Intoxicatia cu tremorgeni

Micotoxinele tremorgene reprezinta metaboliti ai micetilor Penicillium

ciclopium, Penicillium palitans, Penicillium puberulum precum si Aspergillus
versicolor si Aspergillus flavus.
Acesi metaboliti toxici secundari potfi in cantitati variabile si cu potentiale
diferite de a produce semne clinice. Producerea toxinelor depinde de conditiile de
crestere, genul si specia fungilor.
Au fost identificate cel putin 20 de micotoxine tremorgene (neurotoxina
capabila de a induce tremuraturi ce pot dura ore sau zile), dar doar cateva au fost
dovedite a avea insemnatate medicala.
Fungi din genul Penicillium sunt raspanditi pretutindeni, cel mai adesea
găsindu-se in mâncăruri si hrana mucegaite (lactate, nuci, alune, cereale, paste) si
gunoaie.
Micotoxinele tremorgene sunt incadrate in 2 grupuri structurale:
Grupa 1
- penitremul
- tremortinele A si B
- paxilina
Grupa 2
- acidul ciclopiazonic
- acidul tenuazoic
- eritroskirinele
- viridicatumtoxina

Receptivitatea cea mai mare este intalnita la vitei, galinacee si iepuri dar si
cainii pot prezenta intoxicatie.
Cainii obisnuiti sa se plimbe singuri, fara lesa, fara supraveghere pot ajunge sa
scormoneasca prin gunoaie si sa ingere micotoxine tremorgene.
La 2 ore de la ingestie apar primele semne, toxicele ingerate in cantitate mica
pot cauza tremuraturi fine ce pot persista cateva ore sau zile, ocazional animalul se
poate sa vomite inainte de primele tremuraturi fapt ce poate diminua gravitatea
intoxicatiei, o cantitate mare de toxine poate sa induca tremuraturi severe, crize si in
final moartea.
 Modul de acțiune, ca si in cazul multor altor toxice, nu este pe deplin cunoscut.
Cunoastem insa ca activitatea primara a micotoxinelor tremorgene este asupra
sistemului nervos central, avand rol dublu de inhibitor si excitator al
neurotransmisiei.
Penitremul se absoarbe rapid (semnele pot sa apara intre 15 min si cateva ore
de la momentul expunerii)
Au fost propuse cateva mecanisme de actiune care pot varia in functie de
toxic, specie sau individ.
Penitremul inhiba neurotransmitatorii inhibitori ai glicinei la soareci,
experimental s-a dovedit ca maleatul de midazolam (acid agonist gamma-
aminobutyric) reduce tremuraturile la soarecii inoculati cu penitrem, fara a
altera tesutul nervos pe termen lung
Tabloul clinic este reprezentat de tremuraturi musculare generale, extinderea
fortata a membrelor in sprijin, convulsii tonice si clonice, titubari, opistotonus,
pedalari, vomitare, tremuraturi, ataxie, tahicardie, semne ale unei intoxicatii ce
afecteaza sistemul nervos.
Tremuraturile musculare reprezinta semnul patognomonic al intoxicatiei cu
micotoxine tremorgene (poza box1). Una din complicațiile ce pot intervenii este
pneumonia de aspiratie ce poate surveni in cazul necesitatii unei sedari pentru
controlul tremuraturilor.
Examenele paraclinice trebuie sa includa analiza biochimica a sangelui,
dozarea electrolitilor, hemoleucograma si un sumar de urina.
Niveluri crescute ale valorilor hepatice, renale si creatin fosfokinazei au fost
descoperite la cainii intoxicati.
Pacientul se poate deshidrata si pierde electroliti din cauza vomitarii si diareei,
deasemenea coagulare intravasculara diseminata in urma hipertermiei.
In multe cazuri un diagnostic prezumtiv in intoxicatia cu micotoxine
tremorgene este bazat pe semnele clinice si anamneza (unde a avut cainele acces,
gunoi, plimbat). Un diagnostic mai cert poate fi reprezentat de testarea alimentelor
suspicionate, conținutului stomacal sau vomitat.
Post-mortem penitremul poate fi izolat din ficat, rinichi sau creier.
Diagnosticul diferential se face fata de intoxicatia cu pietroide, metaldehide,
brometalin, stricnina, organofosforici, carbamati, metilxantine (cafeina, teobromina,
teofilina), ivermectine, nuci de macadamia, cocaina, amfetamine, etilen glicol si
metale grele.
 Diagnostic diferential nontoxic poate sa includa sindromul de tremor
idiopatic, afectiuni cerebrale, dezechilibre metabolive (hipoglicemie), hipocalcemie,
sindromul hepatoencefalic, rabie.
Modificarile anatomopatologice sunt reprezentate de hepatoza cu vacuolizari
ale hepatocitului, petesii subendocardice si subepicardice, hemoragii la nivel
suprarenal.
Tratamentul consta in administrarea de tranchilizante, vitamina B1, medicatie
lipotropa si solutii glucozate. Scopul tratamentului este de a controla tremuraturile
sau crizele, decontaminarea travtului garstro-intestinal si stabilizarea animalului.
Cei 2 pasi principali in tratarea micotoxicozei
There are two important goals when treating toxicosis:

1. Prevent absorption of the toxin (decontamination).

2. Treat the clinical effects of the intoxication.
Induction of emesis, gastric lavage, and administration of activated charcoal
have all been used to address tremorgenic mycotoxin toxicity. Because of
the rapid absorption of penitrem A and rapid onset of clinical neurologic
signs, the window of opportunity to safely induce emesis and administer
activated charcoal is generally limited.4,9
As the ability to safely induce emesis and/or give activated charcoal may be
limited, gastric lavage may provide some benefit. Patients presenting with
severe signs (eg, notable hyperthermia, severe muscle tremors, seizures)
may require heavy sedation or even anesthesia to control clinical signs.

Once clinical signs are appropriately controlled, patient size and time of
toxin exposure become important factors in deciding whether gastric lavage
should be performed. Radiographs may be useful to assess how much
material is in the stomach. The size of the patient dictates the bore of
orogastric tube that can be used; recovering food material through a small-
bore tube may prove futile.5 Instilling activated charcoal after gastric lavage
via stomach tube may be considered but should be weighed against risk for
aspiration.9

Tratamentul simptomatic
Control of tremors is paramount (Box 2); however, this may be a challenge.
While diazepam and barbiturates are advised, they may not always be
effective (eg, diazepam). Heavy sedation also places the pet at risk for
aspiration. Methocarbamol has been used with success. Other drugs used
to control tremors include propofol and gas anesthesia.
IV fluids should be administered to all patients that do not have physical
contraindications to fluid therapy. Benefits of IV fluids include correction of
electrolyte abnormalities and fluid loss secondary to vomiting or diarrhea,
cooling (in patients with hyperthermia), and minimizing the risk of kidney
injury from myoglobinuria secondary to rhabdomyolysis.

Antiemetics should be used in vomiting patients to limit risk of aspiration,

dehydration, and electrolyte abnormalities.

The patient’s temperature should be monitored closely for hyperthermia.

Management of muscle tremors will help address the cause of
hyperthermia, but other cooling measures may be warranted, such as
wetting the patient, fans, and IV fluids; in severe cases, cold packs or
running the IV fluid line through cool water may be warranted. Cooling
measures should be discontinued when the temperature reaches 102.5°F
to prevent rebound hypothermia.12
Intravenous lipid emulsion (ILE) therapy is a newer therapy that is gaining
popularity in veterinary medicine. Although initially designed to treat local
anesthetic overdoses in humans, its use has been expanded to include a
variety of lipophilic drug overdoses in both humans and veterinary species.

The mechanism of action of ILE therapy is not known; however, it likely

includes a “lipid sink” or “lipid shuttle,” where lipid-soluble drugs are
transiently sequestered in intravenous liposomes, as well as direct
cardiovascular effects.13
Penitrem A is believed to be a lipid-soluble compound, making it a potential
candidate for ILE therapy. However, information regarding the use of ILE
with tremorgenic mycotoxin intoxication is limited.14,15 ILE therapy may be
indicated in patients with a lipophilic toxicosis that does not respond to
standard therapy and when signs are serious or life-threatening.
Evaluation of liver, pancreas, and kidney functions, as well as correction of
any electrolyte abnormities, is best done before administration of ILE.15-
17
Adverse effects of and contraindications to ILE therapy include:
 Allergic or anaphylactoid reactions to components in the lipid emulsion
 Inability or decreased ability to clear lipids from the bloodstream
 Volume overload
 Pancreatitis
 Hemolysis
 Interference with common laboratory testing
 Interference with other treatment modalities (the “lipid sink” is not
selective and may affect lipophilic drugs as well as toxins)
 Recurrence of clinical signs if lipid emulsion is eliminated prior to the
toxin

In concluzie
 Because many dogs have indiscriminate eating habits, tremorgenic
mycotoxicosis is an intoxication small animal veterinarians may see in
practice. Ingestion of moldy foods may not be witnessed; therefore, it
is important for veterinarians to be familiar with clinical signs and
differential diagnoses commonly associated with tremorgenic
mycotoxin intoxication. In addition, because of the potential for rapid
onset and potentially life-threatening signs, prompt care may affect
the outcome in these cases.

CAZURI

A 1-year-old female Staffordshire bull terrier (body weight

15.5 kg) had eaten about 200 g of mouldy dog feed resulting
in convulsions within 30 min. Diarrhoea and fl atulence
accompanied the convulsions, but no vomiting. The conscious
dog was brought to an animal clinic where nystagmus,
tachycardia and hyperaemic mucous membranes were
also observed. On day one, she was anesthetized with tiopentone.
Afterwards, since diazepam relieved the tremors
and muscle cramping for a couple of hours, it was given
several times daily (intravenously (iv) or rectally for a total
of 14 days. She was hand-fed, and had the ability to eat shortly after diazepam was given.
Still six days after ingestion, the dog was in lateral recumbency with tremors
and muscle cramping in the whole body. Tremors and cramping
were intensifi ed by sound, by handling the dog, as well
as when the dog intentionally tried to achieve anything. Ten
days after ingestion, she could sit up by herself without support.
She took her fi rst steps on day 13, still much ataxic
and needed support at that time. Signs gradually decreased,
but still at a recheck four months after intoxication, the dog
had a mild cerebellar syndrome with intention tremors and
mild ataxia. The improvement continued, and after 2–3
months, the dog was asymptomatic and since then has
remained healthy. The dog feed was analyzed and contained
high amounts of P. crustosum (1.18 × 107 CFU/g). Chemical
analysis of the feed demonstrated high concentrations
of the tremorgenic mycotoxins penitrems A, B, D, E and F
with a total concentration of 31.3 mg/kg feed (Table 1),
indicating that the dog ingested a total of about 6 mg
penitrem or approximately 0.4 mg/kg body weight.
Roquefortine C was not quantifi ed in the sample.
Blood samples for haematology and serum chemistry
were taken on day 1, 3, 4, 9, 14 and 140. Liver and kidney
values and muscle enzymes varied as noted in Table 2.
Other clinical parameters, i.e., complete blood count, serum
amylase, calcium, chloride, cholesterol, globulins, glucose,
lipase, phosphorus, potassium, sodium, total bilirubin, total
protein concentrations were not signifi cantly affected.
2

A 6-year-old female basset hound had eaten rotten apples

lying under a tree in a park. About three hours later, when
back at home, the owner observed heavy muscle shivering
and ataxia, but no vomiting. The dog was brought to an
animal hospital immediately, where nystagmus, hypersalivation
and hyperaemic mucous membranes were also
observed. The dog was given active charcoal per os (po),
and diazepam iv symptomatically. The next morning (day
two), she was still ataxic with hyperaemic mucous membranes,
and now exhibited tachycardic and tachypneic. Her
tremor was weaker, EKG normal and nystagmus had disappeared.
When examined on day three, her condition was
nearly normalized, but she still had some shivering in the
pelvic limbs. At a recheck on day 12, the dog had completely
recovered clinically.
A sample from the rotten apples collected by the owner
on site from below the tree was analyzed for moulds and
the presence of Penicillium mycotoxins. The Penicillium
counts in the material were 1.7 × 107 CFU/g and Penicillium
crustosum was recovered in almost pure culture, but
a low number of P. commune colonies were also found.
The mycotoxin analysis was carried out in semiquantitative
mode giving estimates of the analyte concentrations. The
samples contained signifi cant concentrations of penitrem A (approximately 10 g/kg vomit)
and roquefortine C
(approximately100 g/kg vomit). Traces of penitrem E
were also found in the rotten apples.
Blood samples were taken on day 2, 12, 31,198 and 272.
Liver and kidney values, and muscle enzymes are presented
in Table 2. Other parameters, i.e., complete blood count,
serum amylase, calcium, chloride, cholesterol, globulins,
glucose, lipase, phosphorus, potassium, sodium, total bilirubin,
total protein concentrations were not signifi cantly
altered. Urine density is also presented in Table 2.