Mercurial erethism

Erethism also known as mercurial erethism, mad hatter disease or mad hatter syndrome, is a neurological disorder which affects the whole central nervous system, as well as a symptom complex, derived from mercury poisoning. Erethism symptoms include anxiety, irritability, mania, sleep disturbance, depression, and cognitive deficits. Visual disturbance, hearing loss, paresthesias, and tremor may also be present. Mercurial erethism is characterized by behavioral and personality changes such as extreme shyness, excitability, loss of memory and insomnia ¹. Mercurial erethism traditionally is seen in the chronic phase of the inorganic mercury toxicity. Recently, the effects of mercury exposure at levels around 0.05 mg/m³ or lower have been of concern and may include minor renal tubular damage, increased complaints of tiredness, memory disturbance and other symptoms, subclinical finger tremor, abnormal EEG by computerized analysis and impaired performance in neurobehavioral or neuropsychological tests ¹. Abnormal gait, dysarthria, ataxia, deafness and constriction of the visual field are typical of the symptoms of methylmercury poisoning observed in Minamata Bay Japan and Iraqi outbreaks, as well as in occupational methylmercury poisoning cases ¹. Furthermore, an infant born to a mother with excessive methylmercury consumption showed various neurological disturbances and delayed development ¹.

Mercury in any form is poisonous, with mercury toxicity most commonly affecting the neurologic, gastrointestinal and renal organ systems. Poisoning can result from mercury vapor inhalation, mercury ingestion, mercury injection, and absorption of mercury through the skin ².

Mercury has 3 forms: (1) elemental mercury, (2) inorganic salts, and (3) organic compounds. Perhaps the most deadly form of mercury is methylmercury. Only 2–10% of the ingested mercury is absorbed from the gut, and ingested elemental mercury is not absorbed at all; however, 90% of any methylmercury ingested is absorbed into the bloodstream from the gastrointestinal tract ².

Mercury is methylated in the environment ³, whether the origin is natural or man-made. Methylmercury is considered to be formed primarily via bacterial activity. Thus formed, methylmercury enters the aquatic food chain to become the predominant dietary source of mercury in humans ¹. The highest levels of methylmercury are found in predatory fish and sea mammals. Therefore, fish-eating populations are exposed to methylmercury ⁴.

Blood and urine are common samples by which to assess occupational mercury exposure, whereas hair is considered the best indicator for environmental exposure to methylmercury.

Organic mercury compounds, specifically methylmercury, are concentrated in the food chain. Fish from contaminated waters are the most common culprits. Industrial mercury pollution is often in the inorganic form, but aquatic organisms and vegetation in waterways such as rivers, lakes, and bays convert it to deadly methylmercury. Fish eat contaminated vegetation, and the mercury becomes biomagnified in the fish. Fish protein binds more than 90% of the consumed methylmercury so tightly that even the most vigorous cooking methods (eg, deep-frying, boiling, baking, pan-frying) cannot remove it.

For centuries, mercury was an essential part of many different medicines, such as diuretics, antibacterial agents, antiseptics, and laxatives. In the late 18th century, antisyphilitic agents contained mercury. It was during the 1800s that the phrase “mad as a hatter” was coined, owing to the effects of chronic mercury exposure in the hat-making industry, where the metal was used in the manufacturing process.

In 1889, Charcot ⁵, in his Clinical Lectures on Diseases of the Nervous System, attributed some rapid oscillatory tremors to mercury exposure.

In Wilson’s classic textbook of neurology ⁶, published in 1940, Wilson concurred with Charcot’s attribution of tremors to mercury poisoning, but also described mercury-induced cognitive impairments, such as inattention, excitement, and hallucinosis.

In 1961, researchers in Japan correlated elevated urinary mercury levels with the features of the previously mysterious Minamata disease. Before the cause of Minamata disease was discovered, it plagued the residents around Minamata Bay in Japan with tremors, sensory loss, ataxia, and visual field constriction ⁷.

Minamata disease is an example of organic methylmercury toxicity. In Minamata Bay Japan, a factory discharged inorganic mercury into the water. The mercury was methylated by bacteria and subsequently ingested by fish. Local villagers ate the fish and began to exhibit signs of neurologic damage, such as visual loss, extremity numbness, hearing loss, and ataxia. Babies exposed to the methylmercury in utero were the most severely affected. Furthermore, because mercury was also discovered in the breast milk of the mothers, the babies’ exposure continued after birth ⁸.

On January 19, 2013, The Minamata Convention on Mercury was agreed upon at the fifth session of the Intergovernmental Negotiating Committee in Geneva, Switzerland. It is a global treaty to protect human health and the environment from the adverse effects of mercury. The major highlights of the convention included a ban on new mercury mines, the phase-out of existing ones, control measures on air emissions, and the international regulation of the informal sector for artisanal and small-scale gold mining ⁸.

Mercury is still found in many industries, including in battery, thermometer, and barometer manufacturing. Mercury can also be found in fungicides used in the agricultural industry. Before 1990, paints contained mercury as an antimildew agent. In medicine, mercury is used in dental amalgams and various antiseptic agents. (See Etiology and Prognosis.)

Mercury may also be contained in some cosmetics, such as skin-lightening products. One study measured international skin-lightening products for their mercury content, focusing on products available to US consumers either online or in stores. The products were screened for mercury content using a portable x-ray fluorescence spectrometer. Of the 549 products tested, 6% contained mercury levels above 1000 ppm, and 45% contained mercury levels that exceeded 10,000 ppm. Of lightening products purchased in the United States, 3.3% were found to contain mercury in excess of 1000 ppm. According to the authors, the Food and Drug Administration (FDA) limits the amount of mercury in most cosmetic products to 1 ppm ⁹.

Erethism symptoms

Erethism symptoms include anxiety, irritability, mania, sleep disturbance, depression, and cognitive deficits. Visual disturbance, hearing loss, paresthesias, and tremor may also be present. Mercurial erethism is characterized by behavioral and personality changes such as extreme shyness, excitability, loss of memory and insomnia ¹. Recently, the effects of mercury exposure at levels around 0.05 mg/m³ or lower have been of concern and may include minor renal tubular damage, increased complaints of tiredness, memory disturbance and other symptoms, subclinical finger tremor, abnormal EEG by computerized analysis and impaired performance in neurobehavioral or neuropsychological tests ¹. Abnormal gait, dysarthria, ataxia, deafness and constriction of the visual field are typical of the symptoms of methylmercury poisoning observed in Minamata Bay Japan and Iraqi outbreaks, as well as in occupational methylmercury poisoning cases ¹. Furthermore, an infant born to a mother with excessive methylmercury consumption showed various neurological disturbances and delayed development ¹.

Effects of mercury vapor exposure

The signs and symptoms observed in mercury vapor poisoning differ depending on the level and duration of exposure. When exposure is extremely heavy (approximately 5–10mg/m³ or may be higher) such as direct inhalation of mercury vapor generated from heating metallic mercury, erosive bronchitis and bronchiolitis will occur in a few hours. Interstitial pneumonitis will then develop followed by respiratory distress. Excitability and tremors, indicating the central nervous system has been affected, may also be seen. If the amount of mercury inhaled is large enough, renal failure will develop. Such an accidental exposure took place recently in Japan at a chemical factory that was producing sulfuric acid ¹⁰. Workers replaced pipes of a tubular heat exchange apparatus using gas burners. Since sludge inside the pipes contained mercury, mercury vapor was generated during the operation. The workers were exposed to mercury vapor and became ill, and tragically a few died of respiratory distress associated with renal failure. Moderate and repeated exposure (lower than a few mg/m³, but higher than 0.05 mg/m³) causes classical mercury poisoning, which is characterized by a triad of signs, namely,tremor, erethism and gingivitis. Mercurial erethism, which is characterized by behavioral and personality changes such as extreme shyness, excitability, loss of memory, and insomnia are also observed. Gingivitis and excessive salivation are the most common signs. Lower and long lasting exposure causes micro-mercurialism, which is characterized by weakness, fatigue, anorexia, loss of weight, and disturbances in the gastrointestinal tract. Recently, the effects of much lighter mercury vapor exposure [around the previous threshold limit value (TLV) (0.05 mg/m³)] have been investigated, with the following results:

1. Minor renal tubular effects indicated by increased urinary excretion of β-galactosidase ¹¹ and N-acetyl-β-glucosaminidase (NAG) ¹² have been noted.
2. Increased complaints of tiredness, memory disturbanceand other symptoms have been reported in self-administered questionnaires ¹³
3. Subclinical finger tremor has been observed using apparatus analyses ¹⁴
4. Slower and attenuation of power spectrum of EEG ¹⁵
5. Impaired performance in neurobehavioral or neuropsychological tests ¹⁶

Residual or remote effects of mercury vapor Inhalation

More recently, residual effects due to previous exposure have become a concern. Workers with a peak urinary mercury concentration higher than 0.6 mg/L have shown neurobehavioral disturbances 20 to 35 years post-exposure ¹⁷. Among ex-mercury miners in Japan, neurobehavioral disorders related to previous exposure that ceased more than 17 years ago have been reported ¹⁸. Besides neurobehavioral disturbances, an increase in lymphocyte micronuclei stimulated by phytohemagglutinin was also observed ¹⁹. The increase positively correlated with indices of previous exposure. Clearly the effects of mercury vapor exposure last long after cessation of exposure, although typical symptoms and signs, such as tremor, gingivitis and salivation, usually disappear quickly. Mechanisms of long-lasting or remote effects, however, have not been investigated. There are several possible explanations: The first is that the damage caused by mercury vapor exposure remains for a long period of time. The second is that mercury remains in the body where it continues to cause adverse effects. The third is that previous exposure some how stimulates aging, which causes poorer neurobehavioral performance. More complex explanations and combinations of these possibilities are of course inconceivable.

Effects of methylmercury exposure

Previous experiences and animal experiments have shown that central nervous system functions are affected most by methylmercury exposure as opposed to the other forms of mercury. In 1940, Hunter, Bomford and Russel ²⁰ reported four cases of methylmercury poisoning in a factory where fungicidal dusts were manufactured without the use of an enclosed apparatus. The symptoms were severe generalized ataxia, dysarthria and constriction of the visual field. They noted that the characteristic symptoms of mercury vapor poisoning, with the exception of tremors, were not observed. One of the victims suffered from symptoms (mainly ataxia) for 15 years after exposure had ceased. At patient necropsy, generalized ataxia was referable to cerebellar cortical atrophy, selectively involving the granule-cell layer of the neocerebellum ²¹. The concentric constriction of the visual fields was correlated with bilateral cortical atrophy around the calcarine fissures. This was reported in 1954 and later methylmercury poisoning was referred to as Hunter-Russel syndrome. In the Minamata disaster in Japan, abnormal gait, dysarthria, ataxia, deafness and constriction of the visual field were the main symptoms. Emotional lability in the form of euphoria or depression was also common. Serious cases displayed states of mental confusion, drowsiness and stupor ²². Sometimes, however, the victims were restless and prone to shouting, which was often followed by coma. In the infant cases following fetal exposure, a cerebral palsy like syndrome was observed ²³. Examination of these children revealed the following signs and symptoms at high frequency:

• mental retardation,
• cerebellar ataxia,
• primitive reflex and dysarthria,
• seizure, and pyramidal signs.

Sensory disturbance, constriction of the visual fields and hearing impairment could not be assessed due to the serious conditions of the patients.

Effects of in utero methylmercury exposure

Since fetuses are much more sensitive to methylmercury than adults, as shown in the outbreaks in Minamata Japan and Iraq, the possible effects of in utero exposure to methylmercury have been examined in several places such as New Zealand, the Seychelles and the Faeroe Islands. A group of Iraqi mother and infant pairs were examined for the delay in developmental milestones such as walking and talking and the mothers’ exposure to mercury, with the hair mercury content of each mother analyzed to determine the peak mercury concentration during pregnancy. Statistical analysis established a dose-response relationship between the peak mercury concentration during pregnancy and whether first walking or talking was observed or not at the age of 18 or 24 months ²⁴. Based on this dose-response relationship, World Health Organization (WHO) ²⁵ claimed that “A prudent interpretation of the Iraqi data implies that a 5% risk may be associated with the peak mercury level of 10–20 μ/g in maternal hair. Epidemiological prospective studies with more sophisticated examination methods have been carried outsince the mid 1980s.

A study performed in New Zealand investigated the development of children who had prenatal exposure to methylmercury by mothers’ consumption of fish meals during pregnancy ²⁶. The children were tested at the age of 4 using the Denver Developmental Screen Test (DDST), which is a standardized test of a child’s mental development consisting of four major function sectors: gross motor, finemotor, language and personal-social. A developmental delay in an individual item is determined when the child has failed in his/her response and at least 90% of children can pass this item at a younger age. The prevalence for developmental delay was 52% in children whose mothers had been exposed to high levels of mercury and 17% in the reference group. In a follow-up study at the age of 6, each child was tested with the Test of Language Development (TOLD), the Wechsler Intelligence Scale for Children and the McCarthy Scale of Children’s Abilities ²⁶. A principal finding was that high prenatal methylmercury exposure decreased performance in the tests, but contributed only little to the variation in test results, with ethnic background and social class having greater influence.

In the Seychelles Islands, the developmental effects of low level methylmercury exposure in utero from consumption of marine fish by mothers have also been studied ²⁷. An association between in utero mercury exposure was found for Denver Developmental Screen Test Revised (DDST-R) abnormal plus questionable scores combined ²⁸. A subset of this group of children were administered the McCarthy Scales of Children’s Abilities, the Preschool Language Scale, and the Letter-Word Recognition and Applied Problems subtests of the Woodcock-Johnson (W-J) Tests of Achievement that were appropriate to the children’s age. Mercury exposure (measured as maternal hair mercury concentration) was negatively associated with four endpoints: The McCarthy General Cognitive Index and Perceptual Performance subscale; and the Preschool Language Scale Total Language and Auditory Comprehension subscale. When statistically determined outliers and points considered to be influential were removed from the analyses, statistical significance of the association remained only for auditory comprehension.

The main study, which was designed to be prospective and involved 779 mother-child pairs, followed ²⁹. This study involved evaluation of children at 6.5, 19, 26 and 66 months of age. Age-appropriate tests administered included the following: Infantest (or Fagan’s test of visual recognition memory), Bayley Scales of Infant Development (BSID), McCarthy Scales of Children’s Abilities, the Preschool Language Scale and the DDST (6.5 months only). No association with maternal hair mercury was found for any of six endpoints in the children tested at six months. No effects of mercury exposure were seen in the outcome of five test endpoints at 19 months. Investigation at 66 months did not reveal the deviation associated with in utero mercury exposure for the following tests: McCarthy Scales of Children’s Abilities in General Cognitive Index, Preschool Language Scale, Letter-Word Recognition of W-J Tests of Achievement, Applied Problems of W-J Tests of Achievement, Bender Gestalt test and Total T score from the Child Behavior Checklist. The analysis was adjusted for possible confounding factors including birth weight, the rank of birth, sex, medical records of the infants, age of the mother, alcohol consumption and smoking habits during pregnancy, and socioeconomic status.

The overall conclusion of the studies published to date is that it is yet unclear whether an association exists between low level mercury exposure of the mother and neurologic deficits in the child. The authors cautioned in several papers that subtle neurologic and neurobehavioral effects are more likely to be detected in older rather than younger children. The overall conclusion of the authors was that their results require careful interpretation, and that an association between relatively low level mercury exposure in utero and neurologicdeficits has not been conclusively demonstrated ²⁷.

Another large study was initiated in the Faeroe Islands in 1986 ³⁰. Increased mercury exposure was largely attributed to the eating of pilot whale ³¹. The subjects consisted of a group of 917 (of an initial cohort of 1022) children. They were evaluated for their neurophysiological and neuropsychological performances at about 7 years of age. Mercury in maternal hair and cord blood was analyzed, and a subset of cords was determined for polychlorinated biphenyls (PCBs) ³². At seven years children received an examination including a functional neurological examination which emphasized motor coordination and perceptual-motor performance ³³. Neurophysiological tests included the following: pattern-reversal visual evoked potentials; brainstem auditory evoked potentials; and postural sway. Neuropsychological tests included the Neurobehavioral Evaluation System (NES); Tactual Performance Test; Wechsler Intelligence Scale for Children-revised; Bender Visual Motor Gestalt Test; Boston Naming Test; California Verbal Learning Test; Nonverbal Analogue Profile of Mood States.

Although the neurophysiological tests showed no indication of mercury-associated dysfunction, significant negative associations were seen on several neuropsychological tests. Even with inclusion of covariates with uncertain influence on these tests results, multiple regression analysis indicated that 9/20 measures showed mercury related decrements. The authors concluded that in utero exposure to methylmercury affects several domains of cerebral function ³².

The results of these studies are controversial, especially when comparing those of Seychelles and Faeroe Islands. In both studies, doses were principally indicated by mothers’ hair mercury concentration and the difference between both the doses is small. The study designs and test-batteries were similar but not identical. The main difference between the two studies was the source of methylmercury exposure; in the Seychelles by consumption of ocean fish and in the Faeroe Islands blubber (pilot whale fat). One explanation is that contamination by polychlorinated biphenyls (PCBs) and possibly dioxins may confound the results of the Faeroe island study.

Mercurial erethism diagnosis

History and physical examination findings consistent with mercury poisoning are helpful, but blood, urine, and (sometimes) tissue analyses are required to confirm the diagnosis of mercury intoxication (although exact toxicity levels remain undefined).

Correlations have been found between signs, symptoms, and electrophysiologic studies of subjects exposed to mercury with various statistical extrapolations of measures of exposure, such as duration of exposure, peak urinary mercury levels, and estimated cumulative mercury dose.

Whole blood mercury levels are usually less than 2 mcg/dL in unexposed individuals, although individuals with a high dietary fish intake may be an exception.

Obtain a complete blood count (CBC) and serum chemistries to assess possible anemia secondary to GI hemorrhage, to determine if renal failure is present, and to rule out electrolytic abnormalities.

In most laboratories, mercury quantification is not performed on a routine basis; therefore, contact the laboratory to verify the specific collection and precautionary protocols before blood and urinary samples are collected. Reserve neuroimaging and electrophysiologic testing for selected cases. Consider pregnancy tests in women of childbearing age.

Mercury Level Analysis

In the United States, based on the 2003 National Health and Nutrition Examination Survey (NHANES) data, urinary mercury levels of 5 mcg/L and blood mercury levels of 7.1 mcg/L encompassed 95% of the sample. These have been recommended as medically credible comparison levels ³⁴.

Hair

While blood levels are useful for more acute exposures, long-term exposures are best reflected in hair mercury measurements. Hair has high sulfhydryl content. Mercury forms covalent bonds with sulfur and, therefore, can be found in abundance in hair samples.

Because of environmental contamination, hair measurements have been problematic with elemental mercury exposure, but methylmercury hair measurements are considered accurate. [75] A hair value of 1.2 mcg/g encompassed 90% of the NHANES sample ³⁴.

Interestingly, investigators of Minamata disease identified chronic forms of the disease in which hair mercury levels were not elevated. A delayed neurotoxic effect, with symptoms emerging after age-induced neuronal loss, was hypothesized ⁷. Similarly, some researchers have been unable to correlate the fluctuations of mercury blood levels with signs and symptoms of toxicity in mercury vapor exposure ³⁵.

Blood

Methylmercury concentrates in erythrocytes; therefore, mercury levels in blood remain high in acute toxicity. When ingested by humans, methylmercury is easily absorbed and retained by the body; it has a half-life in blood of about 44 days, which makes blood tests useful measures of acute exposure ³⁶.

The blood level correlation with chronic methylmercury toxicity is more variable. Methylmercury exhibits a blood-to-plasma ratio of up to 20:1, a characteristic of organic mercury. This higher ratio may be useful in determining if the patient was exposed to organic or inorganic mercurials. Aryl mercury compounds accumulate in RBCs but are metabolized to inorganic mercury more rapidly, thus, demonstrating lower blood-to-plasma ratios than those observed with methylmercury exposures ³⁷.

Following high exposure to inorganic mercury salts, the blood-to-plasma ratio ranges from a high of 2:1 to 1:1. Paraesthesias are expected if blood mercury levels are higher than 20 mcg/dL.

Inorganic mercury redistributes to other body tissue; thus, its levels in the blood are accurate only after an acute ingestion. In general, blood levels of mercury are helpful for recent exposures and for determining if the toxicity is secondary to organic or inorganic mercury, but they are not useful for a guide to therapy.

Urine

Urinary mercury levels are typically less than 10-20 mcg/L. Excretion of mercury in urine is a good indicator of inorganic and elemental mercury exposure but is unreliable for organic mercury (methylmercury) because this is eliminated mostly in the feces. In cases of chronic mercury toxicity, the urinary mercury measurement may be falsely low ³⁸.

No absolute correlation exists between urinary mercury levels and the onset of symptoms; however, levels higher than 300 mcg/L are associated with overt symptoms. Mercury levels in the urine also can be used to gauge the efficacy of chelation therapy, since chelated mercury is excreted primarily through the kidneys. For workers chronically exposed to mercury compounds, urinary excretion with mercury levels higher than 50 mcg/L is associated with an increased frequency of tremor.

Short-chained alkyl mercury compounds are excreted predominantly by the bile, rendering urinary measurements of these invalid ³⁸.

The position of the American College of Medical Toxicology (ACMT) does not support routine practice of postchallenge urinary metal testing, due to a lack of demonstrable benefits. This practice may be harmful if applied routinely in the assessment and treatment of patients suspected of having metal poisoning ³⁹.

Toenail

Toenail mercury has also been used as a measure of long-term mercury exposure, with mean levels of 0.25-0.45 mcg/g among Western samples. Toenail mercury has been correlated with fish and shellfish consumption ⁴⁰.

Cerebrospinal fluid

Cerebrospinal fluid (CSF) mercury concentrations have been measured with mass spectroscopy, and normal values vary widely. Nevertheless, increased CSF mercury levels have been found in workers with ongoing exposure to mercury vapors, but these CSF levels, unlike blood levels, normalize several months after such exposures have abated ⁴¹.

Exposure markers for methylmercury

Blood and scalp hair are the primary indicators used to assess methylmercury exposure. Methylmercury freely distributes throughout your body, and thus blood is a good indicator medium for estimating methylmercury exposure. Blood levels may not necessarily reflect mercury intake overtime though, as levels fluctuate with dietary intake ⁴². Blood hematocrit and mercury concentration may be measured in both whole blood and plasma/serum, allowing the red blood cell to plasma mercury ratio to be determined, and interference from exposure to elemental or inorganic mercury to be estimated. Scalp hair is also a good indicator for estimating methylmercury exposure ⁴³. Methylmercury is incorporated into scalp hair at the hair follicle in proportion to its content in blood. The hair-to-blood ratio in humans has been estimated as approximately 250–300: 1 expressed as microgram Hg/g hair to mg Hg/L blood. However, some difficulties in measurement do arise, such as, inter-individual variation in body burden, differences in hair growth rates and variations in fresh and salt water fish intake, led to varying estimates ⁴⁴. Methylmercury is stable once incorporated into hair, and therefore the mercury concentration in hair gives a longitudinal history of blood methylmercury levels ⁴³. Analysis of hair mercury levels may be confounded by adsorption of mercury vapor onto the hair strands ⁴⁵. However, inorganic mercury incorporation into hair is negligible. Artificial hair-waving decrease mercury levels in hair due to breaking down methylmercury into inorganicmercury ⁴⁶.

Exposure markers for elemental mercury

In workers chronically exposed to mercury vapor, a good correlation has been observed between intensity of exposure and blood mercury concentration at the end of a work shift ⁴⁷. Mercury in the blood peaks rapidly, however, and decreases with an initial half-life of approximately two to four days ⁴⁸. Thus, evaluation of blood mercury is of limited value if a substantial amount of time has elapsed since exposure. Without selective determination for organic and inorganic mercury (and this is usually the case), dietary methylmercury also contributes substantially to the amount of mercury measured in blood at low levels of elemental mercury exposure, limiting the sensitivity of this biomarker. For most occupational exposure events, urinary mercury has been used to estimate exposure. The toxicokinetics of mercury in urine is much slower than in blood: urinary mercury peaks approximately 2–3 weeks after exposure and decreases at a half-life of 40–60 days for short-term exposures and 90 days for long-term exposures ⁴⁹. Therefore, urine is a more appropriate indicator for longer exposures than blood. Moreover, little dietary methylmercury is excreted in the urine, rendering the contribution of ingested methylmercury less significant. Although good correlation has been observed between urinary mercury levels and air levels of mercury vapor, such correlation was obtained after adjusting data for creatinine or specific gravity and after standardizing the amount of time elapsed after exposure ⁴⁷, as considerable intra- and inter-individual variability hasbeen observed in the urinary excretion rate ⁵⁰. Exhaled air has been suggested as a possible biomarker of exposure to elemental mercury vapor because a portion of absorbed mercury vapor is excreted via the lungs. However, at low levels of exposure, mercury vapor released from dental amalgam may contribute substantially to the measured amount of mercury ⁵¹. The amount of exhaled mercury is surprisingly high after ingestion of alcoholic beverages ⁵², most likely because mercury is repeatedly oxidized and reduced in the body ⁵³ and ethanol is believed to inhibit the activity of catalase, the principal oxidizing pathway. Consequently, this inhibition leads to relatively more reduction of ionic mercury and to an increase in elemental mercury in tissue and blood stream. Mercury vapor thus generated is exhaled via the lungs ⁵⁴. A pilot study clearly showed that exhaled mercury was increased by ingestion of ethanol among the ex-mercury workers but quantitative estimation was not performed.

Imaging studies

Radiography

Obtain a flat plate radiograph of the abdomen to visualize ingested elemental mercury, which appears radiopaque.

MRI

Neuroimaging is probably more helpful in excluding other diagnoses than in ruling in mercury toxicity. Nonetheless, magnetic resonance imaging (MRI) in cases of Minamata disease confirms the clinical and pathologic findings. Marked atrophy of the calcarine and parietal cortices, as well as the cerebellar folia, has been visualized ⁵⁵.

MRI findings in one patient with inorganic mercury toxicity revealed mild cortical atrophy and T2 hyperintensities in the frontal and subcortical regions ⁵⁶. Additionally, a 4-year-old with inorganic mercury poisoning developed transient fluid-attenuated inversion recovery (FLAIR) hyperintensities in cortical white matter during chelation therapy ⁵⁷.

Single-photon emission computed tomography (SPECT)

Single-photon emission computed tomography (SPECT) demonstrated right cingulate hypermetabolism in a 38-year-old man with emotional lability and inattention following exposure to inorganic mercury ⁵⁸.

Electrophysiology

Electrophysiologic studies have demonstrated sensorimotor neuropathy, typically axonal, in some workers exposed to elemental mercury or mercury vapors. Workers with remote exposures, however, have exhibited only minimal conduction velocity slowing ⁵⁹. Abnormalities have also been documented in visual-evoked potential studies among workers exposed to mercury vapors ³⁵.

In the Faroe Islands, intrauterine methylmercury exposure (as determined by maternal hair and cord blood measures) was positively correlated with prolonged brainstem evoked potentials (III and V latency peaks) 14 years after initial exposure ⁶⁰.

Mercurial erethism treatment

Treatment of mercury toxicity consists of removal of the patient from the source of exposure, supportive care, and chelation therapy. Patients with cognitive and emotional complications may require psychotropic medications.

Although laboratory studies are important, acute treatment in critical situations should be based on the patient’s history and clinical presentation, without waiting for laboratory confirmation.

Little information is available about the treatment of mercury-induced tremulousness, but initiation of empiric treatment for patients who are functionally impaired with this complication would be reasonable.

Once the neurologic consequences of Minamata disease appear, they are, unfortunately, irreversible. The goal of medical management in Minamata disease is to reduce the total body burden of mercury and minimize further damage.

Prehospital care

Prehospital management includes gathering information on the time, type, and mode of mercury exposure, as well as the following:

• Initial assessment – Airway, breathing, and circulation (ABCs)
• Oxygen
• Intravenous (IV) access
• Removal from the contaminated area

Gastric lavage is recommended for organic ingestion, especially if the compound is observed on an abdominal radiograph series.

Activated charcoal is indicated for gastrointestinal decontamination because it binds inorganic and organic mercury compounds to some extent.

Whole bowel irrigation may be used until rectal effluent is clear and void of any radiopaque material. However, its effectiveness in decreasing the gastrointestinal transit time of elemental mercury is doubtful because of the high density of elemental mercury and the low density of the whole bowel irrigant solutions. Likewise, whole bowel irrigation has no adsorptive effect on any type of mercury within the gastrointestinal tract.

Use chelating agents if the patient is symptomatic, if systemic absorption is anticipated, or if increased blood or urinary mercury levels are present. Chelating agents contain thiol groups, which compete with endogenous sulfhydryl groups.

Hemodialysis is used in severe cases of toxicity when renal function has declined. The ability of regular hemodialysis to filter out mercury is limited because of mercury’s mode of distribution among erythrocytes and plasma. However, hemodialysis with L-cysteine compound as a chelator has been successful.

Older literature indicates that neostigmine may help motor function in methylmercury toxicity as this toxicity may lead to acetylcholine deficiency ⁶¹.

Surgical care

Surgery does not have a role in the treatment of Minamata disease; however, in other forms of mercury exposure, surgical intervention is sometimes warranted. Surgery occasionally has been employed to remove ingested mercury that has become lodged in the intestine or colon ⁶².

Surgical removal of subcutaneous deposits of self-injected elemental mercury has also been described ⁶³. Early, definitive surgical excisions of the mercury deposits resulted in good outcomes with minimal toxicity.

Inpatient care

All patients in unstable condition should be admitted to an intensive care unit (ICU). After the patient is admitted, supportive measures, decontamination, and careful monitoring should be continued. In cases of inorganic mercuric salt ingestion, carefully monitor the patient’s renal function.

Serious clinical manifestations due to mercury exposure should be managed in a tertiary care facility by physicians experienced with toxicologic emergencies.

Consultations

Consult with the regional poison control center or a medical toxicologist (certified through the American Board of Medical Toxicology and/or the American Board of Emergency Medicine) for additional information and patient care recommendations.

Chelation

Because mercury binds to the body’s ubiquitous cellular sulfhydryl groups, chelating agents should be administered early in treatment.

Chelating agents contain thiol groups, which bind to mercury. For acute, inorganic toxicity, dimercaprol (British antilewisite [BAL]) has traditionally been recommended, but oral agents are gaining prominence. Chelation with 2,3-dimercaptosuccinic acid (DMSA or succimer) has been shown to result in increased mercury excretion, compared with N -acetyl-D,L-penicillamine, in adults with acute mercury vapor exposure. DMSA is generally well tolerated and has also demonstrated efficacy in children exposed to mercury. Chelation treatment may be administered in the outpatient setting with an oral chelator, such as DMSA ⁶⁴.

Polythiol is a nonabsorbable resin that can theoretically help in facilitating the removal of methylmercury (short chain alkyl organic mercury), which is then excreted in the bile after enterohepatic circulation.

Exchange transfusion has been used as a treatment of last resort. Because mercury-chelating agent complexes are large molecules, they may fail to be filtered out by standard hemodialysis membranes, rendering conventional hemodialysis ineffective ⁶⁵.

Despite the increased excretion of mercury with chelating agents, chelation removes only a small portion of the body’s mercury stores. Furthermore, the efficacy of chelating agents in treating neurologic complications has not been established; however, among patients with amalgam fillings, placebo responses to chelation treatment have been reported ⁶⁶.

Finally, caution is warranted, however, as some physicians have documented initial clinical deterioration during chelation therapy ⁵⁷.

Follow-up

Determine follow-up care on a case-by-case basis. Obtain laboratory measurements of toxicity in patients with possible continued sources of exposure.

Activity

Employment and driving should be restricted if patients have significant emotional or cognitive problems.

References

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