass is at a loss as well, ie, there is a degree of what is termed “iatrogenic sarcopenia.” Hamilton shares that in order to maintain the benefits, long-term and potentially indefinite therapy is needed (19). He states that, on average, patients regain two thirds of the weight initially lost over a 12-month period. This rebound is problematic; the proposed “downstream” benefits via other weight loss and retained weight loss would be eroded.
O’Donnell and colleagues report that GLP-1 therapy pharmacologically induces an increase of visceral adipose tissue metabolic activity (45). This upregulation contributes to the weight loss in humans, as does the involvement of delayed gastric emptying.
Given the sparing--and potential sparing--of the consequent development of co-morbidities via weight loss reduction stemming from these treatment agents, some clinical specialists consider them to be first-line therapy in obesity. This worldwide phenomenon of the broadening of the utilization of these particular anorexigenic agents is reflected by an increasing number of medical providers being certified through the American Board of Obesity Medicine. There is distinct demand at the clinical level; the big pharma agents are expensive and, thus, affordability is an issue. Distribution may be inequitable based on socioeconomic factors rather than on medical necessity.
The chief adverse events of these Rx obese modifying agents center around gastrointestinal symptoms, including nausea, vomiting, or diarrhea. Also, with the elicitation of relative gastroparesis, regurgitation and aspiration could arise. Long-term usage is insufficiently understood, as is the usage in pediatric and pregnant populations. Much research is ongoing at the academic and university levels.
Chung lists the available weight loss medications and explains that most are not available for those under 12 years of age (12). This strategy respects issues of growth and pubertal development. Parenthetically, other agents aimed at weight control include metformin (insulin sensitizer), phentermine/topiramate, or orlistat (gastrointestinal lipase inhibitor). The author also supplies an impressive list of medication classes that impact weight.
In neurotherapeutics, Roy and colleagues stress that GLP-1 receptors are widely distributed throughout the brain (55). He and his colleagues list the following in table formats (I and II): (I) comparison of GLP-1 receptor-based therapies for neurodegenerative diseases and, impressively, (2) GLP-1RAs (receptor agonists) in neurotherapeutics with mechanism of action and preclinical findings and key trial outcomes and safety notes. The punch centers around these agents are promising for a wide range of neurologic diseases, including stroke and traumatic brain injury.
The SURMOUNT-OSA phase 3 trials provided evidence that GIPs and GLP-1s render a reduction in the Apnea-Hypopnea Index with a lessened apneic burden that correlated with the reduction in body weight (08). This will attenuate the negative cardiovascular impact of hypoxemic burden. Fang and colleagues summarize the putative mechanisms of these RA-related weight loss benefits in this serial sequence: less peri-neck/peri-oropharyngeal soft tissue (adiposity), so less obstructive sleep apnea/obesity hypoventilation syndrome symptomatology and associated atherosclerotic cardiovascular disease, cerebrovascular accidents, hypertension, arrhythmias, heart failure, myocardial infarction, and sudden cardiac death; reduced metabolic syndrome; reduced HbA1C and diabetes complications; lessened systemic inflammation (oxidative); lessened endothelial dysfunction (antifibrotic); reduction in vascular dementia (hemodynamically); and diminished risk of delirium or depression (15).
DeSousa and associates share data indicating that incretin drugs hold promise in the treatment of peripheral nerve diseases (14). In turn, the peripheral nervous system innervates various organs/metabolically active tissue such that incretin receptor agonists may theoretically stave off both obesity and peripheral neuropathies. As is evident, major overall public health outcomes are at stake in the face of globesity.
To reiterate, there must also be the prioritization of comprehensive lifestyle modification. These therapies include tiered weight management reduction with a multidisciplinary approach. Dietary intervention commonly calls for an overall reduction in usual caloric intake of at least 500 kcal/day (17).
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Richard P Knudsen MD FAASM CNP FAAP
Dr. Knudsen of Arizona Sleep Center has no relevant financial relationships to disclose.
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Editor
-
Federica Provini MD
Dr. Provini of the University of Bologna and IRCCS Institute of Neurological Sciences of Bologna received speakers' fees from Idorsia and Italfarmaco.
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Former Authors
- Peter J Koehler MD PhD
ICD & OMIM codes
- ICD-10
-
- Central sleep apnea: G47.31
- Carpal tunnel syndrome: G56.0
- Idiopathic intracranial hypertension: I87.30
- Meralgia paresthetica: G57.1
- Migraine: G43
- Multiple sclerosis: G35
- Obesity: E66.9
- Obesity hypoventilation syndrome: E66.2
- Obstructive sleep apnea: G47.33
- Vascular cognitive impairment: F01.51
- ICD-11
-
- Neurological disorders due to overweight or obesity in adults or children: 8D42
- Carpal tunnel syndrome: 8C10.0
- Central sleep apnoeas: 7A40
- Dementia due to cerebrovascular disease: 6D81
- Migraine: 8A80
- Multiple sclerosis: 8A40
- Obstructive sleep apnoea: 7A41
- Other specified increased intracranial pressure: 8D60.Y
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