Neurotoxic and Metabolic Injuries

CHAPTER 6

BRUCE J. DIAMOND

JOSEPH E. MOSLEY

KATHERINE MAKAREC

KRISTA DETTLE

OVERVIEW

In this chapter, we briefly examine brain injuries manifested as acute and chronic impairments and disturbances across a variety of cognitive, motor, neuropsychiatric, perceptual-motor, visuospatial, emotional, tissue, systemic, and electro-chemical domains secondary to neurotoxic and metabolic injuries.

Chronic Hepatic Encephalopathy

Chronic hepatic encephalopathy (CHE) is a reversible metabolic neuropsychiatric syndrome (Hilsabeck & Webb, 2013). Mild CHE (M-CHE) requires neuropsychological testing to reveal cognitive impairments. M-CHE is associated with poor quality of life and a high risk for accidents (Bajaj & Mullen, 2010).

Uremic Encephalopathy

Uremic encephalopathy (UE), a potentially debilitating disorder, can be experienced in both acute and chronic renal failure (Seifter & Samuels, 2011). It involves subtle decline in mentation, emotional changes, and progression into full-blown delirium, seizures, coma, cognitive, motor, and neuropsychiatric impairments.

Hyperhomocysteinemia and Alzheimer’s Disease

Homocysteine (Hcy) is a nonessential, nonproteinogenic amino acid synthesized from dietary methionine (Petras et al., 2014). Elevation of total plasma Hcy, known as “hyperhomocysteinemia” (HHcy), is associated with neurodegenerative diseases of the central nervous system (CNS) such as epilepsy, stroke, and dementia, including Alzheimer’s disease (AD) (Petras et al., 2014). HHcy is theorized to be a risk factor that, if properly managed, may help postpone the onset of AD (Van Dam & Van Gool, 2009), although causal links are tenuous and controversial (Farkas et al., 2013).

Metabolic Risk Factors of Sporadic Alzheimer’s Disease

Approximately 95% of AD cases are of the sporadic type in which multifactorial genetic, lifestyle, and environmental influences contribute to pathogenesis (Chakrabarti et al., 2015). This type of AD usually becomes fully symptomatic after age 60, termed “late-onset AD” (LOAD) (Lim, Martins, & Martins, 2014). However, distinct and measurable changes may begin in affected individuals’ brains years before onset (Liu et al., 2014). Accordingly, research has focused on identifying pathogenic mechanisms and early biomarkers of metabolic origin (Chakrabarti et al., 2015).

Organophosphates and Pesticides

Pesticide chemicals are used throughout the United States and the developing world to manage insects, birds, weeds, plant pathogens, mollusks, and biological agents (United States Environmental Protection Agency, 2007).

Wernicke’s Encephalopathy

Wernicke’s encephalopathy (WE) is an acute neuropsychiatric disorder caused by thiamine (B₁) deficiency; left untreated, it can result in Korsakoff’s syndrome (Galvin et al., 2010).

Toxic Metabolic Encephalopathy

The term “encephalopathy” derives from the Greek encephalos (brain) and pathos (suffering or experience). Toxic metabolic encephalopathy (TME) characteristically involves delirium and an acute confusional state accompanied by global cerebral dysfunction in the absence of primary structural brain disease (Chen & Young, 1996).

Lead Poisoning

Lead (Pb) poisoning is insidious but treatable and is now more commonly seen in developing countries, in those living in older homes, or environments with lead contamination in the soil. It can be an acute (less commonly seen and typically due to occupational exposure) (Flora, Gupta, & Tiwari, 2012) or a chronic condition. Lead can be ingested (e.g., recently in a popular noodle brand in India) (Bhullar, Thind, & Singla, 2015), inhaled (e.g., lead dust from deteriorating paints), or absorbed through the skin. The impact on children under 6 years of age can be devastating (developmental delay or, in severe cases, death) if not treated.

HISTORY

Chronic Hepatic Encephalopathy

Associations between hepatic disease and mental disorders were first recorded by Hippocrates. Galen later developed a model of liver functioning that recognized its importance to brain functioning, hypothesizing that the liver used food in the stomach to prepare blood for systemic distribution (Davidson & Summerskill, 1956).

Uremic Encephalopathy

Metabolic encephalopathy was a diagnostic term first used in 1927 to define the clinical presentation of brain dysfunction caused by systemic factors (Varelas & Graffagnino, 2013). UE is one of the most debilitating disorders associated with renal failure.

Hyperhomocysteinemia and Alzheimer’s Disease

In 1992, it was suggested that B vitamin deficiencies might contribute to cognitive decline in patients with dementia. During the same year, three independent groups suggested that because metabolism of Hcy depends on normal levels of B vitamins, Hcy levels might be elevated in patients with AD (McCaddon, 2006), known as the “homocysteine hypothesis of AD” (McCaddon, 2006). Using data from the Framingham Heart Study, Seshadri and colleagues (2002) published the first sufficiently powered epidemiological study investigating relationships between Hcy levels and AD.

Metabolic Risk Factors of Sporadic Alzheimer’s Disease

At the turn of the 20th century, Alois Alzheimer, psychiatrist and neuroanatomist, discovered and characterized the histological alterations that we recognize today as the hallmark features of AD, plaques and neurofibrillary tangles. Although the response in the medical community was not enthusiastic, these histopathological findings and the accompanying symptom profile and illness course described by Alzheimer had not previously been seen or recognized as a disease profile (Hippius & Neundörfer, 2003).

Organophosphates and Pesticides

While many organophosphates and pesticides are known neurotoxins, research is only beginning to characterize the neuropsychological sequelae following exposure (Schultz & Ferraro, 2013). Organophosphates and carbamates contribute to the majority of the available data (National Research Council, 1993).

Wernicke’s Encephalopathy

Wernicke first described WE in 1881 with a characteristic triad of symptoms: confusion, ataxia, and oculomotor abnormality. It was recognized in China over 1,000 years ago as wet beriberi, a disease caused by malnutrition brought on by a limited diet consisting of polished white rice (Fan, 2004).

Toxic Metabolic Encephalopathy

In 1912, Kinnier Wilson coined the term “metabolic encephalopathy” to describe a global cerebral dysfunction induced by systemic factors (Varelas & Graffagnino, 2013).

Lead Poisoning

Lead poisoning is thought to have played a role in the fall of the Roman Empire and has been mined by humans for 6,000 years (Hernberg, 2000). Although lead poisoning was known in the ancient world, it was forgotten until 1772 when Sir George Backer made the connection between lead ingestion and the Devonshire colic (Hernberg, 2000). Tanquerel des Planches provided the first modern description of lead poisoning in 1839 (Hernberg, 2000). Since 1978, lead-based paints stopped being sold in the United States. Most of the developed world stopped producing lead-based gasoline in the 1920s; it was not until the 1990s, after a period of decline, that it was virtually eliminated (Hernberg, 2000).

PATHOPHYSIOLOGY

Chronic Hepatic Encephalopathy

Ammonia neurotoxicity largely mediates observed neuropathology (Hilsabeck & Webb, 2013). When ammonia in the blood reaches the brain, astrocytes attempt to eliminate it by synthesizing glutamine from molecules of ammonia and glutamate (Bajaj & Mullen, 2010). As glutamine accumulates, its osmotic effect causes perivascular astrocytes to absorb water and swell, causing a cascade of events, for example, brain edema, increased intracranial pressure (ICP), alterations in neurotransmission, oxidative stress, and release of proinflammatory cytokines.

Uremic Encephalopathy

The pathogenesis is thought to be complex with accumulation of metabolites, imbalance in excitatory and inhibitory neurotransmitters, elevated parathyroid hormone, and abnormal calcium control (Lacerda, Krummel, & Hirsch, 2010). Buildup of dialyzable uremic toxins such as urea, guanidine compounds, hippuric acid, polyamines, phenols, indolic acids, and myo-inositol are thought to play a role in the pathophysiology (Varelas & Graffagnino, 2013).

Hyperhomocysteinemia and Alzheimer’s Disease

Hcy is considered a potent neurotoxin, and elevated levels are risk factors for AD (Seshadri et al., 2002). Although exact mechanism(s) are unknown, there is evidence that HHcy may promote dementia via multiple pathways, including cerebral microangiopathy, endothelial dysfunction, oxidative stress, neuronal DNA damage, excitotoxicity, and apoptosis (Sachdev, 2005). HHcy may influence pathophysiological processes of AD, such as potentiating the neurotoxicity of amyloid β-peptide, disrupting microtubules by promoting tau phosphorylation, disturbing proteins controlling cell division in the cerebral cortex, and contributing to vascular pathology of AD (Chakrabarti et al., 2015; Sachdev, 2005). The pathogenesis of HHcy in AD in particular remains unclear (Zhuo, Wang, & Praticò, 2011). The increase in Hcy with AD appears to be associated with biochemical damage resulting from oxidative stress (Köseoglu & Karaman, 2007). Other theories have suggested that HHcy damages DNA repair mechanisms, leading to apoptosis and vulnerability to further injury (Kruman et al., 2002). As such, HHcy is linked with hippocampal or cortical atrophy in healthy older adults (den Heijer et al., 2003) and white-matter changes in AD patients (Kim et al., 2009). Still others suggest factors such as inhibition of adult neurogenesis (Kruman, Mouton, Emokpae, Cutler, & Mattson, 2005), immune activation (Schroecksnadel, Leblhuber, Frick, Wirleitner, & Fuchs, 2004), and blockage of the nitric oxide signaling pathway (Selley, 2004).

Metabolic Risk Factors of Sporadic Alzheimer’s Disease

Histopathological study of the AD brain reveals two characteristic findings: (a) extracellular neuritic plaques (NPs) and (b) cytoplasmic neurofibrillary tangles (NFTs) (Chakrabarti et al., 2015). The central cores of NPs contain amyloid beta (Aβ) peptide in oligomerized states, surrounded by detritus composed of degenerating neurons, microglia, and macrophages (Bird & Miller, 2008). By contrast, NFTs are composed of twisted neurofilaments of abnormally phosphorylated tau (τ) protein (Chakrabarti et al., 2015). Concomitant findings include neuronal loss, synaptic degeneration, dendrites, and axons, as well as destruction of cholinergic neurons and the neurotransmitter (NT) acetylcholine (Bird & Miller, 2008; Chakrabarti et al., 2015).

Organophosphates and Pesticides

Given the prevalence of organophosphates and pesticides and the fact that the chronic neurotoxic effects of these substances are not yet clearly established, issues related to neurotoxicity have seen increasing scrutiny in recent years (McElgunn, 2010). Existing evidence suggests that acute, high-level exposure results in complex systemic dysfunction, brought about by biochemical mechanisms directly affecting the nervous system (National Research Council, 1993). More specifically, confusion, agitation, coma, and respiratory failure are triggered by overstimulation of nicotinic and muscarinic acetylcholine receptors in the CNS (Eddleston, Buckley, Eyer, & Dawson, 2008). Data also indicate that lower-level chronic exposure may lead to subtle, but measurable, long-term neurological dysfunction (National Research Council, 1993).

Wernicke’s Encephalopathy

Thiamine is a water-soluble B vitamin, the active form of which is thiamine pyrophosphate that is integral to three major enzymes required for glucose metabolism (Spector, 1982). It is commonly derived from food sources, notably flour-based products (e.g., bread) that have been enriched with B₁ and other vitamins and minerals since WWII in the United States (Isenberg-Grzeda, Kutner, & Nicolson, 2012). Thiamine is found throughout the body, with higher concentrations in skeletal muscle, liver, heart, and brain (Spector & Johanson, 2007).

Toxic Metabolic Encephalopathy

Underlying mechanisms may include disturbances in neurotransmission along with disruption of energy metabolism, cellular depolarization, secretion of cytokines, and changes in blood flow (Campbell et al., 2009; Surtees & Leonard, 1989).

Lead Poisoning

There is no known safe level of lead (Flora et al., 2012) and it impacts almost all major organ systems including blood (binding to red blood cells), renal, cardiovascular, and peripheral and central nervous systems. Lead in the blood is excreted in urine and bile at a rate of 1 to 3 mL/min and has a half-life of 30 days (Mason, Harp, & Han, 2014). Residual lead binds to red blood cells and is stored in bone with a half-life of 20 to 30 years. Lead is known to interfere with developmental aspects of CNS (neuronal migration, neuronal and glial differentiation, and synapse formation) (Mason et al., 2014).

ETIOLOGY

Chronic Hepatic Encephalopathy

Intestinal flora and protein metabolism by deamination of amino acids produce ammonia. Gut-derived ammonia is absorbed into the hepatic portal system, the major source of blood flow from the gut to the liver. A normal liver would rapidly convert ammonia to urea for excretion by the kidneys. However, a cirrhotic (diseased) liver synthesizes ammonia into urea more slowly, or not at all, allowing ammonia to accumulate in the blood.

Uremic Encephalopathy

UE severity tends to be higher with acute renal failure, but can be experienced with chronic renal failure as well (Varelas & Graffagnino, 2013).

Hyperhomocysteinemia and Alzheimer’s Disease

While the direct cause of AD remains unknown, various theories have been explored. A majority of cases are sporadic, with environmental and genetic factors contributing in varying degrees (Zhuo et al., 2011). Determining whether HHcy is an independent causal risk factor, or is secondary to neurodegeneration, remains a significant issue (Farkas et al., 2013). Increased levels of homocysteine are often the result of disturbed methionine metabolism. The amino acid methionine is converted to Hcy, which is then normally (a) converted back to methionine or (b) converted to the amino acid cystathionine (Petras et al., 2014). However, genetically inherited enzyme mutations, end-stage renal disease, hypothyroidism, and dietary vitamin deficiencies can negatively influence the metabolism of methionine, causing hyperhomocysteinemia. Adequate stores of folic acid, vitamin B₁₂, and vitamin B₆ are critical for normal Hcy metabolism (Maron & Loscalzo, 2009).

Metabolic Risk Factors of Sporadic Alzheimer’s Disease

Hyperinsulinemia: In a hyperinsulinemic brain, insulin competes with Aβ for enzymatic degradation, resulting in a state of Aβ accrual. However, evidence suggests that hyperinsulinemia of type 2 diabetes is associated with lower brain and CSF insulin levels (Chakrabarti et al., 2015). Type 2 diabetes would thus involve both insulin deficiency and insulin resistance (Chakrabarti et al., 2015).

Insulin resistance: Although the mechanism is unclear, insulin resistance may directly contribute to the development of AD pathology by potentiating Aβ accumulation and tau phosphorylation (Chakrabarti et al., 2015; Kim & Feldman, 2015). Defective insulin signaling and glucose metabolism may be characteristic of the AD brain (Kim & Feldman, 2015).

Hypercholesterolemia: Cellular cholesterol levels may play a role in both the generation of Aβ and the amyloid cascade (Frisardi et al., 2010). That is, cholesterol-influenced increases in Aβ oligomer levels result in reduced intracellular cholesterol, in turn inducing hyperphosphorylation of tau (Michikawa, 2003). This cascade might ultimately lead to NFTs, decreased synaptic plasticity, and neurodegeneration (Frisardi et al., 2010).

Inadequate vitamin D levels: Vitamin D₃ insufficiency has been associated with CSF Aβ levels, cognitive decline, and increased risk of AD. Patients with AD show decreased phagocytosis of soluble Aβ by macrophages, thereby delaying clearance of Aβ from the brain. Vitamin D₃ alone or combined with curcuminoids may activate macrophages to phagocytize Aβ, increasing its clearance in AD patients (Chakrabarti et al., 2015; Masoumi et al., 2009).

Increased proinflammatory cytokines: AD patients’ brains evidence inflammation activated by microglial release of proinflammatory cytokines. Moreover, increased proinflammatory cytokine levels might promote the phosphorylation of tau or production of Aβ, which contribute to the AD neurodegeneration process (Chakrabarti et al., 2015).

Organophosphates and Pesticides

Pesticide chemicals are used across the country, with the greatest usage in the midwestern states (United States Department of the Interior, 2007). A pertinent clinical issue is that in rural, developing countries, organophosphate self-poisoning claims approximately 200,000 lives each year. Unintentional poisoning has a lesser case fatality of about 15%, but continues to be problematic due to difficulties in medical management (Eddleston et al., 2008).

Wernicke’s Encephalopathy

Neuropsychiatric symptoms appear when levels of thiamine are reduced below 20% of normal limits (Spector & Johanson, 2007).

WE is reported to average 1.3% of consecutive autopsy studies (Galvin et al., 2010).

Among alcoholics, WE is estimated to occur in 9.3% of consecutive autopsy studies (Galvin et al., 2010).

In nonalcoholic patients, the most prevalent contributing factor to the development of WE is digestive abnormalities of various etiologies (e.g., due to treatment of cancer, gastrointestinal surgery, hyperemesis gravidarum, starvation/fasting, gastrointestinal tract disease, AIDS, and malnutrition) (Galvin et al., 2010).

Incidence is higher in developing countries due to higher prevalence of poor nutrition (Neki, 2015).

Toxic Metabolic Encephalopathy

Metabolic encephalopathies are chemical disorders that adversely impact consciousness, cognition and alertness; they are primarily attributable to systemic septic, toxic, or metabolic derangements, but not structural lesions (Krishnan, Leung, & Caplan, 2014; McCandless, 2009; Young & DeRubeis, 1998).

Lead Poisoning

The etiology of lead poisoning is artificial. Lead ingestion can occur through inhalation of dust and particulate matter (e.g., leaded gasoline, phased out in the United States after 1986), orally (lead in plumbing of older homes), in the canning process (eliminated in the United States in 1995), as leaded glazes (in older pottery pieces, etc.), or through the skin (e.g., lead dust in older homes with lead paint, leaded gas). For children, environmental factors are predominant, whereas for adults, the workplace is the more likely source of exposure (Mason et al., 2014). Developing fetuses are at risk beyond external environmental exposure, as lead stored over the lifetime in the maternal bone can cross the placenta, affecting the fetus (Rothenberg et al., 1994). The impact of lead poisoning is greater on children than on adults (Bhullar et al., 2015) due to the impact of developmental processes.

EPIDEMIOLOGY

Chronic Hepatic Encephalopathy

CHE is diagnosable in 60% to 80% of individuals with cirrhosis (Bajaj & Mullen, 2010). CHE is considered a preclinical stage of Overt Hepatic Encephalopathy (Bajaj & Mullen, 2010).

Uremic Encephalopathy

As UE may present in any patient with renal disease, prevalence is difficult to establish. The extent of the problem is evidenced from the perspective that an estimated 1.3 patients per 10,000 develop end-stage renal disease (ESRD). The overall incidence of ESRD is experiencing the fastest growth in patients over 65 and is four times greater in African Americans than in Whites, although men and women are equally affected (Bucurescu, 2014).

Hyperhomocysteinemia and Alzheimer’s Disease

A number of studies have demonstrated HHcy in Alzheimer’s patients (Sachdev, 2005).

Various studies have reported a positive correlation between Hcy levels and AD symptom severity, as well as rate of disease progression (McCaddon, 2006).

In a study of individuals without AD (n = 1,092) followed for 8 or more years, a 5 µmol/L increase in Hcy from baseline levels elevated the risk of developing AD by 40% (Seshadri et al., 2002).

The importance of the link between HHcy and AD is based on the fact that AD is the leading cause of neurodegenerative disease, with over 26 million people affected worldwide (Cummings, 2004) and the prevalence of AD expected to exceed 100 million by 2050 (Brookmeyer, Johnson, Ziegler-Graham, & Arrighi, 2007). HHcy is observed in 5% to 12% of the general population. Individuals with alcoholism, chronic kidney disease, and inadequate vitamin intake have a higher incidence (Davis, 2014). Despite associations between HHcy and cognitive disorders, the clinical benefit of Hcy reduction has yet to translate into palpable gains (Maron, & Loscalzo, 2009), with some theorizing that there may be methodological problems in the research and/or application (Andrieu et al., 2009).

Metabolic Risk Factors of Sporadic Alzheimer’s Disease

An estimated 5.2 million older Americans have AD, the majority of whom are women.

AD is the sixth leading cause of all deaths in the United States.

Older African Americans are twice as likely to develop AD as older European Americans.

Organophosphates and Pesticides

Statistics show that as many as 25 million U.S. workers are at risk for severe intoxication by pesticide (Miller, 2004) and that merely residing in or near a place where pesticides are used appears to have health effects (Eckerman et al., 2007).

Wernicke’s Encephalopathy

WE is found in 1.3% of consecutive autopsy studies (Galvin et al., 2010).

Alcoholics: WE occurs in approximately 9.3% of consecutive autopsy (Galvin et al., 2010).

Incidence is higher in developing countries due to poor nutrition (Neki, 2015).

Toxic Metabolic Encephalopathy

The incidence of delirium has been estimated to be between 5% and 40% for hospitalized patients in general, and between 11% and 80% for critically ill patients (Varelas & Graffagnino, 2013).

Lead Poisoning

National Health and Nutrition Examination Survey estimated blood lead levels of greater than 10 µg/dL among U.S. children (1988–1991) and prevalence at 8.6% but dropping to 1.4% during 1999–2004 (Mason et al., 2014). Lead poisoning is still considered a common health threat in developing countries (Bhullar et al., 2015).

A 2015 review of the literature by White, Bonilha, and Ellis (2015) found the incidence of blood lead levels to be highest among African American, followed by Mexican American, and lowest in White children under the age of 6 years.

In adults, higher lead levels are associated with individuals working in industrial settings (e.g., battery plants), in contrast to children who are exposed to lead in the immediate home environment (e.g., lead paint and in the soil) (Mason et al., 2014).