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Neurological assessment of coma (pdf)
David E Bateman
J Neurol Neurosurg Psychiatry
2001; 71(suppl I); i13Ði17
 
 
 
 
 

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13 mi 2004
The New Engl J Med
1998; 338; 1672-1675
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 Delayed cerebellar disease and death after accidental exposure to dimethylmercury
Nierenberg DW et al
Dep Pharmacology and medicine, Dartmouth-Hitchcock Medical center, Lebanon, GB

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Ingestion of fish or grain contaminated with methylmercury resulted in epidemics of severe neurotoxicity and death in Japan in the 1950s and 1960s' and in Iraq in 1972. The World Health Organization and other organizations have warned of the dangers of methylmercury compounds to the environment and to scientific researchers. Dimethy1mercury may be even more dangerous than methylmercury compounds. The physical properties of dimethylmercury permit transdermal absorption, and the volatility of this liquid permits, toxic exposure through inhalation. Since dimethylmercury is lethal at a dose of approximately 400 mg of mercury (equivalent to a few drops, or about 5 mg per kilogram of body weight), it is supertoxic according to the rating in a classic toxicology textbook.
 
We report a case of accidental dimethylmercury poisoning in a chemist whose research focused on the biologic toxicity of heavy metals.Records suggest that she handled dimethylmercury on only one day, while wearing latex gloves and working under a ventilated hood designed to prevent exposure to chemical fumes. She had delayed but ultimately fatal neurotoxic effects similar to those caused by methylmercury compounds. This case illustrates the potent toxicity of dimethylmercury and the need for additional safety precautions if it is to be used in any scientific rescarch.
 
CASE REPORT
 
A 48-ycar-old chemistry professor was admitted to Dartmouth-Hitchcock Medical Center, in Lebanon, New Hampshire, on January 20, 1997, with a five-day history of progressive deterioration in balance, gait, and speech. She had lost 6.8 kg over a period of two months and had experienced several brief episodes of nausea, diarrhea, and abdominal discomfort.
 
The patient recalled that in August 1996, while transferring liquid dimethylmercury from a container to a capillary tube, she spilled several drops from the tip of the pipette onto the dorsum of her gloved hand. (A subsequent review of her dated laboratory notebooks, a history provided by a coworker, and examination of the dated materials used in the experiment later pinpointed the date as August 14, 1996.) She reported that she had cleaned up the spill and then removed her protective gloves.
 
The patient was thin but appeared healthy and was appropriately concerned about her neurologic problems. The examination showed moderate upper-extremity dysmetria, dystaxic handwriting, a widely based gait, and mild "scanning speech." The results of routine laboratory tests were normal. The results of computed tomography (CT) and magnetic resonance imaging (MRI) of the head were normal except for the incidental finding of a probable meningioma, 1 cm in diameter. The cerebrospinal fluid was clear, with a protein concentration of 42 mg per deciliter and no cells. Because of the possibility of methylmercury neurotoxicity, blood and urine samples were sent for urgent measurement of mercury content. In view of the long interval between the date of exposure to mercury and the onset of neurologic symptoms ( 154 days) as well as the rapid progression of symptoms, other causes of acute cercbellar dysfunction were considered.
 
In the ensuing days, the patient noted tingling in her fingers, brief flashes of light in both eyes, a soft background noise in both ears, and progressive difficulty with speech, walking, hearing, and vision (constricted visual fields). A preliminary laboratory report indicated that the whole-blood mercury concentration was more than 1000 µg per liter. Chelation therapy with oral succimer (10 mg per kilogram orally every eight hours) was begun on day 168 after exposure. The next day, the following laboratory values were reported: whole-blood mercury, 4000 µg pet liter (normal range 1 to 8; toxic level, >200); urinary mercury, 234 µg per liter (normal range 1 to 5; toxic level >50).
 
The patients neurologic deterioration continued, neuropsychiatric testing revealed marked deficits in all areas. Chelation therapy was initially successful, with an increase in urinary excretion of mercury from 257 µg pet 24 hours (before chelation therapy) to 39,800 µg per 24 hours. Vitamin E was added to the regimen as a potentially protective antioxidant.
 
The patient was transferred to Massachusetts General Hospital in Boston. Vitamin E and succimer were continued. An exchange transfusion reduced the imean whole-blood mercury concentration from 2230 µg per liter before the procedure to 1630 µg per liter 2 hours afterward, but reequilibration resulted in a concentration of 2070 µg per liter 16 hours later. The mercury content of bile was 30 to 99 µg per liter. Repeated CT and MRI scans of the head remained normal, with no evidence of occipital or cerebellar damage. Audiometry revealed mild-to-moderate sensorineural hearing loss. Neuro-ophthalmologic testing revealed moderately constricted concentric fields, with no evidence of papilledema. On February 6, 22 days afer the first neurologic symptoms developed (and 176 days after exposure), the patient became unresponsive to all visual, verbal, and light-touch stimuli.
 
The patient was transferred back to Dartmouth -Hitchcock Medical Center, and aggressive general support was continued, along with 21-day cycles of chelation therapy with succimer (10 µg per kilogram given orally every 12 hours). The decline in blood mercury concentrations over time is shown in Figure 1. Mercury half-lives (with chelation therapy) were 29 to 37 days. Urinary excretion of mercury declined rapidly despite ongoing chelation therapy. Analysis of a long strand of hair revealed that alter a brief lag, the mercurv content rose rapidly to almost 1100 µg per milligram (normal level, <0.26 µg per milligram potentially toxic level >50 ng per milligram) and then declined slowly, with a half-life of 74.6 days.
 
The patients neurologic status was marked by periods of spontaneous eye opening, but without awareness of or any response to visual, sound, or light-touch stimuli. The Babinski sign was equivocal, and decerebrate and decorticate posturing were absent. Painful stimuli resulted in limb withdrawal. Corneal and pupillary reflexes were sluggish but present. Spontaneous yawning, moaning, and limb movements occurred, with periods of agitation and crying, requiring large doses of chlorpromazine and lorazepam. Her condition appeared to resemble a persistent vegetative state with spontaneous episodes of agitation and crying.
 
Testing of family members, laboratory coworkers, and laboratory surfaces failed to reveal any unsuspected mercury spills or other cases of toxic blood or urinary mercury concentrations.
 
We could find only three previously reported cases of poisoning with dimethylmercury, all of which were fatal. Equally bleak outcomes have been reported in patients with severe methylMercury toxicity. In view of the dismal prognosis and after more than three months of aggressive treatment and support, the patient's advance directives were followed, and she died peacefully on june 8, 1997, 298 days after exposure.
 
At autopsy, dehydration and bronchopnemonia were noted. The cortex of the cerebral hemispheres was diffusely thinned, to 3 mm. The visual cortex around the calcarine fissure was grossly gliotic, as was the superior surface of the superior temporal gyri. The cerebellum showed diffuse atrophy of both vermal and hemispheric folia. Microscopical study showed extensive neuronal loss and gliosis bilaterally within the primary visual and auditory cortices, with milder loss of neurons and gliosis in the motor and sensory corticcs. There was widespread loss of cerebellar granular-cell neurons, Purkinje cells, and basket-cell neurons, with evidence of loss of parallel fibers in the molecular layer. Bergmann gliosis was well developed and widespread.
 
An extremely high mercury content was found in the frontal lobe and visual cortex (average value, 3.1 µg per gram, or 3100 ppb), livcr (20.1 µg per gram), and kidney cortex (34.8 µg per gram). The mercury content of the brain was approximately six times that of whole blood at the time of death and was much higher then levels in brain samples obtained at autopsy from patients not previously exposed to mercury (2 to 50 ppb).
 
DISCUSSION
 
In 1865, two laboratory assistants died several ,weeks after helping to synthesize dimethylmercury for the first time. Nearly 100 years later, another laboratory worker died after synthesizing the compound. He had a rapid downhill course very similar to that of our patient, and chelation therapy with penicillamine was without clinical benefit.
 
Several conclusions can be drawn from these case reports, the epidemics of poisoning with methylmercury compounds, and the information obtained from this case. First, even an accidental, brief exposure to dimethylmercury can be fatal. The data are consistent with a lag phase after exposure, rapid conversion of dimethylmercury to methy1mercury, rapid movement of methylmercury from blood to hair (half-life of uptake into hair, 5.6 days), and a first-order decline in the mercury content of hair (half-life, 74.6 days) that paralleled the decline in blood mercury. Qualitatively similar observations have been made in mice exposed to dimethylmercury through intravenous or inhilational routes.
 
In our patient, the rapid, monophasic, first-order increase in the mercury content of hair is consistent with either one or several episocles of exposure to dimethylmercury beginning on or about August 14, 1996, and is consistent with the evidence (reports from coworkers and information from labeled vials and laboratory notebooks) that a single accidental exposure to dimethylmercury occurred on August 14. Our findings are also consistent with earlier reports that methylmercury has a half-life of about 78 days in humans, that excretion of methylmercury is first-order in mice and humans, and that the toxicity of dimethylmercury is apparently mediated by methy1mercury metabolites in mice.
 
Second, disposable latex gloves do not provide adequate protection against dimethylmercury. Permeation tests showed that several types of disposable latex or polyvinyl chloride gloves (typically, about 0.1 min thick) had high and maximal rates of permeation by dimethylmercury within 15 seconds. In contrast, gloves designed to be chemically resistant are made of materials specifically selected for their ability to withstand chemical permeation. For example, under standard test conditions, no permeation of a flexible, plastic-laminate glove (SilverShield) was observed after four hours of exposure to dimethylmercury. This thin glove can be wom under a heavyduty outer glove (e.g., one made of neoprene) for increased protection. Our patients accidental exposure may have resulted from both transdermal absorption of the liquid (given the lack of protection provided by disposable latex gloves) and inhalation of vapors (even though the work was conducted under a fume hood).
 
Since research in animals suggests that dimethy1mercury is either promptly exhaled or converted to methylmercury metabolites that can bind to tissues we can estimate the body burden of mercury in our patient. At the time of the diagnosis, the blood concentration was 4000 µg per liter, which represents about 16.8 mg of mercury in the blood (total volume of blood, about 4.2 liters) and about 336 mg in the entire body (since only about 5 percent of an absorbed dose of methylmercury remains in blood). Since dimethylmercury has a density of 3.2 g per milliliter, this amount of mercury is coutained in only 0.11 ml of liquid dimethylmercury. Since the elimination half-life in hair was about 75 days and the interval between exposure and blood studies was just over 150 days, the original body burden of mercury may have been four times the amount at diagnosis, or about 1344 mg, requiring absorption of 0.44 ml of liquid dimethylmercury (perhaps more if a portion of the absorbed dose was promptly excreted through exhalation, as reported in mice exposed to dimethylmercury).
 
Third, the interval between exposure and the onset of neurologic symptoms (154 days) is a longer latent period than that reported after oral ingestion of the more common methylmercury compounds. However, there have been reports of latent periods lasting for years after the administration of methylmercury in monkeys. The reason for this latency is unclear.
 
Fourth, the brain damage caused by dimethylmercury in our patient was similar to that reported previously in patients who died from exposure to either dimethylmercury or methylmercury. In all these cases, the damage involved the cerebral cortex, especially the calcarine area, with necrosis of neurons and gliosis. Extensive neuronal death and loss in the cerebellum was another characteristic finding. In previous cases, most of the mercury found in the brain at autopsy was in anorganic form, which is probably not responsive to chelation therapy. Research in animals indicates that dimethylmercury does not enter the brain until it has been metabolized after several days to methylmercury, a metabolite capable of forming covalent bonds with cellular proteins.
 
Fifth, the role of chelation therapy in such cases remains unclear. Succimer has been recommended as the treatment of first choice for methylmercury poisoning and other chelators used in Iraq failed to show a significant clinical benefit. Dimercaprol may actually be contraindicated in cases of poisoning with organic mercury compounds. One study of chelation therapy in mice exposed to methylinercury suggested that treatment with succimer, begun a few days after exposure, is most effective in reducing brain and blood mercury levels. Our experience confirms previous reports that treatment begun long after exposure to methylmercury, and after serious neurotoxicity has developed, is of little or no clinical benefit (even if urinary excretion and the elimination half-life are improved).
 
Contact with various forms of mercury is possible in occupational or other settings. The american Conference of Governmental Industrial Hygienists has established "threshold limit values" and "biological exposure indices" for a variety of chemicals, including mercury. Material Safety Data Sheets may be inadequate sources of information ou how to handle a particular chemical safely. For example, the Material Safety Data Sheet for dimethylmercury states, "Wear appropriate chernical-resistant gloves," which is simply too vague to provide adequate guidance for glove sclection. Increased awareness of personal protection on the part of scientists and more detailed and specific safety information from manufacturers could make research with toxic chemicals safer.
 
Dimethylmercury appears to be so dangerous that scientists should use less toxic mercury compounds whenever possible. Since dimethylmercury is a "supertoxic" chemical that can quickly permeate common latex gloves and form a toxic vapor after a spill, its synthesis, transportation, and use by scientists should be kept to a minimum, and it should be handled only with extreme caution and with the use of rigorous protective measures.

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