Brain health is maintained by immune system activity

the-scientistDramatic advances in understanding how brain health is maintained by the immune system are described in an excellent article published recently in The Scientist that accompanies the brief video presentation by neuroscientist Michal Schwartz shown below. Only recently has it been recognized that brain immune function is integrated with the systemic immune system.

Until recently, the brain and the spinal cord were considered immune-privileged sites, strictly cordoned off from immune cells unless something went terribly wrong. Researchers knew, for example, that multiple sclerosis (MS) was caused by T cells that breach the selective border called the blood-brain barrier (BBB), enter the CNS, and attack the myelin sheath covering neurons. Even microglia, specialized macrophage-like immune cells that scientists had recognized as normal CNS residents since the 1960s, were mainly studied in the context of disease.”

Now the pervasive role of the immune system in brain function and maintenance is being observed:

“But over the past two decades, researchers have recognized that the entire immune system is very much a part of a functional CNS, with vital roles in cognition, injury repair, neurodegenerative disease, and sensory systems. Microglia pervade the CNS, including the white and gray matter that constitute the organ’s parenchyma. Other immune cells, including T cells, monocytes, and mast cells, reside in the brain and spinal cord’s outer membranes, known as the meninges, and circulate in cerebrospinal fluid (CSF).”

Immune cells in the brain help repair damage

It was formerly thought that immune cell activity in the brain was only harmful.

Macrophages, for example, can damage neurons by secreting cytokines, proteases, or reactive oxygen species, but in rat and mouse models of spinal cord injury, they also produce transforming growth factor-beta (TGFβ), which promotes wound healing,5 and interleukin 10 (IL-10) which helps resolve inflammation. By the late 2000s, researchers recognized that different subtypes of macrophages can benefit neuronal growth in rodents, and that some were critical to recovery. Views also began to change on the clinical side after the 2004 Corticosteroid Randomization After Significant Head Injury (CRASH) study showed that corticosteroids didn’t help brain injury patients recover, but increased their risk of disability and death.”

Cells of the adaptive immune system residing in the tissue lining of the ventricles can also assist in repair.

Her team also showed that T cells present in this lining, called thechoroid plexus, secrete cytokines such as interferon gamma (IFNγ), which allows selective passage of CD4+ T cells and monocytes from the blood into CSF within the ventricles.  In a model of spinal cord bruising, mice deficient for the IFNγ receptor had reduced immune cell trafficking across the choroid plexus and poor recovery of limb movement. And last year, Kipnis’s team reported that IL-4 produced by CD4+ T cells in the CNS signals neurons to regrow axons after spinal cord or optic nerve injury.”

Immune cells in the brainAn intact blood-brain barrier (BBB), however, is essential:

“His team also found that microglia reinforce the BBB, which is composed of endothelial cells, pericytes, and astrocytes. Microglia fill in spaces left by astrocytes killed or damaged during injury. Without a robust barrier, McGavern says, unwanted immune cells may flood the parenchyma and do more harm than good.”

Immune cells residing in the CSF and choroid plexus

Immune cells residing in the CSF and choroid plexus

Brain needs both anti-inflammatory and pro-inflammatory activity for cognition

Neuroinflammation is well known to be a core feature of neurodegenerative disorders, but inflammatory immune activity is also required for healthy cognition.

“…Rivest used two-photon microscopy to monitor monocytes in blood vessels of living mouse brains, and he watched as the cells migrated toward and cleared amyloid-β deposits within veins. When the researchers selectively depleted monocytes, the mice developed more amyloid-β plaques in the cortex and hippocampus. And when they knocked out the innate immune signaling protein MyD88, which mediates signals from several monocyte-activating receptors, the mice also experienced more amyloid-β accumulation, accompanied by accelerated cognitive decline.”

Even in the classic disease of neuroinflammation, MS, immune cell activity is necessary:

“Rivest’s team found that microglia-forming monocytes are beneficial in a model of MS, where microglia are found within the inflammatory lesions. Last year, the researchers reported that inhibiting monocytes from entering the CNS reduced the clearance of damaged myelin and impeded proper remyelination.”

Evidence for the immune system’s role in preventing neurodegeneration continues to mount:

“Schwartz has similarly found evidence for the immune system’s ability to protect against neurodegeneration. Last year, she and her colleagues reported that the choroid plexus epithelium was less permissive to immune cell trafficking in a mouse model of Alzheimer’s disease than in wild-type mice, due to anti-inflammatory signals produced by regulatory T cells (Tregs). They found that depleting Tregs in Alzheimer’s mice allowed macrophages and CD4+ T cells into the brain, reduced the number of amyloid-β plaques, and improved cognition. Similarly, blocking the T-cell checkpoint protein PD1, which normally supports Treg survival while suppressing the activity of other T cells, reduced amyloid-β plaques in mouse brains and improved the animals’ scores in a learning and memory water maze test.”

Clinicians should be alert to evaluate and support balance

Too much neuroinflammation is clearly adverse.

“But there’s a reason that scientists have believed that immune activity contributes to Alzheimer’s damage: microglia, perhaps best known for trimming back synapses, have the potential to become overzealous, and excessive synapse pruning can cause neural damage in a variety of CNS diseases. By blocking the cells’ proliferation in mice, Diego Gomez-Nicola of the University of Southampton in the U.K. has successfully alleviated symptoms of Alzheimer’s disease, amyotrophic lateral sclerosis, and prion disease. And earlier this year, Beth Stevens of the Broad Institute and her colleagues reported that inhibiting a protein that tags synapses for microglial pruning halted over-pruning and loss of synapse signaling strength in two mouse models of Alzheimer’s disease.”

Regulation of stress is critical

Stress has a major effect on which way the ‘two-edged sword’ swings.

“Kipnis says regulation of stress may be linked to T cells’ role in learning. Stress can signal macrophages to secrete proinflammatory cytokines, some of which block a protein called brain-derived neurotrophic factor (BDNF), which astrocytes need to support learning and memory. CD4+ T cells in the meninges make more IL-4 cytokine after mice have been trained in a water maze—a stressful exercise for the animals—suggesting the signaling molecule might let macrophages know when the brain is dealing with the stress of learning something new, not the stress of an infection. “They tell macrophages, ‘Don’t overshoot,’” says Kipnis. In mice whose meninges are depleted of CD4+ T cells and thus deficient for IL-4, macrophages secrete proinflammatory factors unchecked in times of stress, disrupting their ability to learn and form memories.”

But excess suppression of inflammatory activity in the brain could have unwanted consequences as in the case of mast cells:

“Best known for their involvement in allergic responses in the upper airway, skin, and gastrointestinal tract, mast cells have been found in the meninges as well as in perivascular spaces of the thalamus, hypothalamus, and amygdala. They are known to quickly recruit large numbers of other immune cell types to sites of inflammation, and to play a role in MS. But mast cells also release serotonin into the hippocampus, where the molecule aids neurogenesis, supports learning and memory, and regulates anxiety.”

A ‘goldilocks zone’ for immune activity in the brain

As in every condition clinical evaluation must embrace the whole context…

“Thus, like microglia, mast cells are a double-edged sword when it comes to neural health. It’s a reflection of the entire immune system’s love-hate relationship with the CNS, Kipnis says. “Saying the immune system is always good for the brain, it’s wrong; saying it’s always bad for the brain, it’s wrong. It depends on the conditions.”

Neuroscientist Michal Schwartz — Breaking The Wall Between Body and Mind

 

Mood disorders and thyroid autoimmunity

PLOS ONEMood disorders and thyroid autoimmunity are linked by aberrant levels of hematopoietic/neuronal growth factors in an excellent study just published in PLOS One (Public Library of Science). Their fascinating data show how, even before hypothyroidism has developed, and also in relatives of thyroid autoimmunity subjects, growth factors necessary for healthy brain function are at levels associated with a range of mood disorders including bipolar, depression and psychosis. They also include an important reminder that antibodies can predict clinical disease years in advance.

Hypothyroidism predicted years in advance

The authors state:

“Autoimmune hypothyroidism is characterized by a combination of clinical features, elevated serum TSH with reduced free T4 (FT4) levels, the presence of serum antibodies against thyroid antigens, and reduced echogenicity of the thyroid sonogram. It is the most common organ-specific autoimmune disorder with an estimated prevalence of 2%, with a higher prevalence in women and depending on iodine intake. Thyroid peroxidase (TPO) is the major autoantigen and TPO antibodies (TPO-Abs) are present in almost all patients with autoimmune hypothyroidism and precede the clinical phase of autoimmune hypothyroidism by many years. Subclinical autoimmune hypothyroidism (the presence of TPO-Abs with raised TSH and normal FT4 levels) is even more prevalent and affects about 9% of the population. In the Whickham follow-up study, women with TPO-Abs had an eight-fold higher risk of developing clinically overt hypothyroidism over 20 years than did antibody-negative women.”

And family members have a pronounced risk of thyroid autoimmunity showing up down the road:

“In our own studies on the Amsterdam AITD [autoimmune thyroid disease] cohort (euthyroid females with at least one first or second degree relative with a documented autoimmune hyper- or hypothyroidism) TPO-Ab positivity at the start of the study also represented a higher risk to develop overt hypothyroidism in a follow-up of 5 years. In addition, there was a higher conversion rate from TPO-Abs negativity to positivity, showing a familial proneness for thyroid autoimmune reactivity.”

And in another earlier study normal thyroid relatives showed a slew of abnormalities including a ‘background’ higher inflammatory state:

“We concluded that euthyroid females within AITD families show a characteristic pattern of abnormalities in serum levels of growth factors, chemokines, adhesion molecules and cytokines, suggesting an already compromised thyroid-immune system interaction in the euthyroid family members. Also, pre-seroconversion stages might be predicted using serum analytes pointing to a higher inflammatory state.”

Mood disorders and AITD

The emerging evidence shows that depression in association with autoimmune thyroid disease is caused by more than lower thyroid hormone in the brain. Just the presence of anti-thyroid antibodies while thyroid hormone levels are still normal is associated with increased risk of anxiety and mood disorders.

“Autoimmune hypothyroidism is commonly accompanied by depressive symptoms. A large epidemiological Danish nationwide, prospective cohort study showed that various autoimmune diseases including AITD, are associated with subsequent lifetime mood disorder diagnosis (e.g. bipolar affective disorder, unipolar depression, psychotic depression and other remaining mood disorders). In hypothyroid patients the lack of thyroid hormone in the brain is likely an important determinant for these mood disturbances. However, a deficit of thyroid hormone may not be the only cause, as even subjects with TPO-Abs with normal thyroid function have a higher risk to develop anxiety disorders and mood disorders.”

And further evidence supports the assertion of a shared pathogenesis for autoimmune thyroid disease and mood disorders:

“Also offspring of patients with a bipolar affective disorder have a higher prevalence of TPO-Abs, even if they are not affected by the psychiatric disorder. In addition, a higher prevalence of TPO Abs and autoimmune hypothyroidism has been reported in patients with bipolar affective disorder, irrespective of the usage of lithium. Taken together, these associations might imply a shared immune pathogenesis for both AITD and mood disorders.”

Brain growth factors and AITD

To explore this relationship the authors examined data for 64 TPO-Ab-negative females with relatives with AITD. 32 of these subjects did and 32 did not seroconvert to TPO-Ab positivity in their 5-year follow-up. These were compared with 32 healthy controls (HCs). Importantly, they measured serum levels of brain-derived neurotrophic factor (BDNF), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF) and IL-7.

“We therefore additionally determined, in the sera used in the previous study, 5 growth and differentiation factors that have repeatedly* been shown to be abnormally expressed in the circulation of mood disorder patients and that are capable of influencing both immune and/or neuronal cell growth, i.e. SCF, IGFBP-2, EGF, BDNF and IL-7. In addition we studied the inter relationship of these factors with the previously determined factors using a cluster analysis to study patterns of TPO-Ab seroconversion.”

* Authors’ emphasis.

Even relatives of AITD patients are at higher risk of mood disorders

Their data showed an eye-opening correlation:

BDNF was significantly lower (8.2 vs 18.9 ng/ml, P<0.001), while EGF (506.9 vs 307.6 pg/ml, P = 0.003) and IGFBP-2 (388.3 vs 188.5 ng/ml, P = 0.028) were significantly higher in relatives than in HCs. Relatives who seroconverted in the next 5 years had significantly higher levels of SCF than non-seroconverters (26.5 vs 16.7 pg/ml, P = 0.017). In a cluster analysis with the previously published growth factors/cytokines SCF clustered together with IL-1β, IL-6 and CCL-3, of which high levels also preceded seroconversion.”

Serum levels of growth and differentiation factors

Serum levels of growth and differentiation factors in healthy controls (C), Seroconverting (SC) and Non-Seroconverting (NSC) family members.

In other words, abnormal levels of growth factors necessary for brain health and higher levels of biomarkers for inflammation were both observed. Bear in mind that BDNF (brain derived neurotrophic factor) in particular has been identified as important for neurogenesis, plasticity and synaptic transmission. BDNF deficiency is associated with disorders of mood, cognition and memory. And an increase in BDNF is though to be a mechanism by which exercise (and certain medications) exert a beneficial effect on brain-based conditions.

“It is of note that the 5 studied factors have been highlighted as serum biomarkers for major mood disorders in several studies and are involved in neurogenesis, neuroprotection and hematopoietic differentiation. This is in particular known for BDNF. Neurotrophic factors, like BDNF, play an important role in neuronal plasticity, modulating not only axonal and dendritic growth and remodeling, but also neurotransmitter release and synapse formation.”

This makes striking the finding that even euthyroid (normal thyroid) relatives of autoimmune thyroid subjects are at higher risk of mood disorders with markedly lower levels of BDNF.

“The present study shows that euthyroid females, who are relatives of AITD patients and at risk of developing AITD, have an aberrant serum level of 4 of the 5 tested hematopoietic/neuronal growth and differentiation factors, i.e. of BDNF, IGFBP-2, EGF and SCF. BDNF levels were significantly lower and IGFBP-2 and EGF higher expressed in sera of the relatives of the AITD patients (in both SCs and NSCs) than in healthy controls. IL-7 levels were normal. We also found in the healthy relatives, who converted in the following 5 years to TPO-Ab positivity, significantly higher serum levels of SCF than in relatives who did not.”

Earlier diagnosis

This certainly underscores the clinical significance of predictive (low levels of) anti-thyroid antibodies. It also invites the possibility of even earlier diagnoses and interventions as stated by the authors:

“This study and the previous one therefore underscore the widespread changes in immune-neuro-endocrine molecular networks that apparently precede the appearance of TPO-Abs, which opens avenues for developing assays for the detection of individuals at risk for thyroid autoimmunity.”

Moreover…

“We assume that the generally low expression in NSCs in cluster A reflects an immune suppressive state preventing autoimmunity, while a rise of these pro-inflammatory compounds precedes a conversion to TPO-Ab positivity and thus may reflect a very early stage of thyroid auto reactivity.”

Clinical Note

This presents the tantalizing possibility of very early diagnosis and the opportunity to intervene in thyroid and mood disorders at the earliest possible stage when easiest to treat. Meanwhile, clinicians should be attentive to even low levels of anti-thyroid antibodies.

The authors summarize:

“We conclude that subjects at risk for AITD show changes in growth and differentiation factors in serum, which are both active as neuronal and hematopoietic growth and differentiation factors and are abnormally expressed in patients with mood disorders. This suggests that shared growth and differentiation defects in both the hematopoietic and neuronal system may underlie both thyroid autoimmunity and mood disorders.”

Colleagues interested in our practice model incorporating predictive antibodies and bioidentical (human recombinant) low dose BDNF are welcome to contact.

Migraine, depression, Alzheimer’s and lipid metabolism

NeurologyMigraine, with its variety of symptoms associated with aberrant neuronal activation, is linked to abnormal metabolism of a class of bioactive lipids in an important study just published in the journal Neurology. Sphingolipids are involved in a variety of functions in mammalian systems including cell membrane formation, signaling, apoptosis, energy balance and inflammation. The authors set out to assess the levels of sphingolipids in circulation in women migraneurs between migraine attacks compared to control subjects. Their data show that altered sphingolipid metabolism clearly distinguished those with episodic migraine (EM) from controls:

Total ceramide (EM 6,502.9 ng/mL vs controls 10,518.5 ng/mL) and dihydroceramide (EM 39.3 ng/mL vs controls 63.1 ng/mL) levels were decreased in those with EM as compared with controls. Using multivariate logistic regression, each SD increase in total ceramide (odds ratio [OR] 0.07) and total dihydroceramide (OR 0.05) levels was associated with more than 92% reduced odds of migraine. Although crude sphingomyelin levels were not different in EM compared with controls, after adjustments, every SD increase in the sphingomyelin species C18:0 (OR 4.28) and C18:1 (OR 2.93) was associated with an increased odds of migraine. Recursive portioning models correctly classified 14 of 14 randomly selected participants as EM or control.”

Brain-liver axis and migraine

SphingolipidsThese interesting results shed light on a topic that deserves more attention: the role of the brain-liver axis in neuroinflammatory, neurodegenerative and neuropsychiatric disorders including migraine. This may be extended to include metabolism of lipids and other bioactive agents on a cellular level. The authors conclude in regard to sphingolipid metabolism and migraine:

“These results suggest that sphingolipid metabolism is altered in women with EM and that serum sphingolipid panels may have potential to differentiate EM presence or absence…This study provides Class III evidence that serum sphingolipid panels accurately distinguish women with migraine from women without migraine.”

Clinical note: for practitioners using medicines from the TCM (traditional Chinese medicine) and Ayurvedic systems the ‘brain-liver axis’ encompasses not just the visceral entity but consonant functions distributed throughout the organism.

Dementia, multiple sclerosis, obesity, and pain

Beyond migraine, a commentary on the study in Medscape Medical News states:

“The authors, led by B. Lee Peterlin, DO, from Johns Hopkins University School of Medicine, Baltimore, Maryland, note that neurologic disorders that are the result of severe deficiencies in enzymes that regulate sphingolipid metabolism have long been described (eg, Gaucher disease), and recent studies have suggested that even subtle changes of sphingolipid balance may be involved in dementia, multiple sclerosis, obesity, and pain…Now they also are reporting a study showing changes in sphingolipid levels in patients with migraine, implicating in particular two sphingolipid subtypes: ceramide and sphingomyelin…“Taken together, our findings suggest it is possible that migraine is a neurologic disorder of ‘minor’ sphingolipid dysmetabolism,” they conclude.”

Depression and anxiety

BBA - Molecular and Cell Biology of LipidsAlso in addition to migraine, a fascinating paper recently published in Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids reviews the function of neuronal membrane lipids including sphingolipids as a barrier and signaling medium in the brain and their role in depression and anxiety.

“Brain lipids determine the localization and function of proteins in the cell membrane and in doing so regulate synaptic throughput in neurons. Lipids may also leave the membrane as transmitters and relay signals from the membrane to intracellular compartments or to other cells. Here we review how membrane lipids, which play roles in the membrane’s function as a barrier and a signaling medium for classical transmitter signaling, contribute to depression and anxiety disorders and how this role may provide targets for lipid-based treatment approaches. Preclinical findings have suggested a crucial role for the membrane-forming n-3 polyunsaturated fatty acids, glycerolipids, glycerophospholipids, and sphingolipids in the induction of depression- and anxiety-related behaviors.”

This opens the door to a class of treatment options…

“These polyunsaturated fatty acids also offer new treatment options such as targeted dietary supplementation or pharmacological interference with lipid-regulating enzymes. While clinical trials support this view, effective lipid-based therapies may need more individualized approaches. Altogether, accumulating evidence suggests a crucial role for membrane lipids in the pathogenesis of depression and anxiety disorders; these lipids could be exploited for improved prevention and treatment.”

Alzheimer’s disease

Journal of Alzheimer's DiseaseA review in the Journal of Alzheimer’s Disease discusses the metabolism and the presence in biofluids of sphingolipids and other lipids in Alzheimer’s disease (AD):

“With the difficulties of studying the brain directly, it is hoped that identifying the effect of AD on the metabolite composition of biofluids will provide insights into underlying mechanisms of pathology…Sphingolipid, antioxidant, and glutamate metabolism were found to be strongly associated with AD and were selected for detailed investigation of their role in pathogenesis. In plasma, two ceramides increased and eight sphingomyelins decreased with AD, with total ceramides shown to increase in both serum and cerebrospinal fluid. In general antioxidants were shown to be depleted, with oxidative stress markers elevated in a range of biofluids in patients suggesting AD produces a pro-oxidative environment. Shifts in glutamate and glutamine and elevation of 4-hydroxy-2-nonenal suggests peroxidation of the astrocyte lipid bilayer resulting in reduced glutamate clearance from the synaptic cleft, suggesting a excitotoxicity component to AD pathology; however, due to inconsistencies in literature reports, reliable interpretation is difficult.”

In addition to defective clearance of amyloid beta, tau proteins and glutamate, altered sphingolipid metabolism emerges as a significant factor.

“The present review has shown that metabolite shifts in biofluids can provide valuable insights into potential pathological mechanisms in the brain, with sphingolipid, antioxidant, and glutamate metabolism being implicated in AD pathology.”

Sphingolipids in food

Journal of NutritionSphingolipids are in a variety of foods and, though not known to be an ‘essential’ nutrient, have functional effects as discussed in a paper published in the The Journal of Nutrition. The authors state:

“There is no known nutritional requirement for sphingolipids; nonetheless, they are hydrolyzed throughout the gastrointestinal tract to the same categories of metabolites (ceramides and sphingoid bases) that are used by cells to regulate growth, differentiation, apoptosis and other cellular functions…both complex sphingolipids and their digestion products (ceramides and sphingosines) are highly bioactive compounds that have profound effects on cell regulation. This article reviews the structures of sphingolipids, their occurrence in food, digestion and metabolism, biochemical functions and apparent roles in both the etiology and prevention of disease.”

Sphingolipids and cell regulationIn regard to their functional role:

“Studies with experimental animals have shown that feeding sphingolipids inhibits colon carcinogenesis, reduces serum LDL cholesterol and elevates HDL, suggesting that sphingolipids represent a “functional” constituent of food. Sphingolipid metabolism can also be modified by constituents of the diet, such as cholesterol, fatty acids and mycotoxins (fumonisins), with consequences for cell regulation and disease. Additional associations among diet, sphingolipids and health are certain to emerge as more is learned about these compounds. “

The authors offer a table showing sphingolipid levels in various foods.

Systemic inflammation drives brain neurodegeneration

Frontiers in Cellular NeuroscienceIn a richly valuable paper published recently in Frontiers in Cellular Neuroscience the authors describe the ways in which systemic inflammation causes neurodegeneration in the brain associated with cognitive decline and a host of neuropsychiatric disorders. In the short term this manifests the anorexia, malaise, depression, and decreased physical activity known as sickness behavior (SB) that occurs with inflammation due to infection. Permanent cognitive and behavioral changes due to neurodegeneration occur when inflammation is chronic. Discerning and targeting the causes of inflammation offers opportunities for treatment.

Neuroimmune modulation

The nervous system senses inflammation directly and can exert control through the vagus nerve:

“The efferent axis of neuroimmune control is better understood after the cholinergic anti-inflammatory pathway (CAP), a cholinergic reflex system that regulates inflammation via the vagus nerve that stimulates the splenic nerve to release noradrenaline. Noradrenaline in turn stimulates a subset of acetylcholine (ACh)-producing splenic T-cells (CD4+CD44hiCD62Llo) to release ACh, which binds to α7 nicotinic receptors on the surface of macrophages, resulting in down-regulation of TNF by blocking the nuclear translocation of nuclear factor kappa B (NF-κB). Thus far, this is a unique scenario in which an immune cell acts as interneuron in a reflex system. Electrical as well as chemical stimulation of the CAP have been shown to decrease the inflammatory burden and increase survival of experimental sepsis.”

The a cholinergic response expressed through the vagus nerve can wind down inflammation and protect against neurodegeneration.

Sickness behavior

Transient inflammation, such as associated with a cold or flu, produces behavioral symptoms of the same character as those which persist with the chronic systemic inflammation that can drive neurodegeneration.

“The acute effects of systemic inflammation upon cognition and behavior are not limited to the elderly or the critically ill. As we have witnessed in ourselves and those near us, even a minor and self-limited common cold induces a transient syndrome known as sickness behavior (SB) marked by fatigue, depression, lack of drive, malaise, sleep disturbances, decreased physical activity, and social interactions, as well as cognitive impairment. Healthy volunteers develop anxiety, depression, and memory impairment in response to a low dose of lipopolysaccharide (LPS), and the development of such clinical scenario correlates with TNF secretion.”

And patients with chronic infections such as tuberculosis, human immunodeficiency virus (HIV), hepatitis B virus (HVB), and hepatitis C virus (HCV) can have cognitive and behavioral problems due to the persistent inflammatory response.

“This supports the role of large loads of inflammatory cytokines in inducing and sustaining brain dysfunction. Experimentally, NADPH oxidative activity and nitric oxide synthase (iNOS) are induced in the brain shortly after systemic inflammation, potentially leading to NMDA-dependent neurotoxicity”

Sepsis and severe trauma

An overwhelming load of pathogens or severe trauma can unleash an immune inflammatory response that results in neurodegeneration.

“Under normal conditions, inflammation is a well-orchestrated response with constant fine-tuning. Once microorganisms have breached the skin and mucosal barriers, innate immunity is critical in preventing further invasion by launching inflammation. After the infection source has been cleared, the inflammatory response also plays an important role in tissue repair and functional healing. When the source of damage has been controlled, the same mechanisms that initiated and regulated inflammation will dampen the response. Large loads of pathogens, or infection by highly virulent pathogens, can trigger an en-masse systemic response that leads to sepsis and multiple organ failure…The nervous system is particularly vulnerable to damage in response to systemic inflammation.”

Brain milieu changes in response to systemic inflammation

Brain milieu changes in response to systemic inflammation

Inflammation-induced infiltration of immune cells and mediators into the brain leads to profound structural and functional changes. As a consequence, up to 81% of septic patients develop sepsis-associated delirium (SAD), with elderly patients being at particularly high risk. In the elderly, severe sepsis is sufficient to trigger new cognitive decline of sufficient importance as to profoundly interfere with quality of life…Neonatal sepsis is also marked by abnormalities of the white matter (66% of infants in one cohort), and white matter lesions correlate to poorer mental and psychomotor development at 2 years.

Moreover…

“…clearing the trigger of sepsis does not prevent the appearance of persistent brain damage…in a model of endotoxemia in aged rats, a single systemic injection of LPS induced brain inflammation that lasted for at least 30 days…This suggests that even transient bouts of systemic inflammation of only limited significance can cause sustained brain damage.”

Traumatic inflammation also promotes neurodegeneration:

“Severe trauma, as well as surgery can lead to large loads of endogenous pro-inflammatory molecules (damage-associated molecular patterns (DAMPs) being released. A few DAMPs have been shown to induce brain dysfunction in vivo. Of those, TNF and IL-1 can mediate long-standing cognitive and behavioral changes and, in experimental settings, interfering with the effect of TNF reduces the effect of trauma in the formation of contextual memory.”

In this context antioxidants can have neuroprotective effects.

“Experimentally, preemptive administration of the free radical scavenger endarvone before sepsis induction resulted in reduced neuronal damage and blood–brain barrier (BBB) permeability. Administration of the antioxidants N-acetylcysteine and deferoxamine shortly after murine sepsis induction has shown long-term neuroprotective effects.”

Systemic inflammation disrupts brain networks

Human brain connectome

The human brain connectome

The brain is characterized as a ‘small-world’ network with two levels of connection that are susceptible to disruption by inflammation.

“Biological systems, such as the neuronal network of the human brain have “small-world” properties. Small-world networks have two levels of organization. On the local level, groups of neurons specialized in a specific task form functional modules with high short intramodular connectivity. On the global level, different modules are connected through long intermodular connections. The advantage of the latter type of connections is enhanced computational efficiency through parallel processing of information. Anatomically, long intermodular connections are formed by axonal fiber tracts in the white matter. Long fibers are characterized by high energetic “wiring costs”. To provide the energy for the maintenance of these long fibers the brain is relying on a constant energy supply. Recent findings have elegantly identified oligodendrocyte-derived lactate as the main energetic substrates for axonal maintenance. Consistently, disruption of this oligodendrocyte-neuronal metabolic coupling triggered neurodegeneration. Systemic inflammation poses dramatic challenges to the energetic supply of the brain.”

The brain requires a constant stream of nutrients to maintain its ‘wiring’

Autoimmune driven neuroinflammation, among other insults, can disrupt the delivery of nutrients to neurons and contribute to mitochondrial dysfunction.

“To cover its wiring costs the brain is highly reliant on a constant nutrient supply. Nutrient supply through blood vessels can be compromised through vascular pathologies associated with systemic inflammation…Autoimmune disorders have a chronic course of vascular pathology with acute flares. The most common vascular pathology is the autoantibody-associated antiphospholipid syndrome. Patients with antiphospholipid syndrome display cognitive deficits. MRI studies found diffuse infarctions and white matter lesions in these patients…In line with the concept of high “wiring costs” imposed on the brain by long intermodular connections,Hans Lassmann argues that inflammation in MS causes mitochondrial damage and inability of the brain to maintain neuronal processes. The source of mitochondrial damage is radicals formed as a consequence of inflammation in MS.”

Energy crisis for the brain

Systemic inflammation damages connectivity and fuels mitochondrial dysfunction…

“Taken together these findings indicate that systemic inflammation leads to an energy crisis of the brain that reduces its connectivity. Oxidative stress might be the main mediator of this pathology. Thus, inflammation-induced changes in the brain resemble hallmarks of the aged brain where oxidative damage leads to decreased expression of genes associated with synaptic plasticity and increased expression of stress-response genes. Likewise, the brain during systemic inflammation shows hallmarks of neurodegenerative diseases where oxidative stress and mitochondrial damage have consistently been found.”

Balancing act

Normally astrocytes and neurons talk to each other to keep activation of brain immune cells in check. But this can get out of hand in response to a pathogen resulting in serious damage. Balance is maintained, partly by accepting a certain degree of tolerance for pathogens:

“Brain-resident microglia and peripheral immune cells maintain immune surveillance of brain parenchyma, CSF, and perivascular space for infectious agents or damage-associated milieu changes. In the case of brain infection, complete eradication of some invading pathogens can only be achieved at the cost of irreparable damage to brain tissue. To prevent such damage, the immune system has established active mechanisms of pathogen tolerance. Examples for coexistence-prone pathogens are herpes simplex virus type I or Cryptococcus gattii. A growing body of evidence indicates that not only immune tolerance but also resolution of neuroinflammation is a tightly regulated active immunological process. Taken together, anti-inflammatory brain milieu, pathogen tolerance, and resolution of neuroinflammation require a balanced action between different branches of the immune system.”

Dysregulation causing systemic inflammation drives neurodegeneration

There are a number of mechanisms by which dysregulated systemic inflammation promotes neuroinflammation and neurodegeneration. These in include activation of apoptosis through the inflammasome (inflammation signalling chains):

Apoptosis is one of the main drivers of neurodegeneration. Apoptosis and cell death constantly occur under physiological conditions throughout the human body and cell debris is cleared by immune cells mostly without induction of chronic inflammation. However, during systemic inflammation, apoptosis of stressed cells might further exacerbate the underlying pathology. Activators of apoptosis lead to direct or indirect activation of caspases…inflammatory caspases are crucial for the activation of the innate immune system through the inflammasome…Activation of the innate immune system through the inflammasome is a driver of pathology in age-associated and autoimmune neurodegenerative disorders…these finding show an intricate relationship between inflammation and activation of apoptosis”

Microvesicles (MVs) packed with inflammatory messengers are secreted by peripheral and brain immune cells contribute to neurodegeneration:

“Cellular components of innate immunity can pack and secrete inflammatory messengers in microvesicles (MVs). Peripheral macrophages, as well as brain microglia can secrete inflammasome components (caspase-1, IL-1β, and IL-18) in MVs, and the presence of extravesicular inflammatory inducers (e.g., astrocitic ATP) is sufficient to induce the neurotoxicity by the inflammatory load of MVs.”

This correlates with disease activity in multiple sclerosis and also a significant role in Alzheimer’s disease (AD):

“Recent evidence suggest that MVs play a critical role in the spectrum of AD as well. MVs released by activated microglia participate in the neurodegenerative process of AD by promoting the generation of highly neurotoxic soluble forms of β-amyloid. Based on this collective evidence, it is now clear that EVs produced by peripheral myeloid cells, as well as immune brain cells, are novel and potentially critical biomarkers for neuroinflammatory conditions by providing a link between inflammation and neurodegeneration.”

Inflammation leads to neurodegeneration

Inflammation to neurodegeneration

Immune cells and mediators drive neurodegeneration

Immune cells in both the periphery and the brain can cause neuronal apoptosis through multiple pathways that can be targeted for therapy:

“Various triggers of apoptosis have been described with respect to the brain. Neuronal apoptosis can be directly induced by ROS, pro-inflammatory cytokines or activated immune cells…Additionally, damaged mitochondria are a major source of ROS and mediators of apoptosis. Conversely, inactivation of ROS has anti-apoptotic effects. The inflammatory cytokine TNFα and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) directly induce neuronal apoptosis. Additionally, intracerebroventricularly injected TNFα was shown to induce depression-like symptoms. Cytokine mediated induction of apoptosis was also observed by IL-1β.”

Immune cells in the brain and the periphery cause neurodegeneration, with evidence that antiinflammatory interventions can oppose neuronal death.

“Sources of cytokines under systemic inflammation are brain resident, paravascular or peripheral immune cells. Furthermore, activated immune cells can directly induce neuronal cell death. Brain-resident microglia convey neuronal toxicity through various mechanisms including secretion of neurotoxic factors, as well as through activation of cyclooxygenase/prostaglandin E2 (COX/PGE2) pathways. In fact, blocking the COX/PGE2 pathway by experimentally deleting the prostaglandine receptor EP2 increases mitochondrial degradation of β-amyloid, potentially opening a new therapeutic avenue for AD.”

When there is systemic inflammation immune cells in the periphery in the body can gain access to the brain through the blood-brain barrier:

Peripheral immune cells can penetrate the BBB under conditions of systemic inflammation and contribute to brain pathology. Cytotoxic T-cells were shown to be directly neurotoxic in autoimmune and aging-associated neurodegenerative disorders of the CNS. Co-localization of T-cells with neurons and neuron-specific cytotoxicity of T-cells was shown in vivo and in vitro.”

Anti-brain antibodies*

Identification of anti-brain antibodies is a key clinical finding that practitioners in a wide range of disciplines should be alert for.

“B-cell-derived anti-brain antibodies have been identified as drivers of brain pathology in various diseases. In the last decade, an increasing number of anti-brain antibodies has been detected that can affect cognition and behavior…Under pathological conditions, antibodies may penetrate the BBB through different mechanisms including local and systemic inflammation, or antigen mediated endocytosis.”

Anti-NMDA antibodies have been receiving much scrutiny for neuropsychiatric and neurodegenerative disorders.

“Furthermore, NMDA-receptor-specific antibodies to the subunit 2 (GluN2) have been found in a subset of SLE patients with neuropsychiatric symptoms. These antibodies are cross-reactive to DNA…DNA–NMDA receptor antibodies preferentially bind the open configuration of the NMDA receptor and augment NMDA receptor-mediated excitatory postsynaptic potentials…Depending on the antibody concentrations, DNA–NMDA receptor antibodies can cause either neuronal dysfunction by transiently enhancing excitatory postsynaptic potentials or can result in neuronal cell death. This evidence could be of high relevance in terms of reversibility of symptoms…Furthermore, anti-brain antibodies were also shown to induce neuropsychiatric symptoms in patients with other autoimmune disorders such as celiac disease or inflammatory bowel diseases. Taken together, anti-brain antibodies were shown to cause neuropsychiatric pathology in different diseases presenting novel therapeutic options.”

Inflammation disrupts neurogenesis

Both generation of new neurons and the support of synaptic health and plasticity are adversely affected by inflammation and this too is an avenue for treatment.

Neurogenesis is a central mechanism required for neuronal maintenance and adaptive plasticity in the healthy and diseased brain. Inflammatory mediators have various effects on neurogenesis. Impairment of neurogenesis was shown in neurodegenerative diseases such as AD and neuropsychiatric disorders such as depression. Interestingly, approved AD drugs and chronic antidepressant treatment induce neurogenesis. Inflammation and microglial activation is detrimental for neurogenesis that can be restored by anti-inflammatory treatment. Moreover, microglia are not only involved in the maintenance of the neurogenic niche but also in synaptic maintenance. Of interest, systemic immune cells were shown to be involved in regulation of neurogenesis. CD4+ T-cells were shown to promote while CD8+ T-cells impair proliferation of neural progenitor cells…one may speculate that neuropsychiatric symptoms elicited by chronic inflammation may be driven by detrimental changes of neuronal homeostasis. Thus, specific immune modulatory treatment might be beneficial.”

Inflammation is a core issue for brain health, cognition and mood

Case management of neuropsychiatric and neurodegenerative disorders requires discerning and treating the causes of chronic inflammation on an individual case basis. The authors conclude:

Sustained systemic inflammation is a common feature of many autoimmune disorders, and is present in most sepsis survivors. Cognitive impairment is common in sepsis survivors, as well as patients suffering from chronic inflammatory conditions…Moreover, systemic inflammation occurring in a susceptible brain (e.g., patients with AD) may lead to even further disruption in quality of life and activities of daily living. Up to 95% of patients with SLE develop neuropsychiatric dysfunction…In patients with rheumatoid arthritis, the baseline vagal tone of is persistently low, suggesting a possible mechanism for persistent inflammation. Those examples indicate that the normal neuroimmune cross-talk in health can become deleterious during disease, particularly in a primed brain – one with preexistent damage. Recently, cellular, molecular, environmental, and genetic components have been linked to the persistent brain dysfunction of systemic inflammation. Here, we have discussed mechanistic evidence for the intricate interrelation between inflammation and neurodegeneration. Identification of druggable targets derived from these mechanisms holds the promise to prevent long-term disability and improve the quality of life in patients with chronic inflammatory conditions.”

*Note: Transglutaminase-6 antibodies are included in the Wheat/Gluten Proteome Reactivity & Autoimmunity array from Cyrex Laboratories.

Traumatic brain injury and chronic neuroinflammation

Neuropsychiatric Disease and TreatmentTraumatic brain injury (TBI) even in it’s milder forms can initiate a process of chronic neuroinflammation that causes a range of chronic neurodegenerative disorders. The authors of a paper just published in Neuropsychiatric Disease and Treatment detail the secondary injury cascades that exacerbate the damage and can lead to chronic traumatic brain injury.

Mild TBI, sometimes referred to as concussion, is the most prevalent TBI. Although TBI has been traditionally considered an acute injury, accumulating clinical and laboratory evidence has recognized the chronic pathology of the disease. Indeed, TBI can manifest many symptoms of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease…Accumulating laboratory and clinical evidence has implicated neuroinflammation in both acute and chronic stages of TBI, suggesting this secondary cell death pathway may be the key to the disease pathology and treatment…”

Neuroinflammation in traumatic brain injury stands out as a target of inquiry:

“Here, we focus on neuroinflammation, which closely manifests immediately after TBI onset, and equally important, it persists in the chronic stages of the disease, making it an appealing target for understanding TBI pathology and its treatment.”

Mild traumatic brain injury may cause a variety of symptoms to persist

Clinicians need to be alert to a range of possible symptoms long after the original injury.

“Most patients fully recover in a couple hours or days, although it may take a couple of weeks. However, depending on the severity of the injury, there are some cases in which victims do not recover and the symptoms persist for years….Clinical manifestations of mild TBI consist of a combination of physical and neuropsychiatric symptoms, which include behavioral and cognitive disorders…Of the physical symptoms of TBI, headaches are the most common, with around 25%–90% of post–mild TBI patients reporting it. Dizziness and nausea are other common symptoms, along with fatigue, sleep disruption, hearing problems, and visual disturbances. As a result of damage to the frontal or temporal lobe, TBI patients are also prone to seizures, which may present a challenge for diagnosis and treatment (ie, differential diagnosis between TBI and epilepsy).”

Chronic cognitive and behavioral disorders from mild traumatic brain injury

The cascade of neurodegenerative effects stemming from mild traumatic brain injury are tragically life altering.

“Cognitive disorders after TBI primarily include attention deficit, memory problems, and executive dysfunction. Attention deficit is very common and interferes with other functions, making daily tasks harder than before…These include irritability, mood changes, aggression, impulsivity, self-centered behavior, and poor persistence. Other symptoms related to TBI are depression (sadness, low energy and motivation, not liking oneself, hopelessness), anxiety, and posttraumatic stress disorder. In addition, as noted earlier, TBI may increase the risk of developing Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative diseases in the long term.”

Primary and secondary waves of injury

Both short and long term cascades of damage occur when the brain is subject to trauma.

“The initial insult first leads to a primary injury caused by the mechanical damage from shearing, tearing, and/or stretching of neurons, axons, glia, and blood vessels…The primary injury triggers a secondary wave of biochemical cascades, together with metabolic and cellular changes. This occurs within seconds to minutes after the traumatic insult and can last for days, months, or years. It often leads to progressive neurodegeneration and delayed cell death, exacerbating the damage from the primary injury. The secondary wave is mainly detected in the injury site and surrounding tissue, although neurodegeneration in brain areas located far from the primary impact has recently been recognized

The secondary wave consists of excitotoxicity, oxidative stress, mitochondrial dysfunction, blood–brain barrier (BBB) disruption, and inflammation. All these processes contribute to neurological deficits separately, but at the same time, these cell death processes interact, worsening the progressive outcome of TBI.”

Excitotoxicity in traumatic brain injury

Substances released by damaged neurons cause brain cells to be stimulated to death.

“…injured nerve cells secreting large amounts of intracellular glutamate into the extracellular space…overstimulates the AMPA and NMDA receptors of surrounding nerve cells. These receptors stay activated, allowing an influx of sodium and calcium ions into the cell. The high concentration of calcium ions in the cytosol leads to the activation of protein phosphatases, phospholipases, and endonucleases. Eventually, the DNA is fragmented, and structures and membranes of the cell are deteriorated. This results in cell death through a hybrid form of apoptosis and necrosis. The overstimulation of glutamate receptors also results in the increased production of nitric oxide, free radicals, and pro-death transcription factors.”

ROS in traumatic brain injury

A damaging increase in free radical reactive oxygen species (ROS) and reactive nitrogen species (RON), which are normally kept at a low level in the brain by antioxidants and enyzmes, also contributes to neuronal cell death.

“After TBI, a significant increase in ROS and impairment of antioxidants that lower the levels is seen. When the generation of ROS/RON is too large, it leads to major cell dysfunction, as its oxidative capabilities damage all biomolecules. ROS cause lipoperoxidation of the cell membrane, which results in the dysfunction of many structures and organelles, such as the mitochondria and oxidizing proteins that affect membrane pores. It may also fragment DNA, causing mutations. ROS are also related to the infiltration of neutrophil, which induces an inflammatory response that, in turn, increases the generation of ROS. Overall, oxidative stress cascade results in large neuronal cell death.”

Mitochondrial dysfunction in mild TBI

Mitochondrial dysfunction, typically a contributing factor to neurodegeneration in general, also plays a role in neuronal cell death and chronic loss of brain function following traumatic brain injury.

“After TBI, the stabilizing mechanisms of levels of ROS become impaired, resulting in increased concentrations. Lipid peroxidation-mediated oxidative damage to the mitochondrial membrane negatively affects its structure and function. The mitochondria also works as a calcium ion buffer, releasing and absorbing the ions as needed to maintain homeostasis. However, when the calcium ion load becomes too large from excitotoxicity, the function of the mitochondria becomes impaired. The mitochondrial permeability transition pore, associated with the mitochondrial inner membrane, is a calcium ion-dependent pore. With the excess calcium ions, the pore stays active, disrupting the mitochondrial membrane potential. Without a membrane potential, the mitochondria is unable to produce ATP, and the ATP synthase may actually consume ATP instead of producing it. With mitochondrial break down, toxins and apoptotic factors are released into the cell, activating the caspase-dependent apoptosis. This causes the cell to commit suicide.”

Blood-brain barrier disruption

Loss of blood brain barrier (BBB) integrity also contributes to brain cell death following TBI.

“BBB dysfunction is related to neuronal cell death and cognitive decline and limits the effectiveness of therapies. Its dysfunction triggers many other secondary injuries, including cell death, oxidative stress, and inflammation, causing the brain to swell, with higher intracranial pressure and ischemia. The primary injury disrupts the tight junctions, allowing an influx of peripheral immune cells and circulating factors (albumin, thrombin, and fibrinogen). These events affect the interaction between BBB endothelial cells and astrocytic glial cells, further contributing to the effects of BBB dysfunction by increasing its permeability. One of the underlying mechanisms regarding BBB dysfunction after TBI is the up-regulation of protein matrix metallopeptidase 9 (MMP-9). This digests the tight junctions, disrupting its proper function. BBB breakdown also allows an influx of larger molecules such as leukocytes that increase the osmotic force in the brain. This results in edema and higher intracranial pressure, which are directly related to ischemia and further cell death.”

 Neuroinflammation, the ‘big enchilada’

Neuroinflammation in TBI

Red line = damaging neuroinflammation, Green solid = pro-survival inflammation, green dotted = treatment, arrow = initiation of treatment.

Brain inflammation may be the leading contributor to accelerated loss of brain cells in most forms of neurodegeneration. In traumatic brain injury it is triggered immediately after impact and can continue for many years.

“After the initial injury, an endogenous inflammatory response is triggered to defend the injury site from invading pathogens and to repair the damaged cells. The complement is activated to perform these functions and recruits inflammatory cells into the intrathecal compartment. The activation of the complement is also accompanied by the infiltration of neutrophils, monocytes, and lymphocytes across the BBB. These secrete prostaglandins, free radicals, proinflammatory cytokines, and other inflammatory mediators that, in turn, up-regulate the expression of chemokines and cell adhesion molecules. This results in immune cells and microglia mobilizing into the brain parenchyma.”

While the microglial cells perform important positive functions that limit damage and sequester the injured tissue, they fire up neuroinflammation by over-reacting. This is particularly true of the M1 phenotype of glial cells.

“…microglial activation in TBI is excessive, and proinflammatory cytokines such as tumor necrosis factor (TNF)- , IL-1 , IL-6, IL-12, and interferon are released. The up-regulation of these cytokines increases the permeability of the BBB by higher expression of cell adhesion molecules in the endothelial cells and by an increased production of chemokines. This results in an increased inflammatory response. Sustained microglial activation also produces neurotoxic molecules and free radicals, which lead to other mechanisms of secondary cell death…In addition, activated microglial cells increase the expression of major histocompatibility complex class II (MHCII ), which is directly correlated to neurodegeneration.”

Astrocytes too exert beneficial effects by increasing brain-derived neutrophilic factors (BDNF) and regulating extracellular glutamate to reduce excitotoxicity. However…

“…when the presence of astrocytes is too large and they become overactivated, it can lead to detrimental effects in the brain. The astrocytes secrete inhibitory extracellular matrix, building a dense physical and chemical barrier surrounding the injury site (glial scar), which encapsulates and isolates the axons. This protects the remaining healthy brain from the neurotoxic environment of the injury site, but it also interferes and prevents the regeneration and repair of the damaged tissue.”

What to do?

A rational treatment plan should include the various remedial measures that target all of these processes:

  • Wind down glutamate excitotoxicity
  • Oppose oxidative stress
  • Support mitochondrial function
  • Help repair the blood-brain barrier
  • Calm neuroinflammation

These processes play a role in neurodegeneration from other causes besides traumatic brain injury. The clinician should have a repertoire of remedial measures at hand to address them. Past and future posts report on advances in treatment. Calming neuroinflammation plays a premiere role.”

“It takes considerably more time for the inflammatory cells to reach the injured brain and contribute to the secondary cell death damage than it takes other secondary death mechanisms, such as glutamate excitotoxicity. This delayed onset provides an extended window of opportunity in which treatments can be administered, greatly increasing the chances of a successful intervention and preventing further damage.”

One cardinal point must be kept in mind: there is a beneficial ‘housecleaning’ side to neuroinflammation so antiinflammatory therapies should not be overdone.

“Immune cells, astrocytes, cytokines, and chemokines are all necessary components for brain repair, and it is their excessive levels that contribute to the secondary cell death damage in TBI…When considering treatments for neuroinflammation in TBI, it is important to note that inflammation has both beneficial and detrimental effects. Prior studies have shown that high doses of antiinflammatory agents actually lead to worse outcomes. In addition to inhibiting the detrimental effects of neuroinflammation, these robust treatments may also retard the beneficial ones.”

Judicious application of natural anti-inflammatory agents to minimize side-effects along with other measures guided by objective measurements is a standard for treating traumatic brain injury that can be applied to other neurodegenerative disorders as well.

Fatigue commonly caused by iron deficiency without anemia

BMJ 2003; 326Fatigue, often accompanied by depression and anxiety, frequently has iron deficiency shown by suboptimal levels of serum ferritin but occurring without anemia. This often goes unrecognized in clinical practice. An earlier study published in BMJ (British Medical Journal) reports on the effect of iron on unexplained fatigue:

“Fatigue is common in the general population. Prevalence rates of 14% to 27% have been reported in primary care, and in 1-2% of patients fatigue is the main reason for consultation. Women were three times more likely than men to mention fatigue in a study conducted in general practice. Although the symptom of fatigue is related to iron deficiency anaemia, evidence is lacking for any association between iron deficiency and tiredness in the absence of anaemia. Iron deficiency associated with increased fatigue was, however, shown in a recent longitudinal study on women’s health. In a European study, about 20% of women of childbearing age had a serum ferritin concentration less than 15 μg/l, and only 4% of these women had iron deficiency anaemia. We examined the effect of iron therapy in women with unexplained fatigue in the absence of anaemia.”

The authors conducted a double blind randomized placebo controlled trial with 144 women aged 18 to 55 who were assigned to either 80 mg/day of oral ferrous sulphate or placebo for four weeks. Their results were of great significance to any practitioner who deals with fatigue:

“136 (94%) women completed the study. Most had a low serum ferritin concentration; <or= 20 microg/l in 69 (51%) women. Mean age, haemoglobin concentration, serum ferritin concentration, level of fatigue, depression, and anxiety were similar in both groups at baseline. Both groups were also similar for compliance and dropout rates. The level of fatigue after one month decreased by -1.82/6.37 points (29%) in the iron group compared with -0.85/6.46 points (13%) in the placebo group (difference 0.95 points). Subgroups analysis showed that only women with ferritin concentrations <or= 50 μg/l improved with oral supplementation.”

Ferritin reference range is often too low

50 μg/l = 50 ng/L, the level that I and numerous others have found more accurate for serum ferritin than what is often the standard reference range. Regarding this the authors state:

“We found a significant response only in the patients with a baseline serum ferritin concentration ≤ 50 μg/l. This suggests that iron deficiency could be present even with a “normal” concentration of serum ferritin. Indeed, the lower limit for serum ferritin concentration is controversial: iron stores in the bone marrow may serve as a better indicator of iron deficiency. One study compared serum ferritin concentrations with iron stores in the bone marrow and found that a serum ferritin concentration of 50 μg/l was associated with a 50% chance of iron deficiency occurring in the bone marrow. The lower reference limits for serum ferritin and haemoglobin concentrations have been considered too low for women. The authors of that study advocate the adoption of the same reference values for both men and women that “would be expected to have fundamental and positive implications for women’s health and welfare.” Our study indirectly supports their conclusion by showing that women can benefit from iron supplementation even if their red blood cell counts are considered normal.”

Iron, ferritin and neurotransmitters

Iron deficiency without anemia impairs production of the neurotransmitters dopamine and serotonin.

Iron deficiency even in the absence of anaemia is associated with decreased activity of iron dependent enzymes and therefore affects the metabolism of neurotransmitters. In people with iron deficiency anaemia the related symptoms will disappear more quickly than the accompanying increase in haematological indices.”

How many people, especially women, have been fed SSRIs or NSRIs when what they needed was some iron? All of this has widespread significance:

A frequently unrecognized problem

“Women with fatigue often associate their symptoms with psychosocial stressors and not a possible emotional or biomedical cause. Conversely, medical investigators tend to associate fatigue with emotional causes and more rarely with biomedical causes. We found that iron deficiency may be an under-recognised cause of fatigue in women of childbearing age. Thus, identifying iron deficiency without anaemia as a potential cause of fatigue is important. It may avoid the inappropriate attribution of symptoms to putative emotional causes or life stressors and thereby reduce unnecessary use of healthcare resources. Instituting iron therapy early may also improve quality of life.”

The authors conclude:

Non-anaemic women with unexplained fatigue may benefit from iron supplementation. The effect may be restricted to women with low or borderline serum ferritin concentrations.”

Pay attention to serum ferritin below 50 mg/mL

Medical Clinics of North AmericaA paper published in Medical Clinics of North America also recognizes serum ferritin below 50 mg/mL as a marker for fatigue. The authors include these key points:

  •   Further defining a patient’s complaint of “fatigue” as either sleepiness, dyspnea on exertion, weakness, generalized lack of energy, or feeling down or depressed can aid in evaluation and management.
  •   Even in the absence of anemia, in women of child-bearing age with a ferritin less than 50 ng/mL, iron replacement is associated with improvement of subjective fatigue.

 Low ferritin in non-anemic menstruating women

CMAJ Vol 184 (11)Research reported in CMAJ (Canadian Medical Association Journal) offered similar data from a double-blind, placebo-controlled trial:

“The true benefit of iron supplementation for nonanemic menstruating women with fatigue is unknown. We studied the effect of oral iron therapy on fatigue and quality of life, as well as on hemoglobin, ferritin and soluble transferrin receptor levels, in nonanemic iron-deficient women with unexplained fatigue.”

The authors  randomly assigned 198 women aged 18–53 years who complained of fatigue and who had a ferritin level of less than 50 ug/L and hemoglobin greater than 12.0 g/dL to receive either oral ferrous sulfate (80 mg of elemental iron daily) or placebo for 12 weeks and measured fatigue as measured on the Current and Past Psychological Scale along with the biological markers at 6 and 12 weeks:

“The mean score on the Current and Past Psychological Scale for fatigue decreased by 47.7% in the iron group and by 28.8% in the placebo group (difference –18.9%)… Compared with placebo, iron supplementation increased hemoglobin (0.32 g/dL) and ferritin (11.4 μg/L) and decreased soluble transferrin receptor (−0.54 mg/L) at 12 weeks.”

Commenting on these results, the authors state:

“We found that iron supplementation for 12 weeks decreased fatigue by almost 50% from baseline, a significant difference of 19% compared with placebo, in menstruating iron-deficient nonanemic women with unexplained fatigue and ferritin levels below 50 μg/L. Iron supplementation did not have a significant effect on measured indicators of quality of life apart from those directly related to fatigue. However, our results suggest that iron supplementation improves hemoglobin, ferritin, hematocrit, mean corpuscular volume and soluble transferrin as early as six weeks after starting treatment.”

Ferritin, iron and the brain

The effects of iron deficiency on fatigue can be explained by decreased activity of iron-dependent enzymes; for example, those affecting the metabolism of neurotransmitters that enhance neurophysiologic changes. However, we presume that such physiologic changes could be confused with depression or anxiety; thus, the effect of iron supplementation on mood disorders remains unknown…Furthermore, blood markers do not necessarily reflect iron stores in other compartments. A recent study suggests that following blood donation, iron supplementation can improve erythropoiesis without affecting fatigue or muscular function. Therefore, fatigue might only occur once iron deficiency becomes present in brain tissue.”

Ferritin, iron and hemoglobin

“Our results suggest that an increase in erythropoiesis could be limited to women with a hemoglobin concentration below 13.0 g/dL. The appropriateness of the official definition of the lower limit for normal hemoglobin concentrations in women has been debated. The biological definition of iron-deficiency anemia is based on the reduction of erythropoiesis due to a lack of available iron. Hemoglobin cutoff values serve as a surrogate and do not truly reflect all individuals’ erythropoietic function correctly. Our results confirm that some women with 12.0 g/dL or higher hemoglobin concentrations have increased erythropoiesis following iron supplementation, suggesting that they were iron deficient.”

Clinicians should diligently attend to the authors’ concluding recommendations:

“For women with unexplained prolonged fatigue, iron deficiency should be considered when ferritin values are below 50 μg/L, even when hemoglobin values are above 12.0 g/dL. Biological markers can be tested at six weeks to confirm iron deficiency.”

A variety of possible symptoms

Vox SanguinisA program to supplement female blood donors without anemia with iron reported in a paper published in the journal Vox Sanguinis highlights some of the symptoms that can attend low ferritin:

“The determination of serum ferritin levels revealed iron deficiency in many non-anaemic premenopausal female blood donors at our Institution…Substitution lasted 16 weeks and the donation interval was extended… Significant results were serum ferritin increase (from a mean value of 7·12 to 25·2 ng/ml), resolution of prostration, fatigue, sleep disturbances, tension in the neck, hair loss and nail breakage. No case of anaemia occurred….”

 Frequently undiagnosed

PraxisThe problem of iron deficiency without anemia remaining undiagnosed persists since it was recognized in a paper published in the Swiss medical journal Praxis as long as twenty years ago:

Iron deficiency (ID) without anaemia frequently remains undiagnosed when symptoms are attributed to ID with anaemia. Serum ferritin is the primary diagnostic parameter, whereas <10 microg/l represent depleted iron stores, 10-30 microg/l can confirm ID without anaemia and 30-50 microg/l might indicate functional ID.”

Ferritin indicates inflammation when elevated

It’s very important for clinicians to remember that ferritin is an acute phase reactant (like CRP) that indicates inflammation when elevated (in the absence of hemochromatosis):

In case of increased CRP or ALT, normal/elevated ferritin should be interpreted with caution.”

Iron dosage

“Intravenous iron is indicated if oral iron is not effective or tolerated. At ferritin <10 microg/l, a cumulative dose of 1000 mg iron and at ferritin 10-30 microg/l, a cumulative dose of 500 mg is advised. At ferritin 30-50 microg/l a first dose of 200 mg might be considered. Ferritin shall be reassessed not sooner than 2 weeks after the last oral or 8-12 weeks after the last iv iron administration.”

Health care professionals also have undiagnosed iron deficiency

International Journal of Biomedical ScienceA study published in the International Journal of Biomedical Science showed that substantial percentage of educated hospital employees in Switzerland were suffering unknowingly of iron deficiency without anemia:

Iron deficiency (ID) has been associated with depression, chronic fatigue, impaired endurance performance and restless leg syndrome, all of which lead to sleep disturbances…We sought to examine the iron status of reportedly healthy individuals by a framed study design in 58 highly educated Swiss hospital employees and to compare the use of non invasive tests for assessing iron deficiency (ID)… All subjects felt well and were working at their maximum capacity. The male subjects were neither anaemic nor had decreased iron parameters however 50% (23/46) of the women had a serum ferritin of below 22 μg/L, still 33% (15/46) of the women had a ferritin value below the more stringent cut off value of 15 μg/L. In 15% (7/46) of the women we diagnosed iron deficient anaemia. Red meat consumption correlated with ferritin values as did the menstrual blood loss which was estimated by asking the amount of tampons used. Of the additionally analysed iron parameters only the percentage of hypochromic erythrocytes, soluble transferrin receptor and transferrin values were significantly correlated with ferritin and reached an AUCROC of ≥0.7 indicating good predictive tests. Nevertheless neither soluble transferrin receptor nor transferrin showed diagnostic advantages for the diagnosis of ID compared to ferritin alone or together with erythrocyte parameters. Working in a hospital environment and having access to health education does not seem to correlate with prevention of ID or ID anaemia in female hospital employees.”

Clinicians should note that other commonly used tests did not cut the mustard:

“As alternative tests we evaluated serum iron, transferrin and transferrin saturation, since these tests are commonly used to assess ID. We found these alternatives to be of little use. For example serum iron exhibits diurnal variations and may reach reference values after ingestion of red meat by iron depleted subjects. In our study serum iron had a poor diagnostic impact (AUCROC of 0.56), which is even lower than the reported (AUCROC of 0.7) (32). Transferrin saturation had a similarly poor AUCROC of 0.67. Transferrin had some diagnostic value as the AUCROC was found to be 0.8, a finding consistent with earlier studies in patients with ID anaemia. Nevertheless none of the above assays offers any advantage over determination of ferritin alone and should no longer be used for diagnosis.”

Anger, tension and fatigue in iron deficiency without anemia

Biological Trace Element ResearchHow often might biological symptoms be mistaken for neurotic conditions? A study recently published in Biological Trace Element Research demonstrates a correlation between anger and tension along with fatigue in iron deficiency without anemia:

Iron deficiency without anemia (IDNA), the most prevalent nutritional deficiency worldwide, affects young women of reproductive age. This study aimed to elucidate the relationship between IDNA and mental and somatic symptoms including anger and fatigue using the Japanese version of the Cornell Medical Index Health Questionnaire (CMI-J)…The subjects were classified as having IDNA (hemoglobin (Hb)≥12 g/dL and serum ferritin<20 ng/mL; n=29), having iron deficiency anemia (IDA) (Hb<12 g/dL and serum ferritin<20 ng/mL; n=10), or having a normal iron status (Hb≥12 g/dL and serum ferritin≥20 ng/mL; n=36).”

Psychological complaints were clearly higher in iron deficiency without anemia:

“Sections M-R (mental complaints) were significantly higher in the IDNA subjects than in the normal subjects. No significant difference in CMI scores was found between the normal and IDA subjects. Sections I (fatigability), Q (anger), and R (tension) were significantly higher in the IDNA subjects than in the normal subjects, regardless of no significant differences between the normal and IDA subjects in those sections. Young women with IDNA demonstrated a significantly higher proportion of neurotic tendencies (grades II-IV)….The findings suggest that IDNA may be a risk factor for anger, fatigue, and tension in women of childbearing age.”

Mental quality of life and cognitive function

PLOS ONEA study recently published in PLOS One (Public Library of Science) demonstrated improvements in general mental well-being in addition to fatigue from a single dose of IV iron in the form of ferric carboxymaltose:

Unexplained fatigue is often left untreated or treated with antidepressants. This randomized, placebo-controlled, single-blinded study evaluated the efficacy and tolerability of single-dose intravenous ferric carboxymaltose (FCM) in iron-deficient, premenopausal women with symptomatic, unexplained fatigue.”

The authors also note:

“Since iron is not only a component of hemoglobin (Hb) but also a key element of various essential enzymes in all metabolic pathways (e.g. oxidative phosphorylation), ID can have an Hb-independent effect on physical performance and fatigue…A slow onset of ID-associated symptoms may lead patients to adapt to fatigue and consequently, they may not request medical help. Therefore, ID may be broadly unrecognized despite being one of the most prevalent nutrient deficiencies affecting human health.”

In their study that included 290 women, 144 of whom were given the IV FCM and the rest placebo…

Fatigue was reduced in 65.3% (FCM) and 52.7% (placebo) of patients (OR 1.68). A 50% reduction of PFS score was achieved in 33.3% FCM- vs. 16.4% placebo-treated patients At Day 56, all FCM-treated patients had hemoglobin levels ≥120 g/L (vs. 87% at baseline); with placebo, the proportion decreased from 86% to 81%. Mental quality-of-life (SF-12) and the cognitive function scores improved better with FCM.”

The authors concluded:

“A single infusion of FCM improved fatigue, mental quality-of-life, cognitive function and erythropoiesis in iron-deficient women with normal or borderline hemoglobin. Although more side effects were reported compared to placebo, FCM can be an effective alternative in patients who cannot tolerate or use oral iron, the common treatment of iron deficiency. Overall, the results support the hypothesis that iron deficiency can affect women’s health, and a normal iron status should be maintained independent of hemoglobin levels.”

Fatigue, lack of concentration, headache and sleep disorders

Geburtshilfe und FrauenheilkundeEffectiveness of a single IV dose of FCM was also demonstrated in a study published this year in Geburtshilfe und Frauenheilkunde (Obstetrics and Gynecology):

“In total, data from 273 patients was evaluated. 193 of these patients displayed iron deficiency anaemia (IDA), and 68 had iron deficiency without anaemia (ID). The reasons for the ID/IDA were hypermenorrhoea (HyM) (n = 170), post-partum condition (PP) (n = 53) or another indication (n = 53)…The primary, serious accompanying symptoms of anaemia were fatigue (72 %), lack of concentration (42 %), pale mucous membranes (42 %), headache (26 %) and sleep disorders (21 %)…FCM was most frequently administered via infusion (92 %; average infusion duration 21 minutes)…In all subgroups, 92 % of women displayed a marked improvement in all of their symptoms.”

Low ferritin can be obscured by inflammation

New England Journal of MedicineFerritin is, of course, a acute-phase reactant that can increased by inflammation. A recent paper published in The New England Journal of Medicine on microcytic anemia describes how ferritin levels that would otherwise appear low are elevated due to inflammation:

“Although the transcription of ferritin mRNA is up-regulated by inflammation, the synthesis of ferritin is regulated by cellular iron content, with ferritin mRNA being translated to protein only when the cell is iron-replete. Thus, a patient with adequate iron may have a very high ferritin level with inflammation, whereas it is rare for a patient with iron deficiency to have a ferritin level of more than 100 ng per milliliter. The lower limit of the normal range depends on the clinical situation. A ferritin level of 15 ng per milliliter is very specific for iron deficiency, but in older patients or those with inflammatory states, one cannot rule out iron deficiency until the ferritin level is more than 100 ng per milliliter. Guyatt et al. found that the likelihood ratio for iron deficiency is positive up to a ferritin level of 40 ng per milliliter in the absence of inflammation and up to 70 ng per milliliter in the presence of inflammation. Although not perfect, the serum ferritin assay is the test most likely to provide information about a patient’s iron status, but the patient’s age and clinical condition need to be considered in the interpretation of results.”

Clinical Bottom Line

In cases of fatigue unexplained by other causes, depression, sleep disorders, poor concentration, hair loss, and restless legs syndrome (since iron is necessary for the production of dopamine), iron should be considered when serum ferritin is below 50 ng/L even in the absence of anemia and below 70 ng/L in the presence of inflammation.

Benzodiazepines associated with increased Alzheimer’s risk

BMJBenzodiazepines are well known to be deleterious to brain health with more than very short-term use. Research just published in BMJ (British Medical Journal) presents evidence that use of benzodiazepines longer than three months to treat anxiety or insomnia is associated with a substantial increase in the risk of Alzheimer’s disease.The authors note urgent public health concerns regarding dementia:

Rising tide of dementia

Dementia is currently the main cause of dependency in older people and a major public health concern affecting about 36 million people worldwide. Because of population growth and demographic ageing, this number is expected to double every 20 years and to reach 115 million in 2050, resulting in tragic human consequences and social costs. As there are no effective treatments, the search for putative modifying factors remains a priority. Several studies have shown that benzodiazepine use could be one of these. This class of drugs is mainly used to treat anxiety or insomnia. Prevalence of use among elderly patients is consistently high in developed countries and ranges from 7% to 43%. International guidelines recommend short term use, mainly because of withdrawal symptoms that make discontinuation problematic. Although the long term effectiveness of benzodiazepines remains unproved for insomnia and questionable for anxiety, their use is predominantly chronic in older people.”

Benzodiazepines and dementia

“While the acute deleterious effects of benzodiazepines on memory and cognition are well documented, the possibility of an increased risk of dementia is still a matter of debate.”

So they investigated the relation between the risk of Alzheimer’s disease with exposure to benzodiazepines that started at least five years before, in 1796 subjects who ended up developing Alzheimer’s who were matched with 7184 controls and found:

Benzodiazepine ever use was associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density 1.32 for 91-180 prescribed daily doses and 1.84 for >180 prescribed daily doses and with the drug half life (1.43) for short acting drugs and 1.70 for long acting ones.”

Benzodiazepines duration and discontinuation

MedscapeA comment in Medscape Family Medicine states:

“The investigators note that although these medications are important treatment options, clinicians should “comply with good practice guidelines” and prescribe benzodiazepines for as short a time as possible. In addition, use should not exceed 3 months.”

Note: Benzodiazepines in long term use should never be discontinued abruptly and without the guidance of a clinician due to the likelihood of serious adverse withdrawal effects.

The authors conclude:

Benzodiazepine use is associated with an increased risk of Alzheimer’s disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.”

Eating disorders and the causative role of autoimmunity

PLOS ONEEating disorders are multifactorial; like other psychiatric conditions the causative role of auotimmune neuroinflammation is coming to the fore as evidenced by a study just published in PLoS One (Public Library of Science). The authors note regarding earlier reports relevant to autoimmunity in eating disorders:

“A prior autoimmune disease has recently been shown to increase the risk of mood disorders and schizophrenia. In addition, the risk of both mental disorders increased in a dose response pattern when autoimmune diseases and infections were assessed together. The role of autoimmune processes, such as various pathogens triggering autoantibodies cross-reactive with neuronal antigens (brain-reactive autoantibodies), has also been recognized in the pathogenesis of neuropsychiatric disordersincluding autism spectrum disorders, obsessive-compulsive disorder, tic-disorders, ADHD, post-traumatic stress disorder, and narcolepsy. Furthermore, pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) include anorexia nervosa (AN).”

Research suggests autoimmune processes to be involved in psychiatric disorders. We aimed to address the prevalence and incidence of autoimmune diseases in a large Finnish patient cohort with anorexia nervosa, bulimia nervosa, and binge eating disorder.”

Moreover…

Crohn’s disease and celiac disease have been suggested to act as triggers for the development of eating pathology, and individuals with celiac disease are reported to be at increased risk for eating disorders…To our knowledge, no large scale reports of the co-morbidity of autoimmune diseases and eating disorders have been published. 

So they compared 2342 patients with eating disorders compared to 9368 matched controls from the general population and correlated that with data for 30 autoimmune diseases and found a pertinent association:

“Of patients, 8.9% vs. 5.4% of control individuals had been diagnosed with one or more autoimmune disease. The increase in endocrinological diseases was explained by type 1 diabetes, whereas Crohn’s disease contributed most to the risk of gastroenterological diseases. Higher prevalence of autoimmune diseases among patients with eating disorders was not exclusively due to endocrinological and gastroenterological diseases; when the two categories were excluded, the increase in prevalence was seen in the patients both before the onset of the eating disorder treatment and at the end of the follow-up.”

Shared immunological mechanisms

In other words, the crucial point is that there are shared immunological mechanisms:

“We observed an increased risk for several autoimmune diseases among patients with eating disorders supporting the hypothesis of co-morbidity of these disorders and suggesting that immune-mediated mechanisms could play a role in the development of eating disorders. Importantly, our results were not restricted to the association of T1D with eating disorders as shown in previous studies. Instead, the association was seen for several autoimmune diseases with different genetic backgrounds. Our findings thus suggest that the link between eating disorders and autoimmune diseases is based on shared immunological mechanisms, rather than on the shared genetic background, e.g. the shared HLA risk genotype. In addition, our findings support earlier observations suggesting that autoimmune processes contribute to the onset and maintenance of eating disorders, at least in a subpopulation of patients.”

Chronic inflammation in psychiatric disorders

Chronic inflammation must be assessed in psychiatric disorders:

“Studies indicate that psychiatric disorders co-exist with inflammation, infections and autoimmune diseases, and shared vulnerability underlying many psychiatric disorders suggest that findings from one disorder may be relevant across categories. Pro-inflammatory cytokines and antibodies/autoantibodies against neuronal antigens could induce changes in neurotransmitter and neuroendocrine function, which may subsequently yield psychiatric manifestations. Studies suggest that pro-inflammatory cytokines may have a role in eating disorders.”

Pro-inflammatory cytokines

A key clinical point for clinicians, especially those of us who assess serum cytokines, is the fact that they may be elevated in the brain while remaining normal in the blood:

“It has also been suggested that pro-inflammatory cytokines might be overproduced in specific brain areas and act locally without concomitant increase in serum or immune production. Indeed, the pro-inflammatory cytokines are able to activate HPA axis, the hyperactivity of which in eating disorders has been established.”

Gut-brain axis

Regarding the role of the gut-brain axis and autoimmunity:

“Our findings are supported by the immunological studies performed in patients with eating disorders, where autoantibodies against peptides related to appetite-regulation, stress response, and social-emotional functioning (α-MSH, ACTH, ghrelin, oxytocin, vasopressin) were detected. The postulated role of intestinal microflora contributing to the development of cross-reactive neuronal autoantibodies provides a link between gut and brain…Gut microbiota is an important regulator of the immune system and its alteration has been associated with autoimmune diseases and immune-mediated disorders, such as allergies and T1D. Composition of the microbiota affects gut permeability, and the function of both innate and adaptive immune system including development of regulatory T-cells.”

Sex hormones

Practitioners must also bear in mind that sex hormone dysregulation, as noted earlier here, can contribute to loss of immune tolerance:

“…sex hormones modulate microbiota and the development of autoimmunity, as well as the eating disorders risk. The interplay between gut microbiome, immune regulation, and sex hormones thus provide one potential, complex mechanism underlying eating disorders and explaining the partly shared etiopathogenesis of eating disorders and autoimmune diseases.”

Medscape Medical News quotes the lead author:

“I was surprised about the robust link that we found between autoimmune diseases and eating disorders,” lead author Anu Raevuori, MD, PhD, from the Department of Public Health at the University of Helsinki, Finland.

“On the other hand, my clinical impression is that in many patients with eating disorders, particularly those with long-lasting and persistent symptoms, the disorder appears to have a biological background,” said Dr. Raevuori.

“…other lines of research suggest that some of those eating disorder patients that do not have a diagnosable autoimmune disease might have underlying autoimmunological factors, such as autoantibodies against peptides…related to appetite regulation, stress response, and social-emotional functioning, which could explain their symptoms.”

Anyone involved in case management for patients suffering from eating disorders should consider the authors’ summation:

“In conclusion, we observed the association between eating disorders and several autoimmune diseases with different genetic backgrounds. Our data support the findings from other studies indicating the role of immunological mechanisms at least in a subpopulation of patients with eating disorders. We recommend that clinicians treating patients with eating disorders consider the increased risk of autoimmune diseases and the possible role of autoimmune processes underlying these individuals’ somatic and neuropsychiatric symptoms related to mood disturbances, anxiety and disordered eating.”

Benzodiazepines and anxiolytics increase risk for dementia, mortality

BMJBenzodiazepines (Xanax®, Halcion®, Ativan®, Restoril®, lorazepam, Valium®, Klonopin®, Librium®, etc.) are known to increase the risk for dementia as documented in a study published in BMJ (British Medical Journal). The authors examined data for 1063 men and women free of dementia and did not start taking benzodiazepines until at least the third year of follow-up observations and found a significant association:

“During a 15 year follow-up, 253 incident cases of dementia were confirmed. New use of benzodiazepines was associated with an increased risk of dementia (multivariable adjusted hazard ratio 1.60). Sensitivity analysis considering the existence of depressive symptoms showed a similar association (hazard ratio 1.62). A secondary analysis pooled cohorts of participants who started benzodiazepines during follow-up and evaluated the association with incident dementia. The pooled hazard ratio across the five cohorts of new benzodiazepine users was 1.46. Results of a complementary nested case-control study showed that ever use of benzodiazepines was associated with an approximately 50% increase in the risk of dementia compared with never users.”

It’s important to note that other serious symptoms, bad enough on their own, can arise before progressing to full-blown dementia. They note:

Insomnia, depression, and anxiety…can be prodromal symptoms of dementia…As treatment options remain limited, identifying factors contributing to dementia is critical.”

The authors conclude:

“The findings of this large prospective population based study show that new use of benzodiazepines is associated with an approximately 50% increase in the risk of dementia. The results remained robust after control for potential confounders, in pooled analysis across the follow-up time, and in a nested case-control study. Considering the extent to which benzodiazepines are now prescribed, physicians and regulatory agencies should consider the increasing evidence of the potential adverse effects of this drug class for the general population.”

Just as considering only lung cancer when accounting for adverse effects of smoking, the incidence of dementia brings in its train a host of other ill effects for the brain.

BMJ Vol 348, Issue 7950Now another study hot off the presses from BMJ offers evidence that benzodiazepines along with anxiolytics and the Z drugs commonly used for insomnia—zaleplon (Sonata®), zolpidem (Ambien®), and zopiclone—significantly increase the risk of mortality in general. The authors state their intent:

“Evidence of adverse effects including increased risk of dementia and other psychomotor impairments (daytime fatigue, ataxia, falls, and road traffic incidents), cancer, pneumonia, and other infections has increased concerns of an association with premature mortality…A recent study found that the mortality risk extended to those with low levels of use, was greater in younger people, and that heavy use of hypnotics increased the risk of developing cancer…We tested the hypothesis that people taking anxiolytic or hypnotic drugs, or both, are at significantly increased risk of death compared with non-users and to estimate the size of this association after adjusting for a wide range of potential confounders using prescribing data from UK primary care.”

To do so they examined data for 34,727 patients aged 16 years and older who were prescribed anxiolytic or hypnotic drugs, or both and 69,418 patients with no such prescriptions as controls, followed over an average period of 7.6 years for death from all causes. Their data both a significantly increased risk for mortality and an increase in other ills:

Physical and psychiatric comorbidities and prescribing of non-study drugs were significantly more prevalent among those prescribed study drugs than among controls. The age adjusted hazard ratio for mortality during the whole follow-up period for use of any study drug in the first year after recruitment was 3.46 and 3.32 after adjusting for other potential confounders. Dose-response associations were found for all three classes of study drugs (benzodiazepines, Z drugs (zaleplon, zolpidem, and zopiclone), and other drugs). After excluding deaths in the first year, there were approximately four excess deaths linked to drug use per 100 people followed for an average of 7.6 years after their first prescription.”

Commenting on these findings they state:

We found evidence of an association between prescription of anxiolytic and hypnotic drugs and mortality over an average follow-up period of 7.6 years among more than 100,000 age and general practice matched adults. In patients who were prescribed these drugs, there was an estimated overall statistically significant doubling of the hazard of death (hazard ratio 2.08), after adjusting for a wide range of potential confounders, including physical and psychiatric comorbidities, sleep disorders, and other drugs. This association remained significant and followed a dose-response pattern after restricting analyses to those with at least 12 months of follow-up and to those who were only prescribed the study drugs in the first year after recruitment.”

Moreover, a host of other ills (comorbidities) can be experienced along the way to a doubling of mortality risk which can be rendered more difficult to treat due to adverse brain effects of these medications. The authors summarize in their conclusion:

“These findings are consistent with previous evidence of a statistically and clinically significant association between anxiolytic and hypnotic drugs and mortality. Using prescribing data from a large primary care database and after adjusting for a wide range of potential confounders, prescriptions for these drugs were associated with significantly increased risks of mortality over an average follow-up period of 7.6 years. This association followed a dose-response pattern for all three classes of study drug and extended beyond the time of use.”

Hyperexcitable brain syndrome and gluten

Journal of Neurology, Neurosurgery & PsychiatryHyperexcitable brain, with potentially severe consequences, is recognized as among the gluten-related autoiimmune neurological disorders in a paper just published in the Journal of Neurology, Neurosurgery & Psychiatry. The authors state:

Hyperexcitable brain and refractory coeliac disease: a new syndrome Gluten related disorders (GRD) is the newly proposed term to encompass a spectrum of immune mediated diseases triggered by gluten ingestion. Whilst coeliac disease (gluten sensitive enteropathy) remains one of the best characterised GRD, neurological dysfunction is one of the commonest extraintestinal manifestations with a range of presentations such as cerebellar ataxia, neuropathy, sensory ganglionopathy and encephalopathy (headaches and white matter abnormalities). Neurological manifestations can occur with or without enteropathy.”

They documented the clinical and electrophysiological characteristics of this hyperexcitable brain syndrome in a severely afflicted group of seven patients:

“The 7 patients (5 male, 2 female) were identified from a cohort of 540 patients with neurological manifestations of GRD that regularly attend our gluten/neurology clinic. The mean age at onset of the neurological symptoms was 58 years (range 46 to 76). Unlike myoclonic ataxia (eg in the context of opsoclonus myoclonus ataxia syndrome) the myoclonic tremor in these patients was initially focal (face, tongue one arm and/or one leg) but then spread to affect other parts of the body. Epilepsy was a feature in 5 of the patients, 3 of which gave a history of Jacksonian march before progression to generalised seizures. In one patient the neurological presentation was with status epilepticus. All patients had a mild degree of limb ataxia and more prominent gait ataxia. Electrophysiology showed evidence of cortical myoclonus. Four had a phenotype of epilepsia partialis continua and three later developed more widespread jerking. There was clinical, imaging and/or pathological evidence of cerebellar involvement in all cases but this was not the main source of disability by contrast to patients with gluten ataxia, where cerebellar ataxia is the most disabling feature.”

Neuroinflammation due to celiac and non-celiac gluten sensitivity can cause a range of neurological disorders. These cases are notable for their severity and association with refractory celiac disease (CD that fails to heal after gluten is eliminated). They are especially troubling because the damage and hyperexcitable brain symptoms remained after gluten was eliminated:

“All patients adhered to a strict gluten–free diet with elimination of gluten–related antibodies, despite which there was still evidence of enteropathy in keeping with refractory celiac disease (type 1 in 5 and type 2 in 2). One of the 2 patients with type 2 refractory enteropathy died 13 years later from metastatic enteropathy–associated lymphoma. The other died 1 year after the neurological presentation from presumed enteropathy associated lymphoma. Four were treated with mycophenolate and one in addition with rituximab and IV immunoglobulins. Whilst their ataxia improved the myoclonus remained the most disabling feature of their illness with a tendency to spread and affect other parts of the body.”

Clinical note: Practitioners should not underestimate the potential severity of gluten-associated neuroinflammation. We should be alert to the far more common milder manifestations of hyperexcitable brain that can present as sleep disorders, anxiety, attention disorders, sympathetic nervous system hyperarousal syndromes, etc. The authors conclude:

“This syndrome whilst rare, appears to be the commonest neurological manifestation of refractory CD. The clinical manifestations extend from focal reflex jerks to epilepsia partialis continua, covering the whole clinical spectrum of cortical myoclonus. This entity is possibly under–diagnosed and difficult to treat.”