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091301 wild-mushroom intoxication as a cause of

The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne WILD-MUSHROOM INTOXICATION
AS A CAUSE OF RHABDOMYOLYSIS
JEAN P. POMIES, M.D., PH.D., JEAN M. RAGNAUD, M.D., CLAUDE GABINSKI, M.D., STEN DE WITTE, M.D., JEAN C. CHAPALAIN, M.D., AND PIERRE GODEAU, M.D.
HE growing popularity of eating wild mush-rooms has led to an increase in the incidence Tof mushroom poisoning. Most fatalities are due to amatoxin-containing species, which cause fulminanthepatocytolysis, and to cortinarius species, which leadto acute renal damage. A 1996 report described a pa-tient with hepatic failure, encephalopathy, and myop- Figure 1. Tricholoma equestre.
athy related to the ingestion of Amanita phalloides.1 The cap of this species measures 6 to 8 cm, and the stem is 7 to Since 1992, 12 cases of delayed rhabdomyolysis have occurred in France after meals that included largequantities of the edible wild mushroom Tricholomaequestre.2 The circumstances of these 12 cases clearlyimplicate T. equestre as the cause. The mushroom was CASE REPORTS
positively identified, and no other cause, such as bac-terial, viral, fungal, or immune disease or exposure to Seven women (age range, 22 to 60 years) and five men (age range, 24 to 61 years) were hospitalized between 1992 and 2000 a toxin, was found. Three of the 12 patients died.
with severe rhabdomyolysis approximately one week after eating wild The implicated mushrooms were harvested from be- mushrooms. All 12 patients had eaten at least three consecutive neath pine trees on the sandy coast of southwestern meals that included T. equestre, and none had a history of trauma, France, between late fall and midwinter. T. equestre is other known underlying cause, or medication use that could explain widely disseminated throughout the world and is also the occurrence of rhabdomyolysis. All patients reported fatigue andmuscle weakness accompanied by myalgia, mainly in the upper part known as T. flavovirens and colloquially as “bidaou” of the legs, 24 to 72 hours after their last meal containing mush- or “canari” in France, “riddarmusseron” in Sweden, rooms. The weakness worsened over a period of three to four days, “shimokoshi” in Japan, and “man on horseback” or leading to stiffness of the legs and the production of dark urine.
“yellow-knight fungus” in the United States (Fig. 1).3,4 These signs were accompanied by facial erythema, mild nausea with-out vomiting, and profuse sweating in eight of the patients. No fe- We investigated the rhabdomyolysis apparently in- ver was noted, and five patients had hyperpnea. The findings on duced in 12 humans by several consecutive meals of physical examination, which included pulmonary auscultation and T. equestre by administering equivalent doses of ex- a neurologic examination, were unremarkable.
Initial screening tests showed evidence of rhabdomyolysis, with a mean maximal serum creatine kinase activity of 226,067 U perliter in the women and 34,786 U per liter in the men (Fig. 2). No From the Poison Center (R.B.) and the Department of Infectious Dis- hepatic injury was evident. g-Glutamyltransferase values were nor- eases (J.M.R., M.D., D.N.), University Hospital Pellegrin, Bordeaux; the mal (range, 5 to 24 U per liter), and maximal average levels of as- Departments of Toxicology (I.B., E.E.C.) and Mycology (G.D.), Faculty of partate aminotransferase and alanine aminotransferase were 8104 Pharmacy, University Bordeaux 2, Bordeaux; Histotox, La Rochelle (J.P.P.); and 1392 U per liter, respectively, in the women and 1173 and the Departments of Intensive Care (C.G.) and Internal Medicine (S.D.), 325 U per liter, respectively, in the men. Despite the intensity of University Hospital St. André, Bordeaux; the Department of Gastroenter- the clinical rhabdomyolysis, electrolyte levels, including potassium ology, Hospital of Montbrisson, Montbrisson (J.C.C.); and the Depart- values, were normal, and no renal failure occurred. Coagulation ment of Internal Medicine, University Hospital Pitié–Salpetrière, Paris tests were normal. Additional studies were negative for parasites or (P.G.) — all in France. Address reprint requests to Dr. Creppy at the De-partment of Toxicology, University Bordeaux 2, 146 rue Leo-Saignat, 33076 other microorganisms (coxsackievirus, toxoplasma, toxocara, trichi- Bordeaux, France, or at edmond.creppy@tox.u-bordeaux2.fr.
nella, hepatitis B and C viruses, and human immunodeficiency vi- Jacques Beylot, M.D., Department of Internal Medicine, University rus), as well as for systemic diseases (as assessed by complement- Hospital St. André, Bordeaux, France, was also an author.
fixation tests and tests for circulating nuclear antibodies).
798 · N Engl J Med, Vol. 345, No. 11 · September 13, 2001 · www.nejm.org
B R I E F R E P O R T
Figure 2. Serum Creatine Kinase Levels in the 12 Patients during Hospitalization.
Given the absence of evidence of deliberate intoxication, the cium, 5.6 to 8.3 mg per deciliter [1.4 to 2.07 mmol per liter]) and analyses focused on the hypothesis that mushroom intoxication a normal total protein level. The three patients had creatine kinase caused the rhabdomyolysis. Electromyography was performed in values of 632,000, 138,900, and 295,700 U per liter, with isoen- four patients and revealed muscle injury without peripheral-nerve zyme MB making up 0.5 to 0.7 percent of the total. Despite inten- involvement. The greatest changes were in the proximal thigh mus- sive physiological care, including, in one case, continuous veno- cles. Complex and generally myotonic activity was present, without venous hemofiltration, all three patients died. Autopsy revealed fibrillation, even at rest. On stimulation, muscle contractile activity myocardial lesions identical to the muscular lesions in one patient, was particularly prominent. All the motor and sensory potentials renal lesions in one patient, and no hepatic lesions.
were normal. Electromyography of the diaphragm was performedin one patient and showed similar findings, suggesting the presence of rhabdomyolysis of the diaphragm without phrenic involvement.
Additional studies were necessary to demonstrate that T. equestre In six patients, samples of quadriceps muscle were obtained for was the cause of the rhabdomyolysis in the 12 patients. Since it histologic analysis. On light microscopy, the fascicular architecture would have been unethical to administer T. equestre extracts to hu- of the muscles was well preserved, the myofibrils had a “nibbled” man subjects, we chose an established model of myonecrosis in appearance, and in some cases the fibers were separated from each mice.5-7 Extracts of T. equestre were prepared and then administered other by edema in the absence of vacuoles or the accumulation of by gavage (gastric intubation) in a dose equivalent to that ingested glycogen or lipid — signs of a direct muscle injury. In the three by the patients. The animals were then assessed for evidence of rhab- patients who died, samples of the psoas and other muscles (from the domyolysis. Two protocols were employed: a dose-response study arms, myocardium, and diaphragm) also showed evidence of acute with T. equestre alone and one in which mice received extracts of either T. equestre or the nontoxic mushroom Pleurotus ostreatus. Over the next 15 days, in all but three of the patients, the serum enzyme values gradually normalized and most symptoms disap- Mushroom Extracts
peared, although the muscular weakness persisted for several weeks.
In the three patients who died, the increasing dyspnea at rest was Specimens of T. equestre collected in southwestern France were the first symptom of further deterioration and was followed by in- identified by qualified mycologists.2-4 The taxonomic denomination creasing rales at both lung bases, leading to admission to the inten- of T. equestre is synonymous with that of T. flavovirens (Fries) Lun- sive care unit. All three patients had hyperthermia (a temperature of dell.3 Specimens of P. ostreatus obtained commercially were con- up to 42°C); signs of acute myocarditis, including cardiac arrhyth- firmed as such by qualified mycologists. Then 500 g of T. equestre mia, cardiovascular collapse, and widening of the QRS complex was frozen, ground, and mixed with 200 ml of ultrapure water. The without severe acidosis (pH, 7.37, with a serum bicarbonate level resulting mixture was lyophilized to yield 60 g of powder. Extracts of 16 to 20 mmol per liter); and evidence of renal dysfunction, in- were then obtained. A concentrate of 1.35 g of cold aqueous extract cluding elevated levels of blood urea nitrogen (30 to 52 mg per was obtained from 5 g of powdered T. equestre, and a concentrate of deciliter [10.7 to 18.7 mmol per liter]) and serum creatinine (1.4 to 1.65 g of boiled aqueous extract was obtained from 5 g of powdered 2.5 mg per deciliter [126 to 224 µmol per liter]), with hyperkale- T. equestre. A concentrate of 1.3 g was obtained from 10 g of pow- mia (potassium, 6.0 to 7.2 mmol per liter) and hypocalcemia (cal- dered T. equestre after chloroform–methanol (vol/vol) extraction, N Engl J Med, Vol. 345, No. 11 · September 13, 2001 · www.nejm.org · 799
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne and a concentrate of 50 mg of chloroform–methanol lipid-free tine kinase level (up to a mean of 380±25 U per liter).
extract was then obtained from 200 mg of the chloroform–meth- At a total dose of 4 g and 6 g per kilogram, the in- anol extract. We obtained a cold aqueous extract, a boiled aqueous crease was significant when compared with the levels extract, and a chloroform–methanol (vol/vol) extract of P. ostrea-tus in a similar manner.
in controls (mean, 145±40 U per liter; P=0.01 forboth comparisons), although there was variability be- Experimental Intoxication
Adult male Swiss mice (mean [±SE] weight, 30±5 g) (Depre), Mice treated with boiled T. equestre extracts, chloro- were randomly divided into several groups. In each group, T. eques- form–methanol lipid-free extract, and p-phenylenedi- tre powder, T. equestre or P. ostreatus extract, or solvent alone was amine had a significant increase in serum creatine ki- administered to each animal in a standardized fashion.
Twenty-four or 48 hours after the final dose, the mice were anes- nase activity (912±425, 883±500, and 1828±450 U thetized with ether, and blood was collected from the retroorbital per liter, respectively; P=0.01 for each comparison sinus and centrifuged at 2000¬g for 15 minutes at 5°C to recover with base-line levels) (Fig. 3). No such increase was serum. The serum was frozen and stored at ¡20°C until analysis.
observed in mice treated with extracts of P. ostreatus. Creatinine levels were determined by the Jaffé reaction (Merck kit Serum levels of aspartate aminotransferase, alanine 3385). Aspartate aminotransferase and alanine aminotransferase ac-tivities were determined with the use of enzyme kits (Merckotest, aminotransferase, and creatinine were not increased Merck).8 Creatine kinase was measured with a commercial kit (En- significantly in mice treated with extracts of T. eques- zyline kit, Biomérieux). The mice were then killed, and samples of tre or P. ostreatus (data not shown).
striated muscle, liver, and tissues were obtained.
All the treated mice had tachypnea, reduced motor In the first protocol, three groups of three mice each were given 1 ml of powdered T. equestre suspension in water once a day by ga- activity, and occasional diarrhea. Light microscopy of vage for three days. The highest total dose was 6 g per kilogram of muscle fibers showed evident disorganization.
the body weight of the mouse (0.18 g per mouse), corresponding Two mice — one that received boiled aqueous ex- to a hypothetical toxic dose in a 60-kg person of 3 kg of fresh mush- tract and one that received chloroform–methanol lip- rooms eaten over the course of six meals in a period of three days id-free extract — died 72 hours after the last dose.
(72 hours). Creatine kinase activity was determined in serum col-lected 48 hours after the final dose.
These animals were not autopsied because by the time In the second protocol, five groups of five mice each were given the deaths were discovered autolysis had set in.
0.3 ml of tricholoma or pleurotus extract dissolved in water or di-methylsulfoxide once a day by gavage for three days. This dose cor- DISCUSSION
responded to a total dose of 0.18 g of powdered T. equestre suspen-sion. The positive control consisted of p-phenylenediamine (dose, Rhabdomyolysis is a rare but potentially fatal condi- 70 mg per kilogram per day for three days), which is a potent my- tion. Muscle compression is the most common cause, otoxic compound in mice.6 Levels of aspartate aminotransferase, but neither muscle ischemia nor unconsciousness was alanine aminotransferase, creatine kinase, and creatinine were de- noted before the onset of symptoms in our patients.
termined in serum collected 96 hours after the final dose.
Deliberate intoxication with substances including co- Statistical Analysis
caine, amphetamines, alcohol, theophylline, phenothi-azines, p-phenylenediamine,9,10 antihistamines, and an- Data are presented as means ±SE. The results were analyzed with use of the Wilcoxon rank-sum test, a nonparametric statistical test tihyperlipidemic drugs was ruled out.11,12 Medications chosen because of the small number of animals.
that could cause dermatomyositis or polymyositis (pen-icillamine, phenytoin, levodopa, and quinidine) were ruled out by screening tests. Finally, immunologic Mice treated with T. equestre powder (Table 1) had screening as well as muscle biopsies did not indicate a concentration-dependent increase in the serum crea- the presence of other systemic disorders or McArdle’sdisease.13 Toxic rhabdomyolysis has been described after the ingestion of small wild birds that had eaten water hem-lock (Conium maculatum), a direct muscle toxin.14,15Our patients had not eaten such birds. Although TABLE 1. SERUM CREATINE KINASE LEVELS IN
MICE GIVEN A SUSPENSION OF TRICHOLOMA mushroom poisoning is not known to produce rhab- EQUESTRE POWDER (BY GASTRIC INTUBATION) domyolysis, this series of cases clearly associates rhab- domyolysis with the ingestion of T. equestre. Since 75 percent of the patients with large increases TOTAL DOSE
CREATINE KINASE
in creatine kinase survived, a genetic muscular suscep-tibility may be unmasked by the direct muscle toxicant contained in T. equestre when the amount of mush- rooms ingested exceeds a certain threshold. Therefore, physicians should be aware of the possibility of severe rhabdomyolysis after repeated consumption of T. eques- tre. At this time treatment is supportive, and hospi- *Plus–minus values are means ±SE.
talization is recommended for patients with dyspnea, †P=0.01 for the comparison with the control.
signs of acute myocarditis, or even mild renal failure.
800 · N Engl J Med, Vol. 345, No. 11 · September 13, 2001 · www.nejm.org
B R I E F R E P O R T
Chloroform–methanol Boiled aqueous extract Figure 3. Mean (+SE) Serum Creatine Kinase Levels in Mice Treated by Gastric Intubation with Extracts
of Tricholoma equestre and Pleurotus ostreatus Every Day for Three Days.
The total dose of T. equestre powder was 6 g per kilogram of body weight.
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Lechevalier, 1984.
3. Miller OK Jr. Mushrooms of North America. New York: E.P. Dutton,
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del genere Tricholoma (Fr.) Staude. Milan, Italy: Edinatura, 1999.
5. Ponraj D, Gopalakrishnakone P. Renal lesions in rhabdomyolysis caused
Several metabolites have been isolated from vari- by Pseudechis australis snake myotoxin. Kidney Int 1997;51:1956-69.
ous tricholoma species — triterpenoids,16 sterols,17 6. Averbukh Z, Modai D, Leonov Y, et al. Rhabdomyolysis and acute renal
failure induced by paraphenylenediamine. Hum Toxicol 1989;8:345-8.
indoles,18 and acetylenic compounds19 — but their 7. Gutierrez JM, Chaves F, Gene JA, Lomonte B, Camacho Z, Schosinsky
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